Intraventricular drug delivery system for improving outcome after a brain injury affecting cerebral blood flow

Cross-reference to related applications This application claims the benefit of priority to US Provisional Application No. 61 / 471,779 filed on April 5, 2011, and is filed on June 11, 2008. A Drug Delivery System for the Prevention of Cerebral Vasospasm is a partial continuation of US Application No. 12 / 137,320, which is US Provisional Application No. 60 / 976,902 (filed October 29, 2007). And the interests of the priority of No. 60 / 943,124 (filed on June 11, 2007). The contents of each of these applications are incorporated herein by reference in their entirety. Field of Invention The present invention is a delivery system for a therapeutic agent locally delivered to the cerebral artery that prevents or reduces the occurrence or severity of adverse consequences or severity of subarachnoid hemorrhage resulting from a disease, disorder or symptom, or injury. Regarding.

Central Nervous System The central nervous system is a bilateral, essentially symmetrical structure with seven main parts: the spinal cord, medulla oblongata, pons, cerebrum, midbrain, diencephalon, and cerebral hemisphere. Figure 1 shows Stedman's Medical Dictionary, 27.^th It is a side view which shows the human brain from Edition, plate 7 at A7 (2000). The spinal cord, the most caudal part of the central nervous system, receives and processes sensory information from the skin, joints, and muscles of the limbs and torso and controls limb and torso movements. The spinal cord is subdivided into the neck, chest, lumbar and sacral regions. The spinal cord continues rostrally as a brain stem consisting of the spinal cord, pons, and midbrain. The brain stem receives sensory information from the skin and muscles of the head and gives motor control to the muscles of the head. The brainstem also transmits information from the spinal cord to the brain and from the brain to the spinal cord, regulating levels of arousal and consciousness through the reticular formation. The brain stem contains several collections of cell bodies that are the cranial nerve nuclei. Some of these receive information from the skin and muscles of the head, while others control the motor output to the facial, neck, and eye muscles. In addition, others are specialized in special senses: information from hearing, balance and taste. (Kandel, E. et al., Principles of Neural Science, 4^th Ed., P. 8, 2000). The medulla oblongata, just rostral to the spinal cord, contains several centers involved in important autonomic functions, such as digestion, respiration, and heart rate control (Kandel, E. et al., Principles of Neural Science, 4^th Ed., P. 8, 2000). The rostral pons of the spinal cord transmits information about movement from the cerebral hemisphere to the cerebellum (Kandel, E. et al., Principles of Neural Science, 4).^th Ed., P. 8, 2000).

The cerebellum is behind the pons and is connected to the brain stem by several major fiber bundles called the cerebral peduncles. The cerebellum regulates motor intensity and range and is involved in learning motor skills. The cerebellum also contributes to learning and cognition (Kandel, E. et al., Principles of Neural Science, 4)^th Ed., P. 8, 2000). The midbrain on the rostral side of the pons controls many sensory and motor functions, including eye movements and coordination of visual and auditory reflexes (Kandel, E. et al., Principles of Neural Science, 4).^th Ed., P. 8, 2000). The diencephalon is rostral to the midbrain and contains two structures. One is the thalamus, which processes most of the information from the remaining central nervous system that reaches the cerebral cortex and is involved in other functions, including motor control, autonomic nervous function and cognition. The other is the hypothalamus, which regulates autonomic nerves, endocrine, and visceral function (Kandel, E. et al., Principles of Neural Science, 4).^th Ed., P. 8, 2000). The cerebral hemisphere is the wrinkled outer layer, cerebral cortex, and deep gray matter structure-the basal ganglia involved in the regulation of motor capacity; the hippocampus, which is involved in aspects of learning and memory retention; and the amygdala (of emotion). Consists of the amygdala, which coordinates the autonomic and endocrine responses of the state (Kandel, E. et al., Principles of Neural Science, 4)^th Ed., P. 8, 2000). The cerebral cortex is divided into four lobes: frontal lobe, parietal lobe, temporal lobe and occipital lobe. The surface of the cerebral hemisphere contains many grooves or depressions known as fissures and grooves. The part of the brain between these grooves is called the gyrus or gyrus. The lateral sulcus (Sylvian fissure) separates the frontal and temporal lobes. The Central Sulcus (Roland Sulcus) separates the parietal and frontal lobes (Kandel, E. et al., Principles of Neural Science, 4)^th Ed., P. 8, 2000).

1. Meninges of the brain The meninges, the three different connective tissue membranes that surround and protect the brain and spinal cord, are called the dura, arachnoid, and pia mater (from the outer layer to the inner layer). Figure 2 is a descriptive sagittal view showing the human brain (JG Chusid, Correlative Neuroanatomy & Functional Neurology, 18).^th Ed., P. 46, 1982). FIG. 3 is a cross-sectional view of the three meningeal layers covering the brain (Haines, DE, Anatomical Record 230: 3-21, 1991). The dura mater sends in four protrusions that divide the cranial cavity into a series of freely communicating compartments, further protecting different parts of the brain.

1.1. Dura mater The dura mater is a dense fibrous structure that covers the brain and spinal cord. The dura has an inner meningeal layer and an outer periosteal or endosteal layer. The dural layer above the brain is generally fused except where the dural layer separates and provides space for the sinus and where the inner layer forms a septum between the brain parts. .. The outer layer adheres to the inner surface of the skull, delivering dilation of blood vessels and fibers into the bone itself. Around the margin of the foramen magnum (the large opening at the base of the skull that forms the passage from the cranial cavity to the spinal cavity), the outer layer adheres to the bone and continues to the dura mater of the spinal cord. The dura mater is divided into two layers by pits and blood vessels: Two, consisting of fibroblasts, abundant extracellular collagen and several elastic fibers placed in a flat thin film that is incompletely divided into an inner (meningeal) layer and an outer (endosteum) layer. The layers are tightly coupled together, except in certain situations where the two layers separate to form a venous sinus for the passage of venous blood or a septum between parts of the brain. ing. The outer surface of the dura is rough, fibril-like (consisting of fibers) and adheres tightly to the inner surface of the bone, with attachment most often on the opposite side of the skull suture (the skull or the immobile joint between the skulls). The endosteal layer is the periosteum inside the skull and contains blood vessels for supply to them. The inner surface of the meningeal layer is covered with a unique layer of elongated flat fibroblasts called dural boundary cells. There is no collagen in this layer and the cells are not connected by cell-cell connections. Cells are frequently separated by extracellular space filled with amorphous, non-filamentous material. The meningeal layer further contains two thin plates: a compact thin plate and a loose thin plate, the former generally containing solid fibrous tissue and a few blood vessels, while the latter contains several blood vessels. ..

The cerebral dural processes protruding into the cranial cavity are formed by duplication of the inner (or meningeal) layer of the membrane. These protrusions include (1) falx cerebri, (2) cerebellar tentorium, (3) falx cerebri, and (4) saddle diaphragm. A falx cerebri is a powerful bow-shaped protrusion with a sickle-like morphology that descends vertically within the longitudinal fissure between the hemispheres of the cerebrum. The falx cerebri is narrow anteriorly attached to the ethmoid bone (bone at the base of the skull and at the base of the nose) at the ethmoid bone (triangular midline process of the ethmoid bone) Wide posteriorly connected to the arched folds of the membrane). Its upper margin is convex, traces back to the internal occipital ridge and attaches to the medial surface of the midline skull, the upper margin containing the superior sagittal sinus. Its lower margin is unfixed and concave and contains the inferior sagittal sinus. The cerebellar tentorium is a bow-shaped thin film that rises in the center and tilts downward toward the outer circumference. The cerebellar tentorium covers the upper surface of the cerebellum and supports the occipital lobe of the brain. Its anterior edge is unfixed and concave, ascending as well as the cerebral peduncle (a huge bundle of cortical projection nerve fibers that traverses the ventral aspect of the midbrain on each side of the midbrain). It is surrounded by a large oval opening (tent notch) for the passage of sexual sensory fibers and autonomic nerve fibers as well as other fiber bundles. The cerebellar tentorium attaches posteriorly to the transverse ridge on the medial surface of the occipital bone by its convex edge, surrounds the lateral sinus, and anteriorly to the superior angle of the pyramidal part of the temporal bone on either side. It attaches and surrounds the superior petrosal sinus. At the apex of the pyramidal part of the temporal bone, the unfixed and attached edges come into contact, intersect each other, and are anchored to the anterior and posterior clinoids, respectively. The trailing edge of the falx cerebri is attached to the midline of its upper surface. The straight sinus is located at the junction of the falx cerebri and cerebellar tentorium. The falx cerebral sickle is a small triangular protrusion of the dura that separates the two cerebellar hemispheres. Its base is attached upwards to the lower and posterior parts of the tent, and the margins are attached to the lower section of the vertical ridge on the inner surface of the occipital bone. As the falx cerebral sickle descends, it sometimes splits into two smaller folds that are lost on the sides of the foramen magnum.

The saddle membrane covers the sella turcica (a saddle-like protrusion on the upper surface of the sphenoid bone of the skull, located in the middle cranial fossa and bisects it) like a roof and the pituitary gland (pituitary gland). ) Is a small circular horizontal fold that almost completely covers the), and a variable-sized central opening passes through the sphenoid (the sphenoid extension of the hypothalamus that connects the pituitary gland to the base of the brain). There are many dural arteries. The dural branches of the anterior ethmoidal and posterior ethmoidal arteries, the dural branches of the internal carotid artery, and the branches from the middle meningeal artery extend into the dura mater of the anterior cranial fossa. The middle and accessory meningeal arteries of the internal carotid artery, the branch from the ascending pharyngeal artery that enters the skull through the rupture hole, the branch from the internal carotid artery, and the reciprocal branch from the lacrimal artery are the middle cranial. It appears on the dural membrane of the fossa. One through the jugular foramen and the other through the papillary foramen to enter the skull through the middle meningeal branch from the occipital artery, the posterior meningeal artery from the vertebral artery, the jugular foramen and the sublingual nerve canal Accidental dural branches from the ascending pharyngeal artery that enter the skull, as well as branches from the middle meningeal artery, emerge into the dural membrane of the occipital fossa. The veins that return blood from the dura mater are anastomosed to the interplate veins or end in various sinuses. Many dural veins do not open directly into the sinus, but indirectly through a series of bulges called venous hiatus. Dural veins are found on any aspect of the superior sagittal sinus, especially near the middle, and are often invaginated by arachnoid granulation, and dural veins are also found in the lateral and straight sinuses. It also exists in the vicinity. The dural vein communicates with the underlying cerebral vein and also with the interstitial and emissary veins. The nerves of the cerebral dural membrane are fibers derived from the trigeminal ganglion, the lingual ganglion, the stray ganglion, the second and third spinal cord ganglia, the wing palate ganglion, the ear ganglion, and the superior cervical ganglion. It appears in unmyelinated and myelinated sensory and autonomic nerve fibers.

1.2. The arachnoid, the middle meningeal layer, is the delicate avascular membrane that lies between the pia mater and the dura mater. It is separated from the underlying dura by the subdural space and from the underlying buffy coat by the subarachnoid space containing cerebrospinal fluid. The arachnoid consists of the outer cell layer of the low cubic lining. There is a variable thickness space filled with cerebrospinal fluid and traversed by a membrane consisting of trabeculae and cells similar to collagen fibrils and fibroblasts. The inner layer and trabeculae are covered with a slightly lower form of cubic mesothelium, which is sometimes flattened into a paved form and fused with pia mater cells on the deep inner layer. The arachnoid also contains a plexus derived from the motor roots of the trigeminal, facial, and accessory cranial nerves. The arachnoid cranial region (arachnoid mater) loosely surrounds the brain, with the exception of the longitudinal fissures and some other larger sulci and fissures between the gyrus (raised folds or ascents of the brain surface). It does not enter the groove (the depression or fissure on the surface of the brain) or the fissure. On the upper surface of the brain, the arachnoid is thin and transparent, and at the base it is thicker. The arachnoid is slightly opaque towards the center of the brain, where it extends between the two temporal lobes in front of the pons, leaving considerable space between the pons and the brain. The arachnoid surrounds the cranial and spinal nerves and surrounds them with a loose sheath from the skull to their exit points.

Subarachnoid space The space between the subarachnoid cavity and the outer cell layer of the pia mater, the subarachnoid space or subarachnoid space, contains tissue consisting of delicate connective tissue trabeculae and cerebrospinal fluid. Occupied by a continuous channel. This cavity is small on the surface of the hemisphere of the brain, and at the apex of each gyrus, the pia mater and arachnoid are in close contact, but in the triangular space, the pia mater enters the groove, resulting in subarachnoid trabecular tissue. The arachnoid mater is bridged throughout from the gyrus to the gyrus, although it is left in the groove between the gyrus where is seen. At certain parts of the base of the brain, the arachnoids communicate freely with each other and are separated from the pia mater by wide intervals called the subarachnoid cistern, and the subarachnoid tissue of these cisterns is relatively less abundant.

Subarachnoid CISTERNAE (CISTERNAE SUBARACHNOIDALES) The cerebellar medulla oblongata (cisterna magna) has a triangular sagittal cross section and is a spider membrane that bridges the space between the medulla oblongata and the lower surface of the hemisphere of the cerebellum. Due to this, the cerebellar medulla oblongata continues at the level of the cisterna magna to the subarachnoid space of the spinal cord. The pontine cistern is a considerable area of space on the ventral side of the bridge. The pontine cistern contains the basilar artery, which leads to the subarachnoid space of the spinal cord and the cerebellar medulla oblongata cistern behind the pons, and to the interpeduncular cistern anterior to the pons. The interpeduncular cistern (basal cistern) is a large cavity in which the arachnoid extends across between the two temporal lobes. The interpeduncular cistern surrounds the structures contained in the cerebral peduncle and interpeduncular fossa and contains the circle of willis. Anteriorly, the interpeduncular cistern extends anteriorly throughout the optic tract crossing, forming a chiasmatic cistern and extending to the upper surface of the corpus callosum. The arachnoid extends from one cerebral hemisphere to the other just below the free edge of the falx cerebri, leaving space for the anterior cerebral arteries. The lateral cerebral pit is formed anterior to either temporal lobe by the arachnoid mater that bridges the entire lateral sulcus. This cavity contains the middle cerebral artery. The cerebral vena cava occupies the space between the ampulla of the corpus callosum and the upper surface of the cerebellum, and the cerebral vena cava extends between layers of the choroid of the third ventricle and contains the cerebral vein. The subarachnoid space communicates with the entire ventricular space of the brain through three openings, one of which is the Majandi foramen, at the midline of the lower part of the fourth ventricle lid, and the other two ( The Rushka foramen) is at the tip of the lateral recess of its ventricles behind the upper glossopharyngeal nerve root. The arachnoid villi are tufted extensions of the pia mater that protrude through the meningeal layer of the dura and have a thin borderline. The tufted extension of the pia mater, which is composed of numerous arachnoid villi that penetrate the dural venous sinus and results in the movement of cerebrospinal fluid into the venous system, is called the arachnoid granulation. The arachnoid villi represent infiltration of the dura by the arachnoid, whereby the arachnoid mesothelial cells lie directly beneath the vascular endothelium of the large dural venous sinus. Each villi consists of the following parts: (1) Inside, the core of the arachnoid tissue, which follows the network structure of the subarachnoid tissue through the narrow stem where the arachnoid adheres to the arachnoid, (2) this tissue Around, a layer of arachnoid that limits and surrounds the arachnoid tissue, (3) outside this, thinning of the pits that correspond to the potential subarachnoid space and are separated from the arachnoid by the subsequent potential space. If the walls, and (4) villi project into the sagittal sinus, they are simply covered by the very thin wall of the sinus, which can consist of the endothelium. The fluid injected into the subarachnoid space mixes into these villi. Such fluid passes through the venous sinus where it protrudes from the villi.

1.3. Pia mater The pia mater is a thin connective tissue membrane that is applied to the surface of the brain and spinal cord. Blood vessels that exit the brain travel through the buffy coat to the brain. The pia mater is absent in the Majandi foramen and the two Rushka foramen and is considered an incomplete membrane because it is perforated by all vessels as they enter or leave the nervous system. Is done. In the perivascular cavity, the pia mater appears to enter as the lining of the lining of the outer surface of the cavity, and at an indefinite distance from the outside, these cells become unrecognizable and clearly deficient, and the glue glue. Replaced by the element. The inner wall of the perivascular cavity also appears to be covered by mesenteric cells at a certain distance, and as these vessels cross the subarachnoid space, the vessels reverse from the arachnoid that they cover. To do. Pia mater encephali; The pia of the brain) surrounds and invades the entire surface of the brain, the depression between the cerebral gyrus and the cerebellar thin film, the choroid of the third ventricle, and the choroid plexus of the lateral and third ventricles. Is formed. As the pia mater passes over the lid of the fourth ventricle, it forms the choroid and choroid plexus of the fourth ventricle. On the cerebellum, the membrane is more delicate, its deep blood vessels are shorter, and its relationship to the cortex is less intimate. The buffy coat forms a sheath for the cranial nerves.

2. Brain circulation 4, 5, 6 and 7 are schematic views of blood vessels in the brain. Each cerebral hemisphere is exited by the internal carotid artery, which originates from the common carotid artery below the corner of the jaw, enters the skull through the formation of the carotid artery, crosses the cavernous sinus (exposing the ophthalmic artery), and traverses the dura mater. It penetrates and divides into the anterior cerebral artery and the middle cerebral artery. From the superficial bifurcation of the anterior cerebral artery, it exits the cortex and white matter of the inferior frontal lobe, the medial aspect of the frontal and parietal lobes, and the anterior corpus callosum. Smaller penetrating branches exit to the deeper cerebrum and diencephalon, including the limbic structure, caudate nucleus head, and internal capsule forelimbs. From the superficial bifurcation of the middle cerebral artery, it emerges in most cortex and white of the arch hemisphere, including the frontal, parietal, temporal, occipital, and islets. Smaller penetrating branches emerge into deep white matter and limbic structures such as the hind limbs of the internal capsule, putamen, globus pallidus, and caudate nucleus. After exiting the cavernous sinus, the internal carotid artery also exits the anterior choroid plexus artery, which then exits the anterior hippocampus and the hind limbs of the internal capsule at the caudal level. Each vertebra originates from the subclavian artery, enters the skull through the foramen magnum, and exits the anterior spinal artery and posterior inferior cerebral artery. The vertebral arteries connect at the junction of the pons and the medulla to form the basilar artery, which exits the anterior inferior cerebral artery and the internal auditory artery at the level of the pons, and the superior cerebral artery in the middle brain. The basilar artery then divides into two posterior cerebral arteries. From the superficial bifurcation of the posterior cerebral arteries to the inferior temporal lobe, medial occipital lobe and occipital corpus callosum; It appears in the brain structure (see Principles of Neural Sciences, 2d Ed., Eric R. Kandel and James H. Schwartz, Elsevier Science Publishing Co., Inc., New York, pp. 854-56 (1985)).

When part of the vascular supply of the brain is impaired, the interconnection (anastomosis) between the blood vessels protects the brain. Anastomosis is the interconnection between blood vessels that protects the brain when part of the vascular supply of the brain is impaired. In the wheel of the Willis artery, the two anterior cerebral arteries are connected by the anterior communicating artery, and the posterior cerebral artery is connected by the posterior communicating artery to the internal carotid artery. Other important anastomosis includes the orbital connection between the bifurcation of the ophthalmic artery and the external carotid artery, and the connection between the branches of the middle, anterior cerebral, and posterior cerebral arteries on the surface of the brain (Principles of). Neural Sciences, 2d Ed., Eric R. Kandel and James H. Schwartz, Elsevier Science Publishing Co., Inc., New York, pp. 854-56 (1985)). The Willis arterial ring at the base of the brain is the main trunk of the arterial anastomosis of the brain. Blood reaches the Willis arterial ring, primarily through the vertebral and internal carotid arteries (see Figure 4), and anastomosis is via the extracranial artery, which penetrates the skull across the cerebral hemisphere and through various holes. It occurs between the arterial branches of the Willis arterial ring. The Willis annulus is formed by the anastomosis between the internal carotid artery, the basal artery, the anterior communicating artery, the anterior communicating artery, the posterior communicating artery, and the posterior communicating artery. The internal carotid artery terminates within the anterior and middle cerebral arteries. Near its end, the internal carotid artery gives rise to the posterior communicating artery, which connects caudally with the posterior cerebral artery. The anterior cerebral artery connects via the anterior communicating artery.

2.1. Cerebral artery Blood supply to the cerebral cortex is mainly through the cortical branches of the anterior cerebral, middle cerebral, and posterior cerebral arteries, which reach the cortex within the pia mater. FIG. 5 is an explanatory view showing the arterial supply to the cerebral cortex, where 1 is the orbital frontal artery, 2 is the anterior Roland artery, 3 is the Roland artery, and 4 is the frontal parietal artery. , 5 is the posterior parietal artery, 6 is the ocular artery, 7 is the posterior temporal artery, 8 is the anterior temporal artery, 9 is the orbital artery, and 10 is the orbital artery. Correlative Neuroanatomy & Functional Neurology, 18th Ed., P., 11 are the anterior limbal arteries, 12 are the posteromedial frontal arteries, and 13 are the correlative neuroanatomy & Functional Neurology, 18th Ed., P. 50, 1982). The lateral surface of each cerebral hemisphere exits primarily from the middle cerebral artery. The medial and inferior surfaces of the cerebral hemisphere exit the anterior and posterior cerebral arteries. The middle cerebral artery, the terminal branch of the internal carotid artery, enters the lateral cerebral fissure and divides into adjacent frontal, temporal, parietal, and occipital lobe cortical branches. The small penetrating artery, which is the lenticular striatal artery, originates from the base of the middle cerebral artery and exits the internal capsule and adjacent structures. The anterior cerebral artery begins in the internal carotid artery, enters the longitudinal fissure of the cerebrum, extends inward to the corpus callosum knee, where it bends posteriorly in close proximity to the corpus callosum. The anterior cerebral artery serves as a branch to the medial frontal and parietal lobes and to the adjacent cortex along the medial aspect of these lobes. The posterior cerebral artery, at its rostral tip, originates from the basilar artery, usually at midbrain level, bends dorsally around the cerebral peduncle and sends branches to the medial and inferior surfaces of the temporal lobe as well as the medial occipital lobe. Branches include the calcar avis artery and the penetrating branches to the posterior thalamus and abdomen of the thalamus.

The basilar artery is formed by the connection of the vertebral arteries. The basilar artery exits the upper brainstem via a short paramedian branch, a short perimeter branch, and a long perimeter branch. It is delivered to the midbrain by the basilar, posterior cerebrum, and superior cerebellar arteries. The pons is produced by the basilar, anterior, posterior, and superior cerebellar arteries. The medulla oblongata is produced by the vertebrae, anterior spinal nerves, posterior spinal nerves, posterior inferior cerebrum, and basilar arteries. The cerebellum is produced by the cerebellar arteries (superior cerebellar, anterior inferior cerebellar, and posterior inferior cerebellar arteries). The choroid plexus of the third and lateral ventricles is produced by the branches of the internal carotid and posterior cerebral arteries. The choroid plexus of the fourth ventricle is produced by the posterior inferior cerebellar artery. The venous drainage tract from the brain primarily enters the dural venous sinus, a vessel located within the tough structure of the dura. The dural venous sinus contains no valves and is mostly triangular. The upper vertical cave is in the cerebral sickle. Although the human brain makes up only about 2% of total body weight, it receives about 15% of cardiac output and its oxygen consumption is about 20% of the whole body. These values indicate the high metabolic rate and oxygen demand of the brain compensated by the corresponding high rate of blood flow per unit brain mass. For cerebral circulation, it is produced by the internal carotid artery and the vertebral artery. The total blood flow to the brain is about 750-1000 ml / min; of which about 350 ml flows through each internal carotid artery and about 100-200 ml flows through the vertebral basilar artery system. Venous outflow is drained by the internal jugular and vertebral veins.

As used herein, the term "stroke" or "cerebrovascular attack" refers to the usually local and acute neurological symptoms and signs resulting from a disease involving a blood vessel. Stroke is either obstructive (due to obstruction of blood vessels) or hemorrhagic (due to bleeding from blood vessels). As used herein, the term "ischemia" refers to the lack of blood supply and oxygen that occurs when the decrease in perfusion pressure distal to abnormal stenosis of blood vessels (stenosis) is not compensated for by the autoregulatory dilation of resistant blood vessels. Means. When the ischemia is intense and long enough, neurons and other cellular elements die; this condition is called an "infarction." Bleeding can result from rupture of a congenital aneurysm of the Willis arterial ring, eg, on the surface of the brain (outside the parenchyma), causing subarachnoid hemorrhage (SAH). Bleeding can also be intraparenchymal, from rupture of blood vessels damaged by long-term hypertension, for example, and can result in blood clots (intracerebral hematomas) in the brain stem or in the cerebellum. Bleeding can be associated with ischemia or infarction. The mass effect of intracerebral hematomas can impair the blood supply of adjacent brain tissue; Alternatively, subarachnoid hemorrhage can cause reactive vasospasm of cerebral surface blood vessels, which can lead to ischemic brain injury. Infarcted tissue can also cause secondary bleeding. Aneurysms can sometimes rupture in the brain, causing intracerebral hematomas, and also rupture in the ventricles, causing intraventricular hemorrhage. Most obstructive strokes are due to atherosclerosis or thrombosis, and most hemorrhagic strokes are associated with hypertension or aneurysms, but both types of stroke are heart disease, trauma, infections, tumors. Can occur at any age from many causes, including, but not limited to, blood disorders, vascular malformations, immunological disorders and exogenous toxins.

2.2. Vasoconstriction and Vasodilation The term "vasoconstriction" as used herein refers to the narrowing of blood vessels resulting from the contraction of the muscle walls of blood vessels. When blood vessels constrict, blood flow is restricted or slowed. As used herein, the term "vasodilation," which is the reverse of vasoconstriction, means vasodilation. As used herein, the terms "vasoconstrictor," "blood pressure-elevating agent," or "vasoconstrictor" mean factors that cause vasoconstriction. Vasoconstriction usually results in an increase in blood pressure, which may be slight or severe. Vasoconstriction can result from a disease, drug, or psychological state. Drugs that cause vasoconstriction include, but are not limited to, catecholamines, antihistamines, decongestants, methylphenidate, common colds, pseudoephedrine, and caffeine. Vasodilators are drugs or chemicals that relax the smooth muscles of blood vessels and dilate them. Dilation of arterial blood vessels (mainly arterioles) leads to a decrease in blood pressure. Relaxation of smooth muscle depends on removing the stimulus for contraction, which mainly depends on intracellular calcium ion concentration and phosphorylation of myosin light chain (MLC). Thus, vasodilation primarily involves 1) lowering intracellular calcium levels or 2) stimulating myosin L-chain phosphatases and inducing calcium symporters and antiporters (pumping calcium ions from the intracellular compartment). It works by either dephosphorylation of MLC. Reuptake of ions into the sarcoplasmic reticulum of smooth muscle via the exchanger and release of ions throughout the plasma membrane also aid in achieving vasodilation. The specific mechanism for achieving these effects varies from vasodilator to vasodilator and can be classified as endogenous and extrinsic. As used herein, the term "intrinsic" means that it proceeds internally, is internally derived, or originates from a state within the organism rather than externally. As used herein, the term "exogenous" means that it is externally derived, externally derived, or caused externally rather than originating from a state within the organism.

Vasodilation directly affects the relationship between mean arterial pressure and cardiac output and total peripheral resistance (TPR). Cardiac output can be calculated by multiplying the heart rate (beats / minute) by the stroke volume (the amount of blood released during contraction). TPR is determined by several factors and includes, but is not limited to, vessel length, blood viscosity (quantified by hematocrit), and vessel diameter. The most important variable for quantifying resistance is vessel diameter. An increase in either cardiac output or TPR causes an increase in mean arterial pressure. Vasodilation works to reduce TPR and blood pressure by relaxing smooth muscle cells in the medial layer of the aorta and smaller arteries. Vasodilation occurs in the superficial blood vessels of a warm-blooded animal when the surrounding environment of the warm-blooded animal is hot, and this process diverts the flow of heated blood to the skin of the animal, where heat is more easily released into the atmosphere. obtain. Vasoconstriction is the reverse physiological process. Vasodilation and vasoconstriction are caused not only by local paraclinic factors produced by endothelial cells (eg, brazikinin, adenosine, nitrogen oxide, endothelin), but also by the autonomic nervous system and adrenal glands of the organism (both catecholamines, eg norepinephrine, respectively). And epinephrine) are naturally modulated. Patients who use vasodilators to treat symptoms such as angina and congestive heart failure, as well as hypertension in which the patient has abnormally high blood pressure, and develop other heart disorders by maintaining lower blood pressure The risk of

2.3. Ventricles The ventricles, which are the chambers in the brain that contain cerebrospinal fluid, include two lateral ventricles, one third ventricle, and one fourth ventricle. The lateral ventricle is within the cerebral hemisphere. The lateral ventricle drains through the foramen of Monroe into the third ventricle, which is located between the two diencephalic structures of the brain. The third ventricle reaches the fourth ventricle through the Sylvian cerebral aqueduct. The fourth ventricle is located in the posterior fossa between the brain stem and the cerebellum. Cerebrospinal fluid flows from the fourth ventricle through the foramen of Rushka and Majandi into the basilar cistern. Cerebrospinal fluid then penetrates the subarachnoid cistern and drains into the venous system via the arachnoid fur. FIG. 8 is a diagram of the ventricular system of the brain. The system is a series of cavities (chambers) in the brain that are continuous with the subarachnoid space and central canal of the spinal cord. Four ventricles: Left and right lateral ventricles, and midline third and fourth ventricles. The two lateral ventricles are located in the cerebrum and are each connected to the third ventricle by the foramen of Monroe. The third ventricle is located in the diencephalon and is connected to the fourth ventricle by the Sylvian cerebral aqueduct. The fourth ventricle is located in the posterior brain and is, at least developmentally, continuous with the central canal of the spinal cord. Three holes connect the fourth ventricle to the subarachnoid space: the median or Majandi foramen, and the left and right Rushaka lateral ostium (foramen).

2.4. Flow of CSF in the brain Figure 9 shows the flow of CSF from the ventricles to the subarachnoid space. Cerebrospinal fluid (CSF) is a clear body fluid that occupies the ventricular system, the subarachnoid space of the brain, and the central canal of the spinal cord. CSF is produced by the deformed choroid plexus ependymal cells found throughout the ventricular system. In addition, CSF is formed around blood vessels and ventricular walls, probably also from the extracellular space of the brain. CSF flows from the lateral ventricle through the interventricular foramen to the third ventricle. The CSF then flows into the fourth ventricle through the cerebral aqueduct. CSF flows into the subarachnoid space via the midline and the left and right lateral openings. Finally, CSF is reabsorbed into the dural venous sinus through arachnoid granules and arachnoid villi. Arachnoid granules consist of a collection of villi. The villi form a visible hernia of the arachnoid through the dura in the superior sagittal sinus and the lumen of other venous structures. The granules appear to act as a valve that allows unidirectional flow of CSF from the subarachnoid space to venous blood. All components of CSF, including small molecules, proteins, microbes, and red blood cells, come out with the liquid. CSF is produced at a rate of about 0.3-0.37 ml / min or 20 ml / hour or 500 ml / day. The volume of the CSF space is about 150 ml, and the CSF is replaced 3.7 times a day. The choroid plexus maintains the chemical stability of CSF using a mechanism of capillary filtration and epithelial secretion. The capillaries that cross the choroid plexus freely penetrate the plasma solute, but there is a barrier at the level of epithelial cells that form the choroid plexus, which is involved in carrier-mediated active transport. Brain CSF and extracellular fluid are in steady state, and plasma and CSF are in osmotic equilibrium under normal physiological conditions.

2.5. Blood-brain barrier The blood-brain barrier prevents the invasion of blood-derived substances into the brain and maintains a stable environment for neurons to function effectively. The blood-brain barrier arises from the special properties of brain microvascular endothelial cells, the major anatomical sites of the blood-brain barrier, their intercellular connections, and the relative deficiency of vesicle transport, such cells as common capillaries. Will be different. The endothelial cells of the blood-brain barrier are also not fenestrated, instead the endothelial cells of the blood-brain barrier are interconnected by tight junction complex arrays to prevent diffusion across the vessel wall.

3. Subarachnoid hemorrhage The term "subarachnoid hemorrhage" (also called "SAH") means bleeding into the subarachnoid space. SAH may occur spontaneously, usually from a cerebral aneurysm, or may be due to trauma. Symptoms include rapidly developing headaches (sometimes called "thunderclap headaches"), vomiting, and altered levels of consciousness. Diagnosis is generally made by computed tomography (CT scan), sometimes by lumbar puncture. Treatment is by close observation, dosing and early neurosurgical trials and procedures to prevent recurrence and complications. FIG. 10A is a flow chart showing the prognosis following subarachnoid hemorrhage, and FIG. 10B is a flow chart showing a route that may be involved in late complications after subarachnoid hemorrhage. SAH is a medical emergency and can lead to death or severe disability even when initially recognized and treated. Half of all SAH cases are fatal and 10-15% of patients die before arriving at the hospital. SAH is considered a form of stroke and occurs between 1% and 7% of all strokes. When caused by a ruptured intracranial aneurysm, bleeding is seen in the subarachnoid space and is generally less common in the intraventricular and intracerebral spaces. Bleeding due to SAH can lead to brain injury, brain deviation, decreased cerebral perfusion and hydrocephalus. In the United States, the incidence of SAH from a ruptured intracranial aneurysm is estimated to be 1 in 10,000, with approximately 34,000 new cases of SAH occurring each year. Rupture of these aortic aneurysms has a 30-day mortality rate of 45%. In addition, an estimated 30% of survivors will suffer from moderate to severe disability. Figure 11 is a graph showing the annual evolution of the results of subarachnoid hemorrhage in a 7-population-based study of subarachnoid hemorrhage (SAH), showing a 50% reduction in mortality over the next 20 years. ..

Several studies have shown that the incidence of SAH averages 9.1 per 100,000 people each year. Studies in Japan and Finland show higher proportions in those countries for reasons that are not understood at all (22.7 per 100,000 and 19.7 per 100,000, respectively). South America and Central America, in contrast, have an average ratio of 4.2 per 100,000. The group of people at risk for SAH is usually younger than the group affected by stroke, but the risk still increases with age. Young people are less likely than middle-aged people with SAH (risk 0.1 or 10%). The risk continues to increase with age and is more than 60% in the very elderly (over 85) between the ages of 45 and 55. The risk of SAH is greater than about 25% in women over 55 years of age, probably reflecting hormonal changes resulting from menopause. Patients who survive SAH are also at risk for secondary complications. Of these complications, aneurysm rebleeding, angiographic cerebral vasospasm and delayed cerebral ischemia (DCI) are the most prominent. DCI is the occurrence of local neuropathy (eg, unilateral paresis, aphasia, apraxia, hemianopia, or neglect) and / or the Glasgow Comascale (all scores or individual components thereof [eye opening, bilateral movement, Language] is a decrease in one). This may or may not last for at least 1 hour and is not apparent immediately after aneurysm occlusion and other causes by clinical evaluation of the brain, CT or magnetic resonance imaging (MRI) scans, and appropriate laboratory experiments. It cannot be caused by. Cerebral infarction due to DCI is defined as the presence of a stroke on a CT or MRI scan of the brain within 6 weeks after SAH, or on a recent CT or MRI scan made before death within 6 weeks. At necropsy, CT or MRI scans between 24 and 48 hours of early aneurysm occlusion prove to be absent and not due to other causes such as surgical clipping or endovascular procedures. Generally, white matter by CT imaging resulting from ventricular catheters or parenchymal blood is not considered a finding of cerebral infarction from DCI. Angiography Cerebral vasospasm is a radiological test (CT angiography [CTA], MR angiography [MRA]] It is a type of MRA or catheter angiography [CA]) and can be the cause of DCI. The term "angiographic cerebral vasospasm" means the narrowing of the large capacitance arteries at the bottom of the brain (ie, the cerebral arteries) after hemorrhage into the subarachnoid space, leading to reduced perfusion in the distal brain region. Angiographic vasospasm, which is the result of SAH, can occur after any condition that deposits blood in the subarachnoid space.

Symptoms The classic symptom of SAH is thunderclap headache, which is said to be the "worst ever" or "head kicking" that occurs over seconds to minutes, but is only about one-third of all SAH patients. Approximately 10% of patients seeking medical care with have an underlying SAH. Patients may also have vomiting and 1 in 14 has a seizure. Confusion, decreased level of consciousness, or coma As possible, there may be signs of cervical stiffness and other meningitis. Intraocular hemorrhage may occur in response to increased pressure around the brain. Subarachnoid hemorrhage (the vitreous membrane is the glass of the eye) (Covering the body) and vitreous hemorrhage may be visible on fundus examination, known as Telson's syndrome (which occurs in 3-13% of cases) and is more common in more severe SAH. In patients with thunderclap headache, none of the above symptoms are effective in confirming or eliminating bleeding, but attacks are more common when bleeding is the result of a rupture of the aortic aneurysm as opposed to other causes. There is a motor-eye nerve abnormality (affected downward and outward eye movements, the eyelids cannot be lifted to the same side, but the pupillary reflex is normal), causing bleeding from an aneurysm near the posterior traffic artery It can be shown that the isolated dilation of the pupil can also reflect brain hernia as a result of elevated intracranial pressure. As a result of hemorrhage, the body releases large amounts of adrenaline and similar hormones, which causes a sharp rise in blood pressure. The heart undergoes substantial tension, and neurogenic pulmonary edema, stunned myocardium, cardiac arrhythmia, electrocardiographic changes (sometimes due to giant negative "cerebral" T-waves) and cardiac arrest (3%) occur rapidly after the onset of hemorrhage. SAH can also occur in people with head trauma. Symptoms can include headache, decreased consciousness level or unilateral insufficiency paralysis. SAH is especially with lower grass go comba scale levels. If involved, it is considered a severe complication of head trauma.

Diagnosis The early stages of assessing a person suspected of having SAH are the medical history and physical examination. Since only 10-25% of patients admitted to the hospital for thunderclap headache have SAH, other possible causes such as meningitis, migraine, cerebral vein sinus thrombosis are usually considered at the same time. Will be done. Intracerebral hemorrhage, which is twice as common as SAH, is sometimes misdiagnosed as SAH. The diagnosis of SAH is not made on a therapeutic background alone. In general, medical images of the brain are needed to confirm or rule out bleeding [usually high-sensitivity computed tomography (CT> 95% accurate identification on day 1 after bleeding)). scan)]. Compared to CT scans, magnetic resonance imaging (MRI scans) can be more sensitive even after a few days. In people with normal CT or MRI scans, lumbar puncture, in which cerebrospinal fluid (CSF) is needled out of the lumbar sac, shows signs of bleeding in 3% of the group found to be normal CT. Lumbar puncture is considered mandatory if the diagnostic imaging is negative. Examine the yellow appearance of xanthochromia, centrifuges, or spectrophotometric methods on bilirubin, a degradation product of hemoglobin in the CSF sample. After SAH is confirmed, its origin needs to be determined. Generally, CT angiography (visualizing blood vessels by CT scan) to confirm an aneurysm is the first step, but more invasive catheter angiography (injecting contrast medium through a catheter that advances into the cerebral artery). ) Is a criterion test, but the risk of complications is greater. Catheter angiography is useful at the same time if there is a plan to remove the source of bleeding, such as an aneurysm.

Cause Spontaneous SAH is often due to a ruptured cerebral aneurysm (85%). A cerebral aneurysm is a weakening of the wall of an enlarged cerebral artery. Cerebral aneurysms tend to be located within the Willis aneurysm and its bifurcations. Most cases of SAH are due to bleeding from a small aneurysm, and larger aneurysms (rare) are more prone to rupture. No aneurysm is detected on the first angiography in 15-20% of cases of spontaneous SAH. Non-aneurysmal peri-midbrain hemorrhage, in which blood is confined to areas of the midbrain, causes another 10% of SAH cases. In this, aneurysms are generally not seen. The remaining 5% of cases are due to vasculitis damage to arteries, other disorders affecting blood vessels, spinal vascular disorders, and bleeding to various tumors. Most traumatic SAHs occur in the vicinity of skull fractures or intracerebral contusions.

Classification Several rating scales are available for SAH. These evaluation scales were derived by retroactively adapting patient characteristics and results. In addition to the ubiquitous Glasgow Coma Scale (GCS), three other special scores are used. For all scores, higher numbers are associated with worse results. The first measure of severity was described by Hunt & Hess in 1968 (Hunt and Hess Classification) and classifies the clinical condition of patients. The Fischer assessment classifies the appearance of SAH on CT scans. The Fisher scale has been modified by Claassen and collaborators (Claassen scale) to reflect additional risk from SAH size and is associated with intraventricular hemorrhage. The World Neurosurgery Classification uses GCS and local neurological deficiencies to measure the severity of symptoms. A comprehensive classification system was proposed by Ogilvy & Carter to predict outcomes and measure treatments. The Ogilvy system has 5 ratings and 1 point is assigned to the presence or absence of each of the 5 factors: ages over 50 years; Hunt & Hess Rating 4 or 5; Fisher Scale 3 or 4; Aneurysm size greater than 10 mm; and posterior circulatory aneurysm 25 mm or greater.

Treatment SAH management consists of general treatments to stabilize the patient, specific treatments to prevent rebleeding by removing the source of bleeding, prevention of vascular spasms, and prevention and treatment of complications.

General Treatment The highest priority is to stabilize the patient. Patients with reduced levels of consciousness may require intubation and mechanical ventilation. Blood pressure, pulse rate, respiratory rate and Glasgow Coma Scale are often monitored. Once the diagnosis is confirmed, admission to the intensive care unit is preferred, especially given that 15% of such patients have further onset (rebleeding) in the first few hours after admission. Nutrition is an early priority and oral or nasogastric feeding is preferred over parenteral routes. Analgesia (pain management) is generally limited to non-sedatives such as codeine, as sedation can affect mental status and thus impair the ability to monitor consciousness levels. Deep vein thrombosis is prevented by compression stockings, intermittent air compression of the calf, or both.

Prevention of rebleeding Patients with large hematomas associated with decreased levels of consciousness or local neurological symptoms may be candidates for emergency surgical removal of blood and obstruction of bleeding aneurysms. A catheter or tube can be inserted into the ventricles to treat hydrocephalus. The remaining patients are more extensively stabilized and later undergo transfemoral catheter angiography or CT angiography. After the first 24 hours, the risk of rebleeding continues to remain at about 40% for 4 weeks, suggesting that treatment should be aimed at reducing this risk. Rebleeding is difficult to predict but can occur at any time, with a dark prognosis. Therefore, measures to prevent rebleeding are taken as soon as possible. If the cerebral aneurysm is confirmed by angiography, two procedures can be used to reduce the risk of further bleeding from the same aneurysm: neurosurgical clipping and intravascular coiling. Clipping requires a craniotomy (opening the skull) to locate the aneurysm, followed by placement of one or more clips throughout the neck of the aneurysm. Coiling is done through the large blood vessels: A catheter is inserted into the femoral artery in the groin and advanced through the aorta to the arteries that supply the brain (both carotid and bivertebral arteries). When the aneurysm is located, a metal coil is placed that leads to the formation and occlusion of blood clots in the aneurysm. The decision as to whether treatment will be given is typically made by a multidisciplinary team, often including a neurosurgeon and a neuroradiologist. Middle cerebral artery and related vascular aneurysms are difficult to reach optimal placement of intravascular coiling and tend to follow clipping, basilar and posterior cerebral artery aneurysms are difficult to reach surgically and intravascular management Tends to be more available. The main drawback of coiling is the potential for aneurysms to recur, and this risk is extremely low in surgical procedures. Patients who have undergone coiling are typically followed up for many years by angiography or other procedures to ensure early confirmation of aneurysm recurrence.

Early Prognosis Mortality and Mortality SAH mortality is between 40% and 50%. Of the patients who survive initial hospitalization, treatment and complications, at least 25% have serious lifestyle restrictions and less than 20% have no sequelae. A mild delay in the diagnosis of SAH without coma (or mistaken a sudden headache for a migraine) contributes to the adverse consequences. Risk factors for adverse results include older age, poorer neurological assessment, more blood and larger aneurysms on initial CT scans, aneurysm location in posterior circulation, systolic hypertension, and heart attack, hypertension. Includes previous diagnosis of liver disease or previous SAH. During hospitalization, the development of delayed ischemia due to vascular spasm, the development of intracerebral hematoma or intraventricular hemorrhage (bleeding into the ventricles), and fever on the 8th day of hospitalization also worsen the prognosis. SAHs that do not show an aneurysm by full catheter angiography can be called "angiographic negative SAH". This provides a better prognosis than SAH from aneurysms, however, is still associated with the risk of ischemia, rebleeding and hydrocephalus. However, peri-midbrain SAH (bleeding around the midbrain) has a very low rate of rebleeding or delayed ischemia, and the prognosis for this subtype is good.

Long-term consequences Symptoms such as fatigue, mood disorders, depression, executive function dysfunction, and associated neurocognitive symptoms are common to people with SAH. Anxiety, depression, post-traumatic stress disorders and cognitive impairment are common even in people with good neurological recovery. Over 60% of people report frequent headaches. Aneurysmic SAH can result in damage to the hypothalamus and pituitary gland, and these two regions of the brain play a central role in hormone regulation and production. Studies have shown that at least 25% of people with previous SAH can develop a deficiency of one or more hypothalamic-pituitary hormones such as growth hormone, prolactin or thyroid stimulating hormone.

4. Vasospasm Angiography Cerebral vasospasm is the most common cause of local ischemia after SAH. Vascular spasm adversely affects the prognosis of SAH patients, accounting for up to 23% of SAH-related disorders and deaths. Among all types of ischemic stroke, vasospasm is unique in that it is somewhat predictable, preventable, and treatable (Macdonald, RL and Weir, B. In Cerebral Vasospasm. Academic Press, Burlington, MA, See USA (2001)). Vascular spasm results in decreased cerebral blood flow and increased cerebral vascular resistance. Although not limited by theory, vasospasm generally includes other causes of atherosclerosis and local trauma to blood vessels, such as traumatic head trauma, aneurysm subarachnoid hemorrhage and subarachnoid hemorrhage. It is considered that it is caused by the structural damage of. Cerebral vasospasm is a naturally occurring vasoconstriction that can also be triggered by the presence of blood in the CSF, a common occurrence after an aneurysm rupture or a traumatic head injury. Cerebral vasospasm can ultimately lead to brain cell damage in the form of cerebral ischemia and infarct formation due to interruptions in blood supply. DCI is a multifactorial process due to early brain injury, as well as at least these processes. Angiography Angiographic vasospasm is a process involved in DCI. Other processes that may be involved in DCI are cortical spreading ischemia and the formation of microthrombogenic embolisms. Cortical spreading ischemia has been described as a novel mechanism that can cause DCI in animal models of SAH. DCI has been detected in humans with SAH and angiographic vasospasm.

Each year, about 1 in 10,000 people have a ruptured aneurysm. Mortality and morbidity increase with bleeding volume and reflect the patient's age and health, and the likelihood of developing an aneurysm increases steadily with age. Rebleeding is exceptionally detrimental due to increased SAH levels as well as increased potential for expansion into the brain and ventricles. Most deaths due to aneurysm rupture occur outside the hospital or shortly after admission due to the effects of initial bleeding or early rebleeding. Potential signs of symptoms of vasospasm occur only in patients who survive past the first few days. The incidence of vascular spasm is lower than the incidence of SAH (because only some patients with SAH develop vascular spasm). The incidence of vascular spasm depends on the type of patient accepted by the given hospital and the method by which vascular spasm is diagnosed. The unconditional term "vascular spasm" is usually used with respect to the angiographically determined arterial narrowing as defined above. Clinical vasospasm is often used synonymously with late-onset cerebral ischemia (DCI). This must be specified when used in other methods, such as vascular spasms based on increased mesocerebral artery transcranial Doppler velocity. Some degree of angiographic narrowing occurs in at least two-thirds of patients angiographically performed between 4 and 12 days after SAH. The number of patients who develop neurological decline from this DCI is estimated to be about one-third, depending on the effort to monitor the patients and the effectiveness of prevention. Of the hospitalized SAH patients, 5% die of vasospasm. Compared to moderate post-SAH patients, very good post-SAH patients probably do not develop vasospasm due to low SAH levels, and very poor post-SAH patients are probably early onset. Die in stage. The presence of rich, widespread subarachnoid blood clots that can be visualized by computed tomography (CT) scans, which occur almost in close proximity to the onset of hemorrhage, is a key prognostic factor. The likelihood of vasospasm and the resulting DCI is reduced by factors that reduce the amount of time it is exposed to blood clots. Conversely, the incidence of vasospasm and DCI is increased by the use of antifibrinolytics that prolong the time that arteries are exposed to blood clots and possibly cause ischemia by other mechanisms. Poor inpatient clinical evaluation is associated with DCI, probably because both antifibrinolytic use and DCI show high levels of SAH. No clear relationship has been established between age, hypertension, or gender and DCI. Smokers appear to be more prone to vascular spasms and DCI. Factors unrelated to the development of vasospasm include season, geography, contrast media, and diabetes.

Patients who develop vasospasm are worse than those who do not. Results tend to be better when surgery or aneurysm coiling is performed early (within the first day) than when treatment is delayed. Results were generally poor when surgery was prioritized during peak vascular spasms. Vascular spasm is not due to early surgery or coiling; Early surgery or coiling allows for more active treatment of vascular spasms. Careful removal should be attempted in the presence of thick blood clots. The amount of residual blood clot after surgery is a prognostic factor for DCI. Open surgery exposes the patient to retractor pressure, venous sacrifice, temporary clipping ischemia, brain removal, and arterial injury. Studies have shown post-surgical reductions in cerebral blood flow, local cerebral oxygen metabolism, and oxygen extraction. Vascular spasms and DCI can be more common in patients undergoing neurosurgical clipping of ruptured aortic aneurysms compared to intravascular coiling. Independent variables such as neurological evaluation on admission, aging, and heavy intracranial or intraventricular hemorrhage are more closely associated with outcome than vascular spasm. Since vasospasm is a gradual process, only extreme cases are expected to result in infarction in the absence of systemic hypotension, cardiac dysfunction, anoxia, and increased intracranial pressure. Existing hypertension and old age also strongly influence the vulnerability of the brain to ischemia. The etiology of vascular spasm and infarction in fatal cases has not been discussed. There is evidence that vascular spasm can be reduced by surgically or pharmacologically removing blood clots. Some data suggest that DCI can be reduced by calcium channel blockers as well as hypertension and hypercirculatory blood volume. Vascular spasms can also be abolished mechanically or temporarily by pharmacological angioplasty.

Incidence of vasospasm The incidence of angiographic vasospasm depends on the time interval after SAH. Peak incidence occurs after SAH 6-8 days (range, 3-12 days). In addition to the time after SAH, another major factor affecting the prevalence of vascular spasm is the volume and distribution of subarachnoid blood.

Prognostic Factors for Vascular Spasms The prognostic factors for vasospasm include: Blood from CT scans; Hypertension; Anatomical and systemic factors; Clinical grade; Patients receiving antifibrinolytics; Age Smoking; physiological parameters; and hydrocephalus.

Diagnosis The diagnosis of angiographic vasospasm is based on a comparison of vascular imaging. The diagnosis of late-onset cerebral ischemia (DCI) is primarily clinical. Angiographic vasospasm can be asymptomatic; however, when cerebral blood flow is below the ischemic threshold, symptoms become apparent, which is called DCI. Symptoms typically occur subacutely and can fluctuate. Symptoms may include excessive drowsiness, lethargy, stupor, unilateral paresis or hemiplegia, lack of will, speech disorders, visual field defects, gaze disorders, and cranial nerve palsy. Some symptoms are localized, but not a diagnosis of a particular pathological process; therefore, other diagnoses, such as rebleeding, hydrocephalus, and seizures, use x-ray photography, clinical and laboratory evaluations. Must be excluded immediately. Cerebral angiography is the most standard for visualizing and studying cerebral arteries; Transcranial Doppler ultrasonography is also used. The pathophysiology of vasospasm can be accompanied by structural and biochemical changes within the vascular endothelium and smooth muscle cells. The presence of blood in the subarachnoid space can initiate these changes. In addition, insufficient blood volume and reduced brain autoregulation can simultaneously impede cerebral perfusion. The cumulative effects of these processes can lead to a severe decrease in cerebral blood flow that causes cerebral ischemia and leads to infarction. In addition, severe systole can lead to morphological changes in the walls of the cerebral arteries, allowing vasoactive material to remain narrow in the absence of continuous presence. The area of the brain that is then supplied by the affected arteries experiences ischemia (meaning limited blood supply).

Other complications Hydrocephalus (prominent over-accumulation of CSF causing ventricular enlargement and increased intracranial pressure) may be accompanied by SAH, both short-term and long-term, and can be detected by CT scan. Surgical drainage of excess fluid (eg, by ventricular drain or shunt) is sometimes required when the level of consciousness is reduced. Pneumonia and cardiac decompensation, as well as blood pressure fluctuations and electrolyte disorders, can occur in approximately 50% of inpatients with SAH and worsen prognosis. These are managed symptomatically. Seizures occur in about one-third of all cases of SAH.

Treatment Nimodipine, an oral calcium channel blocker, has been shown to reduce the likelihood of adverse results in clinical trials, but nimodipine can hardly reduce the amount of vascular spasm detected by angiography. Other calcium channel blockers and magnesium sulphate have also been investigated but are not currently recommended. There was no evidence of benefit when nimodipine was given intravenously, but the experiments performed included a small number of patients. The efficacy of oral nimodipine remains a problem in traumatic SAH. Hemodynamic manipulation, formerly known as "triple H" therapy, is often used as a procedure to treat vasospasm. This involves the use of intravenous infusions and vasoconstrictors to achieve conditions of hypertension (high blood pressure), hypercirculatory blood volume (excessive fluid in the circulation) and blood dilution (gentle dilution of blood). Although the induction of hypertension is considered to be the most important component of this treatment, the evidence for the use of this method is uncertain and so far enough randomized controlled trials to demonstrate its benefits. Has not been done. If symptomatic vasospasm, also known as DCI, resists medical treatment, angiography is attempted to identify the site of the vasospasm and administer a vasodilator (a drug that relaxes the walls of blood vessels) directly into the arteries. Often (pharmacological angioplasty), mechanical angioplasty (opening the constricted area with a balloon) may be performed.

6. Potential-opening ion channel A potential-opening ion channel is a type of integral membrane protein that allows the passage of selected inorganic ions throughout the cell membrane by opening and closing in response to changes in intramembrane voltage. (Sands, Z. et al., "Voltage-gated ion channels", Current Biology, 15 (2): R44-R47 (2005)). This type of ion channel is particularly important in neurons, but many It is common in types of cells. It has an important role in excitatory neurons and muscle tissue so that ion channels allow rapid regulated depolarization in response to triggering voltage changes. When placed at synapses along axons, potential-opening ion channels directionally transmit electrical signals.

Structure Potassium-opening potassium, sodium and calcium ion channels are considered to have a similar overall structure. (Sands, Z. et al., "Voltage-gated ion channels", Current Biology, 15 (2): R44-R47 (2005)). Potential-opening ion channels are generally composed of several subunits arranged so that there is a central pore through which the ions can travel below their electrochemical gradient. Channels tend to be very ion-specific, but ions of similar size and charge can pass through the channel to some extent.

Mechanism Crystallographic structural studies of potassium channels assume that this structure remains perfect in the corresponding plasma membrane, and when a potential difference is introduced through the membrane, the associated electromagnetic field is constrained within the potassium channel. It suggests that it causes a change in the target. The conformational change sufficiently distorts the shape of the channel protein, allowing the channel or cavity to open and the inflow or outflow of ions to occur throughout the membrane under its electrochemical gradient. This continues to generate enough current to depolarize the cell membrane. Potential-opening sodium channels and calcium channels are composed of a single polypeptide with four homologous domains. Each domain contains 6 transmembrane alpha helices. The potential-sensing helix, S4, has multiple positive charges, and high positive charges outside the cell repel the helix and cause a conformational change, allowing ions to flow into the channel. Potassium channels function in a similar manner, except that they are composed of four separate polypeptide chains, each containing one domain. The potential sensing protein domains (potential sensors) of these channels, commonly known as paddles due to their shape, contain regions composed of S3b and S4 helices that appear to be conserved sequences. ..

6.1. Voltage-gated calcium channels Voltage-gated calcium channels (VDCCs) are a group of voltage-gated ion channels that control calcium influx into cells in response to changes in membrane potential. (Van Petegem F. et al., Biochemical Society Transactions, 34 (5): 887-893 (2006)). Voltage-gated calcium channels are found in excitatory cells (eg, muscles, glial cells, neurons, etc.). .. At physiological or resting membrane potentials, VDCC is normally closed. VDCC is activated (ie, opens) at a depolarized membrane potential. Ca due to activation of specific VDCC²⁺Can flow into cells, resulting in muscle contraction, neuronal excitement, upregulation of gene expression, or release of hormones or neurotransmitters, depending on the cell type. (Catterall WA et al., "International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels", Pharmacol. Rev., 57 (4): 411-25 (2005); Yamakage M. et al. al, "Calcium channels--basic aspects of their structure, function and gene encoding; anesthetic action on the channels--a review", Can. J. Anaesth., 49 (2): 151-64 (2002)). Dependent calcium channels have several different subsystems: α₁, Α₂δ, β_1-4And γ as a complex. The alpha subunit forms an ionic conductive pore, and the associated subunit has several functions, including modulation of gating. (Dolphin AC "A short history of voltage-gated calcium channels", Br. J. Pharmacol., 147 (Suppl 1): S56-62 (2006))

α₁Subunit α₁The subunit pore (molecular weight of about 190 kDa) is the main subunit required for a functioning channel in VDCC and consists of four characteristic homologous I-IV domains, each containing six transmembrane α-helices. Alpha subunit is Ca²⁺It forms a selective pore, which contains a voltage sensing mechanism and a drug / toxin-binding site. Ten alpha subunits have been identified in humans. (Dolphin AC "A short history of voltage-gated calcium channels", Br. J. Pharmacol., 147 (Suppl 1): S56-62 (2006))

α₂δ subunit α₂The δ gene has two subunits, α₂And δ are coded. They are linked to each other via disulfide bonds and have a combined molecular weight of 170 kDa. α₂Is the extracellular glycosylation subunit that interacts most with the α1 subunit. The delta subunit has a single intracellular and extracellular region with a short intracellular portion, which helps to anchor the protein within the plasma membrane. 4 α₂δ genes: There are CACNA2D1 (CACNA2D1), (CACNA2D2), (CACNA2D3), and (CACNA2D4). α₂Simultaneous expression of δ increases the expression level of the α1 subunit and causes an increase in current amplitude, faster activation and inactivation kinetics, and a voltage-dependent hyperpolarization shift of inactivation. Some of these effects are observed in the absence of beta subunits, while others require co-expression of beta. α₂The subunits of δ-1 and α2δ-2 are the binding sites of at least two anticonvulsants, gabapentin and pregabalin, used to treat chronic neuropathic pain. (Dolphin AC "A short history of voltage-gated calcium channels", Br. J. Pharmacol., 147 (Suppl 1): S56-62 (2006))

β subunit The intracellular β subunit (55 kDa) is an intracellular membrane-associated guanylate kinase (MAGUK) -like protein containing a guanylate kinase (GK) domain and a SH3 (src homology 3) domain. The guanylic acid kinase domain of the β subunit binds to the alpha subunit I-II cytoplasmic loop and regulates HVGCC activity. There are four known isotypes of the β subunit: CACNB1, CACNB2, CACNB3, and CACNB4. (Dolphin AC "A short history of voltage-gated calcium channels", Br. J. Pharmacol., 147 (Suppl 1): S56-62 (2006)) Although not limited by theory, the cytoplasmic β subunit stabilizes the final alpha subunit structure and delivers it to the cell membrane by its ability to mask the endoplasmic reticulum retention signal in the alpha subunit. It is assumed to have a major role. The endoplasmic reticulum retention brake is contained in the I-II loop of the alpha subunit, which is masked when the β subunit binds. Therefore, the β subunit first functions to regulate the current density by controlling the amount of alpha subunit expressed on the cell membrane. In addition to this voltage-gated role, the β subunit has an important additional function of regulating activation and inactivation kinetics and hyperpolarizing the voltage dependence of activation of the alpha subunit pore, so more. Current passes due to less depolarization. The β subunit acts as an important modulator of channel electrophysiological properties. The highly conserved 18-amino acid region (alpha interaction domain, AIDBP) on the intracellular linker of the αl subunit between domains I and II and the region on the GK domain of the β subunit (alpha interaction domain binding pocket) Interactions between are involved in the regulatory effects exhibited by the β subunit. Furthermore, the SH3 domain of the β subunit also provides additional regulatory effects on channel function, indicating that the β subunit may have multiple regulatory interactions with the αl subunit pore. The alpha interaction domain sequence is thought to contain no endoplasmic reticulum retention signal, which may be located in other regions of the I ~ IIα1 subunit linker.

γ subunit The γ1 subunit is known to be associated with the skeletal muscle VGCC complex, but evidence is not conclusive with respect to other subtypes of calcium channels. The γl subunit glycoprotein (33 kDa) is composed of four transmembrane helices. The γl subunit does not affect transport and most do not require regulation of the channel complex. However, γ2, γ3, γ4 and γ8 are also non-glutamates that mediate rapid synaptic transmission in the α-amino-3-hydroxy-S-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor, CNS. -NMDA-type is associated with a ionic transmembrane receptor. The NMDA-type receptor is a receptor to which NMDA (N-methyl-D-aspartic acid) specifically binds. There are eight genes in the γ subunit: γ1 (CACNG1), γ2 (CACNG2), γ3 (CACNG3), γ4 (CACNG4), (CACNG5) (CACNG6), (CACNG7), and (CACNG8). (Chu PJ et al., "Calcium channel gamma subunits provide insights into the evolution of this gene family", Gene, 280 (1-2): 37-48 (2002)). Voltage-gated calcium channels vary greatly in structure and shape. Calcium channels are classified as L-, N-, P / Q, T- and R-types according to their pharmacological and electrophysiological properties. These channel subtypes have different physiological functions. Molecular cloning revealed the αl subunit sequence of each channel. The αl subunit has a specific role in inducing activity in individual channels. Nonetheless, selective blockers of this channel subtype are required to identify specific channels involved in each activity. Nerve N-type channels are blocked by ω-conotoxin GVIA, R-type channels are resistant to other blockers and toxins, are blocked by SNX-482, and may be involved in processes in the brain. , Closely related P / Q type channels are blocked by ω-agatoxin. Dihydropyridine-sensitive L-type channels are involved in excitatory-contraction coupling of skeletal muscle, smooth muscle and myocardium, and are involved in hormone secretion in endocrine cells, and are further antagonized by phenylalkylamine and benzothiazepine.

6.2. Types of Potential Opening Calcium Channels L-Type Calcium Channels L-type Potential Opening Calcium Channels open when smooth muscle cells are depolarized. This depolarization can be brought about by cell elongation, by agonist binding of its G protein-coupled receptor (GPCR), or by autonomic nervous system stimulation. Opening of L-type calcium channel is extracellular Ca²⁺Causes an influx of calmodulin and then binds calmodulin. The activated calmodulin molecule activates myosin light chain kinase (MLCK), which phosphorylates thick filaments of myosin. Phosphorylated myosin can crosslink with fine actin filaments, and smooth muscle fibers (ie, cells) contract by a slip filament mechanism. (Yamakage M. et al, "Calcium channels--basic aspects of their structure, function and gene encoding; anesthetic action on the channels--a review", Can. J. Anaesth., 49 (2): 151-64 (2002)) L-type calcium channels are also abundant in striated muscle cells, such as the t-tubules of skeletal and myocardial fibers. Like smooth muscle, L-type calcium channels open when these cells are depolarized. In skeletal muscle, L-type calcium channels and calcium free channels (ryanodine receptors, or RYRs) mechanically open and close each other, the latter being located in the sarcoplasmic reticulum (SR), thus opening L-type calcium channels. Creates an opening in the RYR. In the myocardium, the opening of L-type calcium channels allows the influx of calcium into cells. Calcium binds to and opens calcium-free channels (RYRs) in SR (called "calcium-induced calcium release" or "CICR"). Ca²⁺Is released from the SR and can bind to troponin C on actin filaments by mechanical gate opening and closing or CICR, regardless of how the RYR opens. The muscle then contracts by a sliding filament mechanism, resulting in sarcomere shortening and muscle contraction.

R-type voltage-gated calcium channels R-type voltage-gated calcium channels (VDCCs) are involved in the regulation of calcium flow rates. R-type VDCC plays an important role in the decrease in cerebral blood flow observed after SAH. Although not limited by theory, R-type voltage-gated Ca can be located in the small-diameter cerebral artery because the concentration of intracellular free calcium ions determines the contractile state of vascular smooth muscle.²⁺Channels can regulate global and local cerebral blood flow. Yamakage M. et al, "Calcium channels--basic aspects of their structure, function and gene encoding; anesthetic action on the channels--a review", Can. J. Anaesth., 49 (2): 151-64 (2002) ). R-type potential-dependent calcium channel inhibitors are calcium influx blockers, the main pharmacological action of which is to prevent or slow the influx of calcium into cells by R-type potential-opening calcium channels. .. Gene Ca_v2.3 encodes the major pore-forming units of R-type voltage-gated calcium channels expressed in neurons.

N-type calcium channels N-type (N in Neural) calcium channels are found primarily at presynaptic terminals and are involved in neurotransmitter release. Strong depolarization due to action potentials opens these channels and Ca²⁺Allows the influx of vesicles and initiates vesicle fusion and release of stored neurotransmitters. Type N channels are blocked by ω-conotoxin. Yamakage M. et al, "Calcium channels--basic aspects of their structure, function and gene encoding; anesthetic action on the channels--a review", Can. J. Anaesth., 49 (2): 151-64 (2002) ).

P / Q-type calcium channels P-type (P in Purkinje cells) calcium channels are similar to N-type calcium channels in neurotransmitter release at presynaptic terminals and in many neuronal integrations. Play a role. P-type calcium channels are also found in Purkinje fibers in the electrical conduction system of the heart (Winds, R., et al., J. Physiol. (Lond.) 305: 171-95 (1980); Llinds, R. et al., Proc. Natl. Acad. Sci. USA 86 (5): 1689-93 (1989)). Q-type calcium channel blockers appear to be present in cerebellar granule cells. Q-type calcium channel blockers have a high threshold of activation and a relatively slow kinetics. Yamakage M. et al, "Calcium channels--basic aspects of their structure, function and gene encoding; anesthetic action on the channels--a review", Can. J. Anaesth., 49 (2): 151-64 (2002).

T-type calcium channels T-type (transient "T") calcium channel blockers are low voltage-gated activators. T-type calcium channel blockers are common in neurons and cells with pacemaker activity and on bone cells. Mibefradil shows some selectivity for T-type over other types of VDCC. Yamakage M. et al, "Calcium channels--basic aspects of their structure, function and gene encoding; anesthetic action on the channels--a review", Can. J. Anaesth., 49 (2): 151-64 (2002) ).

6.3. Calcium Channel Blockers and Inhibitors Calcium channel blockers are a type of drug and natural substance that act on many excitatory cells of the body, such as heart muscle, vascular smooth muscle or neuronal cells. The main action of calcium channel blockers is to lower blood pressure. Some calcium channel blockers reduce myocardial contractility. This is known as the "negative inotropic effect" of calcium channel blockers. Most calcium channel blockers are not the preferred treatment choice in individuals with cardiomyopathy due to this negative inotropic effect. Some calcium channel blockers delay the conduction of electrical activity in the heart by blocking calcium channels during the plateau phase of the heart's action potentials. This "negative chronotropic effect" can cause a decrease in heart rate and cause heart block (known as the "negative chronotropic effect" of calcium channel blockers). The negative chronotropic effects of calcium channel blockers make them the commonly used types of drugs for controlling the heart rate of individuals with atrial fibrillation or flutter. Calcium channel blockers act on voltage-gated calcium channels (VGCCs) in heart and vascular muscle cells. Blocking calcium channels prevents a large increase in intracellular calcium levels when stimulated, leading to continued reduction in muscle contraction. In the heart, a decrease in calcium available at each beat results in a decrease in cardiac contractility. In blood vessels, the decrease in calcium reduces the contraction of vascular smooth muscle, resulting in an increase in blood vessel diameter. The resulting vasodilation reduces total peripheral resistance and reduced cardiac contractility reduces cardiac output. Blood pressure decreases because it is partially determined by cardiac output and peripheral resistance.

Calcium channel blockers do not reduce the heart's responsiveness to inputs from the sympathetic nervous system. Because blood pressure regulation takes place in the sympathetic nervous system (by baroreceptor reflexes), calcium channel blockers can maintain blood pressure more efficiently than beta-blockers. However, because calcium channel blockers lower blood pressure, baroreceptor reflexes often begin a reflexive increase in sympathetic nerve activity, leading to increased heart rate and contractility. Lowering blood pressure also probably reflects the direct effect of vascular smooth muscle VDCC antagonism, leading to vasodilation. Beta-blockers can be combined with calcium channel blockers to minimize these effects. Blockers for L, N and P / Q type calcium channels are used to distinguish channel subtypes. For R-type calcium channel subtypes, ω-agatoxin IIIA exhibits blocking activity, even though its selectivity is rather low. This peptide binds to all high potential active channels, including L, N and P / Q subtypes (J. Biol. Chem., 275, 21309 (2000)). Toxins from the putative R-type (or class αlE) selective blocker, SNX-482, Tarantula hysterocrates gigas, are composed of three disulfide bonds (1-4, 2-5 and 3-6). It is a 41 amino acid residue peptide having a configuration) (Biochemistry, 37, 15353 (1998), Peptides 1998, 748 (1999)). This peptide blocks class E calcium channels (IC50 = 15nM to 30nM) and R-type calcium currents at nerve pituitary nerve endings at 40 nM concentrations. R-type (class E) calcium channel blocking activity is highly selective and K⁺And Na⁺No effect was observed on currents and L, P / Q and T-type calcium currents. The N-type calcium current is weak at 300 nM to 500 nM and is cut off only 30-50%. Locally, different sensitivities of R-type currents to SNX-482 were observed, with little effect on R-type currents in neuronal cell body, retinal ganglion cell and hippocampal pyramidal cell specimens. Using SNX-482, three alpha E-calcium subunits with different pharmacological properties are found in cerebellar R-type calcium channels (J. Neurosci., 20, 171 (2000)). Similarly, it was shown that oxytocin secretion is regulated by R-type calcium currents at the neuropituitary terminal, but vasopressin secretion is not regulated (J. Neurosci., 19, 9235 (1999)).

Dihydropyridine calcium channel blockers are often used to reduce systemic vascular resistance and arterial pressure, but are not used to treat angina because vasodilation and decreased blood pressure can lead to reflex tachycardia (chronic stable angina). Except for amlodipine, which is needed to treat vasospasm angina as well as illness). This calcium channel blocker class is easily identified by the suffix "-zipine". Phenylalkylamine calcium channel blockers are relatively selective for the myocardium. This reduces myocardial oxygen demand and reverses coronary vascular spasm. It has a minimal vasodilatory effect compared to dihydropyridines. This action is intracellular. Benzodiazepine calcium channel blockers are an intermediate class between phenylalkylamines and dihydropyridines in this selectivity of vascular calcium channels. Benzodiazepines can reduce arterial pressure due to this cardiosuppressive and vasodilatory effects without producing the same degree of reflex cardiac stimulation caused by dihydropyridines.

L-type VDCC inhibitors are calcium influx blockers, whose main pharmacological action is to prevent or delay the influx of calcium into cells by L-type voltage-gated calcium channels. Examples of L-type calcium channel inhibitors include, but are not limited to: Dihydropyridine L-type blockers such as nisoldipine, nicardipine, nifedipine, AHF (eg (4aR, 9aS)-(+)-4a-amino-1,2,3,4,4a, 9a-hexahydro-4aH-fluorene, HC1) , Isradipine (eg 4- (4-benzofrazanyl) -1,-4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl 1-methylethyl ester), calciseptine (eg dendroaspice polylepis polylepis) Dendroaspis polylepis Isolated from polylepis), H-Arg-Ile-Cys-Tyr-Ile-His-Lys-Ala-Ser-Leu-Pro-Arg-Ala-Thr-Lys-Thr-Cys-Val-Glu-Asn -Thr-Cys-Tyr-Lys-Met-Phe-Ile-Arg-Thr-Gln-Arg-Glu-Tyr-Ile-Ser-Glu-Arg-Gly-Cys-Gly-Cys-Pro-Thr-Ala-Met -Trp-Pro-Tyr-G1-n-Thr-Glu-Cys-Cys-Lys-Gly-Asp-Arg-Cys-Asn-Lys-OH, Calcicludine (eg Dendroaspis) Angusticeps) (isolated from Eastern Green Mamba)), (H-Trp-Gln-Pro-Pro-Trp-Tyr-Cys-Lys-Glu-Pro-Val-Arg-Ile-Gly-Ser-Cys- Lys-Lys-Gln-Phe-Ser-Ser-Phe-Tyr-Phe-Lys-Trp-Thr-Ala-Lys-Lys-Cys-Leu-Pro-Phe-Leu-Phe-Ser-Gly-Cys-Gly- Gly-Asn-Ala-Asn-Arg-Phe-Gln-Thr-Ile-Gly-Glu-Cys-Arg-Lys-Lys-Cys-Leu-Gly-Lys-OH, silnidipine, (eg also FRP-8653, Dihydropyridine type inhibitor), Dilanchisem (eg (2S, 3S)-(+)-cis-3-acetoxy-5- (2-dimethylaminoethyl) -2,3-dihydro-2- (4-methoxyphenyl)- 1,5-benzothiazepine-4 (5H) -on hydrochloride), zythiazem (eg, bee) Nzothiazepine-4 (5H) -one, 3- (acetoxy) -5- [2- (dimethylamino) ethyl] -2,3-dihydro-2- (4-methoxyphenyl),-, (+)-cis- , Monohydrochloride), ferrodipine (eg 4- (2,3-dichlorophenyl) -1,4-dihydro-2,6-dimethyl-3,5-pyridinecarboxylic acid ethylmethyl ester), FS-2 (eg dendroaspice) Polyrepis polyrepis venom isolate), FTX-3.3 (eg isolate from Agelenopsis aperta), neomycin sulfate (eg C)₂₃H₄₆N₆O₁₃ 3H2SO4), nicardipine (eg 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenylmethyl-2-[methyl (phenylmethyl) amino] -3,5-pyridinedicarboxylic acid ethyl ester hydrochloride) , YC-93, Nifedipine (eg 1,4-dihydro-2,6-dimethyl-4- (2-nitrophenyl) -3,5-pyridinedicarboxylic acid dimethyl ester), Nimodipine (eg 4-dihydro-2) , 6-Dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 2-methoxyethyl 1-methylethyl ester) or (isopropyl2-methoxyethyl 1,4-dihydro-2,6-dimethyl- 4- (m-nitrophenyl) -3,5-pyridinedicarboxylate), nitrenenedin (eg 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid) Ethyl methyl ester), S-petacin (eg (3S, 4aR, 5R, 6R)-[2,3,4,4a, 5,6,7,8-octahydro-3- (2-propenyl) -4a, 5) -Dimethyl-2-oxo-6-naphthyl] Z-3'-methylthio-1'-propenoate), floretin (eg 2', 4', 6'-trihydroxy-3- (4-hydroxyphenyl) propiophenone , Also 3- (4-hydroxyphenyl) -1- (2,4,6-trihydroxyphenyl) -1-propanol, and b- (4-hydroxyphenyl) -2,4,6-trihydroxypro. Piophenone), Protopin (eg C)₂₀H₁₉NO₅C1), SKF-96365 (eg 1- [b- [3- (4-methoxyphenyl) propoxy] -4-methoxyphenethyl] -1H-imidazole, HC1), tetrandin (eg 6,6', 7,12- Tetramethoxy-2,2'-dimethylvelvaman), (. +-.)-Methoxybelpamil or (+)-belpamil (eg 5-[N- (3,4-dimethoxyphenylethyl) methylamino]- 2- (3,4-dimethoxyphenyl) -2-isopropylvaleronitrile hydrochloride), and (R)-(+)-Bay K8644 (eg R-(+)-1,4-dihydro-2,6-dimethyl) -5-Nitro-4- [2- (trifluoromethyl) phenyl] -3-pyridinecarboxylic acid methyl ester). The aforementioned examples can be specific for L-type open-pot calcium channels or can inhibit a wider range of potential-opening calcium channels, such as N, P / Q, R, and T types.

7. Endothelin Endothelin is a vasoconstrictive peptide produced primarily in the endothelium that increases blood pressure and vascular tone. This peptide family includes endothelin-1 (ET-1), endothelin-2 (ET-2) and endothelin-3 (ET-3). These small peptides (21 amino acids) play an important role in vascular homeostasis. ET-1 is mostly secreted by vascular endothelial cells. The major ET-1 isotype is expressed in the vasculature and is the most potent vasoconstrictor. ET-1 also has inotropic, chemotactic and fission-promoting properties. ET-1 stimulates the sympathetic nervous system and affects salts and water homeostasis by its action on the renin-angiotensin-aldosterone system (RAAS), vasopressin and atrial natriuretic peptides. Endothelin is one of the strongest known vasoconstrictors and has been implicated in vascular disease of several organ systems, including the heart, systemic circulation and the brain. There are two key endothelin receptor types, ETA and ETB. ETA and ETB have different pharmacological properties. ETA-receptor affinity is much higher for ET-1 than for ET-3. ETA-receptors are located on vascular smooth muscle cells but not on endothelial cells. Binding of endothelin to ETA increases vasoconstriction and sodium retention, leading to elevated blood pressure. ETB receptors are located primarily on endothelial cells that line the interior of blood vessels. Endothelin, which binds to the ETB receptor, lowers blood pressure by increasing natriuretics and polyuria and releasing nitric oxide. ET-1 and ET-3 equally activate ETB-receptors and lead to vasodilation by the production of NO and prostaglandins. Endothelin-1 (ET-1) has also been shown to induce vascular smooth muscle contraction by ETA-receptor stimulation and NO production in endothelial cells by ETB-receptor. Some ETB-receptors are located in vascular smooth muscle, where they can mediate vasoconstriction. Many endothelin receptors are regulated by a variety of factors. Angiotensin II and phorbol esters down-regulate endothelin receptors, whereas ischemia and cyclosporine increase the number of endothelin receptors.

Many peptide and non-peptide ET antagonists have been studied. ETA-receptor antagonists include A-127722 (non-peptide), ABT-627 (non-peptide), BMS 182874 (non-peptide), BQ-123 (peptide), BQ-153 (peptide), BQ-162 (peptide). ), BQ-485 (peptide), BQ-518 (peptide), BQ-610 (peptide), EMD-122946 (non-peptide), FR 139317 (peptide), IPI-725 (peptide), L-744453 (non-peptide) ), LU 127043 (non-peptide), LU 135252 (non-peptide), PABSA (non-peptide), PD 147953 (peptide), PD 151242 (peptide), PD 155080 (non-peptide), PD 156707 (non-peptide), RO 611790 (Non-peptide), SB-247083 (Non-peptide), Clazocentan (Non-peptide), Atlascentan (Non-peptide), Citaxsentan Sodium (Non-peptide), TA-0201 (Non-Peptide), TBC Examples include, but are not limited to, 11251 (non-peptide), TTA-386 (peptide), WS-7338B (peptide), ZD-1611 (non-peptide), and aspirin (non-peptide). ETA / B-receptor antagonists include A-182086 (non-peptide), CGS 27830 (non-peptide), CP 170687 (non-peptide), J-104132 (non-peptide), L-751281 (non-peptide), L- 754142 (non-peptide), LU 224332 (non-peptide), LU 302872 (non-peptide), PD 142893 (peptide), PD 145065 (peptide), PD 160672 (non-peptide), RO-470203 (bosentan, non-peptide), RO 462005 (non-peptide), RO 470203 (non-peptide), SB 209670 (non-peptide), SB 217242 (non-peptide), and TAK-044 (peptide) can be, but are not limited to. ETB receptor antagonists include A-192621 (non-peptide), A-308165 (non-peptide), BQ-788 (peptide), BQ-017 (peptide), IRL. 1038 (peptide), IRL 2500 (peptide), PD-161721 (non-peptide), RES 701-1 (peptide), and RO 468443 (peptide) can be, but are not limited to.

ET-1 is first translated into 212 amino acid peptides (preproendothelin-1). ET-1 is further converted to proendothelin-1 after removal of the secretory sequence. Proendothelin-1 is then cleaved by furin to produce the biologically inactive precursor bigendothelin-1. Mature ET-1 is formed upon cleavage of big endothelin-1 by one of several endothelin converting enzymes (ECEs). There are two splicing variants of ECE-1; These are ECE-1a and ECE-1b. Each has a functionally different role and tissue distribution. ECE-1a is expressed in the Golgi network of endothelin-producing cells and cleaves big endothelin-1 to form ET-1. ECE-1b localizes to the plasma membrane and cleaves extracellular big endothelin-1. Both ECE-1a and ECE-1b are inhibited by the metalloprotease inhibitor phosphoramidone. ECE is also located on α-actin filaments in smooth muscle cells. Inhibition of ECE by phosphoramidone completely blocks vasoconstriction against big endothelin-1. ECE inhibitors include B-90063 (non-peptide), CGS 26393 (non-peptide), CGS 26303 (non-peptide), CGS 35066 (non-peptide), phosphoramidon (peptide), PP-36 (peptide), SM-19712. (Non-peptide), and TMC-66 (non-peptide) may be included, but not limited to these. In healthy individuals, the delicate balance between vasoconstriction and vasodilatoration is maintained on the one hand by endothelin and other vasoconstrictors, and on the other hand by nitric oxide, prostacyclin and other vasodilators. Endothelin antagonists may play a role in the treatment of heart, vascular and renal disorders associated with local or systemic vasoconstriction and cell proliferation, such as essential hypertension, pulmonary hypertension, chronic heart failure, chronic renal failure.

8. 8. Transient Receptor Potential Channels The Transient Receptor Potential (TRP) channel family is part of the calcium channel family. These channels include transient receptor potential proteins and their homologues, vanilloid receptor subtype I, non-selective cation channels that can suppress elongation, olfactory mechanic channels, and insulin-like growth factor I-regulated calcium channels. And vitamin D responsive apical, epithelial calcium channel (ECaC). Each of these molecules is at least 700 amino acids in length and shares certain conserved structural characteristics. The six transmembrane domains are the major of these structural features, with additional hydrophobic loops between the 5th and 6th transmembrane domains. This loop is thought to be essential for the activity of the pores of the channels formed during membrane insertion. TRP channel proteins also contain one or more ankyrin domains and often show proline-rich regions at the N-terminus. Transient receptor potential (TRP) cation channels are present in vascular smooth muscle and are involved in smooth muscle depolarizing response to stimuli such as membrane stretch. Uridine triphosphate (UTP) exhibits an inward rectifying effect, is not rapidly desensitized, and is Gd.³⁺Causes membrane depolarization and vascular smooth muscle contraction by activating cation currents blocked by. Standard transient receptor potential (TRPC) proteins are found in Ca in various mammalian tissues.²⁺It forms a permeable, non-selective cation channel. Inhibition of TRPC6, a part of this family of channels, has been reported to block alpha-adrenergic receptor-activated cation currents in cultured rabbit portal vein myocytes. However, inhibition of TRPC6 channels in cerebrovascular smooth muscle does not attenuate UTP-induced membrane depolarization and vasoconstriction. In contrast, TRPC3, unlike TRPC6, was found to mediate agonist-induced depolarization as observed in rat cerebral arteries after UTP activation of P2Y receptors. Thus, TRPC3 channels in vascular smooth muscle mediate agonist-induced depolarization that contributes to vasoconstriction in resistance-sized cerebral arteries.

The TRP1 channel family includes hordes of channels that mediate an array of signal and sensory transduction pathways. Proteins in the mammalian TRPC subfamily are the product of at least seven genetic codings of cation channels that appear to be activated in response to phospholipase C (PLC) -coupled receptors. The putative ion channel subunits TRPC3, TRPC6, and TRPC7 include structurally related subgroups of the mammalian TRPC channel family. The ion channels formed by these proteins appear to be activated downstream of phospholipase C (PLC). PLC-dependent activation of TRPC6 and TRPC7 has been shown to require diacylglycerols and is independent of G protein or inositol 1,4,5-trisphosphate (IP3). TRPC channels are widely expressed among cell types and are receptor-mediated Ca²⁺It can play an important role in signal transduction. TRPC3 channels are activated in response to PLC-coupled receptors Ca²⁺It is known to be a conduction channel. The TRPC3 channel has been shown to interact directly with the intracellular inositol 1,4,5-triphosphate receptor (InsP3R). That is, channel activation is mediated by binding to InsP3R. Drugs that are effective in increasing arterial blood flow, inhibiting vasoconstriction, or inducing vasodilation are drugs that block TRP channels. These inhibitors include compounds that are TRP channel antagonists. Such inhibitors are referred to as activity inhibitors or TRP channel activity inhibitors. As used herein, the term "activity inhibitor" means an agent that interferes with or prevents the activity of TRP channels. Activity inhibitors can interfere with the ability of TRP channels to bind agonists such as UTP. The activity inhibitor can be an agent that competes with the naturally occurring activator of the TRP channel for interaction with the activation binding site on the TRP channel. Alternatively, the activity inhibitor may bind to the TRP channel at a site different from the activation binding site, which may cause the activity inhibitor to, for example, cause a conformational change in the TRP channel, which activates. It is transmitted to the binding site, which interferes with the binding of natural activators. Alternatively, the activity inhibitor may interfere with components upstream or downstream of the TRP channel, but interferes with the activity of the TRP channel. This latter type of activity inhibitor is called a functional antagonist. Non-limiting examples of TRP channel inhibitors that are activity inhibitors are gadolinium chloride, lanthanum chloride, SKF 96365 and LOE-908.

<p> Current treatments to prevent or reduce cerebral vasospasm consist of treatments that prevent or minimize secondary brain damage and use calcium channel blockers, hemodynamic control and intravascular therapy. Treatment is often initiated prophylactically in patients and may include the following steps: maintaining normal blood volume (in step 1), controlling blood pressure, and oral L-potential-opening calcium channel blockers: Hemodynamic stabilization, including administration; And (in stage 2) further hemodynamic manipulation or injection of vasodilators into the vasospastic arteries or balloon dilation of the vasospastic arteries. However, the above treatments are expensive, time consuming and only partially effective. For over 35 years, physicians have endeavored to prevent or reduce the occurrence of adverse consequences of SAH, including angiographic vasospasm and DCI, and their effectiveness is limited due to side effects or lack of efficacy of current drugs. Has been done. Currently, there are no FDA-approved drugs for the prevention of vascular spasms or the reduction of late-onset ischemic neuropathy, also known as late-onset cerebral ischemia (DCI). Current prophylaxis of vascular spasms have failed due to ineffectiveness or safety issues, primarily hypertension and cerebral edema. Currently, the only FDA-approved drug available is nimodipine, which improves the prognosis of SAH patients but does not reduce vasospasm. Potential-opening calcium channel blockers may be effective in preventing and to some extent ameliorating vasospasm, but prior art treatments administer doses that are too low to exert maximum pharmacological effects. Endothelin receptor antagonists may also be effective in preventing and to some extent ameliorating vascular spasm, but this recovery or prevention of vascular spasm does not significantly improve prognosis as predicted by reduction of vascular spasm. Although not limited by theory, systemic delivery of potential-opening calcium channel blockers may cause side effects that reduce the beneficial effects on vasospasm, such as systemic hypotension, pulmonary vasodilation due to pulmonary edema, and more systemic. Interfere with the administration of target doses. Dilation of blood vessels in the lungs can also cause pulmonary edema and lung damage. Second, but not limited by theory, it is assumed that systemic delivery of potential-opening calcium channel blockers can limit other effects of SAH involved in DCI, including cortical spreading ischemia and microthrombogenic embolism. Will be done. While traditional treatments have focused on treating cerebrovascular spasms after subarachnoid hemorrhage, accumulating evidence has shown that there are additional complications resulting from subarachnoid hemorrhage, spiders. There is a need to target therapeutic treatments to improve the prognosis after treatment for subarachnoid hemorrhage. The present invention provides such a method.</p>

<p> According to one aspect, the present invention is a method of treating at least one cerebral artery in the submucosal cavity at risk of interference due to brain damage in a human subject, (a) (i) therapeutically. A microparticle formulation comprising an amount of at least one therapeutic agent, wherein the microparticle formulation comprises a plurality of microparticles having a uniform particle size distribution, the therapeutic agent is dispersed throughout each microparticle, and is therapeutic. To prepare a flowable sustained release microparticle composition comprising the formulation and (ii) pharmaceutical carrier, the amount of which is an effective amount to treat late complications of cerebral artery obstruction. ; In addition, (b) the composition is locally administered to the ventricles, and after the microparticle formulation has flowed from the cerebrospinal fluid (CSF) in the ventricles to the cerebrospinal fluid (CSF) in the subarachnoid space, the therapeutic agent is released. The method is provided which comprises contacting and flowing around at least one cerebral artery in the subarachnoid space without entering the body circulation in an amount released into the subarachnoid space and causing an undesired side effect of the therapeutic agent. According to one embodiment, each microparticle contains a matrix. According to other embodiments, the at least one therapeutic agent is a calcium channel blocker, an endothelin antagonist, a transient receptor potential (TRP) protein antagonist, or a combination thereof. According to other embodiments, late complications are from angiographic vasospasm, formation of multiple microthrombogenic embolisms, cortical spreading ischemia, late cerebral ischemia (DCI), or a combination thereof. Selected from the group of According to other embodiments, the at least one therapeutic agent is an L-type voltage-gated calcium channel inhibitor, an R-type voltage-gated calcium channel inhibitor, an N-type voltage-gated calcium channel inhibitor, and a P / Q-type potential. It is a calcium channel blocker selected from the group consisting of a dependent calcium channel inhibitor, a T-type voltage-gated calcium channel inhibitor, or a combination thereof. According to one embodiment, the L-type potential-dependent calcium channel inhibitors are amlodipine, alanidipine, azernidipine, varnidipine, benidipine, sinardipin, ehonidipine, felodipine, isladipine, lasidipine, remildipine, relcanidipine, nicaldipine, nifedipine, nilvadipine, nifedipine. A dihydropyridine selected from the group consisting of nisoldipine, nitorendine, manidipine, pranidipine, or a combination thereof. According to one embodiment, the dihydropyridine is nimodipine. According to another embodiment, the fine particle formulation comprises a powder suspension of fine particles. According to another embodiment, the microparticle formulation further comprises a delayed release compound. According to one embodiment, the delayed release compound is a biodegradable polymer. To. According to one embodiment, the biodegradable polymer is selected from the group consisting of polylactide-polyglycolide, poly (orthoester), and poly (anhydride). According to other embodiments, administration is via a surgical infusion device. According to another embodiment, the surgical infusion device is a needle, cannula, catheter, or a combination thereof. According to another embodiment, the flowable sustained release microparticle composition is capable of releasing a therapeutic amount of therapeutic agent prior to the onset of late complications. According to another embodiment, sustained release of the therapeutic amount of the therapeutic agent takes place within a half-life ranging from 1 to 30 days after delivery of the composition to the ventricles. According to another embodiment, the ventricles are at least 0.001 mm from the cerebral arteries within the subarachnoid space. According to other embodiments, the ventricles are the lateral ventricles, the third ventricle, the fourth ventricle, or a combination thereof. According to another embodiment, the flowable sustained release microparticle composition produces predominantly local effects around the cerebral arteries within the subarachnoid space. According to other embodiments, therapeutic amounts of therapeutic agents are effective in increasing the inner diameter of the cerebral arteries within the subarachnoid space. According to another embodiment, the pharmaceutical carrier is a buffer solution. It is at 001 mm. According to other embodiments, the ventricles are the lateral ventricles, the third ventricle, the fourth ventricle, or a combination thereof. According to another embodiment, the flowable sustained release microparticle composition produces predominantly local effects around the cerebral arteries within the subarachnoid space. According to other embodiments, therapeutic amounts of therapeutic agents are effective in increasing the inner diameter of the cerebral arteries within the subarachnoid space. According to another embodiment, the pharmaceutical carrier is a buffer solution. It is at 001 mm. According to other embodiments, the ventricles are the lateral ventricles, the third ventricle, the fourth ventricle, or a combination thereof. According to another embodiment, the flowable sustained release microparticle composition produces predominantly local effects around the cerebral arteries within the subarachnoid space. According to other embodiments, therapeutic amounts of therapeutic agents are effective in increasing the inner diameter of the cerebral arteries within the subarachnoid space. According to another embodiment, the pharmaceutical carrier is a buffer solution.</p><p> According to another aspect, the invention is a flowable sustained release microparticle composition comprising (i) a microparticle formulation comprising at least one therapeutic agent and (ii) a pharmaceutically acceptable carrier. There, the microparticle formulation contains multiple microparticles with a uniform particle size distribution, at least one therapeutic agent is dispersed throughout each microparticle, and the composition is suitable for delivery to the ventricles and the brain. Provided are the compositions that can flow in cerebrospinal fluid (CSF) from the ventricles to the subarachnoid space. According to one embodiment, the therapeutic agent is a calcium channel blocker, an endothelin antagonist, a transient receptor potential (TRP) protein antagonist, or a combination thereof. According to another embodiment, the microparticles contain a matrix. According to another embodiment, the flowable sustained release microparticle composition is delivered from the cerebrospinal fluid (CSF) in the ventricles to the cerebrospinal fluid (CSF) in the subarachnoid space upon delivery to the ventricles. It can flow, after which the therapeutic agent is sustained-release in the subarachnoid space. According to other embodiments, the therapeutic agent is an L-type voltage-gated calcium channel inhibitor, an R-type voltage-gated calcium channel inhibitor, an N-type voltage-gated calcium channel inhibitor, or a P / Q-type voltage-gated calcium channel. A calcium channel blocker selected from the group consisting of channel inhibitors, T-type voltage-gated calcium channel inhibitors, or combinations thereof. According to one embodiment, the L-type potential-dependent calcium channel inhibitors are amlodipine, alanidipine, azernidipine, varnidipine, benidipine, sinardipin, ehonidipine, felodipine, isladipine, lasidipine, remildipine, relcanidipine, nicaldipine, nifedipine, nilvadipine, nifedipine. A dihydropyridine selected from the group consisting of nisoldipine, nitorendine, manidipine, pranidipine, or a combination thereof. According to another embodiment, the dihydropyridine is nimodipine. According to another embodiment, the fine particle formulation comprises a powder suspension of fine particles. According to another embodiment, the fine particle formulation is further modified. Contains delayed release compounds. According to one embodiment, the delayed release compound is a biodegradable polymer. According to one embodiment, the biodegradable polymer is selected from the group consisting of polylactide-polyglycolide, poly (orthoester), and poly (anhydride). According to another embodiment, sustained release of a therapeutic amount of the therapeutic agent can be performed within a half-life ranging from 1 to 30 days after delivery of the composition to the ventricles. According to another embodiment, the ventricles are at least 0.001 mm from the cerebral arteries within the subarachnoid space. According to other embodiments, the ventricles are the lateral ventricles, the third ventricle, the fourth ventricle, or a combination thereof. According to another embodiment, the flowable sustained release microparticle composition produces predominantly local effects around the cerebral arteries within the subarachnoid space. According to other embodiments, therapeutic amounts of therapeutic agents are effective in increasing the inner diameter of the cerebral arteries within the subarachnoid space. According to another embodiment, the pharmaceutical carrier is a buffer solution.</p><p> According to another aspect, the invention is a sterilization kit for treating at least one cerebral artery in the submembrane cavity at risk of interference due to brain damage: (i) Surgical injection sterilizer; (ii) First sterile syringe with barrel and plunger; (iii) Second sterile syringe with barrel and plunger; (iv) Female sterile luer cap; (v) Male sterile luer cap; ( vi) Female sterile syringe connector; (vii) A sterile microparticle formulation suitable for administration into the ventricles containing a therapeutic amount of at least one therapeutic agent, the therapeutic amount of which delays the obstruction of the cerebral arteries within the subarachnoid space. An amount effective in reducing idiopathic complications, wherein the microparticle formulation contains a plurality of microparticles with a uniform particle size distribution, and at least one therapeutic agent is dispersed throughout each microparticle. The kit comprises the formulation and (viii) a pharmaceutically acceptable sterile carrier. According to one embodiment, the surgical infusion device is a needle, cannula, catheter, or a combination thereof. According to another embodiment, the fine particle formulation comprises a powder suspension of fine particles. According to other embodiments, the microparticles have a diameter ranging from about 30 μm to about 100 μm. According to another embodiment, the microparticle formulation further comprises a delayed release compound. According to one embodiment, the delayed release compound is a biodegradable polymer. According to one embodiment, the biodegradable polymer is selected from the group consisting of polylactide-polyglycolide, poly (orthoester), and poly (anhydride). According to other embodiments, the at least one therapeutic agent is a calcium channel blocker, an endothelin antagonist, a transient receptor potential (TRP) protein antagonist, or a combination thereof. According to other embodiments, the calcium channel blocker is an L-type voltage-gated calcium channel inhibitor, an R-type voltage-gated calcium channel inhibitor, an N-type voltage-gated calcium channel inhibitor, and a P / Q-type voltage-gated agent. It is selected from the group consisting of sex calcium channel inhibitors, T-type voltage-gated calcium channel inhibitors, or combinations thereof. According to one embodiment, the L-type potential-dependent calcium channel inhibitors are amlodipine, alanidipine, azernidipine, barnidipine, benidipine, sinardipin, ehonidipine, felodipine, isladipin, lasidipine, remildipine, relcanidipine, nimodipine, nifedipine, nilvadipine, nifedipine. Nisoldipine, nitrendipine, mani A dihydropyridine selected from the group consisting of dipin, pranidipine, or a combination thereof. According to another embodiment, the dihydropyridine is nimodipine. According to another embodiment, the pharmaceutical carrier is a buffer solution. According to another embodiment, the kit further comprises at least two sterile vessels, the first sterile vessel is suitable for holding the sterile microparticle formulation, and the second sterile vessel holds the sterile pharmaceutical carrier. Suitable for According to other embodiments, the container is a vial, bottle, tube, bag, packet, pillow, ampoule, or a combination thereof. According to another embodiment, the microparticle formulation is pre-filled in the first syringe. According to another embodiment, the pharmaceutical carrier is pre-filled in a second syringe.</p><p> According to another aspect, the invention is a method of preparing a flowable sustained release sterile microparticle composition: (a) a sterile microparticle formulation comprising a therapeutic amount of at least one therapeutic agent. The therapeutic amount is an effective amount to reduce the late complications of obstruction of the cerebral artery in the submembrane cavity, and the fine particle formulation has a uniform particle size. The step (b) the sterile microparticle formulation of step (a), wherein the distribution comprises a plurality of microparticles and at least one therapeutic agent is dispersed throughout each microparticle, the first syringe barrel, the first. Steps of drawing into a first sterile syringe equipped with a syringe plunger and a female luer cap to remove air trapped in the first syringe; (c) preparing a pharmaceutically acceptable sterile carrier; (d) ) Step (c) pulling the sterile pharmaceutical carrier into a second sterilized syringe compatible with a male luer cap with a second syringe barrel and a second syringe plunger; (e) male mold in step (c) The process of replacing the lure cap with a female sterile syringe connector; (f) Contains a first sterile syringe containing the sterile microparticle formulation of step (b) and a pharmaceutically acceptable sterile carrier of step (c) via the female syringe connector of step (d). Step of connecting with a second sterile syringe; (g) Step of pressing the first sterile syringe plunger to mix the sterile microparticle formulation with the sterile pharmaceutical carrier in the second sterile syringe barrel; (h) Second The step of pressing the sterile syringe plunger to mix the sterile microparticle formulation with the sterile pharmaceutical carrier in the first sterile syringe barrel; And (i) step (g) and step (i) are repeated at least 5-50 times to provide a flowable sterile sustained release microparticle composition suitable for delivery to the ventricles. According to one embodiment, the microparticle formulation comprises a powder suspension of microparticles. According to another embodiment, each microparticle contains a matrix. According to another embodiment, the microparticle formulation further comprises a delayed release compound. According to one embodiment, the delayed release compound is a biodegradable polymer. According to one embodiment, the biodegradable polymer is selected from the group consisting of polylactide-polyglycolide, poly (orthoester), and poly (anhydride). According to other embodiments, the therapeutic agent is a calcium channel blocker, an endothelin antagonist, a transient receptor potential (TRP) protein antagonist, or a combination thereof. According to other embodiments, the therapeutic agent is an L-type voltage-gated calcium channel inhibitor, an R-type voltage-gated calcium channel inhibitor, an N-type voltage-gated calcium channel inhibitor, or a P / Q-type voltage-gated calcium channel. A calcium channel blocker selected from the group consisting of channel inhibitors, T-type voltage-gated calcium channel inhibitors, or combinations thereof. According to other embodiments, the L-type potential-dependent calcium channel inhibitors are amlodipine, alanidipine, azernidipine, barnidipine, benidipine, sinardipin, ehonidipine, felodipine, isladipine, lasidipine, remildipine, relcanidipine, nicaldipine, nifedipine, nifedipine, nifedipine, nifedipine. , Nisoldipine, nitrendipine, manidipine, pranidipine, or dihydropyridines selected from the group consisting of combinations thereof. According to another embodiment, the dihydropyridine is nimodipine. According to another embodiment, the pharmaceutical carrier is a buffer solution. According to another embodiment, the surgical infusion device is a needle, cannula, catheter, or a combination thereof.</p>

<figref num="1">FIG. 1 is a descriptive side view showing the human brain (Stedman's Medical Dictionary, 27).^th Edition, plate 7 at A7 (2000)).</figref><figref num="2">Figure 2 is a descriptive sagittal view showing the human brain (Correlative Neuroanatomy &amp; Functional Neurology, 18).^th Ed., P. 46 (1982)).</figref><figref num="3">FIG. 3 is a descriptive cross-sectional view showing the intact meninges from the inner surface (upper) of the skull to the outer surface (lower) of the brain. Collagen is present in the periosteum and meningeal dura (large dots, no fibril orientation shown) and in the subarachnoid space (SAS), which is usually a stack of trabecular cells. The dural border cell layer is free of extracellular collagen, has few intercellular connections, has an expanded extracellular space (without basement membrane), and is distinctly different from fibroblasts in the outer part of the dura. Has. The arachnoid barrier cell layer essentially has no extracellular space, more cell-cell connections, more plump cells, and a relatively continuous basement membrane on its surface towards SAS. Note the relationship between the continuous cell layer from the arachnoid to the dura, the characteristic appearance of the arachnoid trabeculae, and the pia mater (Source: Haines DE: On the question of subdural space. Anat Rec) 230: 3-21, 1991).</figref><figref num="4">FIG. 4 is an explanatory diagram showing the Willis arterial ring and major arteries of the brain (Correlative Neuroanatomy &amp; Functional Neurology, 18).^th Ed., P. 48 (1982)).</figref><figref num="5">FIG. 5 is an explanatory diagram showing the arterial supply of the cerebral cortex. 1: Orbital frontal artery, 2: Anterior Roland artery, 3: Roland artery, 4: Front parietal artery, 5: Posterior parietal artery, 6: Ocular artery, 7: Posterior temporal artery, 8: Anterior temporal artery, 9 : Orthodontic artery, 10: Anterior pole artery, 11: Corridor marginal artery, 12: Posterior medial frontal artery, 13: Perivascular artery. (Correlative Neuroanatomy &amp; Functional Neurology, 18^th Ed., P. 50 (1982)).</figref><figref num="6">FIG. 6 is an explanatory diagram showing a cerebral artery.</figref><figref num="7">FIG. 7 is an explanatory view showing the cerebral artery. (Source: Netter FH. The CIBA Collection of Medical Illustrations: Volumes 1, Nervous System. Vol. 1. Part I. CIBA: USA. 1986. Pp. 256).</figref><figref num="8">FIG. 8 is an explanatory diagram showing the ventricles (page 192, Ross LM, Lamperti ED, Taub E (eds), Schuenke M, Schulte E, Schumacher U. Thieme Atlas of Anatomy. Georg Thieme Verlag: Stuttgart. 2006. pp. 541).</figref><figref num="9">FIG. 9 is an explanatory diagram showing the flow of CSF from the ventricles to the subarachnoid space (page 194, Ross LM, Lamperti ED, Taub E (eds), Schuenke M, Schulte E, Schumacher U. Thieme Atlas of Anatomy. . Georg Thieme Verlag: Stuttgart. 2006. pp. 541).</figref><figref num="10A">FIG. 10A is a simple flow chart showing the prognosis of subarachnoid hemorrhage.</figref><figref num="10B">FIG. 10B is a flow chart showing the pathways that may be involved in late complications after subarachnoid hemorrhage.</figref><figref num="11">Figure 11 is a graph showing the temporal trend of the results of subarachnoid hemorrhage in a 7-population-based experiment of subarachnoid hemorrhage (SAH), showing a 50% reduction in mortality over 20 years.</figref><figref num="12">FIG. 12 is a scanning electron micrograph (SEM) image showing the fine particle nimodipine formulation of the present invention.</figref><figref num="13">FIG. 13 is a graph showing the in vitro cumulative release of an exemplary fine particle nimodipine formulation expressed as% by weight over time.</figref><figref num="14">FIG. 14 is an exemplary diagram showing the application of a microparticle composition of the invention containing a calcium channel blocker, endothelin receptor antagonist, or TRP protein antagonist into the ventricles through an intraventricular catheter (in the figure). Source: Mccomb JG: Techniques of CSF diversion. In: Scott RM (ed). Hydrocephalus. Vol. 3. Williams &amp; Wilkins: Baltimore. 1990. page 48, pp. 128).</figref><figref num="15">FIG. 15 shows a microparticle composition of the invention containing a calcium channel blocker, endothelin receptor antagonist, or TRP protein antagonist, or a combination thereof, in or on the microparticles from the ventricles to the subarachnoid space by CSF flow. It is a schematic diagram showing that it is carried to the artery of the cavity (Pollay M: Cerebrospinal fluid. In: Tindall GT, Cooper PR, Barrow DL (eds). The Practice of Neurosurgery. Vol. 1. Williams &amp; Wilkins: Baltimore. 1996 . page 36, pp. 1381).</figref><figref num="16">FIG. 16 shows dogs treated with placebo microparticle composition (placebo, n = 8), oral nimodipine and placebo microparticle composition (oral nimodipine, n = 8), or 100 mg ventricular nimodipine microparticles (n = 8). It is a bar graph showing the percentage change of the angiographic diameter of the basilar artery on the 8th and 15th days after subarachnoid hemorrhage (SAH). Analysis of variance showed little angiographic vasospasm on days 8 and 15 after SAH in dogs treated with intraventricular nimodipine microparticles (P &lt;0.05, values are mean ± mean standard error). ).</figref><figref num="17">FIG. 17 shows dogs treated with placebo microparticle composition (placebo, n = 8), oral nimodipine and placebo microparticle composition (oral nimodipine, n = 8), or 100 mg ventricular nimodipine microparticles (n = 8). It is a graph which shows the plot line of the averaged behavior score of the dog subjected to subarachnoid hemorrhage (SAH). The value is the mean ± standard error of the mean (n = 8 per measurement).</figref><figref num="18">FIG. 18 is a graph showing plot lines of plasma concentrations of nimodipine (ng / ml) in two groups treated with oral nimodipine (administered for 21 days [504 hours]) or intraventricular nimodipine microparticles. Both groups had similar plasma concentrations and showed systemic exposure to nimodipine after intraventricular microparticle injection (values are mean ± standard error of mean [n = 8 per measurement]).</figref><figref num="19">FIG. 19 is a graph showing plot lines of CSF concentrations in cerebrospinal fluid (CSF) of nimodipine obtained from the cisterna magna in two groups treated with oral nimodipine or intraventricular nimodipine microparticles. The value is the mean ± standard error of the mean (n = 8 per measurement).</figref><figref num="20">FIG. 20 is a diagram showing a cross-sectional view used in the dog model experiment.</figref>

Glossary As used herein, the term "activity" means a component, component or component of the composition of the invention that is involved in the intended therapeutic effect. As used herein, "additive effect" means the combined effect of two chemicals equal to the sum of the effects of each agent administered alone. As used herein, the term "antagonist" means a substance that interferes with the action of other substances. Functional or physiological antagonism occurs when two substances have opposite effects on the same physiological function. Chemical antagonism or inactivation is the reaction between two substances that neutralizes these effects. Attribute antagonism is a change in the attributes of a substance (its absorption, biotransformation, distribution, or excretion), so that a smaller amount of the drug reaches the target or its persistence there. Antagonism at the receptor of a substance involves blocking the action of the antagonist by an appropriate antagonist that antagonizes the same site. As used herein, the term "administer" includes in vivo administration as well as direct ex vivo administration to tissues. In general, compositions are commonly used non-toxic, either orally, orally, parenterally, topically, by inhalation or aeration (ie, through the mouth or nose), or rectal. Can be administered systemically in unit dose formulations containing pharmaceutically acceptable carriers, adjuvants, and desired excipients, or by means not limited to inhalation, implantation, transplantation, topical application, or parenteral. Can be administered topically.

As used herein, the term "agonist" means a chemical substance capable of activating a receptor to elicit a global or partial pharmacological response. Receptors can be activated or inactivated by either endogenous or extrinsic agonists and antagonists, resulting in stimulation or inhibition of the biological response. Physiological agonists are substances that provoke the same physical response but do not bind to the same receptor. An endogenous agonist of a particular receptor is a compound naturally produced by the body that binds to and activates that receptor. Superagonists are compounds that are capable of producing greater maximal responses than endogenous agonists of the target receptor, so their efficiency is greater than 100%. This does not necessarily mean that it is more potent than an endogenous agonist, but rather a comparison of the maximum possible responses that can occur inside the cell after receptor binding. A fully agonist binds and activates a receptor, which is fully potent. Partial agonists also bind to and activate certain receptors, but have only partial potency at the receptor compared to full agonists. An inverse agonist is a substance that binds to the same receptor binding site as the agonist of the receptor and reverses the constitutive activity of the receptor. Inverse agonists exhibit the opposite pharmacological effects of receptor agonists. An irreversible agonist is a type of agonist that permanently binds to a receptor in such a way that it is permanently activated. This differs from simple agonists in that the association of the agonist with the receptor is reversible, but the binding of the irreversible agonist to the receptor is considered irreversible. This causes the compound to produce a short burst of agonist activity, followed by receptor desensitization and internalization, resulting in more antagonist-like action with long-term treatment. Selective agonists are specific for one particular type of receptor.

The terms "anastomosis (singular)" and "anastomosis (plural)" are used interchangeably to mean the interconnection between blood vessels. This interconnection protects the brain when part of the vascular supply of the brain is impaired. In the Willis Ring, the two anterior communicating arteries are connected by the anterior communicating artery, and the posterior communicating artery connects the internal carotid artery. Other important anastomosis includes the connection between the branches of the ophthalmic artery and the external carotid artery by the ophthalmic foramen, and the connection of the brain surface between the branches of the middle cerebral artery, anterior cerebral artery, and posterior cerebral artery. (Principles of Neural Sciences, 2d Ed., Eric R. Kandel and James H. Schwartz, Elsevier Science Publishing Co., Inc., New York, pp. 854-56 (1985)). As used herein, the term "angiographic vasospasm" means a reduction in vascular size that can be detected in angiographic tests, including but not limited to computed tomography, magnetic resonance or catheter angiography. It occurs in about 50% of patients after subarachnoid hemorrhage. On the other hand, the term "clinical vasospasm" as used herein means signs of confusion and decreased consciousness associated with decreased blood flow to the brain parenchyma, which occurs in 30% of patients and is now defined as DCI. Has been done. As used herein, the term "antagonist" means a substance that opposes the action of another substance. As used herein, the term "ataxia" means the inability to regulate muscle activity during voluntary movements. As used herein, the term "biocompatibility" means that it does not cause clinically relevant tissue irritation, damage, toxic or immune responses to living tissue. As used herein, the term "biodegradable" means a substance that is actively or passively degraded over time by simple chemical processes, by the action of enzymes in the body, or by other similar bioactive mechanisms. .. As used herein, the term "blood vessel" means a structure, eg, a tube or duct that carries or contains blood. Exemplary blood vessels include, but are not limited to, arteries, arterioles, capillaries, veins, and venules. As shown in Figure 1, the term "cerebral artery" or its numerous grammatical forms, in particular, the anterior communication artery, middle cerebral artery, internal carotid artery, anterior cerebral artery, ocular artery, anterior choroidal artery, posterior It means a traffic artery, a basal artery, and a vertebral artery. As used herein, the term "cerebral vasospasm" means the delayed occurrence of narrowing of the basilar artery in the basilar artery after subarachnoid hemorrhage, often associated with diminished perfusion in the area distal to the affected vessel. To do. Cerebral vasospasm can occur at any time after the aneurysm ruptures, but when blood is absorbed by the body, it mostly peaks 7 days after bleeding and often subsides within 14 days.

As used herein, the term "proximity" includes, but is not limited to, less than 10 mm, less than 9.9 mm, less than 9.8 mm, less than 9.7 mm, 9.6 from blood vessels at risk of obstruction caused by brain damage. Less than mm, less than 9.5 mm, less than 9.4 mm, less than 9.3 mm, less than 9.2 mm, less than 9.1 mm, less than 9.0 mm, less than 8.9 mm, less than 8.8 mm, less than 8.7 mm, less than 8.6 mm, less than 8.5 mm, less than 8.4 mm , Less than 8.3mm, less than 8.2mm, less than 8.1mm, less than 8.0mm, less than 7.9mm, less than 7.8mm, less than 7.7mm, less than 7.6mm, less than 7.5mm, less than 7.4mm, less than 7.3mm, less than 7.2mm, 7.1 Less than mm, less than 7.0 mm, less than 6.9 mm, less than 6.8 mm, less than 6.7 mm, less than 6.6 mm, less than 6.5 mm, less than 6.4 mm, less than 6.3 mm, less than 6.2 mm, less than 6.1 mm, less than 6.0 mm, less than 5.9 mm , Less than 5.8mm, less than 5.7mm, less than 5.6mm, less than 5.5mm, less than 5.4mm, less than 5.3mm, less than 5.2mm, less than 5.1mm, less than 5.0mm, less than 4.9mm, less than 4.8mm, less than 4.7mm, 4.6 Less than mm, less than 4.5 mm, less than 4.4 mm, less than 4.3 mm, less than 4.2 mm, less than 4.1 mm, less than 4.0 mm, less than 3.9 mm, less than 3.8 mm, less than 3.7 mm, less than 3.6 mm, less than 3.5 mm, less than 3.4 mm , Less than 3.3mm, less than 3.2mm, less than 3.1mm, less than 3.0mm, less than 2.9mm, less than 2.8mm, less than 2.7mm, less than 2.6mm, less than 2.5mm, less than 2.4mm, less than 2.3mm, less than 2.2mm, 2.1 Less than mm, less than 2.0 mm, less than 1.9 mm, less than 1.8 mm, less than 1.7 mm, less than 1.6 mm, less than 1.5 mm, less than 1.4 mm, less than 1.3 mm, less than 1.2 mm, less than 1.1 mm, less than 1.0 mm, less than 0.9 mm , Less than 0.8mm, less than 0.7mm, less than 0.6mm, less than 0.5mm, less than 0.4mm, less than 0.3mm, less than 0.2mm, less than 0.1mm, 0.Less than 09mm, less than 0.08mm, less than 0.07mm, less than 0.06mm, less than 0.05mm, less than 0.04mm, less than 0.03mm, less than 0.02mm, less than 0.01mm, less than 0.009mm, less than 0.008mm, less than 0.007mm, 0.006mm, It means less than 0.005 mm, less than 0.004 mm, less than 0.003 mm, less than 0.002 mm, less than 0.001 mm in the submucosal cavity.

As used herein, the term "complication" means a pathological process or phenomenon during a disorder that may result from a disorder or an independent cause rather than a major part of the disease. Late complications occur several times after the triggering action. Complications associated with subarachnoid hemorrhage include, but are not limited to, angiographic vasospasm, microthrombogenic embolism, and cortical spreading ischemia. As used herein, the term "symptomatology" means a variety of health conditions, including disorders or diseases caused by any underlying mechanism or disorder, injury, and promotion of healthy tissues and organs. means. As used herein, the term "contact" and all its grammatical forms mean a state or symptom of proximity or a state or symptom of direct or local proximity. The term "release control" means any drug-containing formulation in which the method and profile of drug release from the formulation is regulated. This means not only immediate release preparations but also non-immediate release preparations, and non-immediate release preparations include, but are not limited to, sustained release preparations and delayed release preparations. As used herein, the term "cortical spreading depolarization" or "CSD" refers to near-perfect neuronal depolarization in the brain that activates when passive cation influx throughout the cell membrane exceeds ATP-dependent sodium and calcium pumping activity. It means the wave motion of polarization and swelling of neurons. After the influx of cations, the influx of water continues and the extracellular space contracts by about 70%. If normal ion homeostasis is not restored by additional supplementation of sodium and calcium pump activity, cell swelling is retained and the process is retained, as cell swelling potentially leads to cell death due to delayed intracellular calcium surge and mitochondrial depolarization. In that case, it is called "cytotoxic edema". CSD induces dilation of resistant blood vessels in healthy tissue; therefore, partial cerebral blood flow increases during the neuronal depolarization phase. (Dreier, JP et al., Brain 132: 1866-81 (2009).

The term "cortical spreading ischemia" or "CSI", or "reverse haemodynamic response" means severe microvascular spasms that bind to the neuronal depolarizing phase. The resulting diffuse perfusion injury prolongs neuronal depolarization [as reflected by a long-term negative shift in extracellular direct current (DC) potential], resulting in a surge in intracellular sodium and calcium. Hypoperfusion is significant enough to create a mismatch between neuronal energy supply and demand. (Ibid.). As used herein, the term "delayed cerebral ischemia" or "DCI" refers to the occurrence of local neuropathy (eg, unilateral paresis, aphasia, apraxia, hemianopia, or neglect), or the Glasgow Comascale (total). Means a decrease in score or by one of its individual components [eye, bilateral movement, language]. This may or may not last for at least 1 hour and is not apparent immediately after aneurysm occlusion and may be due to other causes by clinical evaluation of the brain, CT or magnetic resonance imaging (MRI) scans, and appropriate basic research. It cannot be caused. Angiography Cerebral vasospasm is a radiological examination (CT angiography [CTA], MR angiography [MRA]] A type of MRA or catheter angiography [CA]) that can be the cause of DCI. The term "delayed release", as used herein in its general sense, means a drug formulation with a time delay between administration of the formulation and release of the drug from it. A "delayed release" may or may not include a gradual release of the drug over an extended period of time and may thus be a "sustained release". As used herein, the term "diffusion pharmacological action" means a pharmacological action that broadly spreads, disperses, or scatters a space or surface. As used herein, the term "disease" or "disorder" means a symptom of a health disorder or abnormal functioning.

As used herein, the term "dispersion" means a two-phase system, or continuous phase, in which one phase is distributed as particles or droplets into the second phase. In these systems, the dispersed phase is often referred to as the discontinuous or internal phase, and the continuous phase is referred to as the external or dispersion medium. For example, the particle size in the course dispersion is 0.5 μm. The dispersed particle size in the colloidal dispersion is in the range of about 1 nm to 0.5 μm. Molecular dispersion is a dispersion in which the dispersed phase consists of individual molecules; If the numerator is smaller than the colloidal size, the result is a true solution. As used herein, the term "arranged" means arranged, arranged or distributed in a particular manner. As used herein, the term "drug" means a non-food therapeutic agent or any substance used to prevent, diagnose, ameliorate, treat, or cure a disease. The term "effective amount" means an amount necessary or sufficient to understand the desired biological effect. As used herein, the term "emulsion" means a two-phase system prepared by combining two immiscible liquid carriers, one uniformly dispersed throughout the other and the largest colloidal particle diameter. Consists of globules with diameters equal to or greater than. The globules are important and must be sized so that the system achieves maximum stability. Normally, two-phase separation occurs when the third substance, the emulsifier, is not incorporated. Thus, the basic emulsion contains at least three ingredients, two immiscible liquid carriers and emulsifiers as well as active ingredients. Most emulsions incorporate the aqueous phase into the non-aqueous phase (and vice versa). However, it is possible to prepare emulsions that are basically non-aqueous, for example, immiscible glycerin and olive oil anionic and cationic surfactants.

As used herein, the term "fluidity" means one that can flow or move as if it were flowing due to continuous changes in relative position. As used herein, the term "granulomatous inflammation" means an inflammatory response characterized by a regular predominance against epithelioid macrophages with or without polynuclear giant cells and connective tissue. As used herein, the term "hydrogel" means a substance that provides a solid, semi-solid, quasi-plastic, or plastic structure that contains the aqueous components necessary to form a gelatinous or jelly-like mass. As used herein, the term "hypertension" means high body blood pressure; a temporary or persistent increase in body blood pressure relative to levels that are likely to induce cardiovascular damage or other adverse consequences. As used herein, the term "hypotension" means subnormal systemic arterial pressure; any kind of low pressure or pressure drop. As used herein, the term "implant" means grafting, embedding, or inserting a substance, composition, or device in place within a tissue. The term "impregnation" as used herein in its various grammatical forms is injected or penetrated throughout; It means filling the gap with a substance. As used herein, the term "infarction" means a sudden shortage of arterial or venous blood supply due to embolism, thrombus, mechanical factors, or pressure resulting in a visible necrotic area. As used herein, the term "cerebral infarction" means loss of brain tissue following a temporary or permanent reduction in blood circulation and / or oxygen delivery to the cerebral region of the brain. As used herein, the term "inflammation" refers to the physiological process by which vascularized tissue responds to damage. For example, FUNDAMENTAL IMMUNOLOGY, 4th Ed., William E. Paul, ed. Lippincott-Raven Publishers, Philadelphia (1999) p. See 1051-1053, which is incorporated herein by reference. During the inflammatory process, cells involved in detoxification and repair are recruited to sites damaged by inflammatory transmitters. Inflammation is often characterized by strong infiltration of white blood cells, especially neutrophils (polymorphonuclear cells), at the site of inflammation. These cells enhance tissue damage by releasing toxic substances in the walls of blood vessels or intact tissue. Traditionally, inflammation is divided into acute and chronic reactions.

As used herein, the term "damage" means damage or damage to the structure or function of the body by an external substance or force, which may be physical or chemical. As used herein, the term "interference" and its various grammatical forms refer to blood flow through a blood vessel resulting from vasodilation or stenosis induced by chemical, mechanical, and / or physical action. Means a change in the continuity of. As used herein, the term "ischemia" refers to the lack of blood supply and oxygen that occurs when the distal perfusion pressure drop is not compensated for by the autoregulatory dilation of resistant blood vessels due to abnormal vascular narrowing (stenosis). means. As used herein, the term "isolated molecule" means a molecule that is substantially pure and free of other substances commonly found in natural or in vivo systems to the extent practical and appropriate for intended use. To do. The terms "in the body", "void volume", "excision pocket", "recess", "injection site", "deposition site" or "implantation site" or "delivery site" as used herein are unlimited. It means that it includes all tissues of the body, as its non-limiting examples from injection, surgical incision, tumor or tissue removal, tissue damage, abscess formation by the action of clinical evaluation, treatment or physiological response to a disease or condition. It can mean a space formed within, or any other similar cavity, space, or pocket thus formed. As used herein, the phrase "local administration" means administering a therapeutic agent at a specific location in the body where local pharmacological or diffusive pharmacological effects can occur. As used herein, the phrase "local pharmacological action" means a pharmacological action that is confined to a location, i.e., close to a location, location, region or site. As used herein, the phrase "mainly topical pharmacological action" is limited to a location that is at least one to three orders of magnitude more reliable than that achieved with topical administration compared to systemic administration. It means the pharmacological action of the drug.

As used herein, the term "long-term" release means that the implant is constructed and placed to deliver therapeutic levels of the active ingredient for at least 7 days and potentially for about 30 to about 60 days. As used herein, the term "microparticle composition" comprises a microparticle formulation and a pharmaceutically acceptable carrier, wherein the microparticle formulation comprises a therapeutic agent and a plurality of microparticles. means. As used herein, the term "microthrombogenic embolus" (or multiple "microthrombogenic embolisms") means a small fragment of a clot that causes obstruction or obstruction of a blood vessel. As used herein, the term "modulate" means to adjust, change, adapt, or adjust to a standard or proportion. As used herein, the term "onset of late complications" means the onset or onset of symptoms associated with late complications. The term "as needed" as used herein may or may not contain a pharmaceutically acceptable carrier for the pharmaceutical composition of the invention as a potential opening calcium channel blocker and pharmaceutically acceptable. Means to include a pharmaceutical composition containing both a microgranular formulation of an acceptable carrier. As used herein, the term "parenteral" refers to, for example, subcutaneous (ie, injection under the skin), intramuscular (ie, intramuscular injection); intravenous (ie, intravenous injection), spinal cord. Means intracavitary (ie, injection into the space around the spinal cord or subspinal space of the brain), intrathoracic injection, or introduction into the body by injection outside the gastrointestinal tract (ie, administration by injection), including injection techniques. To do. Parenteral administration compositions are delivered using needles, such as surgical needles. As used herein, the term "surgical needle" means any needle adapted for delivery of a fluid (ie, flowable) composition to a selected anatomical structure. Injectable formulations, such as sterile injectable aqueous or oily suspensions, can be formulated according to known techniques with suitable dispersants or wetting agents and anti-precipitation agents.

As used herein, the term "paresis" means partial or incomplete paralysis. As used herein, the term "particle" or "fine particles" is a very small component that can contain at least one therapeutic agent described herein in whole or in part, such as nanoparticles or. Fine particles). The particles may contain the therapeutic agent (one or more) within the core surrounded by the coating. Therapeutic agents (one or more) can also be dispersed throughout the particles. Therapeutic agents (one or more) can also be adsorbed on the particles. Particles are zero-order release, primary release, secondary release, delayed release, sustained release, immediate release including such exit, and any combination thereof, may have any order release kinetics. Particles include, but are not limited to, erosive, non-erosive, biodegradable, or non-biodegradable substances or combinations thereof, in addition to therapeutic agents (one or more). Any of the substances routinely used in technology can be included. The particles may be microcapsules containing a potential opening calcium channel blocker in solution or in a semi-solid state. The particles can have virtually any shape. As used herein, the term "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers, diluents or encapsulants suitable for administration to humans or other vertebrates. means. As used herein, the term "carrier" facilitates application in which active ingredients are combined without causing significant irritation to the organism and without excluding biological activity and the properties of the active compounds of the compositions of the invention. Means natural or synthetic, organic or inorganic components. The components of the pharmaceutical composition can also be mixed in such a way that there are no interactions that substantially impair the desired pharmaceutical efficiency. The carrier must be sufficiently pure and sufficiently low toxicity to be suitable for administration to the mammal being treated. The carrier may be inert and the carrier may have pharmaceutical and / or cosmetic benefits. The terms "excipient", "carrier" or "formulator" have the same meaning to mean a carrier material suitable for formulation and administration of the pharmaceutically acceptable compositions described herein. Used in. Carriers and excipients effective herein include any such material known in the art that is non-toxic and does not interact with other ingredients.

As used herein, the term "pharmaceutical composition" means a composition used to prevent, reduce intensity, cure or treat a targeted condition or disease. As used herein, the term "pharmacological action" means the result or outcome of exposure to an activator. As used herein, the term "prognosis" means the expected future causes and consequences of a disease or disorder based on medical knowledge. The term "release" and its various grammatical forms mean the dissolution of activator components and the diffusion of dissolved or solubilized species by a combination of the following processes: (1) matrix hydration, (2). ) Diffusion of the solution into the matrix; (3) Dissolution of the drug; and (4) Diffusion of the dissolved drug from the matrix. As used herein, the term "reduced" or "reduced" is the degree, intensity, range, size, quantity, density, number or reduction, reduction, attenuation, limitation of disability in an individual at risk of disability. Or it means remission. As used herein, the term "subacute inflammation" refers to the tissue response typically seen following an early inflammatory process characterized by a mixture of neutrophils, lymphocytes, and sometimes macrophages and / or plasma cells. means.

The term "subarachnoid hemorrhage" or "SAH" is used herein to mean a condition in which blood collects under the arachnoid membrane. This area, called the subarachnoid space, generally contains cerebrospinal fluid. Accumulation of blood in this subarachnoid space can lead to stroke, seizures, and other complications. In addition, SAH can cause permanent brain injury and many harmful biochemical events in the brain. Causes of SAH include hemorrhage from cerebral aneurysms, angioplasty, trauma, and extension into the subarachnoid space from primary intracerebral hemorrhage. Symptoms of SAH include, for example, sudden and severe headache, nausea and / or vomiting, signs of meningism (eg, neck stiffness, back pain, leg pain), photophobia and visual changes, and / or loss of consciousness. Can be mentioned. SAH is often a secondary form of angiopathy known as head injury or aneurysm. In some cases, SAH can induce angiographic vasospasm, which in turn can lead to ischemic stroke or DCI. A common symptom of SAH is the presence of blood in the CSF. Subjects with SAH can be confirmed by many signs. For example, a subject with subarachnoid hemorrhage usually has a large amount of blood under the arachnoid. Subjects with subarachnoid hemorrhage can also be confirmed by intracranial pressure, which approximates mean arterial pressure, by a drop in cerebral perfusion pressure, or by rapid transient loss of consciousness (sometimes preceded by a painful headache). In approximately half of the cases, the subject has a severe headache that can be accompanied by physical activity. Other signs associated with subarachnoid hemorrhage include nausea, vomiting, memory loss, hemiparesis and aphasia. Subjects with SAH can be confirmed by the presence of creatine kinase BB isoenzyme activity in their CSF. This enzyme is abundant in the brain, but is usually not present in the CSF. Therefore, its presence in the CSF indicates a "leakage" from the brain into the subarachnoid space. Analysis of creatine kinase BB isoenzyme activity in CSF was performed by Coplin et al. (Coplin et al 1999 Arch Neurol 56, 1348-1352). In addition, spinal or lumbar puncture can be used to demonstrate the presence of blood in the CSF or strong signs of subarachnoid hemorrhage. Blood in the subarachnoid region can be confirmed by cranial CT scan or MRI. Angiography can also be used to determine not only if bleeding has occurred, but also the location of the bleeding. Subarachnoid hemorrhage generally results from a ruptured intracranial saccular aneurysm or a malformation of the arteriovenous system that connects to the brain. Therefore, subjects at risk of subarachnoid hemorrhage include those with saccular aneurysms as well as those with arteriovenous malformations. Common sites for saccular aneurysms are the apex of the basilar artery and the junction of the basilar artery with the superior or anterior inferior cerebellar artery. For subjects with subarachnoid hemorrhage, slow eye movements may suggest brain damage, as confirmed by eye examination. Subjects with saccular aneurysms can be identified by routine medical imaging techniques such as CT and MRI. Sacral and cerebral aneurysms form mushroom-like or berry-like shapes (often referred to as "necked dome" shapes). Angiography Angiographic vasospasm

The terms "subject" or "individual" or "patient" are used interchangeably to mean a member of an animal species of mammalian origin, including humans. As used herein, the phrase "subject with cerebral vasospasm" refers to a diagnostic marker that has signs of cerebral vasospasm or has been diagnosed with cerebral vasospasm and / or has angiographic vasospasm. Means the subject to be shown. Subjects at risk for cerebral vasospasm are those who have one or more predispositions to the development of cerebral vasospasm. Predisposition includes, but is not limited to, the occurrence of subarachnoid hemorrhage. Subjects who have recently experienced SAH are at significantly higher risk of developing cerebral vasospasm than those who have not recently experienced SAH. Cerebral vasospasm can be diagnosed using MR angiography, CT angiography and catheter angiography. Angiography is a technique in which a contrast medium is introduced into the bloodstream to examine the bloodstream and / or arteries. Contrast media is needed because blood flow and / or arteries often appear weak on routine MR scans, CT scans, or radiographic films for catheter angiography. The appropriate contrast agent depends on the image processing method used. For example, gadolinium is commonly used as a contrast agent used in MR scans. Suitable contrast agents for other MRs are also known in the art. Diagnostic markers include the presence of blood in the CSF, a recent history of SAH and / or a decrease in the vascular lumen of the cerebral artery observed on the catheter, computed tomography or magnetic resonance 1-14 days after SAH or TBI. Angiography includes, but is not limited to. The presence of blood in the CSF can be detected using a CT scan. However, lumbar puncture is justified if the blood volume is so low that it cannot be detected by CT.

As used herein, the phrase "subject with delayed cerebral ischemia" or "DCI" means a subject who indicates a diagnostic marker associated with DCI. Diagnostic markers include the presence of blood in the CSF, the recent history of SAH and / or the occurrence of neurological exacerbations 1-14 days after SAH, other causes, seizures, which can be diagnosed. Examples include, but are not limited to, hydrocephalus, increased intracranial pressure, infection, intracranial hemorrhage or other systemic factors, but not due to, but not limited to. DCI-related symptoms include paralysis on one side of the body, inability to speak or understand spoken or written words, and inability to perform tasks that require spatial analysis. Not limited. Such symptoms may occur over several days, or their appearance may fluctuate, or the symptoms may appear unexpectedly. As used herein, the phrase "subject with microthrombogenic embolism" means a subject who indicates a diagnostic marker associated with microthrombogenic embolism. Diagnostic markers include the presence of blood in the CSF, the recent history of SAH and / or the occurrence of neurological exacerbations 1-14 days after SAH, other causes, seizures, which can be diagnosed. Examples include, but are not limited to, hydrocephalus, increased intracranial pressure, infection, intracranial hemorrhage or other systemic factors, but not due to, but not limited to. Another diagnostic marker can be the embolic signal detected by transcranial Doppler ultrasound of the large conductive cerebral artery. Symptoms associated with microthrombosis include paralysis on one side of the body, inability to speak or understand spoken or written words, and inability to perform tasks that require spatial analysis. , Not limited to these. Such symptoms may occur over several days, or their appearance may fluctuate, or the symptoms may appear unexpectedly.

As used herein, the phrase "subject with intracortical spreading ischemia" means a subject showing a diagnostic marker associated with intracortical spreading ischemia. Diagnostic markers include the presence of blood in the CSF, the recent history of SAH and / or the occurrence of neurological exacerbations 1-14 days after SAH, other causes, seizures, which can be diagnosed. Examples include, but are not limited to, hydrocephalus, increased intracranial pressure, infection, intracranial hemorrhage or other systemic factors, but not due to, but not limited to. Another diagnostic marker may be the detection of propagating depolarized waves due to vasoconstriction detected by electrocorticography. Intracortical spreading ischemia-related symptoms include paralysis on one side of the body, inability to speak or understand spoken or written words, and inability to perform tasks that require spatial analysis. However, it is not limited to these. Such symptoms may occur over several days, or their appearance may fluctuate, or the symptoms may appear unexpectedly. Subjects at risk for DCI, microthrombogenic embolism, cortical spreading ischemia, or angiographic vasospasm are those who have one or more predispositions to the development of these symptoms. Predisposition includes, but is not limited to, the presence of SAH. Subjects who have recently experienced SAH are at significantly higher risk of developing angiographic vasospasm and DCI than those who have not recently experienced SAH. MR angiography, CT angiography and catheter angiography can be used to diagnose DCI, microthrombogenic embolism, cortical spreading ischemia or angiographic angiography. Angiography is a technique in which a contrast medium is introduced into the bloodstream to examine the bloodstream and / or arteries. Contrast media is needed because blood flow and / or arteries often appear weak on routine MR scans, CT scans, or radiographic films for catheter angiography. The appropriate contrast agent depends on the image processing method used. For example, gadolinium is commonly used as a contrast agent used in MR scans. Suitable contrast agents for other MRs are also known in the art.

The term "suitable for delivery" as used herein is either prone to release only in the subarachnoid space, suitable for its release, designed for its release, or suitable for its release. Means that As used herein, the term "substantially pure" means the condition of a therapeutic agent and is substantially separated from substances that may be associated with it in the biological system or during synthesis. According to some embodiments, a substantially pure therapeutic agent is at least 70% pure, at least 75% pure, at least 80% pure, at least 85% pure, at least 90% pure, at least 95% pure, at least 96. % Pure, at least 97% pure, at least 98% pure, or at least 99% pure. The term "sustained release" (also referred to as "long-term release") is used herein in its conventional sense, with a gradual release of the drug over a long period of time, and preferably, but not necessarily, a long-term. Means a drug formulation that results in a substantially constant blood level of the drug over. Alternatively, delayed absorption of the dosage form administered parenterally is achieved by dissolving or suspending the drug in an oily excipient. Non-limiting examples of sustained release biodegradable polymers include polyesters, polyester polyethylene glycol copolymers, polyamino-derived biopolymers, polyanhydrides, polyorthoesters, polyphosphazene, SAIB, photopolymerizable biopolymers, protein polymers, collagen. , Polysaccharides, chitosan, and arginates. As used herein, the term "syndrome" means a pattern of symptoms that indicates a disease or symptom. As used herein, the term "synergistic effect" means that the combined effect of two chemical products is greater than the sum of the effects of each drug administered alone.

As used herein, the phrase "systemic administration" means administration of a therapeutic agent that has a pharmacological effect on the whole body. Systemic administration includes enteral administration through the gastrointestinal tract (eg, oral) and parenteral administration outside the gastrointestinal tract (eg, intravenous, intramuscular, etc.). One or more of the terms "therapeutic amount", "therapeutically effective amount" or "effective amount" of a therapeutic agent is an amount sufficient to provide the intended therapeutic benefit. Combined with the teachings presented herein, by selecting various active compounds and metric factors such as potency, relative bioavailability, patient weight, severity of side effects and preferred method of administration. Effective prophylactic or therapeutic treatments that do not cause toxic but are effective in treating specific subjects will be planned. The therapeutically effective amounts of therapeutic agents that can be used generally range from 0.1 mg / kg body weight to about 50 mg / kg body weight. The therapeutically effective amount for any particular application may depend on factors such as the disease or symptom being treated, the particular therapeutic agent administered, the size of the subject, or the severity of the disease or symptom. One of ordinary skill in the art can empirically determine the effective amount of a specific inhibitor and / or other therapeutic agent without the need for undue experimentation. In general, it is preferred that the maximum dose, i.e. the safest dose, be used according to some medical judgment. However, dose levels are based on a variety of factors and include the type of injury, age, weight, gender, patient's medical condition, severity of symptoms, route of administration, and the specific therapeutic agent used. Therefore, dosing regimens can vary widely, but can be routinely determined by the surgeon using standard methods. "Dose" and "dosage" are used interchangeably herein.

As used herein, the term "therapeutic agent" means an agent, molecule, nucleic acid, protein, composition or other substance that provides a therapeutic effect. The terms "therapeutic agent" and "active agent" are used interchangeably. The activator can be a calcium channel blocker, an endothelin antagonist or a transient receptor potential (TRP) protein antagonist. Therapeutic agents (one or more) containing calcium channel blockers, endothelin antagonists, or transient receptor potential (TRP) protein antagonists can be delivered in particles. As used herein, the term "therapeutic ingredient" means a therapeutically effective dose (ie, dose and number of doses) that excludes, weakens, or impedes the progression of a particular disease symptom as a percentage of the population. .. An example of a commonly used therapeutic ingredient is ED50, where the dose is described as an individual dosage at which 50% of the population is therapeutically effective for a particular disease condition. As used herein, the term "therapeutic effect" means the outcome of treatment that is determined to be desirable and beneficial. Therapeutic effects may include, directly or indirectly, the cessation, reduction, or elimination of disease symptoms. Therapeutic effects can also directly or indirectly include stopping, reducing or eliminating the progression of disease symptoms. The term "topical" means administering the composition to or just below the point of application. The phrase "apply topically" describes application on one or more surfaces, including epithelial surfaces. Topical administration, in contrast to transdermal administration, generally provides a local effect rather than a systemic effect.

As used herein, the term "transient receptor potential (TRP) protein antagonist" is structurally different from other calcium channel blockers and blocks or blocks intracellular calcium elevation in cells due to receptor-mediated calcium influx. Means an antagonistic protein. Transient receptor potential (TRP) protein antagonists include SK &amp; F 96365 (1- (beta- [3- (4-methoxyphenyl) propoxy] -4-methoxyphenethyl) -1H-imidazole hydrochloride) and LOE 908 ( RS)-(3,4-dihydro-6,7-dimethoxyisoquinolin-l-gamma 1) -2-phenyl-N, N-di [2- (2,3,4-trimethoxyphenyl) ethyl] acetamide However, it is not limited to these. The term "treatment" or "treat" refers to stopping, substantially stopping, delaying or reversing the progression of a disease, symptom or disorder, substantially reducing the clinical or aesthetic signs of the symptom. It includes improving, substantially preventing the appearance of clinical or aesthetic signs of disease, symptoms, or disorders, and protecting against harmful or unpleasant signs. Treatment means achieving one or more of the following: (a) reducing the severity of the disorder; (b) developing symptoms specific to the disorder being treated (one or more): (C) Limiting the exacerbation of symptoms specific to the disorder being treated (one or more); (d) Disability (1) in patients who previously had a disorder (one or more) Limiting the recurrence of one or more); And (e) limit the recurrence of symptoms in patients whose disability (one or more) was previously asymptomatic. As used herein, the term "vasoconstriction" means the narrowing of blood vessels resulting from the contraction of the muscle walls of blood vessels. Blood flow is restricted or reduced when blood vessels constrict. The term "vasodilation," which is the opposite of vasoconstriction as used herein, means to dilate a blood vessel. As used herein, the terms "vasoconstrictor," "blood pressure-elevating agent," or "hypertensive agent" mean factors that cause vasoconstriction.

As used herein, the term "vascular spasm" means a decrease in the inner diameter of the cerebral artery resulting from the contraction of smooth muscle within the walls of the artery that causes a decrease in blood flow, but generally does not increase systemic vascular resistance. .. Vascular spasm results in decreased cerebral blood flow and increased cerebral vascular resistance. Although not limited by theory, in general, vasospasm is another structure that includes local damage to blood vessels, such as atherosclerosis and traumatic head trauma, aneurysms subarachnoid hemorrhage and other causes of subarachnoid hemorrhage. Probably due to damage. Cerebral vasospasm is a naturally occurring vasoconstriction that can also be triggered by the presence of blood in the CSF, a common occurrence after an aneurysm rupture or a traumatic head injury. Cerebral vasospasm can ultimately lead to brain cell damage in the form of cerebral ischemia and infarct formation due to impaired blood supply. As used herein, the term "cerebral vasospasm" further refers to the delayed occurrence of narrowing of the basilar artery in the basilar artery after subarachnoid hemorrhage, often associated with diminished perfusion in the area distal to the affected vessel. Means. Cerebral vasospasm can occur at any time after the rupture of an aneurysm, but when blood is absorbed by the body, it mostly peaks 7 days after bleeding and often subsides within 14 days. Angiographic vasospasm, which is the result of SAH, can occur after any condition that deposits blood in the subarachnoid space. More specifically, the term "angiographic cerebral vasospasm" means the narrowing of the large volume arteries (ie, the cerebral arteries) in the basilar artery after hemorrhage in the subarachnoid space, resulting in reduced perfusion in the distal brain region. Connect.

Anatomical term When referring to an animal that typically has one end with the head and oral cavity and the other end often with the anus and tail, the head end is called the cranial end and the caudal end is It is called the tail end. Within the head itself, the rostral side points towards the end of the nose and the caudal side points towards the caudal. Apart from attraction, the surface or side of the animal's body, which is usually in the upward direction, is the dorsal; the opposite side, typically the most on the ground when walking, swimming or flying with all paws. The closest one is the ventral side. For limbs or other appendages, the point closer to the body is the "proximal"; The farther points are the "distal". Three basic reference planes are used in zoological anatomy. The "sagittal" plane divides the body into left and right parts. The "mid-sagittal" plane is at the midline. That is, the mid-sagittal plane passes through a midline structure such as the spine, and all other sagittal planes are parallel to the mid-sagittal plane. The "coronal" plane divides the body into a dorsal and ventral part. The "transverse" plane divides the body into a cranial and caudal part. With reference to humans, the body and its parts are always described assuming the body is upright. The part of the body closer to the end of the head is "upper" (corresponding to the cranial side in animals) and the farther part is "lower" (corresponding to the caudal side in animals). Objects near the front of the body are called "anterior" (corresponding to the ventral side of the animal); Objects near the back of the body are called "rear" (corresponding to the dorsal side of the animal). The lateral, axial, or horizontal plane is the XY plane parallel to the ground, which separates the lower / foot from the upper / head. The coronal or frontal plane is the YZ plane perpendicular to the ground, which separates the rear from the front. The sagittal plane is the XZ plane perpendicular to the ground and frontal plane, which divides from right to left. The mid-sagittal plane is exactly the specific sagittal plane in the center of the body. The structure near the midline is called the inside, and the structure near the sides of the animal is called the outside. Therefore, the inner structure is closer to the mid-sagittal plane and the outer structure is farther from the mid-sagittal plane. The structure at the midline of the body is midline. For example, the tip of the nose of a human subject is at the midline. Ipsilateral means on the same side, contralateral means on the other side, and both sides mean on both sides. Structures closer to the center of the body are proximal or central, and structures farther away are distal or peripheral. For example, the hand is at the distal end of the arm and the shoulder is at the proximal end.

I. Composition In one aspect, the invention is a flowable sustained release microparticle composition: (i) at least one microparticle formulation; And (ii) a pharmaceutically acceptable carrier, the microparticle formulation containing multiple microparticles with a uniform particle size distribution, at least one therapeutic agent dispersed throughout each microparticle, and composition. Provided are said compositions that are suitable for delivery to the ventricles and capable of flowing through cerebrospinal fluid (CSF) from the ventricles to the subarachnoid space. According to one embodiment, upon delivery to the ventricles, the flowable sustained release microparticle composition can be dispersed from the ventricles without releasing at least one therapeutic agent into the ventricles. According to another embodiment, upon delivery to the ventricles, the flowable sustained release microparticle composition sustaineds release of at least one therapeutic agent in therapeutic amounts at the site of release of the subarachnoid space. be able to. According to one embodiment, the release site is in close proximity to at least one blood vessel within the subarachnoid space at risk of interference caused by brain injury. According to one embodiment, the at least one blood vessel is at least one cerebral artery in the subarachnoid space. According to another embodiment, upon delivery to the ventricles, the flowable sustained release microparticle composition is from cerebrospinal fluid (CSF) in the ventricles to cerebrospinal fluid (CSF) in the subarachnoid space. The therapeutic agent can be sustained-release in the subarachnoid space after flowing to. According to some embodiments, the ventricles to which the flowable sustained release microparticle composition can be delivered are the lateral ventricles, the third ventricle, the fourth ventricle, or a combination thereof. Will be selected. According to some embodiments, the ventricles are the lateral ventricles. According to one embodiment, the ventricles are the right ventricles. According to another embodiment, the ventricles are the left ventricles. According to one embodiment, the ventricle is the third ventricle. According to another embodiment, the ventricle is the fourth ventricle.

According to some embodiments, the ventricles are at least 0.001 mm to at least 10 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to one embodiment, the ventricles are at least 0.001 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 0.005 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 0.01 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 0.05 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 0.1 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 0.5 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 1.0 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 1.5 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 2.0 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 2.5 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to other embodiments, the ventricles are at least 3. from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. It is at 0 mm. According to another embodiment, the ventricles are at least 3.5 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 4.0 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 4.5 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 5.0 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 5.5 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 6.0 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 6.5 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 7.0 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 7.5 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 8.0 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 8.5 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 9. from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. It is at 0 mm. According to another embodiment, the ventricles are at least 9.5 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 1 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 1.5 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 2.0 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 2.5 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 3.0 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 3.5 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 4.0 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 4.5 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 5.0 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 5.5 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to other embodiments, the ventricles are at least 6. From at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. It is at 0 cm. According to another embodiment, the ventricles are at least 6.5 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 7.0 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 7.5 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 8.0 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 8.5 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 9.0 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 9.5 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 10 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. It is at 5 cm. According to another embodiment, the ventricles are at least 9.0 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 9.5 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 10 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. It is at 5 cm. According to another embodiment, the ventricles are at least 9.0 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 9.5 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 10 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury.

According to some embodiments, the flowable sustained release microparticle composition has a half-life (t) in the range of 1 to 30 days._1/2) Can be sustained-release within a therapeutic amount of at least one therapeutic agent. According to one embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a daily half-life. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 2 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 3 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 4 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 5 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 6 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 7 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 8 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 9 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 10 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 12 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 14 days. According to another embodiment, the flowable sustained release The microparticle composition is capable of sustained release of at least one therapeutic agent in therapeutic amounts within a half-life of 16 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 18 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 20 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 22 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 24 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 26 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 28 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 30 days. A capable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 26 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 28 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 30 days. A capable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 26 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 28 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 30 days.

According to some embodiments, the flowable sustained release microparticle composition is at least one therapeutic amount prior to the onset of delayed complications associated with cerebral artery obstruction caused by brain injury. The therapeutic drug can be sustained-release. According to some embodiments, late complications consist of angiographic vasospasm, multiple microthrombogenic embolisms, cortical spreading ischemia, late cerebral ischemia (DCI), or a combination thereof. Will be selected. According to one embodiment, the late complication is angiographic vasospasm. According to other embodiments, the late complication is multiple microthrombogenic embolisms. According to another embodiment, the late complication is cortical spreading ischemia. According to another embodiment, the late complication is late cerebral ischemia (DCI). According to some embodiments, the brain injury is the result of the underlying symptoms. Exemplary underlying symptoms include, but are not limited to, aneurysms, sudden traumatic head injuries, subarachnoid hemorrhage (SAH), or a combination thereof. According to one embodiment, the underlying symptom is an aneurysm. According to other embodiments, the underlying symptom is traumatic head injury. According to other embodiments, the underlying symptom is subarachnoid hemorrhage (SAH). According to other embodiments, the underlying symptom is a combination of an aneurysm, sudden traumatic head injury, and subarachnoid hemorrhage (SAH). According to some embodiments, the flowable sustained release microparticle composition interferes when released in close proximity to at least one cerebral artery within the subarachnoid space at risk of interference caused by brain injury. It is effective in reducing vascular spasm so that the inner diameter of at least one cerebral artery in the subarachnoid space is increased compared to the control. According to some embodiments, the flowable sustained release microparticle delivery composition is released in close proximity to at least one cerebral artery within the subarachnoid space at risk of interference caused by brain injury. It is effective in preventing or reducing the occurrence or severity of late complications associated with cerebral artery obstruction. According to one embodiment, predominantly local pharmacological effects are increased such that the inner diameter of at least one cerebral artery in the subarachnoid space at risk of obstruction is increased compared to an untreated control. It is a reduction of spasm. According to one embodiment, the flowable sustained release of the microparticle composition is such that the inner diameter of at least one cerebral artery in the subarachnoid space at risk of obstruction is increased compared to an untreated control. It is effective in reducing vascular spasm.

According to one embodiment, a therapeutic amount of at least one therapeutic agent in close proximity to at least one cerebral artery in the subarachnoid space can produce predominantly local pharmacological effects. According to some embodiments, predominantly local pharmacological effects are such that the inner diameter of at least one cerebral artery in the submembrane cavity at risk of obstruction is increased compared to an untreated control. At least one cerebral artery is at least 10 mm, at least 9.9 mm, at least 9.8 mm, at least 9.7 mm, at least 9.6 mm, at least 9.5 mm, at least 9.4 mm, at least from the site of release in the submucosal space. 9.3mm, at least 9.2mm, at least 9.1mm, at least 9.0mm, at least 8.9mm, at least 8.8mm, at least 8.7mm, at least 8.6mm, at least 8.5mm, at least 8.4mm, at least 8.3mm, at least 8.2mm, at least 8.1mm , At least 8.0mm, at least 7.9mm, at least 7.8mm, at least 7.7mm, at least 7.6mm, at least 7.5mm, at least 7.4mm, at least 7.3mm, at least 7.2mm, at least 7.1mm, at least 7.0mm, at least 6.9mm, at least 6.8mm, at least 6.7mm, at least 6.6mm, at least 6.5mm, at least 6.4mm, at least 6.3mm, at least 6.2mm, at least 6.1mm, at least 6.0mm, at least 5.9mm, at least 5.8mm, at least 5.7mm, at least 5.6mm , At least 5.5mm, at least 5.4mm, at least 5.3mm, at least 5.2mm, at least 5.1mm, at least 5. It is at 0 mm. According to one embodiment, the predominantly local pharmacological effect is such that the inner diameter of at least one cerebral artery at least 10 mm from the site of release in the subarachnoid space is increased compared to an untreated control. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 9.9 mm from the site of release in the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 9.8 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 9.7 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 9.6 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 9.5 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 9.4 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 9.3 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are at least 9. Relief of vascular spasm such that the inner diameter of at least one cerebral artery at 2 mm is increased compared to an untreated control. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 9.1 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 9.0 mm from the site of release in the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 8.9 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 8.8 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 8.7 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 8.6 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 8.5 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are at least 8. Relief of vascular spasm such that the inner diameter of at least one cerebral artery at 4 mm is increased compared to an untreated control. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 8.3 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 8.2 mm from the site of release in the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 8.1 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 8.0 mm from the site of release in the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 7.9 mm from the site of release in the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 7.8 mm from the site of release in the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 7.7 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are at least 7. from the site of release within the subarachnoid space. Relief of vascular spasm such that the inner diameter of at least one cerebral artery at 6 mm is increased compared to an untreated control. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 7.5 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 7.4 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 7.3 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 7.2 mm from the site of release in the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 7.1 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 7.0 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 6.9 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are at least 6. from the site of release within the subarachnoid space. Relief of vascular spasm such that the inner diameter of at least one cerebral artery at 8 mm is increased compared to an untreated control. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 6.7 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 6.6 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 6.5 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 6.4 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 6.3 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 6.2 mm from the site of release in the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 6.1 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are at least 6. from the site of release within the subarachnoid space. Relief of vascular spasm such that the inner diameter of at least one cerebral artery at 0 mm is increased compared to an untreated control. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 5.9 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 5.8 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 5.7 mm from the site of release in the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 5.6 mm from the site of release in the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 5.5 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 5.4 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 5.3 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are at least 5. from the site of release within the subarachnoid space. Relief of vascular spasm such that the inner diameter of at least one cerebral artery at 2 mm is increased compared to an untreated control. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 5.1 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 5.0 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm.

According to one embodiment, sustained release of at least one therapeutic agent in a therapeutic amount close to at least one cerebral artery in the subarachnoid space has a predominantly local pharmacological effect over the desired amount of time. Can occur. According to one embodiment, the release of a therapeutic amount of at least one therapeutic agent in close proximity to at least one cerebral artery within the subarachnoid space results in predominantly local pharmacological effects for one day. According to other embodiments, the release of a therapeutic amount of at least one therapeutic agent in close proximity to at least one cerebral artery within the subarachnoid space results in a predominantly localized pharmacological effect for two days. According to other embodiments, the release of a therapeutic amount of at least one therapeutic agent in close proximity to at least one cerebral artery within the subarachnoid space results in predominantly local pharmacological effects for 3 days. According to other embodiments, the release of a therapeutic amount of at least one therapeutic agent in close proximity to at least one cerebral artery within the subarachnoid space results in predominantly local pharmacological effects for 4 days. According to other embodiments, the release of a therapeutic amount of at least one therapeutic agent in close proximity to at least one cerebral artery within the subarachnoid space results in predominantly local pharmacological effects for 5 days. According to other embodiments, the release of a therapeutic amount of at least one therapeutic agent in close proximity to at least one cerebral artery within the subarachnoid space results in predominantly local pharmacological effects for 6 days. According to other embodiments, the release of a therapeutic amount of at least one therapeutic agent in close proximity to at least one cerebral artery within the subarachnoid space results in predominantly local pharmacological effects for 7 days. According to other embodiments, the release of a therapeutic amount of at least one therapeutic agent in close proximity to at least one cerebral artery within the subarachnoid space results in predominantly local pharmacological effects for 8 days. According to other embodiments, the release of a therapeutic amount of at least one therapeutic agent in close proximity to at least one cerebral artery within the subarachnoid space results in predominantly local pharmacological effects for 15 days. According to other embodiments, the release of a therapeutic amount of at least one therapeutic agent in close proximity to at least one cerebral artery within the subarachnoid space results in predominantly local pharmacological effects for 30 days.

Therapeutic Agents According to some embodiments, the at least one therapeutic agent is a calcium channel blocker, an endothelin antagonist, a transient receptor potential (TRP) protein antagonist, or a combination thereof. According to one example, at least one therapeutic agent is a calcium channel blocker. According to some embodiments, the calcium channel blocker is an L-type voltage-gated calcium channel inhibitor, an R-type voltage-gated calcium channel inhibitor, an N-type voltage-gated calcium channel inhibitor, and a P / Q-type potential. It is selected from the group consisting of a dependent calcium channel inhibitor, a T-type voltage-gated calcium channel inhibitor, or a combination thereof. According to one embodiment, the calcium channel blocker is an L-type voltage-gated calcium channel inhibitor. According to one embodiment, the calcium channel blocker is an R-type voltage-gated calcium channel inhibitor. According to one embodiment, the calcium channel blocker is an N-type voltage dependent calcium channel inhibitor. According to one embodiment, the calcium channel blocker is a P / Q voltage-gated calcium channel inhibitor. According to one embodiment, the calcium channel blocker is a T-type voltage-gated calcium channel inhibitor.

For example, L-type voltage-gated calcium channel inhibitors include dihydropyridine L-type blockers such as nisoldipine, nicardipine or nifedipine, AHF (eg 4aR, 9aS)-(+)-4a-amino-1,2,3,4. , 4a, 9a-hexahydro-4aH-fluorene, HC1), isradipine (eg 4- (4-benzofrazanyl) -1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl 1-methylethyl ester ), Calciseptine (eg, Dendroaspis polylepis) (Separated from polylepis)), H-Arg-Ile-Cys-Tyr-Ile-His-Lys-Ala-Ser-Leu-Pro-Arg-Ala-Thr-Lys-Thr-Cys-Val-Glu-Asn- Thr-Cys-Tyr-Lys-Met-Phe-Ile-Arg-Thr-Gln-Arg-Glu-Tyr-Ile-Ser-Glu-Arg-Gly-Cys-Gly-Cys-Pro-Thr-Ala-Met- Trp-Pro-Tyr-G1n-Thr-Glu-Cys-Cys-Lys-Gly-Asp-Arg-Cys-Asn-Lys-OH, Calcicludine (eg Dendroaspis) (separated from angusticeps) (Eastern Green Mamba)), (H-Trp-Gln-Pro-Pro-Trp-Tyr-Cys-Lys-Glu-Pro-Val-Arg-Ile-Gly-Ser-Cys-Lys- Lys-Gln-Phe-Ser-Ser-Phe-Tyr-Phe-Lys-Trp-Thr-Ala-Lys-Lys-Cys-Leu-Pro-Phe-Leu-Phe-Ser-GlyCys-G1y-Gly-Asn- Ala-Asn-Arg-Phe-Gln-Thr-Ile-Gly-Glu-Cys-Arg-Lys-Lys-Cys-Leu-Gly-Lys-OH, silnidipine (eg A and FRP-8653 also dihydropyridine-type inhibition Agent), Dilantizem (eg (2S, 3S)-(+)-cis-3-acetoxy-5- (2-dimethylaminoethyl) -2,3-dihydro-2- (4-methoxyphenyl)- 1,5-benzothiazepine-4 (5H) -one hydrochloride), zyrrhizem (eg benzothiazepine-4 (5H) -one, 3- (acetyloxy) -5- [2- (dimethylamino) ethyl] -2,3-dihydro-2- (4-methoxyphenyl)-, (+)-cis-, monohydrochloride), ferrodipine (eg 4- (2,3-dichlorophenyl) -1,4-dihydro-2 , 6-Dimethyl-3,5-pyridinecarboxylic acid ethylmethyl ester), FS-2 (eg isolate from Dendroapsis polylepis polylepis poison), FTX-3.3 (eg isolate from Agelenopsis aperta), Neomycin sulfate (eg C₂₃H₄₆N₆O₁₃ 3H₂SO₄), Nicaldipine (eg 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenylmethyl-2-[methyl (phenyl) methylamino] -3,5-pyridinedicarboxylic acid ethyl ester hydrochloride, and also YC-93 also contains nifedipine (eg 1,4-dihydro-2,6-dimethyl-4- (2-nitrophenyl) -3,5-pyridinecarboxylic acid dimethyl ester), nimodipin (eg 4-dihydro-2,6). -Dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 2-methoxyethyl 1-methylethyl ester) or (isopropyl2-methoxyethyl 1,4-dihydro-2,6-dimethyl-4- (m-Nitrophenyl) -3,5-pyridinedialvoxylate), nitrenenedin (eg 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylate ethyl Methyl ester), S-petacin (eg (3S, 4aR, 5R, 6R)-[2,3,4,4a, 5,6,7,8-octahydro-3- (2-propenyl) -4a, 5- Dimethyl-2-oxo-6-naphthyl] Z-3'-methylthio-1'-propenoate), floretin (eg 2', 4', 6'-trihydroxy-3- (4-hydroxyphenyl) propiophenone, Also 3- (4-hydroxyphenyl) -1- (2,4,6-trihydroxyphenyl) -1-propanol and b- (4-hydroxyphenyl) -2,4,6-trihydroxypropiophenone ) Also protopin (eg C)₂₀H₁₉NO₅Cl), SKF-96365 (eg 1- [b- [3- (4-methoxyphenyl) propoxy] -4-methoxyphenethyl] -1H-imidazole, HC1), tetrandin (eg 6,6', 7,12- Tetramethoxy-2,2'-dimethylvelvaman), (. +-.)-Methoxybellapamil or (+)-bellapamil (eg 54N- (3,4-dimethoxyphenylethyl) methylamino] -2- (3, 4-Dimethoxyphenyl) -2-iso-propylvaleronitrile hydrochloride), and (R)-(+)-Bay K8644 (eg R-(+)-1,4-dihydro-2,6-dimethyl-5- Examples include, but are not limited to, nitro-4- (2- (trifluoromethyl) phenyl) -3-pyridinecarboxylic acid methyl ester). The above examples can be specific for L-type open-pot calcium channels or can inhibit a wider range of potential-opening calcium channels, such as N, P / Q, R and T-types.

According to some embodiments, the L-type voltage-gated calcium channel inhibitor is dihydropyridine. Typical dihydropyridines include amlodipine, alanidipine, azelnidipine, vanidipine, benidipine, sinardipin, ehonidipine, felodipine, islazipin, lasidipine, remildipine, relcanidipine, nicaldipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nisoldipine, nimodipine, nisoldipine, nimodipine, nisoldipine. However, it is not limited to these. According to one embodiment, the dihydropyridine is nimodipine. According to one embodiment, nimodipine has a half-life of 7-10 days when formulated as described herein and has adequate lipophilicity. According to some embodiments, the L-type voltage-gated calcium channel inhibitor is a phenylalkylamine. Examples of exemplary phenylalkylamines include, but are not limited to, gallopamil, verapamil and the like. According to some embodiments, the L-type voltage-gated calcium channel inhibitor is 1-4 benzothiazepines. According to one embodiment, 1-4 benzothiazepines are diltiazem. According to one embodiment, the L-type voltage-gated calcium channel inhibitor is bepridil. According to other embodiments, the at least one therapeutic agent is an endothelin antagonist. Exemplary endothelin antagonists include A-127722, ABT-627, BMS 182874, BQ-123, BQ-153, BQ-162, BQ-485, BQ-518, BQ-610, EMD-122946, FR 139317, IPI-725, L-744453, LU 127043, LU 135252, PABSA, PD 147953, PD 151242, PD 155080, PD 156707, RO 611790, SB-247083, Clazocentan, Atlascentan, Citaxsentan Sodium, TA-0201, TBC 11251, TTA-386, WS-7338B, ZD-1611, Aspirin, A-182086, CGS 27830, CP 170687, J-104132 , L-751281, L-754142, LU 224332, LU 302872, PD 142893, PD 145065, PD 160672, RO-470203, Bosentan, RO 462005, RO 470203, SB 209670, SB 217242, TAK-044, A-192621, Examples include, but are not limited to, A-308165, BQ-788, BQ-017, IRL 1038, IRL 2500, PD-161721, RES 701-1, RO 468443, etc. According to other embodiments, the at least one therapeutic agent is a transient receptor potential (TRP) protein antagonist. Exemplary transient receptor potential (TRP) protein antagonists include gadolinium chloride, lanthanum chloride, and SKF 96365. (1- (β- [3- (4-Methoxy-phenyl) propoxy] -4-methoxyphenethyl) -1H-imidazole hydrochloride), and LOE 908 ((RS)-(3,4-dihydro-6,7) -Dimethoxyisoquinoline-1-gamma 1) -2-phenyl-N, N-di- [2- (2,3,4-trimethoxyphenyl) ethyl] acetamide), but not limited to these. According to some embodiments, the at least one therapeutic agent is a separated molecule. According to some embodiments, the at least one therapeutic agent is substantially pure.

Microparticle Formulation According to one embodiment, the flowable sustained release microparticle composition comprises a plurality of microparticles containing at least one therapeutic agent. According to some embodiments, the at least one therapeutic agent is supplied in the form of particulates. According to other embodiments, the at least one therapeutic agent is located on or in the microparticles. According to one embodiment, at least one therapeutic agent is dispersed throughout each microparticle. According to some embodiments, at least one therapeutic agent is impregnated on the surface of each microparticle. According to other embodiments, the at least one therapeutic agent is contained within a fine particle core surrounded by a coating. According to other embodiments, at least one therapeutic agent is adsorbed on each of the microparticles. According to some such embodiments, the microparticles have a uniform particle size distribution. According to some embodiments, a uniform distribution of particle size is achieved by a homogenization process that forms a uniform emulsion containing the particles. According to some such embodiments, each microparticle contains a matrix. According to some embodiments, the matrix comprises at least one therapeutic agent. According to some embodiments, the microparticles may have an arbitrary order release kinetics including zero order release, primary release, secondary release, delayed release, sustained release, immediate release, and combinations thereof. Fine particles include, but are not limited to, erosive, non-erosive, biodegradable, or non-biodegradable substances or combinations thereof, in addition to therapeutic agents (one or more). Any of the substances routinely used in technology can be included.

According to some embodiments, the microparticles are microcapsules containing at least one therapeutic agent in solution or in a semi-solid state. According to some embodiments, the microparticles contain at least one therapeutic agent, in whole or in part. According to some embodiments, the microparticles are nanoparticles that contain at least one therapeutic agent in whole or in part. According to some embodiments, the microparticles can have substantially any shape. According to some embodiments, each microparticle is loaded with at least 40% by weight to at least 80% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 40% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 45% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 50% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 55% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 60% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 63% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 65% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 70% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 75% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 80% by weight of at least one therapeutic agent.

According to some embodiments, the particle size is from about 25 μm to about 100 μm. According to some embodiments, the particle size is from about 30 μm to about 80 μm. According to one embodiment, the particle size is at least about 25 μm. According to other embodiments, the particle size is at least about 30 μm. According to other embodiments, the particle size is at least about 35 μm. According to other embodiments, the particle size is at least about 40 μm. According to other embodiments, the particle size is at least about 45 μm. According to other embodiments, the particle size is at least about 50 μm. According to other embodiments, the particle size is at least about 55 μm. According to other embodiments, the particle size is at least about 60 μm. According to other embodiments, the particle size is at least about 65 μm. According to other embodiments, the particle size is at least about 70 μm. According to other embodiments, the particle size is at least about 75 μm. According to other embodiments, the particle size is at least about 80 μm. According to other embodiments, the particle size is at least about 85 μm. According to other embodiments, the particle size is at least about 90 μm. According to other embodiments, the particle size is at least about 95 μm. According to other embodiments, the particle size is at least about 100 μm. According to other embodiments, at least one therapeutic agent can be supplied in the string. The string may contain at least one therapeutic agent in a core surrounded by a coating, or at least one therapeutic agent may be dispersed throughout the string, or at least one therapeutic agent is absorbed by the string. May be good. Strings can have arbitrary order release kinetics, including zero order release, primary release, secondary release, delayed release, sustained release, immediate release, and combinations thereof. Strings include, but are not limited to, erosive, non-erodible, biodegradable, or non-biodegradable substances or combinations thereof, in addition to therapeutic agents (one or more). Any of the substances routinely used in technology can be included.

According to other embodiments, the at least one therapeutic agent may be supplied in at least one sheet. The sheet may contain at least one therapeutic agent and at least one additional therapeutic agent in a core surrounded by a coating, or at least one therapeutic agent and at least one additional therapeutic agent are dispersed throughout the sheet. Alternatively, at least one therapeutic agent may be absorbed into the sheet. Sheets can have arbitrary order release kinetics, including zero order release, primary release, secondary release, delayed release, sustained release, immediate release, and combinations thereof. Sheets include, but are limited to, erosive, non-erosive, biodegradable, or non-biodegradable substances or combinations thereof, in addition to at least one therapeutic agent and at least one additional therapeutic agent. Any of the substances routinely used in dispensing and pharmaceutical technology that are not used can be included. According to some embodiments, the microparticle formulation comprises a suspension of microparticles. According to one embodiment, the microparticle formulation comprises a suspension of microparticles. According to some embodiments, the microparticle formulation further comprises at least one of an anti-precipitation agent, a stabilizer and a dispersant. According to some such embodiments, the microparticle formulation exists as a suspension. According to some such embodiments, the microparticle formulation exists as a solution. According to some such embodiments, the microparticle formulation exists as an emulsion.

According to some embodiments, the microparticle formulation comprises at least one aqueous solution of a therapeutic agent in a water-soluble form. According to some embodiments, the microparticle formulation comprises an oily suspension of at least one therapeutic agent. An oily suspension of at least one therapeutic agent can be prepared with a suitable lipophilic solvent. Exemplary lipophilic solvents or excipients include, but are not limited to, fatty oils such as sesame oil or synthetic fatty acid esters such as ethyloleate or triglycerides. According to some embodiments, the microparticle formulation comprises an aqueous suspension of at least one therapeutic agent. Aqueous infusion suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxylmethyl cellulose, sorbitol, hyaluronic acid, or dextran. If desired, the suspension may also contain suitable stabilizers or substances that increase the solubility of the compound to allow the preparation of highly concentrated solutions. Alternatively, at least one therapeutic agent may be in powder form to form with a suitable excipient, eg, sterile water free of pyrogens, prior to use. The fine particle mixture is dispersed in an excipient to form a dispersion having fine particles as a dispersion phase and an excipient as a dispersion medium. The microparticle formulation is contained, for example, in a microcapsule encapsulating form, a liposome coated on microscopic gold particles, if appropriate, in a pellet for implantation in a tissue. Or may be included with one or more dried excipients on the object to be rubbed against the tissue. As used herein, the term "microencapsulated" means that very small droplets or particles are surrounded or coated with a continuous film of biocompatible, biodegradable polymer or non-polymeric material, non-pareil, pellets, crystals. , Aggregates, microspheres, or nanoparticles, but refers to the process of obtaining an integral structure. Microparticle formulations delayed the release of granules, beads, powders, tablets, coated tablets, (micro) capsules, suppositories, syrups, emulsions, suspensions, creams, drops or active compounds. In the formulation, excipients and additives and / or adjuvants such as disintegrants, binders, coatings, swelling agents, lubricants or solubilizers are usually in the form of formulations as described above. Used for. The microparticle formulation is suitable for use in a variety of drug delivery systems. For a brief review of drug delivery methods, see Langer (1990) Science 249, 1527-1533, which is incorporated herein by reference.

Microencapsulation process Microencapsulation process and product examples; Emulsion-based microparticle production method; Emulsion-based microparticle and its production method; Solvent extraction with adjustable extraction rate Microcapsulation encapsulation; Microencapsulation with solvent and salt Process; Continuous double emulsion process to create fine particles; Drying method to adjust fine particle properties, emission control system from polymer blend; Polymer mixture containing polymers with different non-repetitive units and its production and usage And the emulsion-based process for preparing microparticles and the workhead assembly used therein are described in US Pat. No. 5,407,609 (referred to as microencapsulation process and its products), US Patent Application Publication No. 10 / 553,003 (Emulsion). (Referred to as a method for producing base fine particles), US Patent Application Publication No. 11 / 799,700 (referred to as emulsion-based fine particles and a method for producing the same), US Patent Application Publication No. 12 / 557,946 (with variable extraction rate). US Patent Application Publication No. 12 / 779,138 (referred to as hyaluronic acid (HA) injectable excipient), US Patent Application Publication No. 12 / 562,455 (referred to as solvent and salt encapsulation). Microencapsulation process), US Patent Application Publication No. 12 / 338,488 (referred to as a method for preparing fine particles with a low residual solvent volume); US Patent Application Publication No. 12 / 692,027 (from a polymer blend). It is called an emission control system); U.S. Patent Application Publication No. 12 / 692,020 (referred to as a polymer mixture containing polymers with different non-repetitive units and its production and use); U.S. Patent Application Publication No. 10 / 565,401 ("Release Control Composition"). US Patent Application Publication No. 12 / 692,029 (referred to as "drying method for adjusting fine particle properties"); US Patent Application Publication No. 12 / 968,708 ("Emulsion-based process for preparing fine particles and It is referred to as the workhead used); and is disclosed and described in US Patent Publication No. 13/074542 (referred to as "compositions and methods that improve retention of the pharmaceutical composition at the site of topical administration"). .. The contents of each of these are incorporated herein by reference in their entirety. According to some embodiments, delivery of at least one therapeutic agent using microparticle technology requires bioreabsorbable polymer particles that enclose at least one therapeutic agent and at least one additional therapeutic agent.

Fine Particle Polymer Matrix According to one embodiment, the fine particles contain a matrix. According to some embodiments, the at least one therapeutic agent is impregnated in or on a naturally occurring biopolymer matrix, synthetic polymer matrix, or a combination thereof. According to one embodiment, the polymer is a sustained release polymer. According to one embodiment, the polymer is a biodegradable polymer. According to one embodiment, the polymer is poly (D, L-lactide-co-glycolide). According to another embodiment, the polymer is a poly (orthoester). According to another embodiment, the polymer is poly (anhydride). According to another embodiment, the polymer is polylactide-polyglycolide. Both non-biodegradable and biodegradable polymeric materials can be used in the production of particles to deliver therapeutic agents. Such polymers can be natural or synthetic polymers. The polymer is selected based on the desired duration of release. Bioadhesive polymers of particular interest include Sawhney et al in Macromolecules (1993) 26, Examples include, but are not limited to, the bioerosive hydrogels described by 581-587. The teachings of this document are incorporated herein by reference. Exemplary bioerodible hydrogels include polyhyaluronic acid, casein, gelatin, glutin, polyan anhydride, polyacrylic acid, arginate, chitosan, poly (methyl methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate). ), Poly (isobutyl methacrylate), poly (hexyl methacrylate), poly (isodecyl methacrylate), poly (lauryl methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate) , And poly (octadecyl acrylate), but are not limited thereto. According to one embodiment, the bioadhesive polymer is hyaluronic acid. In some such embodiments, the bioadhesive polymer contains less than about 2.3% hyaluronic acid.

According to another embodiment, the polymer enhances the water solubility of the microparticle formulation. Examples of suitable polymers are polyethylene glycol, poly- (d-glutamic acid), poly- (1-glutamic acid), poly- (1-glutamic acid), poly- (d-aspartic acid), poly- (1-aspartic acid). Acids), poly- (1-aspartic acid) and copolymers thereof, but not limited to these. Polyglutamic acid having a molecular weight of about 5,000 to about 100,000, a molecular weight of about 20,000 to about 80,000 can be used, and a molecular weight of about 30,000 to about 60,000 can also be used. The polymer is ester-bonded to one or more hydroxyls of the epothilones of the invention using the protocol essentially described by US Pat. No. 5,977,163, which is incorporated herein by reference. Specific binding sites include the hydroxyl of carbon-21 in the case of the 21-hydroxy derivative of the invention. Other binding sites include, but are not limited to, carbon 3 hydroxyl and / or carbon 7 hydroxyl. According to some embodiments, the at least one therapeutic agent is impregnated in or on the polyglycolide (PGA) matrix. PGA is a linear aliphatic polyester developed for use in suturing. Studies have reported PGA copolymers formed with trimethylene carbonate, polylactic acid (PLA), and polycaprolactone. Some of these copolymers can be formulated as microparticles for sustained drug release. According to some embodiments, the at least one therapeutic agent is impregnated in the polyester-polyethylene glycol matrix or on the polyester-polyethylene glycol matrix. Polyester-polyethylene glycol compounds can be synthesized; they are soft and can be used for drug delivery.

According to some embodiments, the at least one therapeutic agent is impregnated in or on a poly (amino) -derived biopolymer matrix. Examples of poly (amino) -derived biopolymers include those containing lactic acid and lysine as aliphatic diamines (see, for example, US Pat. No. 5,399,665), and tyrosine-derived polycarbonates and polyacrylates. Not limited to. Modification of polycarbonate can change the length of the alkyl chain of the ester (ethyl to octyl), and modification of polyarylate can further include changing the length of the alkyl chain of the diacid (eg). , Succinic acid to sebacic acid), which allows for greater substitution of the polymer and greater flexibility of the polymer properties. According to some embodiments, the at least one therapeutic agent is impregnated in or on the polyanhydride matrix. Polyanhydrides are prepared by dehydration of two diacid molecules by melt polymerization (see, eg, US Pat. No. 4,757,128). These polymers decompose by surface erosion (compared to polyester, which decomposes by total erosion). The release of the drug can be controlled by the hydrophilicity of the monomer selected. According to some embodiments, the at least one therapeutic agent is impregnated in or on the photopolymerizable biopolymer matrix. Photopolymerizable biopolymers include, but are not limited to, lactic acid / polyethylene glycol / acrylate copolymers. According to some embodiments, the at least one therapeutic agent is impregnated in or on the hydrogel matrix. The term "hydrogel" means a substance that provides a solid, semi-solid, pseudoplastic or plastic structure containing the aqueous components necessary to form a gelatinous or jelly-like mass. Hydrogels generally include various polymers including hydrophilic polymers, acrylic acid, acrylamide and 2-hydroxyethyl methacrylate (HEMA).

According to some embodiments, the at least one therapeutic agent is impregnated in or on a naturally occurring biopolymer matrix. Naturally occurring biopolymers include, but are not limited to, protein polymers, collagen, polysaccharides and photopolymerizable compounds. According to some embodiments, the at least one therapeutic agent is impregnated in or on the protein polymer matrix. Protein polymers are synthesized from self-assembled protein polymers such as silk fibroin, elastin, collagen, and combinations thereof. According to some embodiments, the at least one therapeutic agent is impregnated in or on a naturally occurring polysaccharide matrix. Naturally occurring polysaccharides include chitin and its derivatives, hyaluronic acid, dextran and cellulosic (generally non-denaturing and non-biodegradable), and sucrose acetate isobutyrate (SAIB). Not limited to. According to some embodiments, the at least one therapeutic agent is impregnated in or on the chitin matrix. Chitin is mainly composed of 2-acetamido-2-deoxy-D-glucose groups and is found in yeast, fungi and marine invertebrates (shrimp, crustaceans), which are the main components of the exoskeleton. Chitin is not water-soluble, and only deacetylated chitin and chitosan are soluble in acidic solutions (eg, acetic acid). Studies have shown that it is water-soluble, very high molecular weight (greater than 2,000,000 daltons), viscoelastic, non-toxic, biocompatible and cross-linked with peroxides, glutaraldehyde, glyoxal and other aldehydes and carbodiamides. A chitin derivative capable of forming a gel has been reported. According to some embodiments, the at least one therapeutic agent is impregnated in or on the hyaluronic acid (HA) matrix. Hyaluronic acid (HA) found in mammalian extracellular matrix, synovial fluid, umbilical cord and comb, which is composed of alternating glucuronide and glucosaminide bonds and is separated and purified, can also be produced by the fermentation process.

Pharmaceutically Acceptable Carriers According to some embodiments, the flowable sustained release microparticle composition comprises (ii) a pharmaceutically acceptable carrier. According to one embodiment, the pharmaceutically acceptable carrier is a solid carrier or an excipient. According to other embodiments, the pharmaceutically acceptable carrier is a gel phase carrier or an excipient. Examples of carriers or excipients include, but are limited to, calcium carbonate, calcium phosphate, various monosaccharides and polysaccharides (including but not limited to hyaluronic acid), starches, cellulose derivatives, gelatin, and polymers. Not done. An exemplary carrier may also include a saline excipient such as hydroxylpropyl methylcellulose (HPMC) in phosphate buffered saline (PBS). According to other embodiments, the pharmaceutically acceptable carrier is a buffer solution. An exemplary buffer may include, but is not limited to, phosphate buffered saline (PBS).

According to some embodiments, the pharmaceutically acceptable carrier imparts stickiness to the composition. According to one embodiment, the pharmaceutically acceptable carrier comprises hyaluronic acid. According to some embodiments, the pharmaceutically acceptable carrier contains 0% -5% hyaluronic acid. According to one embodiment, the pharmaceutically acceptable carrier contains less than 0.05% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.1% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.2% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.3% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.4% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.5% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.6% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.7% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.8% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.9% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.0% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.1% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.2% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.3% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.4% hyaluronic acid. According to other embodiments, pharmaceutically acceptable carriers are: 1. Contains less than 5% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.6% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.7% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.8% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.9% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.0% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.1% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.2% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.3% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.4% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.5% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.6% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.7% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.8% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.9% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 3.0% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 3.5% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 4.0% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 4.5% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier is 5.

In some embodiments, pharmaceutically acceptable carriers include, but are not limited to, gels, sustained release solids or semi-solid compounds, and may optionally be sustained release gels. In some such embodiments, the at least one therapeutic agent is embedded in a pharmaceutically acceptable carrier. In some embodiments, the at least one therapeutic agent is coated on a pharmaceutically acceptable carrier. The coating can be any desired material, preferably a polymer or a mixture of different polymers. If desired, the polymer may be used during the granulation step to form a matrix with the active ingredient to obtain the desired release pattern of the active ingredient. The gel, sustained release solid or semi-solid compound can release the activator over a desired period of time. Gels, sustained release solids or semi-solid compounds can be implanted in tissues within the parenchyma of the human brain, including, but not limited to, blood vessels, eg, in close proximity to the cerebral arteries. According to other embodiments, the pharmaceutically acceptable carrier comprises a sustained release solid compound. According to one such embodiment, the at least one therapeutic agent is embedded in a sustained release solid compound or coated with a sustained release solid compound. According to yet another embodiment, the pharmaceutically acceptable carrier comprises sustained release microparticles containing at least one therapeutic agent. According to other embodiments, the pharmaceutically acceptable carrier is a gel compound, such as a biodegradable hydrogel.

Additional Ingredients According to some embodiments, the flowable sustained release microparticle composition further comprises a preservative. According to some such embodiments, the flowable sustained release microparticle delivery composition is present in unit dosage form. Exemplary unit dosage forms include, but are not limited to, ampoules or multi-dose containers. A fluid sustained-release microparticle composition for parenteral (including, but not limited to, subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intrathecal, intraventricular and intra-articular) administration. Aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, bacteriostats and solutes to make the formulation isotonic with the blood or CSF of the intended recipient; And aqueous and non-aqueous sterile suspensions which may contain anti-precipitation agents and thickeners. According to some embodiments, the flowable sustained release microparticle composition is formulated for parenteral infusion, surgical transplantation, or a combination thereof. According to some such embodiments, the flowable sustained release microparticle composition is a pharmaceutically acceptable aqueous or non-aqueous sterile solution, dispersion, suspension or emulsion or sterile solution for injection. Alternatively, it is in the form of a sterilized powder reconstituted into a dispersion. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, dichloromethane, acetonitrile, ethyl acetate, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, Examples include, but are not limited to, vegetable oils (eg olive oil) and organic esters for injection, such as ethyloleate. Appropriate fluidity can be maintained, for example, by the use of coatings such as lecithin, the maintenance of particle size required in the case of dispersions, and the use of surfactants. The suspension further contains anti-precipitation agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, polyoxyethylene sorbitan ester, microcrystan cellulose, aluminum metahydroxydo, bentonite, agar, tragacanth, and mixtures thereof. May contain.

According to some embodiments, the flowable sustained release microparticle composition is formulated in the form of an injectable depot. The injectable depot form is produced by forming a microencapsulated matrix of therapeutic agent in a biodegradable polymer. The rate of drug release can be controlled by the ratio of drug to polymer and the specific type of polymer used. Such long-acting formulations can be used with suitable polymeric or hydrophobic materials (eg, as emulsions in acceptable oils) or ion exchange resins, or as slightly sparing derivatives, eg, slightly sparingly soluble. Can be formulated as a salt. Examples of biodegradable polymers include, but are not limited to, polylactide-polyglycolide, poly (orthoester) and poly (anhydride). Depot formulations for injection are also prepared by encapsulating the drug in liposomes or microemulsions that are compatible with body tissue. According to some embodiments, the flowable sustained release microparticle composition further comprises an adjuvant. Exemplary adjuvants include, but are not limited to, preservatives, wetting agents, emulsifying agents, and dispersants. Blocking the action of microorganisms can be ensured by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid and the like. Isotonic agents such as sugar, sodium chloride and the like may also be included. Long-term absorption of the injectable pharmaceutical form can be brought about by the use of substances that delay absorption, such as aluminum monostearate or gelatin.

The flowable sustained release microparticle composition is a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile medium for injection, eg, by final gamma irradiation, filtration through a bacterial retention filter, or shortly before use. It can be sterilized by incorporating a sterilizing agent in the form. Injectable formulations, such as sterile aqueous or oily suspensions for injection, can be formulated according to known techniques with suitable dispersants or wetting agents and anti-precipitation agents. Injectable sterile formulations also include injectable sterile solutions, suspensions or emulsions in non-toxic parenterally acceptable diluents or solvents such as 1,3-butanediol, dichloromethane, ethyl acetate, acetonitrile. It can be dissolved in or the like. Water, Ringer's solution, USP and isotonic saline can be used in acceptable excipients and solvents. In addition, sterile fixed oils are typically used as solvents or suspension media. For this purpose, non-irritating fixed oils containing synthetic monoglycerides or diglycerides can be used. In addition, fatty acids such as oleic acid are used in the preparation of injections. Suitable buffers include acetic acid and salt (1-2% w / v); citric acid and salt (1-3% w / v); boric acid and salt (0.5-2.5% w / v); And phosphoric acid and salt (0.8-2% w / v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w / v); chlorobutanol (0.3-0.9% w / v); paraben (0.01-0.25% w / v) and thimerosal (0.004-0.02%). w / v) can be mentioned.

II. Therapeutic method According to another aspect, the present invention is a method of treating at least one cerebral artery in the submucosal space at risk of interference due to brain damage in a human subject, (a) (i). A microparticle formulation comprising a therapeutic amount of at least one therapeutic agent, wherein the microparticle formulation comprises a plurality of microparticles having a uniform particle size distribution, the therapeutic agent is dispersed throughout each microparticle, and A flowable sustained release microparticle composition comprising the above formulation and (ii) a pharmaceutical carrier, wherein the therapeutic amount is an effective amount for treating late complications of cerebral artery obstruction. Preparation stage; And (b) because the composition is administered locally into the ventricles, the therapeutic agent is released after the microparticle formulation has flowed from the cerebrospinal fluid (CSF) in the ventricles to the cerebrospinal fluid (CSF) in the subarachnoid space. A step in which the therapeutic agent is released into the subarachnoid space, including the step of contacting and flowing around at least one cerebral artery in the subarachnoid space without entering the body circulation in an amount that causes unwanted side effects. The method is provided. According to one embodiment, the flowable sustained release microparticle composition, upon delivery to the ventricles, at least one treatment in a therapeutic amount during or at the site of release within the subarachnoid space. The drug can be released slowly. According to one embodiment, the release site is in close proximity to at least one cerebral artery within the subarachnoid space at risk of obstruction.

According to some embodiments, the flowable sustained release microparticle composition has a half-life (t) in the range of 1 to 30 days._1/2) Can be sustained-release within a therapeutic amount of at least one therapeutic agent. According to one embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a daily half-life. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 2 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 3 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 4 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 5 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 6 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 7 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 8 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 9 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 10 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 12 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 14 days. According to another embodiment, the flowable sustained release The microparticle composition is capable of sustained release of at least one therapeutic agent in therapeutic amounts within a half-life of 16 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 18 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 20 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 22 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 24 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 26 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 28 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 30 days. A capable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 26 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 28 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 30 days. A capable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 26 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 28 days. According to another embodiment, the flowable sustained release microparticle composition is capable of sustained release of at least one therapeutic agent in a therapeutic amount within a half-life of 30 days.

According to some embodiments, the flowable sustained release microparticle composition is at least one therapeutic amount prior to the onset of delayed complications associated with cerebral artery obstruction caused by brain injury. The therapeutic drug can be sustained-release. According to some embodiments, late complications consist of angiographic vasospasm, multiple microthrombogenic embolisms, cortical spreading ischemia, late cerebral ischemia (DCI), or a combination thereof. Will be selected. According to one embodiment, the late complication is angiographic vasospasm. According to other embodiments, the late complication is multiple microthrombogenic embolisms. According to another embodiment, the late complication is cortical spreading ischemia. According to another embodiment, the late complication is late cerebral ischemia (DCI). According to some embodiments, the brain injury is the result of the underlying symptoms. Exemplary underlying symptoms include, but are not limited to, aneurysms, sudden traumatic head injuries, subarachnoid hemorrhage (SAH), or a combination thereof. According to one embodiment, the underlying symptom is an aneurysm. According to other embodiments, the underlying symptom is traumatic head injury. According to other embodiments, the underlying symptom is subarachnoid hemorrhage (SAH). According to other embodiments, the underlying symptom is a combination of an aneurysm, sudden traumatic head injury, and subarachnoid hemorrhage (SAH). According to some embodiments, the flowable sustained release microparticle composition interferes when released in close proximity to at least one cerebral artery within the subarachnoid space at risk of interference caused by brain injury. It is effective in reducing vascular spasm so that the inner diameter of at least one cerebral artery in the subarachnoid space is increased compared to the control. According to some embodiments, the flowable sustained release microparticle composition is released into the brain in close proximity to at least one cerebral artery within the subarachnoid space at risk of interference caused by brain injury. It is effective in preventing or reducing the occurrence or severity of late complications associated with arterial obstruction. According to one embodiment, predominantly local pharmacological effects are increased such that the inner diameter of at least one cerebral artery in the subarachnoid space at risk of obstruction is increased compared to an untreated control. It is a reduction of spasm. According to one embodiment, the flowable sustained release of the microparticle composition is such that the inner diameter of at least one cerebral artery in the subarachnoid space at risk of obstruction is increased compared to an untreated control. It is effective in reducing vascular spasm.

According to one embodiment, a therapeutic amount of at least one therapeutic agent in close proximity to at least one cerebral artery in the subarachnoid space can produce predominantly local pharmacological effects. According to some embodiments, predominantly local pharmacological effects are such that the inner diameter of at least one cerebral artery in the submembrane cavity at risk of obstruction is increased compared to an untreated control. At least one cerebral artery is at least 10 mm, at least 9.9 mm, at least 9.8 mm, at least 9.7 mm, at least 9.6 mm, at least 9.5 mm, at least 9.4 mm, at least from the site of release in the submucosal space. 9.3mm, at least 9.2mm, at least 9.1mm, at least 9.0mm, at least 8.9mm, at least 8.8mm, at least 8.7mm, at least 8.6mm, at least 8.5mm, at least 8.4mm, at least 8.3mm, at least 8.2mm, at least 8.1mm , At least 8.0mm, at least 7.9mm, at least 7.8mm, at least 7.7mm, at least 7.6mm, at least 7.5mm, at least 7.4mm, at least 7.3mm, at least 7.2mm, at least 7.1mm, at least 7.0mm, at least 6.9mm, at least 6.8mm, at least 6.7mm, at least 6.6mm, at least 6.5mm, at least 6.4mm, at least 6.3mm, at least 6.2mm, at least 6.1mm, at least 6.0mm, at least 5.9mm, at least 5.8mm, at least 5.7mm, at least 5.6mm , At least 5.5mm, at least 5.4mm, at least 5.3mm, at least 5.2mm, at least 5.1mm, at least 5. It is at 0 mm. According to one embodiment, the predominantly local pharmacological effect is such that the inner diameter of at least one cerebral artery at least 10 mm from the site of release in the subarachnoid space is increased compared to an untreated control. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 9.9 mm from the site of release in the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 9.8 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 9.7 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 9.6 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 9.5 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 9.4 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 9.3 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are at least 9. Relief of vascular spasm such that the inner diameter of at least one cerebral artery at 2 mm is increased compared to an untreated control. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 9.1 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 9.0 mm from the site of release in the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 8.9 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 8.8 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 8.7 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 8.6 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 8.5 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are at least 8. Relief of vascular spasm such that the inner diameter of at least one cerebral artery at 4 mm is increased compared to an untreated control. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 8.3 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 8.2 mm from the site of release in the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 8.1 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 8.0 mm from the site of release in the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 7.9 mm from the site of release in the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 7.8 mm from the site of release in the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 7.7 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are at least 7. from the site of release within the subarachnoid space. Relief of vascular spasm such that the inner diameter of at least one cerebral artery at 6 mm is increased compared to an untreated control. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 7.5 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 7.4 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 7.3 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 7.2 mm from the site of release in the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 7.1 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 7.0 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 6.9 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are at least 6. from the site of release within the subarachnoid space. Relief of vascular spasm such that the inner diameter of at least one cerebral artery at 8 mm is increased compared to an untreated control. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 6.7 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 6.6 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 6.5 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 6.4 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 6.3 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 6.2 mm from the site of release in the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 6.1 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are at least 6. from the site of release within the subarachnoid space. Relief of vascular spasm such that the inner diameter of at least one cerebral artery at 0 mm is increased compared to an untreated control. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 5.9 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 5.8 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 5.7 mm from the site of release in the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 5.6 mm from the site of release in the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 5.5 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 5.4 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 5.3 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are at least 5. from the site of release within the subarachnoid space. Relief of vascular spasm such that the inner diameter of at least one cerebral artery at 2 mm is increased compared to an untreated control. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 5.1 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm. According to other embodiments, predominantly local pharmacological effects are increased compared to untreated controls with an inner diameter of at least one cerebral artery at least 5.0 mm from the site of release within the subarachnoid space. It is a reduction of vascular spasm.

According to one embodiment, sustained release of at least one therapeutic agent in a therapeutic amount close to at least one cerebral artery in the subarachnoid space has a predominantly local pharmacological effect over the desired amount of time. Can occur. According to one embodiment, the release of a therapeutic amount of at least one therapeutic agent in close proximity to at least one cerebral artery within the subarachnoid space results in predominantly local pharmacological effects for one day. According to other embodiments, the release of a therapeutic amount of at least one therapeutic agent in close proximity to at least one cerebral artery within the subarachnoid space results in a predominantly localized pharmacological effect for two days. According to other embodiments, the release of a therapeutic amount of at least one therapeutic agent in close proximity to at least one cerebral artery within the subarachnoid space results in predominantly local pharmacological effects for 3 days. According to other embodiments, the release of a therapeutic amount of at least one therapeutic agent in close proximity to at least one cerebral artery within the subarachnoid space results in predominantly local pharmacological effects for 4 days. According to other embodiments, the release of a therapeutic amount of at least one therapeutic agent in close proximity to at least one cerebral artery within the subarachnoid space results in predominantly local pharmacological effects for 5 days. According to other embodiments, the release of a therapeutic amount of at least one therapeutic agent in close proximity to at least one cerebral artery within the subarachnoid space results in predominantly local pharmacological effects for 6 days. According to other embodiments, the release of a therapeutic amount of at least one therapeutic agent in close proximity to at least one cerebral artery within the subarachnoid space results in predominantly local pharmacological effects for 7 days. According to other embodiments, the release of a therapeutic amount of at least one therapeutic agent in close proximity to at least one cerebral artery within the subarachnoid space results in predominantly local pharmacological effects for 8 days. According to other embodiments, the release of a therapeutic amount of at least one therapeutic agent in close proximity to at least one cerebral artery within the subarachnoid space results in predominantly local pharmacological effects for 15 days. According to other embodiments, the release of a therapeutic amount of at least one therapeutic agent in close proximity to at least one cerebral artery within the subarachnoid space results in predominantly local pharmacological effects for 30 days.

Dosing Stage According to some embodiments, the flowable sustained release microparticle composition is administered by parenteral infusion using a surgical infusion device. According to some embodiments, administration is by catheterization or catheterization. The term "cathetering" means minimally invasive surgery in which a fluid, sustained release microparticle composition can approach desired areas of the brain, which may mean less risk of complications and shorter recovery. According to some embodiments, the catheter is a silicone catheter. According to some embodiments, the catheter is a flexible catheter. According to some embodiments, the catheter is a flexible catheter. According to some embodiments, the catheter is a flexible catheter. More generally, intracerebroventricular delivery of the flowable sustained release microparticle composition of the present invention provides many advantages over systemic administration. As an example, nimodipine has been approved to be administered as a continuous intravenous infusion or as a pill given orally every 2-4 hours. Intraventricular delivery may locally supply a higher concentration of therapeutic agent in cerebrospinal fluid (CSF), where the therapeutic agent dispersed by the microparticles may be effective. As a result, a systemic effect, for example, a local pharmacological effect can be obtained without entering the systemic circulation in an amount that causes hypotension. Furthermore, direct administration to the ventricles overcomes the blood-brain barrier, allowing less therapeutic doses than required for systemic administration. Although not limited by theory, intraventricular administration of a fluid, sustained-release microparticle formulation of a therapeutic amount of a therapeutic agent that allows delivery of a therapeutic amount over several days may prevent DCI. .. According to another embodiment, the flowable sustained release microparticle composition is administered by parenteral infusion locally via a surgical infusion device into the ventricles, so that the composition is carried by the CSF circulation. It comes into contact and flows around the cerebral arteries in the subarachnoid space at risk of obstruction. According to some such embodiments, the surgical infusion device is a needle, cannula, catheter, or a combination thereof. According to some embodiments, the surgical infusion device is inserted into the ventricles. According to some embodiments, the ventricles are selected from the group consisting of the lateral ventricles, the third ventricle, the fourth ventricle, or a combination thereof. According to some embodiments, the ventricles are the lateral ventricles. According to one embodiment, the ventricles are the right ventricles. According to another embodiment, the ventricles are the left ventricles. According to one embodiment, the ventricle is the third ventricle. According to another embodiment, the ventricle is the fourth ventricle.

According to some embodiments, the ventricles are at least 0.001 mm to at least 10 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to one embodiment, the ventricles are at least 0.001 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 0.005 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 0.01 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 0.05 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 0.1 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 0.5 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 1.0 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 1.5 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 2.0 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 2.5 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to other embodiments, the ventricles are at least 3. from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. It is at 0 mm. According to another embodiment, the ventricles are at least 3.5 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 4.0 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 4.5 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 5.0 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 5.5 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 6.0 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 6.5 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 7.0 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 7.5 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 8.0 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 8.5 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 9. from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. It is at 0 mm. According to another embodiment, the ventricles are at least 9.5 mm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 1 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 1.5 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 2.0 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 2.5 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 3.0 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 3.5 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 4.0 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 4.5 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 5.0 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 5.5 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to other embodiments, the ventricles are at least 6. From at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. It is at 0 cm. According to another embodiment, the ventricles are at least 6.5 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 7.0 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 7.5 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 8.0 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 8.5 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 9.0 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 9.5 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 10 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. It is at 5 cm. According to another embodiment, the ventricles are at least 9.0 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 9.5 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 10 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. It is at 5 cm. According to another embodiment, the ventricles are at least 9.0 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 9.5 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury. According to another embodiment, the ventricles are at least 10 cm from at least one cerebral artery in the subarachnoid space at risk of interference caused by brain injury.

The ventricles can be cannulated or catheterized, as is well known in the art and as described in various neurosurgery textbooks. This is called ventricular catheter or drain insertion or ventricular fistula plasty. According to some embodiments, holes of various sizes can be drilled into the skull and the outer dura mater covering the brain can be incised. The buffy coat is incised and a catheter (generally a hollow tube made of silicone elastomer of some other biocompatible non-absorbable compound) is inserted through the cerebrum into the ventricles of choice. This is usually the lateral ventricle, but any ventricle can be catheterized. Catheter can be used to monitor pressure in the head, drain CSF, or administer a substance to CSF. FIG. 14 is an exemplary illustration showing the application of a microparticle composition of the invention containing a calcium channel blocker, endothelin receptor antagonist, or TRP protein antagonist, or a combination thereof, into the ventricles through an intraventricular catheter. (Source of figure Mccomb JG: Techniques of CSF diversion. In: Scott RM (ed). Hydrocephalus. Vol. 3. Williams &amp; Wilkins: Baltimore. 1990. page 48, pp. 128). FIG. 15 shows a microparticle composition of the invention containing a calcium channel blocker, endothelin receptor antagonist, or TRP protein antagonist, or a combination thereof, in or on the microparticles from the ventricles to the subarachnoid space by CSF flow. It is a schematic diagram showing that it is carried to the artery of the cavity (Pollay M: Cerebrospinal fluid. In: Tindall GT, Cooper PR, Barrow DL (eds). The Practice of Neurosurgery. Vol. 1. Williams &amp; Wilkins: Baltimore. 1996 . page 36, pp. 1381).

According to some embodiments, the flowable sustained release microparticle composition comprising at least one therapeutic agent may be delivered to the ventricles and the subarachnoid space by the flow of cerebrospinal fluid (CSF). It is carried to the CSF inside. CSF circulation is often slowed after SAH, and the subarachnoid space contains clots. Thus, the flowable sustained release microparticle composition will be trapped in a clot, which facilitates the local release of the drug (one or more) from the composition and the drug-adjacent arteries and Shows pharmacological effects on the brain. According to one embodiment, the release of the therapeutic agent occurs in the CSF of the subarachnoid space. According to one embodiment, the flowable sustained release microparticle composition comprising at least one therapeutic agent inserts the catheter into the ventricles such that the composition exits the ventricles locally from the ends of the catheter. It can be delivered by injecting a flowable sustained release microparticle composition through a catheter. According to another embodiment, the flowable sustained release microparticle composition is administered as a single bolus injection. According to another embodiment, the injection is repeated after a predetermined time. According to some such embodiments, the predetermined time can range from 1 minute or more to 10 days or more. For example, repeated injections may be given if monitoring the patient shows that the patient still has evidence of cerebral artery obstruction.

Therapeutic Agents According to some embodiments, the at least one therapeutic agent is a calcium channel blocker, an endothelin antagonist, a transient receptor potential (TRP) protein antagonist, or a combination thereof. According to one example, at least one therapeutic agent is a calcium channel blocker. According to some embodiments, the calcium channel blocker is an L-type voltage-gated calcium channel inhibitor, an R-type voltage-gated calcium channel inhibitor, an N-type voltage-gated calcium channel inhibitor, and a P / Q-type potential. It is selected from the group consisting of a dependent calcium channel inhibitor, a T-type voltage-gated calcium channel inhibitor, or a combination thereof. According to one embodiment, the calcium channel blocker is an L-type voltage-gated calcium channel inhibitor. According to one embodiment, the calcium channel blocker is an R-type voltage-gated calcium channel inhibitor. According to one embodiment, the calcium channel blocker is an N-type voltage dependent calcium channel inhibitor. According to one embodiment, the calcium channel blocker is a P / Q voltage-gated calcium channel inhibitor. According to one embodiment, the calcium channel blocker is a T-type voltage-gated calcium channel inhibitor.

For example, L-type voltage-gated calcium channel blockers include dihydropyridine L-type blockers such as nisoldipine, nicardipine or nifedipine, AHF (eg 4aR, 9aS)-(+)-4a-amino-1,2,3,4. , 4a, 9a-hexahydro-4aH-fluorene, HC1), isradipine (eg 4- (4-benzofrazanyl) -1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl 1-methylethyl ester ), Calciseptine (eg, Dendroaspis polylepis) (Separated from polylepis)), H-Arg-Ile-Cys-Tyr-Ile-His-Lys-Ala-Ser-Leu-Pro-Arg-Ala-Thr-Lys-Thr-Cys-Val-Glu-Asn- Thr-Cys-Tyr-Lys-Met-Phe-Ile-Arg-Thr-Gln-Arg-Glu-Tyr-Ile-Ser-Glu-Arg-Gly-Cys-Gly-Cys-Pro-Thr-Ala-Met- Trp-Pro-Tyr-G1n-Thr-Glu-Cys-Cys-Lys-Gly-Asp-Arg-Cys-Asn-Lys-OH, Calcicludine (eg Dendroaspis) (separated from angusticeps) (Eastern Green Mamba)), (H-Trp-Gln-Pro-Pro-Trp-Tyr-Cys-Lys-Glu-Pro-Val-Arg-Ile-Gly-Ser-Cys-Lys- Lys-Gln-Phe-Ser-Ser-Phe-Tyr-Phe-Lys-Trp-Thr-Ala-Lys-Lys-Cys-Leu-Pro-Phe-Leu-Phe-Ser-GlyCys-G1y-Gly-Asn- Ala-Asn-Arg-Phe-Gln-Thr-Ile-Gly-Glu-Cys-Arg-Lys-Lys-Cys-Leu-Gly-Lys-OH, silnidipine (eg A and FRP-8653 also dihydropyridine-type inhibition Agent), Dilantizem (eg (2S, 3S)-(+)-cis-3-acetoxy-5- (2-dimethylaminoethyl) -2,3-dihydro-2- (4-methoxyphenyl)- 1,5-benzothiazepine-4 (5H) -one hydrochloride), zyrrhizem (eg benzothiazepine-4 (5H) -one, 3- (acetyloxy) -5- [2- (dimethylamino) ethyl] -2,3-dihydro-2- (4-methoxyphenyl)-, (+)-cis-, monohydrochloride), ferrodipine (eg 4- (2,3-dichlorophenyl) -1,4-dihydro-2 , 6-Dimethyl-3,5-pyridinecarboxylic acid ethylmethyl ester), FS-2 (eg isolate from Dendroapsis polylepis polylepis poison), FTX-3.3 (eg isolate from Agelenopsis aperta), Neomycin sulfate (eg C₂₃H₄₆N₆O₁₃ 3H₂SO₄), Nicaldipine (eg 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenylmethyl-2-[methyl (phenyl) methylamino] -3,5-pyridinedicarboxylic acid ethyl ester hydrochloride, and also YC-93 also contains nifedipine (eg 1,4-dihydro-2,6-dimethyl-4- (2-nitrophenyl) -3,5-pyridinecarboxylic acid dimethyl ester), nimodipin (eg 4-dihydro-2,6). -Dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 2-methoxyethyl 1-methylethyl ester) or (isopropyl2-methoxyethyl 1,4-dihydro-2,6-dimethyl-4- (m-Nitrophenyl) -3,5-pyridinedialvoxylate), nitrenenedin (eg 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylate ethyl Methyl ester), S-petacin (eg (3S, 4aR, 5R, 6R)-[2,3,4,4a, 5,6,7,8-octahydro-3- (2-propenyl) -4a, 5- Dimethyl-2-oxo-6-naphthyl] Z-3'-methylthio-1'-propenoate), floretin (eg 2', 4', 6'-trihydroxy-3- (4-hydroxyphenyl) propiophenone, Also 3- (4-hydroxyphenyl) -1- (2,4,6-trihydroxyphenyl) -1-propanol and b- (4-hydroxyphenyl) -2,4,6-trihydroxypropiophenone ) Also protopin (eg C)₂₀H₁₉NO₅Cl), SKF-96365 (eg 1- [b- [3- (4-methoxyphenyl) propoxy] -4-methoxyphenethyl] -1H-imidazole, HC1), tetrandin (eg 6,6', 7,12- Tetramethoxy-2,2'-dimethylvelvaman), (. +-.)-Methoxybellapamil or (+)-bellapamil (eg 54N- (3,4-dimethoxyphenylethyl) methylamino] -2- (3, 4-Dimethoxyphenyl) -2-iso-propylvaleronitrile hydrochloride), and (R)-(+)-Bay K8644 (eg R-(+)-1,4-dihydro-2,6-dimethyl-5- Examples include, but are not limited to, nitro-4- (2- (trifluoromethyl) phenyl) -3-pyridinecarboxylic acid methyl ester). The above examples can be specific for L-type open-pot calcium channels or can inhibit a wider range of potential-opening calcium channels, such as N, P / Q, R and T-types.

According to some embodiments, the L-type voltage-gated calcium channel inhibitor is dihydropyridine. Typical dihydropyridines include amlodipine, alanidipine, azelnidipine, vanidipine, benidipine, sinardipin, ehonidipine, felodipine, islazipin, lasidipine, remildipine, relcanidipine, nicaldipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nisoldipine, nimodipine, nisoldipine, nimodipine, nisoldipine. However, it is not limited to these. According to one embodiment, the dihydropyridine is nimodipine. According to one embodiment, nimodipine has a half-life of 7-10 days when formulated as described herein and has adequate lipophilicity. According to some embodiments, the L-type voltage-gated calcium channel inhibitor is a phenylalkylamine. Examples of exemplary phenylalkylamines include, but are not limited to, gallopamil, verapamil and the like. According to some embodiments, the L-type voltage-gated calcium channel inhibitor is 1-4 benzothiazepines. According to one embodiment, 1-4 benzothiazepines are diltiazem. According to one embodiment, the L-type voltage-gated calcium channel inhibitor is bepridil.

According to other embodiments, the at least one therapeutic agent is an endothelin antagonist. Exemplary endothelin antagonists include A-127722, ABT-627, BMS 182874, BQ-123, BQ-153, BQ-162, BQ-485, BQ-518, BQ-610, EMD-122946, FR 139317, IPI-725, L-744453, LU 127043, LU 135252, PABSA, PD 147953, PD 151242, PD 155080, PD 156707, RO 611790, SB-247083, Clazocentan, Atlascentan, Citaxcentan sodium, TA-0201, TBC 11251, TTA-386, WS-7338B, ZD-1611, Aspirin, A-182086, CGS 27830, CP 170687, J-104132, L-751281, L-754142, LU 224332, LU 302872, PD 142893, PD 145065, PD 160672, RO-470203, Bosentan, RO 462005, RO 470203, SB 209670, SB 217242, TAK-044, A-192621, A-308165, BQ-788, BQ-017, IRL 1038, IRL 2500, PD-161721, RES 701-1, RO 468443, etc., but are not limited thereto. According to other embodiments, the at least one therapeutic agent is a transient receptor potential (TRP) protein antagonist. Exemplary transient receptor potential (TRP) protein antagonists include gadolinium chloride, lanthanum chloride, SKF 96365 (1-(β- [3- (4-methoxy-phenyl) propoxy] -4-methoxyphenethyl)-. 1H-imidazole hydrochloride), and LOE 908 ((RS)-(3,4-dihydro-6,7-dimethoxyisoquinolin-1-gamma 1) -2-phenyl-N, N-di- [2- (2) , 3,4-Trimethoxyphenyl) ethyl] acetamide), but not limited to these. According to some embodiments, the at least one therapeutic agent is a separated molecule. According to some embodiments, the at least one therapeutic agent is substantially pure.

Microparticle Formulation According to one embodiment, the flowable sustained release microparticle composition comprises a plurality of microparticles containing at least one therapeutic agent. According to some embodiments, the at least one therapeutic agent is supplied in the form of particulates. According to other embodiments, the at least one therapeutic agent is located on or in the microparticles. According to one embodiment, at least one therapeutic agent is dispersed throughout each microparticle. According to some embodiments, at least one therapeutic agent is impregnated on the surface of each microparticle. According to other embodiments, the at least one therapeutic agent is contained within a fine particle core surrounded by a coating. According to other embodiments, at least one therapeutic agent is adsorbed on each of the microparticles. According to some such embodiments, the microparticles have a uniform particle size distribution. According to some embodiments, a uniform distribution of particle size is achieved by a homogenization process that forms a uniform emulsion containing the particles. According to some such embodiments, each microparticle contains a matrix. According to some embodiments, the matrix comprises at least one therapeutic agent. According to some embodiments, the microparticles may have an arbitrary order release kinetics including zero order release, primary release, secondary release, delayed release, sustained release, immediate release, and combinations thereof. Fine particles include, but are not limited to, erosive, non-erosive, biodegradable, or non-biodegradable substances or combinations thereof, in addition to therapeutic agents (one or more). Any of the substances routinely used in technology can be included.

According to some embodiments, the microparticles are microcapsules containing at least one therapeutic agent in solution or in a semi-solid state. According to some embodiments, the microparticles contain at least one therapeutic agent, in whole or in part. According to some embodiments, the microparticles are nanoparticles that contain at least one therapeutic agent in whole or in part. According to some embodiments, the microparticles can have substantially any shape. According to some embodiments, each microparticle is loaded with at least 40% by weight to at least 80% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 40% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 45% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 50% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 55% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 60% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 63% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 65% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 70% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 75% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 80% by weight of at least one therapeutic agent.

According to some embodiments, the particle size is from about 25 μm to about 100 μm. According to some embodiments, the particle size is from about 30 μm to about 80 μm. According to one embodiment, the particle size is at least about 25 μm. According to other embodiments, the particle size is at least about 30 μm. According to other embodiments, the particle size is at least about 35 μm. According to other embodiments, the particle size is at least about 40 μm. According to other embodiments, the particle size is at least about 45 μm. According to other embodiments, the particle size is at least about 50 μm. According to other embodiments, the particle size is at least about 55 μm. According to other embodiments, the particle size is at least about 60 μm. According to other embodiments, the particle size is at least about 65 μm. According to other embodiments, the particle size is at least about 70 μm. According to other embodiments, the particle size is at least about 75 μm. According to other embodiments, the particle size is at least about 80 μm. According to other embodiments, the particle size is at least about 85 μm. According to other embodiments, the particle size is at least about 90 μm. According to other embodiments, the particle size is at least about 95 μm. According to other embodiments, the particle size is at least about 100 μm. According to other embodiments, at least one therapeutic agent can be supplied in the string. The string may contain at least one therapeutic agent in a core surrounded by a coating, or at least one therapeutic agent may be dispersed throughout the string, or at least one therapeutic agent is absorbed by the string. May be good. Strings can have arbitrary order release kinetics, including zero order release, primary release, secondary release, delayed release, sustained release, immediate release, and combinations thereof. Strings include, but are not limited to, erosive, non-erodible, biodegradable, or non-biodegradable substances or combinations thereof, in addition to therapeutic agents (one or more). Any of the substances routinely used in technology can be included.

According to other embodiments, the at least one therapeutic agent may be supplied in at least one sheet. The sheet may contain at least one therapeutic agent and at least one additional therapeutic agent in a core surrounded by a coating, or at least one therapeutic agent and at least one additional therapeutic agent are dispersed throughout the sheet. Alternatively, at least one therapeutic agent may be absorbed into the sheet. Sheets can have arbitrary order release kinetics, including zero order release, primary release, secondary release, delayed release, sustained release, immediate release, and combinations thereof. Sheets include, but are limited to, erosive, non-erosive, biodegradable, or non-biodegradable substances or combinations thereof, in addition to at least one therapeutic agent and at least one additional therapeutic agent. Any of the substances routinely used in dispensing and pharmaceutical technology that are not used can be included. According to some embodiments, the microparticle formulation comprises a suspension of microparticles. According to one embodiment, the microparticle formulation comprises a suspension of microparticles. According to some embodiments, the microparticle formulation further comprises at least one of an anti-precipitation agent, a stabilizer and a dispersant. According to some such embodiments, the microparticle formulation exists as a suspension. According to some such embodiments, the microparticle formulation exists as a solution. According to some such embodiments, the microparticle formulation exists as an emulsion.

According to some embodiments, the microparticle formulation comprises at least one aqueous solution of a therapeutic agent in a water-soluble form. According to some embodiments, the microparticle formulation comprises an oily suspension of at least one therapeutic agent. An oily suspension of at least one therapeutic agent can be prepared with a suitable lipophilic solvent. Exemplary lipophilic solvents or excipients include, but are not limited to, fatty oils such as sesame oil or synthetic fatty acid esters such as ethyloleate or triglycerides. According to some embodiments, the microparticle formulation comprises an aqueous suspension of at least one therapeutic agent. Aqueous infusion suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxylmethyl cellulose, sorbitol, hyaluronic acid, or dextran. If desired, the suspension may also contain suitable stabilizers or substances that increase the solubility of the compound to allow the preparation of highly concentrated solutions. Alternatively, at least one therapeutic agent may be in powder form to form with a suitable excipient, eg, sterile water free of pyrogens, prior to use. The fine particle mixture is dispersed in an excipient to form a dispersion having fine particles as a dispersion phase and an excipient as a dispersion medium. The microparticle formulation is contained, for example, in a microcapsule encapsulating form, a liposome coated on microscopic gold particles, if appropriate, in a pellet for implantation in a tissue. Or may be included with one or more dried excipients on the object to be rubbed against the tissue. As used herein, the term "microencapsulated" means that very small droplets or particles are surrounded or coated with a continuous film of biocompatible, biodegradable polymer or non-polymeric material, non-pareil, pellets, crystals. , Aggregates, microspheres, or nanoparticles, but refers to the process of obtaining an integral structure. Microparticle formulations delayed the release of granules, beads, powders, tablets, coated tablets, (micro) capsules, suppositories, syrups, emulsions, suspensions, creams, drops or active compounds. In the formulation, excipients and additives and / or adjuvants such as disintegrants, binders, coatings, swelling agents, lubricants or solubilizers are usually in the form of formulations as described above. Used for. The microparticle formulation is suitable for use in a variety of drug delivery systems. For a brief review of drug delivery methods, see Langer (1990) Science 249, 1527-1533, which is incorporated herein by reference.

Microencapsulation process Microencapsulation process and product examples; Emulsion-based microparticle production method; Emulsion-based microparticle and its production method; Solvent extraction with adjustable extraction rate Microcapsulation encapsulation; Microcapsulation encapsulation with solvent and salt Process; Continuous double emulsion process to create fine particles; Drying method to adjust fine particle properties, emission control system from polymer blend; Polymer mixture containing polymers with different non-repetitive units and its production and use method; And the emulsion-based process for preparing microparticles and the workhead assembly used therein are described in US Pat. No. 5,407,609 (referred to as microencapsulation process and its products), US Patent Application Publication No. 10 / 553,003 (Emulsion). (Referred to as a method for producing base fine particles), US Patent Application Publication No. 11 / 799,700 (referred to as emulsion-based fine particles and a method for producing the same), US Patent Application Publication No. 12 / 557,946 (with variable extraction rate). US Patent Application Publication No. 12 / 779,138 (referred to as hyaluronic acid (HA) injectable excipient), US Patent Application Publication No. 12 / 562,455 (referred to as solvent and salt encapsulation). Microencapsulation process), US Patent Application Publication No. 12 / 338,488 (referred to as a method for preparing fine particles with a low residual solvent volume); US Patent Application Publication No. 12 / 692,027 (from a polymer blend). It is called an emission control system); U.S. Patent Application Publication No. 12 / 692,020 (referred to as a polymer mixture containing polymers with different non-repetitive units and its production and use); U.S. Patent Application Publication No. 10 / 565,401 ("Release Control Composition"). US Patent Application Publication No. 12 / 692,029 (referred to as "drying method for adjusting fine particle properties"); US Patent Application Publication No. 12 / 968,708 ("Emulsion-based process for preparing fine particles and It is referred to as the workhead used); and is disclosed and described in US Patent Publication No. 13/074542 (referred to as "compositions and methods that improve retention of the pharmaceutical composition at the site of topical administration"). .. The contents of each of these are incorporated herein by reference in their entirety. According to some embodiments, delivery of at least one therapeutic agent using microparticle technology requires bioreabsorbable polymer particles that enclose at least one therapeutic agent and at least one additional therapeutic agent.

Fine Particle Polymer Matrix According to one embodiment, the fine particles contain a matrix. According to some embodiments, the at least one therapeutic agent is impregnated in or on a naturally occurring biopolymer matrix, synthetic polymer matrix, or a combination thereof. According to one embodiment, the polymer is a sustained release polymer. According to one embodiment, the polymer is a biodegradable polymer. According to one embodiment, the polymer is poly (D, L-lactide-co-glycolide). According to another embodiment, the polymer is a poly (orthoester). According to another embodiment, the polymer is poly (anhydride). According to another embodiment, the polymer is polylactide-polyglycolide. Both non-biodegradable and biodegradable polymeric materials can be used in the production of particles to deliver therapeutic agents. Such polymers can be natural or synthetic polymers. The polymer is selected based on the desired duration of release. Bioadhesive polymers of particular interest include Sawhney et al in Macromolecules (1993) 26, Examples include, but are not limited to, the bioerosive hydrogels described by 581-587. The teachings of this document are incorporated herein by reference. Exemplary bioerodible hydrogels include polyhyaluronic acid, casein, gelatin, glutin, polyan anhydride, polyacrylic acid, arginate, chitosan, poly (methyl methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate). ), Poly (isobutyl methacrylate), poly (hexyl methacrylate), poly (isodecyl methacrylate), poly (lauryl methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate) , And poly (octadecyl acrylate), but are not limited thereto. According to one embodiment, the bioadhesive polymer is hyaluronic acid. In some such embodiments, the bioadhesive polymer contains less than about 2.3% hyaluronic acid.

According to another embodiment, the polymer enhances the water solubility of the microparticle formulation. Examples of suitable polymers are polyethylene glycol, poly- (d-glutamic acid), poly- (1-glutamic acid), poly- (1-glutamic acid), poly- (d-aspartic acid), poly- (1-aspartic acid). Acids), poly- (1-aspartic acid) and copolymers thereof, but not limited to these. Polyglutamic acid having a molecular weight of about 5,000 to about 100,000, a molecular weight of about 20,000 to about 80,000 can be used, and a molecular weight of about 30,000 to about 60,000 can also be used. The polymer is ester-bonded to one or more hydroxyls of the epothilones of the invention using the protocol essentially described by US Pat. No. 5,977,163, which is incorporated herein by reference. Specific binding sites include the hydroxyl of carbon-21 in the case of the 21-hydroxy derivative of the invention. Other binding sites include, but are not limited to, carbon 3 hydroxyl and / or carbon 7 hydroxyl. According to some embodiments, the at least one therapeutic agent is impregnated in or on the polyglycolide (PGA) matrix. PGA is a linear aliphatic polyester developed for use in suturing. Studies have reported PGA copolymers formed with trimethylene carbonate, polylactic acid (PLA), and polycaprolactone. Some of these copolymers can be formulated as microparticles for sustained drug release. According to some embodiments, the at least one therapeutic agent is impregnated in the polyester-polyethylene glycol matrix or on the polyester-polyethylene glycol matrix. Polyester-polyethylene glycol compounds can be synthesized; they are soft and can be used for drug delivery.

According to some embodiments, the at least one therapeutic agent is impregnated in or on a poly (amino) -derived biopolymer matrix. Examples of poly (amino) -derived biopolymers include those containing lactic acid and lysine as aliphatic diamines (see, for example, US Pat. No. 5,399,665), and tyrosine-derived polycarbonates and polyacrylates. Not limited to. Modification of polycarbonate can change the length of the alkyl chain of the ester (ethyl to octyl), and modification of polyarylate can further include changing the length of the alkyl chain of the diacid (eg). , Succinic acid to sebacic acid), which allows for greater substitution of the polymer and greater flexibility of the polymer properties. According to some embodiments, the at least one therapeutic agent is impregnated in or on the polyanhydride matrix. Polyanhydrides are prepared by dehydration of two diacid molecules by melt polymerization (see, eg, US Pat. No. 4,757,128). These polymers decompose by surface erosion (compared to polyester, which decomposes by total erosion). The release of the drug can be controlled by the hydrophilicity of the monomer selected. According to some embodiments, the at least one therapeutic agent is impregnated in or on the photopolymerizable biopolymer matrix. Photopolymerizable biopolymers include, but are not limited to, lactic acid / polyethylene glycol / acrylate copolymers. According to some embodiments, the at least one therapeutic agent is impregnated in or on the hydrogel matrix. The term "hydrogel" means a substance that provides a solid, semi-solid, pseudoplastic or plastic structure containing the aqueous components necessary to form a gelatinous or jelly-like mass. Hydrogels generally include various polymers including hydrophilic polymers, acrylic acid, acrylamide and 2-hydroxyethyl methacrylate (HEMA). According to some embodiments, the at least one therapeutic agent is impregnated in or on a naturally occurring biopolymer matrix. Naturally occurring biopolymers include, but are not limited to, protein polymers, collagen, polysaccharides and photopolymerizable compounds.

According to some embodiments, the at least one therapeutic agent is impregnated in or on the protein polymer matrix. Protein polymers are synthesized from self-assembled protein polymers such as silk fibroin, elastin, collagen, and combinations thereof. According to some embodiments, the at least one therapeutic agent is impregnated in or on a naturally occurring polysaccharide matrix. Naturally occurring polysaccharides include chitin and its derivatives, hyaluronic acid, dextran and cellulosic (generally non-denaturing and non-biodegradable), and sucrose acetate isobutyrate (SAIB). Not limited to. According to some embodiments, the at least one therapeutic agent is impregnated in or on the chitin matrix. Chitin is mainly composed of 2-acetamido-2-deoxy-D-glucose groups and is found in yeast, fungi and marine invertebrates (shrimp, crustaceans), which are the main components of the exoskeleton. Chitin is not water-soluble, and only deacetylated chitin and chitosan are soluble in acidic solutions (eg, acetic acid). Studies have shown that it is water-soluble, very high molecular weight (greater than 2,000,000 daltons), viscoelastic, non-toxic, biocompatible and cross-linked with peroxides, glutaraldehyde, glyoxal and other aldehydes and carbodiamides. A chitin derivative capable of forming a gel has been reported. According to some embodiments, the at least one therapeutic agent is impregnated in or on the hyaluronic acid (HA) matrix. Hyaluronic acid (HA) found in mammalian extracellular matrix, synovial fluid, umbilical cord and comb, which is composed of alternating glucuronide and glucosaminide bonds and is separated and purified, can also be produced by the fermentation process.

Pharmaceutically Acceptable Carriers According to some embodiments, the flowable sustained release microparticle composition comprises (ii) a pharmaceutically acceptable carrier. According to one embodiment, the pharmaceutically acceptable carrier is a solid carrier or an excipient. According to other embodiments, the pharmaceutically acceptable carrier is a gel phase carrier or an excipient. Examples of carriers or excipients include, but are limited to, calcium carbonate, calcium phosphate, various monosaccharides and polysaccharides (including but not limited to hyaluronic acid), starches, cellulose derivatives, gelatin, and polymers. Not done. An exemplary carrier may also include a saline excipient such as hydroxylpropyl methylcellulose (HPMC) in phosphate buffered saline (PBS). According to other embodiments, the pharmaceutically acceptable carrier is a buffer solution. An exemplary buffer may include, but is not limited to, phosphate buffered saline (PBS).

According to some embodiments, the pharmaceutically acceptable carrier imparts stickiness to the composition. According to one embodiment, the pharmaceutically acceptable carrier comprises hyaluronic acid. According to some embodiments, the pharmaceutically acceptable carrier contains 0% -5% hyaluronic acid. According to one embodiment, the pharmaceutically acceptable carrier contains less than 0.05% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.1% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.2% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.3% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.4% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.5% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.6% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.7% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.8% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.9% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.0% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.1% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.2% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.3% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.4% hyaluronic acid. According to other embodiments, pharmaceutically acceptable carriers are: 1. Contains less than 5% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.6% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.7% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.8% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.9% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.0% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.1% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.2% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.3% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.4% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.5% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.6% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.7% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.8% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.9% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 3.0% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 3.5% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 4.0% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 4.5% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier is 5.

In some embodiments, pharmaceutically acceptable carriers include, but are not limited to, gels, sustained release solids or semi-solid compounds, and may optionally be sustained release gels. In some such embodiments, the at least one therapeutic agent is embedded in a pharmaceutically acceptable carrier. In some embodiments, the at least one therapeutic agent is coated on a pharmaceutically acceptable carrier. The coating can be any desired material, preferably a polymer or a mixture of different polymers. If desired, the polymer may be used during the granulation step to form a matrix with the active ingredient to obtain the desired release pattern of the active ingredient. The gel, sustained release solid or semi-solid compound can release the activator over a desired period of time. Gels, sustained release solids or semi-solid compounds can be implanted in tissues within the parenchyma of the human brain, including, but not limited to, blood vessels, eg, in close proximity to the cerebral arteries. According to other embodiments, the pharmaceutically acceptable carrier comprises a sustained release solid compound. According to one such embodiment, the at least one therapeutic agent is embedded in a sustained release solid compound or coated with a sustained release solid compound. According to yet another embodiment, the pharmaceutically acceptable carrier comprises sustained release microparticles containing at least one therapeutic agent. According to other embodiments, the pharmaceutically acceptable carrier is a gel compound, such as a biodegradable hydrogel.

Additional Ingredients According to some embodiments, the flowable sustained release microparticle composition further comprises a preservative. According to some such embodiments, the flowable sustained release microparticle delivery composition is present in unit dosage form. Exemplary unit dosage forms include, but are not limited to, ampoules or multi-dose containers. A fluid sustained-release microparticle composition for parenteral (including, but not limited to, subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intrathecal, intraventricular and intra-articular) administration. Aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, bacteriostats and solutes to make the formulation isotonic with the blood or CSF of the intended recipient; And aqueous and non-aqueous sterile suspensions which may contain anti-precipitation agents and thickeners. According to some embodiments, the flowable sustained release microparticle composition is formulated for parenteral infusion, surgical transplantation, or a combination thereof. According to some such embodiments, the flowable sustained release microparticle composition is a pharmaceutically acceptable aqueous or non-aqueous sterile solution, dispersion, suspension or emulsion or sterile solution for injection. Alternatively, it is in the form of a sterilized powder reconstituted into a dispersion. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, dichloromethane, acetonitrile, ethyl acetate, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, Examples include, but are not limited to, vegetable oils (eg olive oil) and organic esters for injection, such as ethyloleate. Appropriate fluidity can be maintained, for example, by the use of coatings such as lecithin, the maintenance of particle size required in the case of dispersions, and the use of surfactants. The suspension further contains anti-precipitation agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, polyoxyethylene sorbitan ester, microcrystan cellulose, aluminum metahydroxydo, bentonite, agar, tragacant, and mixtures thereof. May contain.

According to some embodiments, the flowable sustained release microparticle composition is formulated in the form of an injectable depot. The injectable depot form is produced by forming a microencapsulated matrix of therapeutic agent in a biodegradable polymer. The rate of drug release can be controlled by the ratio of drug to polymer and the specific type of polymer used. Such long-acting formulations can be used with suitable polymeric or hydrophobic materials (eg, as emulsions in acceptable oils) or ion exchange resins, or as slightly sparing derivatives, eg, slightly sparingly soluble. Can be formulated as a salt. Examples of biodegradable polymers include, but are not limited to, polylactide-polyglycolide, poly (orthoester) and poly (anhydride). Depot formulations for injection are also prepared by encapsulating the drug in liposomes or microemulsions that are compatible with body tissue. According to some embodiments, the flowable sustained release microparticle composition further comprises an adjuvant. Exemplary adjuvants include, but are not limited to, preservatives, wetting agents, emulsifying agents, and dispersants. Blocking the action of microorganisms can be ensured by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid and the like. Isotonic agents such as sugar, sodium chloride and the like may also be included. Long-term absorption of the injectable pharmaceutical form can be brought about by the use of substances that delay absorption, such as aluminum monostearate or gelatin.

The flowable sustained release microparticle composition is a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile medium for injection, eg, by final gamma irradiation, filtration through a bacterial retention filter, or shortly before use. It can be sterilized by incorporating a sterilizing agent in the form. Injectable formulations, such as sterile aqueous or oily suspensions for injection, can be formulated according to known techniques with suitable dispersants or wetting agents and anti-precipitation agents. Injectable sterile formulations also include injectable sterile solutions, suspensions or emulsions in non-toxic parenterally acceptable diluents or solvents such as 1,3-butanediol, dichloromethane, ethyl acetate, acetonitrile. It can be dissolved in or the like. Water, Ringer's solution, USP and isotonic saline can be used in acceptable excipients and solvents. In addition, sterile fixed oils are typically used as solvents or suspension media. For this purpose, non-irritating fixed oils containing synthetic monoglycerides or diglycerides can be used. In addition, fatty acids such as oleic acid are used in the preparation of injections. Suitable buffers include acetic acid and salt (1-2% w / v); citric acid and salt (1-3% w / v); boric acid and salt (0.5-2.5% w / v); And phosphoric acid and salt (0.8-2% w / v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w / v); chlorobutanol (0.3-0.9% w / v); paraben (0.01-0.25% w / v) and thimerosal (0.004-0.02%). w / v) can be mentioned.

III. Methods of Preparing a Flowable Sustained Release Microparticle Composition In another aspect, the invention is a method of preparing a flowable sustained release microparticle composition: (a) a therapeutic amount. A step in preparing a sterile microparticle formulation containing at least one therapeutic agent, in an amount effective in reducing late complications of obstruction of the cerebral arteries in the submucosal space. Yes, the microparticle formulation contains a plurality of microparticles with a uniform particle size distribution, and at least one therapeutic agent is dispersed throughout each microparticle. The step of drawing an object into a first sterile syringe equipped with a first syringe barrel, a first syringe plunger and a female luer cap, and removing air trapped in the first syringe; (c) Steps of preparing a pharmaceutically acceptable sterile carrier; (d) Step (c) The step (c) of the sterile pharmaceutical carrier fitted with a second syringe barrel and a male luer cap with a second syringe plunger. Step of pulling into a sterile syringe; (e) Replacing the male lure cap in step (c) with a sterile female syringe connector; (f) Step (b) First sterilization containing the sterile microparticle formulation Connecting the syringe to a second sterile syringe containing a pharmaceutically acceptable sterile carrier in step (c) via the female syringe connector in step (d); (g) Attaching the first sterile syringe plunger. Press and therefore the step of mixing the sterile microparticle formulation and the sterile pharmaceutical carrier in the second sterile syringe barrel; (h) Press the second sterile syringe plunger so that the sterile microparticle formulation and the sterile pharmaceutical carrier are the first Mixing in a sterile syringe barrel; and (i) Steps (g) and (i) are repeated at least 5-50 times to create a flowable sustained release sterile microparticle composition suitable for delivery to the ventricles. It includes the process of obtaining a product.

According to one embodiment, the method of preparing a flowable sustained release microparticle composition is: (A) a sterile microparticle formulation comprising at least one therapeutic agent and multiple microparticles with a uniform particle size distribution. In the preparatory step, the therapeutic agent is dispersed throughout each microparticle and the microparticle formulation is pre-packaged in a first syringe with a first syringe barrel, a first syringe plunger and a female luer cap. The step; (B) the step of removing the air trapped in the first syringe; (C) the step of preparing a pharmaceutically acceptable sterilization carrier, which is pharmaceutically acceptable sterilization. The carrier is pre-packaged in a second syringe with a second syringe barrel, a second syringe plunger, and a male lure cap; the second syringe male lure in step (D) (C). Step of replacing the cap with a female syringe connector; (E) The first syringe containing the sterile microparticle formulation of step (B) through the female syringe connector of step (D) and the pharmaceutical of step (C) The step of connecting with a second sterile syringe containing a sterile carrier that is acceptable; (F) Pressing the first sterile syringe plunger, thus mixing the sterile microparticle formulation with a pharmaceutically acceptable sterile carrier in the second sterile syringe barrel; (G) Second sterile syringe plunger. Press and thus mix the sterile microparticle formulation with the pharmaceutically acceptable sterile carrier in the first sterile syringe barrel; and (H) Steps (F) and (G) are repeated at least 5-50 times. It comprises the step of obtaining a flowable sustained release sterile microparticle composition for which the dosage form is ready.

According to one embodiment, the sterile microparticle formulation can be stored frozen, for example at -20 ° C or -80 ° C. According to another embodiment, the sterile microparticle formulation can be stored refrigerated, eg at 4 ° C. According to other embodiments, the sterile microparticle formulation can be stored at room temperature. According to one embodiment, the pharmaceutically acceptable sterile carrier can be stored frozen, eg, at -20 ° C or -80 ° C. According to other embodiments, the pharmaceutically acceptable sterile carrier can be stored refrigerated, eg at 4 ° C. According to other embodiments, the pharmaceutically acceptable sterile carrier can be stored at room temperature. According to one embodiment, the method of preparing a flowable sustained release microparticle composition is such that (i) step (g) and step (h) are repeated at least 5 times so that the dosage form is ready to flow. Includes a step of obtaining a sustained-release fine particle composition. According to another embodiment, the method for preparing a flowable sustained release microparticle composition is such that (i) step (g) and step (h) are repeated at least 10 times to prepare the flow of the dosage form. Including the step of obtaining a possible sustained release fine particle composition. According to another embodiment, the method for preparing a flowable sustained release microparticle composition is such that (i) step (g) and step (h) are repeated at least 15 times to prepare the flow of the dosage form. Including the step of obtaining a possible sustained release fine particle composition. According to another embodiment, the method for preparing a flowable sustained release microparticle composition is such that (i) step (g) and step (h) are repeated at least 20 times to prepare the flow of the dosage form. Including the step of obtaining a possible sustained release fine particle composition. According to another embodiment, the method for preparing a flowable sustained release microparticle composition is such that (i) step (g) and step (h) are repeated at least 25 times to prepare the flow of the dosage form. Including the step of obtaining a possible sustained release fine particle composition. According to another embodiment, the method for preparing a flowable sustained release microparticle composition is such that (i) step (g) and step (h) are repeated at least 30 times to prepare the flow of the dosage form. Including the step of obtaining a possible sustained release fine particle composition. According to another embodiment, the method of preparing a flowable sustained release microparticle composition is such that (i) step (g) and step (h) are repeated at least 35 times to prepare the flow of the dosage form. Including the step of obtaining a possible sustained release fine particle composition. According to another embodiment, the method for preparing a flowable sustained release microparticle composition is such that (i) step (g) and step (h) are repeated at least 40 times to prepare the flow of the dosage form. Including the step of obtaining a possible sustained release fine particle composition. According to another embodiment, the method for preparing a flowable sustained release fine particle composition involves repeating (i) step (g) and step (h) at least 45 times. In turn, it comprises the step of obtaining a flowable sustained release microparticle composition for which the dosage form is ready. According to another embodiment, the method for preparing a flowable sustained release microparticle composition is such that (i) step (g) and step (h) are repeated at least 50 times to prepare the flow of the dosage form. Including the step of obtaining a possible sustained release fine particle composition.

According to one embodiment, the method for preparing a flowable sustained release microparticle composition is to repeat steps (H) (F) and (G) at least 5 times so that the dosage form is ready to flow. Includes a step of obtaining a sustained-release fine particle composition. According to another embodiment, the method for preparing a flowable sustained release microparticle composition is to repeat steps (H) (F) and (G) at least 10 times to prepare a flow of dosage form. Including the step of obtaining a possible sustained release fine particle composition. According to another embodiment, the method for preparing a flowable sustained release microparticle composition is to repeat steps (H) (F) and (G) at least 15 times to prepare a flow of dosage form. Including the step of obtaining a possible sustained release fine particle composition. According to another embodiment, the method for preparing a flowable sustained release microparticle composition is to repeat steps (H) (F) and (G) at least 20 times to prepare a flow of dosage form. Including the step of obtaining a possible sustained release fine particle composition. According to another embodiment, the method for preparing a flowable sustained release microparticle composition is to repeat steps (H) (F) and (G) at least 25 times to prepare a flow of dosage form. Including the step of obtaining a possible sustained release fine particle composition. According to another embodiment, the method for preparing a flowable sustained release microparticle composition is to repeat steps (H) (F) and (G) at least 30 times to prepare a flow of dosage form. Including the step of obtaining a possible sustained release fine particle composition. According to another embodiment, the method for preparing a flowable sustained release microparticle composition is to repeat steps (H) (F) and (G) at least 35 times to prepare a flow of dosage form. Including the step of obtaining a possible sustained release fine particle composition. According to another embodiment, the method for preparing a flowable sustained release microparticle composition is to repeat steps (H) (F) and (G) at least 40 times to prepare a flow of dosage form. Including the step of obtaining a possible sustained release fine particle composition. According to another embodiment, the method for preparing a flowable sustained release fine particle composition involves repeating steps (H) (F) and (G) at least 45 times. In turn, it comprises the step of obtaining a flowable sustained release microparticle composition for which the dosage form is ready. According to another embodiment, the method for preparing a flowable sustained release microparticle composition is to repeat steps (H) (F) and (G) at least 50 times to prepare a flow of dosage form. Including the step of obtaining a possible sustained release fine particle composition.

Therapeutic Agents According to some embodiments, the at least one therapeutic agent is a calcium channel blocker, an endothelin antagonist, a transient receptor potential (TRP) protein antagonist, or a combination thereof. According to one example, at least one therapeutic agent is a calcium channel blocker. According to some embodiments, the calcium channel blocker is an L-type voltage-gated calcium channel inhibitor, an R-type voltage-gated calcium channel inhibitor, an N-type voltage-gated calcium channel inhibitor, and a P / Q-type potential. It is selected from the group consisting of a dependent calcium channel inhibitor, a T-type voltage-gated calcium channel inhibitor, or a combination thereof. According to one embodiment, the calcium channel blocker is an L-type voltage-gated calcium channel inhibitor. According to one embodiment, the calcium channel blocker is an R-type voltage-gated calcium channel inhibitor. According to one embodiment, the calcium channel blocker is an N-type voltage dependent calcium channel inhibitor. According to one embodiment, the calcium channel blocker is a P / Q voltage-gated calcium channel inhibitor. According to one embodiment, the calcium channel blocker is a T-type voltage-gated calcium channel inhibitor.

For example, L-type voltage-gated calcium channel blockers include dihydropyridine L-type blockers such as nisoldipine, nicardipine or nifedipine, AHF (eg 4aR, 9aS)-(+)-4a-amino-1,2,3,4. , 4a, 9a-hexahydro-4aH-fluorene, HC1), isradipine (eg 4- (4-benzofrazanyl) -1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl 1-methylethyl ester ), Calciseptine (eg, Dendroaspis polylepis) (Separated from polylepis)), H-Arg-Ile-Cys-Tyr-Ile-His-Lys-Ala-Ser-Leu-Pro-Arg-Ala-Thr-Lys-Thr-Cys-Val-Glu-Asn- Thr-Cys-Tyr-Lys-Met-Phe-Ile-Arg-Thr-Gln-Arg-Glu-Tyr-Ile-Ser-Glu-Arg-Gly-Cys-Gly-Cys-Pro-Thr-Ala-Met- Trp-Pro-Tyr-G1n-Thr-Glu-Cys-Cys-Lys-Gly-Asp-Arg-Cys-Asn-Lys-OH, Calcicludine (eg Dendroaspis) (separated from angusticeps) (Eastern Green Mamba)), (H-Trp-Gln-Pro-Pro-Trp-Tyr-Cys-Lys-Glu-Pro-Val-Arg-Ile-Gly-Ser-Cys-Lys- Lys-Gln-Phe-Ser-Ser-Phe-Tyr-Phe-Lys-Trp-Thr-Ala-Lys-Lys-Cys-Leu-Pro-Phe-Leu-Phe-Ser-GlyCys-G1y-Gly-Asn- Ala-Asn-Arg-Phe-Gln-Thr-Ile-Gly-Glu-Cys-Arg-Lys-Lys-Cys-Leu-Gly-Lys-OH, silnidipine (eg A and FRP-8653 also dihydropyridine-type inhibition Agent), Dilantizem (eg (2S, 3S)-(+)-cis-3-acetoxy-5- (2-dimethylaminoethyl) -2,3-dihydro-2- (4-methoxyphenyl)- 1,5-benzothiazepine-4 (5H) -one hydrochloride), zyrrhizem (eg benzothiazepine-4 (5H) -one, 3- (acetyloxy) -5- [2- (dimethylamino) ethyl] -2,3-dihydro-2- (4-methoxyphenyl)-, (+)-cis-, monohydrochloride), ferrodipine (eg 4- (2,3-dichlorophenyl) -1,4-dihydro-2 , 6-Dimethyl-3,5-pyridinecarboxylic acid ethylmethyl ester), FS-2 (eg isolate from Dendroapsis polylepis polylepis poison), FTX-3.3 (eg isolate from Agelenopsis aperta), Neomycin sulfate (eg C₂₃H₄₆N₆O₁₃ 3H₂SO₄), Nicaldipine (eg 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenylmethyl-2-[methyl (phenyl) methylamino] -3,5-pyridinedicarboxylic acid ethyl ester hydrochloride, and also YC-93 also contains nifedipine (eg 1,4-dihydro-2,6-dimethyl-4- (2-nitrophenyl) -3,5-pyridinecarboxylic acid dimethyl ester), nimodipin (eg 4-dihydro-2,6). -Dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 2-methoxyethyl 1-methylethyl ester) or (isopropyl2-methoxyethyl 1,4-dihydro-2,6-dimethyl-4- (m-Nitrophenyl) -3,5-pyridinedialvoxylate), nitrenenedin (eg 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylate ethyl Methyl ester), S-petacin (eg (3S, 4aR, 5R, 6R)-[2,3,4,4a, 5,6,7,8-octahydro-3- (2-propenyl) -4a, 5- Dimethyl-2-oxo-6-naphthyl] Z-3'-methylthio-1'-propenoate), floretin (eg 2', 4', 6'-trihydroxy-3- (4-hydroxyphenyl) propiophenone, Also 3- (4-hydroxyphenyl) -1- (2,4,6-trihydroxyphenyl) -1-propanol and b- (4-hydroxyphenyl) -2,4,6-trihydroxypropiophenone ) Also protopin (eg C)₂₀H₁₉NO₅Cl), SKF-96365 (eg 1- [b- [3- (4-methoxyphenyl) propoxy] -4-methoxyphenethyl] -1H-imidazole, HC1), tetrandin (eg 6,6', 7,12- Tetramethoxy-2,2'-dimethylvelvaman), (. +-.)-Methoxybellapamil or (+)-bellapamil (eg 54N- (3,4-dimethoxyphenylethyl) methylamino] -2- (3, 4-Dimethoxyphenyl) -2-iso-propylvaleronitrile hydrochloride), and (R)-(+)-Bay K8644 (eg R-(+)-1,4-dihydro-2,6-dimethyl-5- Examples include, but are not limited to, nitro-4- (2- (trifluoromethyl) phenyl) -3-pyridinecarboxylic acid methyl ester). The above examples can be specific for L-type open-pot calcium channels or can inhibit a wider range of potential-opening calcium channels, such as N, P / Q, R and T-types.

According to some embodiments, the L-type voltage-gated calcium channel inhibitor is dihydropyridine. Typical dihydropyridines include amlodipine, alanidipine, azelnidipine, vanidipine, benidipine, sinardipin, ehonidipine, felodipine, islazipin, lasidipine, remildipine, relcanidipine, nicaldipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nisoldipine, nimodipine, nisoldipine, nimodipine, nisoldipine. However, it is not limited to these. According to one embodiment, the dihydropyridine is nimodipine. According to one embodiment, nimodipine has a half-life of 7-10 days when formulated as described herein and has adequate lipophilicity. According to some embodiments, the L-type voltage-gated calcium channel inhibitor is a phenylalkylamine. Examples of exemplary phenylalkylamines include, but are not limited to, gallopamil, verapamil and the like. According to some embodiments, the L-type voltage-gated calcium channel inhibitor is 1-4 benzothiazepines. According to one embodiment, 1-4 benzothiazepines are diltiazem. According to one embodiment, the L-type voltage-gated calcium channel inhibitor is bepridil.

According to other embodiments, the at least one therapeutic agent is an endothelin antagonist. Exemplary endothelin antagonists include A-127722, ABT-627, BMS 182874, BQ-123, BQ-153, BQ-162, BQ-485, BQ-518, BQ-610, EMD-122946, FR 139317, IPI-725, L-744453, LU 127043, LU 135252, PABSA, PD 147953, PD 151242, PD 155080, PD 156707, RO 611790, SB-247083, Clazocentan, Atlascentan, Citaxcentan sodium, TA-0201, TBC 11251, TTA-386, WS-7338B, ZD-1611, Aspirin, A-182086, CGS 27830, CP 170687, J-104132, L-751281, L-754142, LU 224332, LU 302872, PD 142893, PD 145065, PD 160672, RO-470203, Bosentan, RO 462005, RO 470203, SB 209670, SB 217242, TAK-044, A-192621, A-308165, BQ-788, BQ-017, IRL 1038, IRL 2500, PD-161721, RES 701-1, RO 468443, etc., but are not limited thereto. According to other embodiments, the at least one therapeutic agent is a transient receptor potential (TRP) protein antagonist. Exemplary transient receptor potential (TRP) protein antagonists include gadolinium chloride, lanthanum chloride, SKF 96365 (1-(β- [3- (4-methoxy-phenyl) propoxy] -4-methoxyphenethyl)-. 1H-imidazole hydrochloride), and LOE 908 ((RS)-(3,4-dihydro-6,7-dimethoxyisoquinolin-1-gamma 1) -2-phenyl-N, N-di- [2- (2) , 3,4-Trimethoxyphenyl) ethyl] acetamide), but not limited to these. According to some embodiments, the at least one therapeutic agent is a separated molecule. According to some embodiments, the at least one therapeutic agent is substantially pure.

Microparticle Formulation According to one embodiment, the flowable sustained release microparticle composition comprises a plurality of microparticles containing at least one therapeutic agent. According to some embodiments, the at least one therapeutic agent is supplied in the form of particulates. According to other embodiments, the at least one therapeutic agent is located on or in the microparticles. According to one embodiment, at least one therapeutic agent is dispersed throughout each microparticle. According to some embodiments, at least one therapeutic agent is impregnated on the surface of each microparticle. According to other embodiments, the at least one therapeutic agent is contained within a fine particle core surrounded by a coating. According to other embodiments, at least one therapeutic agent is adsorbed on each of the microparticles. According to some such embodiments, the microparticles have a uniform particle size distribution. According to some embodiments, a uniform distribution of particle size is achieved by a homogenization process that forms a uniform emulsion containing the particles. According to some such embodiments, each microparticle contains a matrix. According to some embodiments, the matrix comprises at least one therapeutic agent. According to some embodiments, the microparticles may have an arbitrary order release kinetics including zero order release, primary release, secondary release, delayed release, sustained release, immediate release, and combinations thereof. Fine particles include, but are not limited to, erosive, non-erosive, biodegradable, or non-biodegradable substances or combinations thereof, in addition to therapeutic agents (one or more). Any of the substances routinely used in technology can be included.

According to some embodiments, the microparticles are microcapsules containing at least one therapeutic agent in solution or in a semi-solid state. According to some embodiments, the microparticles contain at least one therapeutic agent, in whole or in part. According to some embodiments, the microparticles are nanoparticles that contain at least one therapeutic agent in whole or in part. According to some embodiments, the microparticles can have substantially any shape. According to some embodiments, each microparticle is loaded with at least 40% by weight to at least 80% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 40% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 45% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 50% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 55% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 60% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 63% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 65% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 70% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 75% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 80% by weight of at least one therapeutic agent.

According to some embodiments, the particle size is from about 25 μm to about 100 μm. According to some embodiments, the particle size is from about 30 μm to about 80 μm. According to one embodiment, the particle size is at least about 25 μm. According to other embodiments, the particle size is at least about 30 μm. According to other embodiments, the particle size is at least about 35 μm. According to other embodiments, the particle size is at least about 40 μm. According to other embodiments, the particle size is at least about 45 μm. According to other embodiments, the particle size is at least about 50 μm. According to other embodiments, the particle size is at least about 55 μm. According to other embodiments, the particle size is at least about 60 μm. According to other embodiments, the particle size is at least about 65 μm. According to other embodiments, the particle size is at least about 70 μm. According to other embodiments, the particle size is at least about 75 μm. According to other embodiments, the particle size is at least about 80 μm. According to other embodiments, the particle size is at least about 85 μm. According to other embodiments, the particle size is at least about 90 μm. According to other embodiments, the particle size is at least about 95 μm. According to other embodiments, the particle size is at least about 100 μm. According to other embodiments, at least one therapeutic agent can be supplied in the string. The string may contain at least one therapeutic agent in a core surrounded by a coating, or at least one therapeutic agent may be dispersed throughout the string, or at least one therapeutic agent is absorbed by the string. May be good. Strings can have arbitrary order release kinetics, including zero order release, primary release, secondary release, delayed release, sustained release, immediate release, and combinations thereof. Strings include, but are not limited to, erosive, non-erodible, biodegradable, or non-biodegradable substances or combinations thereof, in addition to therapeutic agents (one or more). Any of the substances routinely used in technology can be included.

According to other embodiments, the at least one therapeutic agent may be supplied in at least one sheet. The sheet may contain at least one therapeutic agent and at least one additional therapeutic agent in a core surrounded by a coating, or at least one therapeutic agent and at least one additional therapeutic agent are dispersed throughout the sheet. Alternatively, at least one therapeutic agent may be absorbed into the sheet. Sheets can have arbitrary order release kinetics, including zero order release, primary release, secondary release, delayed release, sustained release, immediate release, and combinations thereof. Sheets include, but are limited to, erosive, non-erosive, biodegradable, or non-biodegradable substances or combinations thereof, in addition to at least one therapeutic agent and at least one additional therapeutic agent. Any of the substances routinely used in dispensing and pharmaceutical technology that are not used can be included. According to some embodiments, the microparticle formulation comprises a suspension of microparticles. According to one embodiment, the microparticle formulation comprises a suspension of microparticles. According to some embodiments, the microparticle formulation further comprises at least one of an anti-precipitation agent, a stabilizer and a dispersant. According to some such embodiments, the microparticle formulation exists as a suspension. According to some such embodiments, the microparticle formulation exists as a solution. According to some such embodiments, the microparticle formulation exists as an emulsion.

According to some embodiments, the microparticle formulation comprises at least one aqueous solution of a therapeutic agent in a water-soluble form. According to some embodiments, the microparticle formulation comprises an oily suspension of at least one therapeutic agent. An oily suspension of at least one therapeutic agent can be prepared with a suitable lipophilic solvent. Exemplary lipophilic solvents or excipients include, but are not limited to, fatty oils such as sesame oil or synthetic fatty acid esters such as ethyloleate or triglycerides. According to some embodiments, the microparticle formulation comprises an aqueous suspension of at least one therapeutic agent. Aqueous infusion suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxylmethyl cellulose, sorbitol, hyaluronic acid, or dextran. If desired, the suspension may also contain suitable stabilizers or substances that increase the solubility of the compound to allow the preparation of highly concentrated solutions. Alternatively, at least one therapeutic agent may be in powder form to form with a suitable excipient, eg, sterile water free of pyrogens, prior to use. The fine particle mixture is dispersed in an excipient to form a dispersion having fine particles as a dispersion phase and an excipient as a dispersion medium. The microparticle formulation is contained, for example, in a microcapsule encapsulating form, a liposome coated on microscopic gold particles, if appropriate, in a pellet for implantation in a tissue. Or may be included with one or more dried excipients on the object to be rubbed against the tissue. As used herein, the term "microencapsulated" means that very small droplets or particles are surrounded or coated with a continuous film of biocompatible, biodegradable polymer or non-polymeric material, non-pareil, pellets, crystals. , Aggregates, microspheres, or nanoparticles, but refers to the process of obtaining an integral structure. Microparticle formulations delayed the release of granules, beads, powders, tablets, coated tablets, (micro) capsules, suppositories, syrups, emulsions, suspensions, creams, drops or active compounds. In the formulation, excipients and additives and / or adjuvants such as disintegrants, binders, coatings, swelling agents, lubricants or solubilizers are usually in the form of formulations as described above. Used for. The microparticle formulation is suitable for use in a variety of drug delivery systems. For a brief review of drug delivery methods, see Langer (1990) Science 249, 1527-1533, which is incorporated herein by reference.

Microencapsulation process Microencapsulation process and product examples; Emulsion-based microparticle production method; Emulsion-based microparticle and its production method; Solvent extraction with adjustable extraction rate Microcapsulation encapsulation; Microcapsulation encapsulation with solvent and salt Process; Continuous double emulsion process to create fine particles; Drying method to adjust fine particle properties, emission control system from polymer blend; Polymer mixture containing polymers with different non-repetitive units and its production and use method; And the emulsion-based process for preparing microparticles and the workhead assembly used therein are described in US Pat. No. 5,407,609 (referred to as microencapsulation process and its products), US Patent Application Publication No. 10 / 553,003 (Emulsion). (Referred to as a method for producing base fine particles), US Patent Application Publication No. 11 / 799,700 (referred to as emulsion-based fine particles and a method for producing the same), US Patent Application Publication No. 12 / 557,946 (with variable extraction rate). US Patent Application Publication No. 12 / 779,138 (referred to as hyaluronic acid (HA) injectable excipient), US Patent Application Publication No. 12 / 562,455 (referred to as solvent and salt encapsulation). Microencapsulation process), US Patent Application Publication No. 12 / 338,488 (referred to as a method for preparing fine particles with a low residual solvent volume); US Patent Application Publication No. 12 / 692,027 (from a polymer blend). It is called an emission control system); U.S. Patent Application Publication No. 12 / 692,020 (referred to as a polymer mixture containing polymers with different non-repetitive units and its production and use); U.S. Patent Application Publication No. 10 / 565,401 ("Release Control Composition"). US Patent Application Publication No. 12 / 692,029 (referred to as "drying method for adjusting fine particle properties"); US Patent Application Publication No. 12 / 968,708 ("Emulsion-based process for preparing fine particles and It is referred to as the workhead used); and is disclosed and described in US Patent Publication No. 13/074542 (referred to as "compositions and methods that improve retention of the pharmaceutical composition at the site of topical administration"). .. The contents of each of these are incorporated herein by reference in their entirety. According to some embodiments, delivery of at least one therapeutic agent using microparticle technology requires bioreabsorbable polymer particles that enclose at least one therapeutic agent and at least one additional therapeutic agent.

Fine Particle Polymer Matrix According to one embodiment, the fine particles contain a matrix. According to some embodiments, the at least one therapeutic agent is impregnated in or on top of a naturally occurring biopolymer matrix, synthetic polymer matrix, or a combination thereof. According to one embodiment, the polymer is a sustained release polymer. According to one embodiment, the polymer is a biodegradable polymer. According to one embodiment, the polymer is poly (D, L-lactide-co-glycolide). According to another embodiment, the polymer is a poly (orthoester). According to another embodiment, the polymer is poly (anhydride). According to another embodiment, the polymer is polylactide-polyglycolide. Both non-biodegradable and biodegradable polymeric materials can be used in the production of particles to deliver therapeutic agents. Such polymers can be natural or synthetic polymers. The polymer is selected based on the desired duration of release. Bioadhesive polymers of particular interest include Sawhney et al in Macromolecules (1993) 26, Examples include, but are not limited to, the bioerosive hydrogels described by 581-587. The teachings of this document are incorporated herein by reference. Exemplary bioerodible hydrogels include polyhyaluronic acid, casein, gelatin, glutin, polyan anhydride, polyacrylic acid, arginate, chitosan, poly (methyl methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate). ), Poly (isobutyl methacrylate), poly (hexyl methacrylate), poly (isodecyl methacrylate), poly (lauryl methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate) , And poly (octadecyl acrylate), but are not limited thereto. According to one embodiment, the bioadhesive polymer is hyaluronic acid. In some such embodiments, the bioadhesive polymer contains less than about 2.3% hyaluronic acid.

According to another embodiment, the polymer enhances the water solubility of the microparticle formulation. Examples of suitable polymers are polyethylene glycol, poly- (d-glutamic acid), poly- (1-glutamic acid), poly- (1-glutamic acid), poly- (d-aspartic acid), poly- (1-aspartic acid). Acids), poly- (1-aspartic acid) and copolymers thereof, but not limited to these. Polyglutamic acid having a molecular weight of about 5,000 to about 100,000, a molecular weight of about 20,000 to about 80,000 can be used, and a molecular weight of about 30,000 to about 60,000 can also be used. The polymer is ester-bonded to one or more hydroxyls of the epothilones of the invention using the protocol essentially described by US Pat. No. 5,977,163, which is incorporated herein by reference. Specific binding sites include the hydroxyl of carbon-21 in the case of the 21-hydroxy derivative of the invention. Other binding sites include, but are not limited to, carbon 3 hydroxyl and / or carbon 7 hydroxyl. According to some embodiments, the at least one therapeutic agent is impregnated in or on the polyglycolide (PGA) matrix. PGA is a linear aliphatic polyester developed for use in suturing. Studies have reported PGA copolymers formed with trimethylene carbonate, polylactic acid (PLA), and polycaprolactone. Some of these copolymers can be formulated as microparticles for sustained drug release. According to some embodiments, the at least one therapeutic agent is impregnated in the polyester-polyethylene glycol matrix or on the polyester-polyethylene glycol matrix. Polyester-polyethylene glycol compounds can be synthesized; These are soft and can be used for drug delivery. According to some embodiments, the at least one therapeutic agent is impregnated in or on a poly (amino) -derived biopolymer matrix. Examples of poly (amino) -derived biopolymers include those containing lactic acid and lysine as aliphatic diamines (see, for example, US Pat. No. 5,399,665), and tyrosine-derived polycarbonates and polyacrylates. Not limited to. Modification of polycarbonate can change the length of the alkyl chain of the ester (ethyl to octyl), and modification of polyarylate can further include changing the length of the alkyl chain of the diacid (eg). , Succinic acid to sebacic acid), which allows for greater substitution of the polymer and greater flexibility of the polymer properties.

According to some embodiments, the at least one therapeutic agent is impregnated in or on the polyanhydride matrix. Polyanhydrides are prepared by dehydration of two diacid molecules by melt polymerization (see, eg, US Pat. No. 4,757,128). These polymers decompose by surface erosion (compared to polyester, which decomposes by total erosion). The release of the drug can be controlled by the hydrophilicity of the monomer selected. According to some embodiments, the at least one therapeutic agent is impregnated in or on the photopolymerizable biopolymer matrix. Photopolymerizable biopolymers include, but are not limited to, lactic acid / polyethylene glycol / acrylate copolymers. According to some embodiments, the at least one therapeutic agent is impregnated in or on the hydrogel matrix. The term "hydrogel" means a substance that provides a solid, semi-solid, pseudoplastic or plastic structure containing the aqueous components necessary to form a gelatinous or jelly-like mass. Hydrogels generally include various polymers including hydrophilic polymers, acrylic acid, acrylamide and 2-hydroxyethyl methacrylate (HEMA). According to some embodiments, the at least one therapeutic agent is impregnated in or on a naturally occurring biopolymer matrix. Naturally occurring biopolymers include, but are not limited to, protein polymers, collagen, polysaccharides and photopolymerizable compounds.

According to some embodiments, the at least one therapeutic agent is impregnated in or on the protein polymer matrix. Protein polymers are synthesized from self-assembled protein polymers such as silk fibroin, elastin, collagen, and combinations thereof. According to some embodiments, the at least one therapeutic agent is impregnated in or on a naturally occurring polysaccharide matrix. Naturally occurring polysaccharides include chitin and its derivatives, hyaluronic acid, dextran and cellulosic (generally non-denaturing and non-biodegradable), and sucrose acetate isobutyrate (SAIB). Not limited to. According to some embodiments, the at least one therapeutic agent is impregnated in or on the chitin matrix. Chitin is mainly composed of 2-acetamido-2-deoxy-D-glucose groups and is found in yeast, fungi and marine invertebrates (shrimp, crustaceans), which are the main components of the exoskeleton. Chitin is not water-soluble, and only deacetylated chitin and chitosan are soluble in acidic solutions (eg, acetic acid). Studies have shown that it is water-soluble, very high molecular weight (greater than 2,000,000 daltons), viscoelastic, non-toxic, biocompatible and cross-linked with peroxides, glutaraldehyde, glyoxal and other aldehydes and carbodiamides. A chitin derivative capable of forming a gel has been reported. According to some embodiments, the at least one therapeutic agent is impregnated in or on the hyaluronic acid (HA) matrix. Hyaluronic acid (HA) found in mammalian extracellular matrix, synovial fluid, umbilical cord and comb, which is composed of alternating glucuronide and glucosaminide bonds and is separated and purified, can also be produced by the fermentation process.

Pharmaceutically Acceptable Carriers According to some embodiments, the flowable sustained release microparticle composition comprises (ii) a pharmaceutically acceptable carrier. According to one embodiment, the pharmaceutically acceptable carrier is a solid carrier or an excipient. According to other embodiments, the pharmaceutically acceptable carrier is a gel phase carrier or an excipient. Examples of carriers or excipients include, but are limited to, calcium carbonate, calcium phosphate, various monosaccharides and polysaccharides (including but not limited to hyaluronic acid), starches, cellulose derivatives, gelatin, and polymers. Not done. An exemplary carrier may also include a saline excipient such as hydroxylpropyl methylcellulose (HPMC) in phosphate buffered saline (PBS). According to other embodiments, the pharmaceutically acceptable carrier is a buffer solution. An exemplary buffer may include, but is not limited to, phosphate buffered saline (PBS).

According to some embodiments, the pharmaceutically acceptable carrier imparts stickiness to the composition. According to one embodiment, the pharmaceutically acceptable carrier comprises hyaluronic acid. According to some embodiments, the pharmaceutically acceptable carrier contains 0% -5% hyaluronic acid. According to one embodiment, the pharmaceutically acceptable carrier contains less than 0.05% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.1% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.2% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.3% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.4% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.5% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.6% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.7% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.8% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.9% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.0% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.1% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.2% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.3% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.4% hyaluronic acid. According to other embodiments, pharmaceutically acceptable carriers are: 1. Contains less than 5% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.6% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.7% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.8% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.9% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.0% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.1% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.2% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.3% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.4% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.5% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.6% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.7% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.8% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.9% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 3.0% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 3.5% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 4.0% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 4.5% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier is 5.

In some embodiments, pharmaceutically acceptable carriers include, but are not limited to, gels, sustained release solids or semi-solid compounds, and may optionally be sustained release gels. In some such embodiments, the at least one therapeutic agent is embedded in a pharmaceutically acceptable carrier. In some embodiments, the at least one therapeutic agent is coated on a pharmaceutically acceptable carrier. The coating can be any desired material, preferably a polymer or a mixture of different polymers. If desired, the polymer may be used during the granulation step to form a matrix with the active ingredient to obtain the desired release pattern of the active ingredient. The gel, sustained release solid or semi-solid compound can release the activator over a desired period of time. Gels, sustained release solids or semi-solid compounds can be implanted in tissues within the parenchyma of the human brain, including, but not limited to, blood vessels, eg, in close proximity to the cerebral arteries. According to other embodiments, the pharmaceutically acceptable carrier comprises a sustained release solid compound. According to one such embodiment, the at least one therapeutic agent is embedded in a sustained release solid compound or coated with a sustained release solid compound. According to yet another embodiment, the pharmaceutically acceptable carrier comprises sustained release microparticles containing at least one therapeutic agent. According to other embodiments, the pharmaceutically acceptable carrier is a gel compound, such as a biodegradable hydrogel.

Additional Ingredients According to some embodiments, the flowable sustained release microparticle composition further comprises a preservative. According to some such embodiments, the flowable sustained release microparticle delivery composition is present in unit dosage form. Exemplary unit dosage forms include, but are not limited to, ampoules or multi-dose containers. A fluid sustained-release microparticle composition for parenteral (including, but not limited to, subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intrathecal, intraventricular and intra-articular) administration. Aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, bacteriostats and solutes to make the formulation isotonic with the blood or CSF of the intended recipient; And aqueous and non-aqueous sterile suspensions which may contain anti-precipitation agents and thickeners. According to some embodiments, the flowable sustained release microparticle composition is formulated for parenteral infusion, surgical transplantation, or a combination thereof. According to some such embodiments, the flowable sustained release microparticle composition is a pharmaceutically acceptable aqueous or non-aqueous sterile solution, dispersion, suspension or emulsion or sterile solution for injection. Alternatively, it is in the form of a sterilized powder reconstituted into a dispersion. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, dichloromethane, acetonitrile, ethyl acetate, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, Examples include, but are not limited to, vegetable oils (eg olive oil) and organic esters for injection, such as ethyloleate. Appropriate fluidity can be maintained, for example, by the use of coatings such as lecithin, the maintenance of particle size required in the case of dispersions, and the use of surfactants. The suspension further contains anti-precipitation agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, polyoxyethylene sorbitan ester, microcrystan cellulose, aluminum metahydroxydo, bentonite, agar, tragacant, and mixtures thereof. May contain.

According to some embodiments, the flowable sustained release microparticle composition is formulated in the form of an injectable depot. The injectable depot form is produced by forming a microencapsulated matrix of therapeutic agent in a biodegradable polymer. The rate of drug release can be controlled by the ratio of drug to polymer and the specific type of polymer used. Such long-acting formulations can be used with suitable polymeric or hydrophobic materials (eg, as emulsions in acceptable oils) or ion exchange resins, or as slightly sparing derivatives, eg, slightly sparingly soluble. Can be formulated as a salt. Examples of biodegradable polymers include, but are not limited to, polylactide-polyglycolide, poly (orthoester) and poly (anhydride). Depot formulations for injection are also prepared by encapsulating the drug in liposomes or microemulsions that are compatible with body tissue. According to some embodiments, the flowable sustained release microparticle composition further comprises an adjuvant. Exemplary adjuvants include, but are not limited to, preservatives, wetting agents, emulsifying agents, and dispersants. Blocking the action of microorganisms can be ensured by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid and the like. Isotonic agents such as sugar, sodium chloride and the like may also be included. Long-term absorption of the injectable pharmaceutical form can be brought about by the use of substances that delay absorption, such as aluminum monostearate or gelatin.

The flowable sustained release microparticle composition is a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile medium for injection, eg, by final gamma irradiation, filtration through a bacterial retention filter, or shortly before use. It can be sterilized by incorporating a sterilizing agent in the form. Injectable formulations, such as sterile aqueous or oily suspensions for injection, can be formulated according to known techniques with suitable dispersants or wetting agents and anti-precipitation agents. Injectable sterile formulations also include injectable sterile solutions, suspensions or emulsions in non-toxic parenterally acceptable diluents or solvents such as 1,3-butanediol, dichloromethane, ethyl acetate, acetonitrile. It can be dissolved in or the like. Water, Ringer's solution, USP and isotonic saline can be used in acceptable excipients and solvents. In addition, sterile fixed oils are typically used as solvents or suspension media. For this purpose, non-irritating fixed oils containing synthetic monoglycerides or diglycerides can be used. In addition, fatty acids such as oleic acid are used in the preparation of injections. Suitable buffers include acetic acid and salt (1-2% w / v); citric acid and salt (1-3% w / v); boric acid and salt (0.5-2.5% w / v); And phosphoric acid and salt (0.8-2% w / v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w / v); chlorobutanol (0.3-0.9% w / v); paraben (0.01-0.25% w / v) and thimerosal (0.004-0.02%). w / v) can be mentioned.

IV. Kits for Preparing Flowable Sustained Release Microparticle Compositions In other embodiments, the present invention is a kit for treating at least one cerebral artery in the subarachnoid space at risk of interference due to brain damage. And: (i) Sterilization Surgical Injection Device; (ii) First Sterilization Syringe with Barrel and Plunger; (iii) Second Sterilization Syringe with Barrel and Plunger; (iv) Female Sterilization Luer Cap; (v) Male sterile lure cap; (vi) Female sterile syringe connector; (vii) A sterile microparticle formulation suitable for administration into the ventricles containing a therapeutic amount of at least one therapeutic agent, the therapeutic amount of delayed obstruction of the cerebral arteries within the submucosal space. The formulation, which is an effective amount to reduce sexual complications, wherein the microparticle formulation contains a plurality of microparticles with a uniform particle size distribution, and at least one therapeutic agent is dispersed throughout each microparticle. The kit is provided with the material and (vii) a pharmaceutically acceptable sterile carrier. According to some embodiments, the surgical infusion device is a needle, cannula, catheter or a combination thereof. According to one embodiment, the surgical injection device is a needle. According to another embodiment, the surgical infusion device is a cannula. According to another embodiment, the surgical infusion device is a catheter. According to some embodiments, the surgical infusion device can be in the range of 18 gauge to 10 gauge. According to one embodiment, the surgical infusion device is an 18 gauge surgical infusion device. According to another embodiment, the surgical infusion device is a 17 gauge surgical infusion device. According to another embodiment, the surgical infusion device is a 16 gauge surgical infusion device. According to another embodiment, the surgical infusion device is a 15 gauge surgical infusion device. According to another embodiment, the surgical infusion device is a 14 gauge surgical infusion device. According to another embodiment, the surgical infusion device is a 13 gauge surgical infusion device. According to another embodiment, the surgical infusion device is a 12 gauge surgical infusion device. According to another embodiment, the surgical infusion device is an 11 gauge surgical infusion device. According to another embodiment, the surgical infusion device is a 10 gauge surgical infusion device.

According to some embodiments, each syringe has a volume between 1 ml and 10 ml. According to one embodiment, each syringe is a 1 ml syringe. According to another embodiment, each syringe is a 2 ml syringe. According to another embodiment, each syringe is a 3 ml syringe. According to another embodiment, each syringe is a 4 ml syringe. According to another embodiment, each syringe is a 5 ml syringe. According to another embodiment, each syringe is a 6 ml syringe. According to another embodiment, each syringe is a 7 ml syringe. According to another embodiment, each syringe is an 8 ml syringe. According to another embodiment, each syringe is a 9 ml syringe. According to another embodiment, each syringe is a 10 ml syringe. According to one embodiment, the kit further comprises at least two biocompatible sterile containers, the microparticle formulation is stored in the first container, and the pharmaceutically acceptable carrier is in the second container. It is stored. According to some embodiments, the container can be a vial, bottle, tube, bag, packet, pillow, ampoule, or the like. According to another embodiment, the sterile microparticle formulation is pre-packaged in a first sterile syringe. According to another embodiment, the pharmaceutically acceptable sterile carrier is pre-packaged in a second sterile syringe. According to one embodiment, the sterile microparticle formulation can be stored frozen, for example at -20 ° C or -80 ° C. According to another embodiment, the sterile microparticle formulation can be stored refrigerated, eg at 4 ° C. According to other embodiments, the sterile microparticle formulation can be stored at room temperature. According to one embodiment, the pharmaceutically acceptable sterile carrier can be stored frozen, eg, at -20 ° C or -80 ° C. According to other embodiments, the pharmaceutically acceptable sterile carrier can be stored refrigerated, eg at 4 ° C. According to other embodiments, the pharmaceutically acceptable sterile carrier can be stored at room temperature.

Therapeutic Agents According to some embodiments, the at least one therapeutic agent is a calcium channel blocker, an endothelin antagonist, a transient receptor potential (TRP) protein antagonist, or a combination thereof. According to one example, at least one therapeutic agent is a calcium channel blocker. According to some embodiments, the calcium channel blocker is an L-type voltage-gated calcium channel inhibitor, an R-type voltage-gated calcium channel inhibitor, an N-type voltage-gated calcium channel inhibitor, and a P / Q-type potential. It is selected from the group consisting of a dependent calcium channel inhibitor, a T-type voltage-gated calcium channel inhibitor, or a combination thereof. According to one embodiment, the calcium channel blocker is an L-type voltage-gated calcium channel inhibitor. According to one embodiment, the calcium channel blocker is an R-type voltage-gated calcium channel inhibitor. According to one embodiment, the calcium channel blocker is an N-type voltage dependent calcium channel inhibitor. According to one embodiment, the calcium channel blocker is a P / Q voltage-gated calcium channel inhibitor. According to one embodiment, the calcium channel blocker is a T-type voltage-gated calcium channel inhibitor.

For example, L-type voltage-gated calcium channel blockers include dihydropyridine L-type blockers such as nisoldipine, nicardipine or nifedipine, AHF (eg 4aR, 9aS)-(+)-4a-amino-1,2,3,4. , 4a, 9a-hexahydro-4aH-fluorene, HC 1), isradipine (eg 4- (4-benzofrazanyl) -1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate methyl 1-methylethyl Esther), calciseptine (eg, Dendroaspis polylepis) (Separated from polylepis)), H-Arg-Ile-Cys-Tyr-Ile-His-Lys-Ala-Ser-Leu-Pro-Arg-Ala-Thr-Lys-Thr-Cys-Val-Glu-Asn- Thr-Cys-Tyr-Lys-Met-Phe-Ile-Arg-Thr-Gln-Arg-Glu-Tyr-Ile-Ser-Glu-Arg-Gly-Cys-Gly-Cys-Pro-Thr-Ala-Met- Trp-Pro-Tyr-G1n-Thr-Glu-Cys-Cys-Lys-Gly-Asp-Arg-Cys-Asn-Lys-OH, Calcicludine (eg Dendroaspis) (separated from angusticeps) (Eastern Green Mamba)), (H-Trp-Gln-Pro-Pro-Trp-Tyr-Cys-Lys-Glu-Pro-Val-Arg-Ile-Gly-Ser-Cys-Lys- Lys-Gln-Phe-Ser-Ser-Phe-Tyr-Phe-Lys-Trp-Thr-Ala-Lys-Lys-Cys-Leu-Pro-Phe-Leu-Phe-Ser-GlyCys-G1y-Gly-Asn- Ala-Asn-Arg-Phe-Gln-Thr-Ile-Gly-Glu-Cys-Arg-Lys-Lys-Cys-Leu-Gly-Lys-OH, silnidipine (eg A and FRP-8653 also dihydropyridine-type inhibition Agent), Dilantizem (eg (2S, 3S)-(+)-cis-3-acetoxy-5- (2-dimethylaminoethyl) -2,3-dihydro-2- (4-methoxyphenyl)- 1,5-benzothiazepine-4 (5H) -one hydrochloride), zyrrhizem (eg benzothiazepine-4 (5H) -one, 3- (acetyloxy) -5- [2- (dimethylamino) ethyl] -2,3-dihydro-2- (4-methoxyphenyl)-, (+)-cis-, monohydrochloride), ferrodipine (eg 4- (2,3-dichlorophenyl) -1,4-dihydro-2 , 6-Dimethyl-3,5-pyridinecarboxylic acid ethylmethyl ester), FS-2 (eg isolate from Dendroapsis polylepis polylepis poison), FTX-3.3 (eg isolate from Agelenopsis aperta), Neomycin sulfate (eg C₂₃H₄₆N₆O₁₃ 3H₂SO₄), Nicaldipine (eg 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenylmethyl-2-[methyl (phenyl) methylamino] -3,5-pyridinedicarboxylic acid ethyl ester hydrochloride, and also YC-93 also contains nifedipine (eg 1,4-dihydro-2,6-dimethyl-4- (2-nitrophenyl) -3,5-pyridinecarboxylic acid dimethyl ester), nimodipin (eg 4-dihydro-2,6). -Dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 2-methoxyethyl 1-methylethyl ester) or (isopropyl2-methoxyethyl 1,4-dihydro-2,6-dimethyl-4- (m-Nitrophenyl) -3,5-pyridinedialvoxylate), nitrenenedin (eg 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylate ethyl Methyl ester), S-petacin (eg (3S, 4aR, 5R, 6R)-[2,3,4,4a, 5,6,7,8-octahydro-3- (2-propenyl) -4a, 5- Dimethyl-2-oxo-6-naphthyl] Z-3'-methylthio-1'-propenoate), floretin (eg 2', 4', 6'-trihydroxy-3- (4-hydroxyphenyl) propiophenone, Also 3- (4-hydroxyphenyl) -1- (2,4,6-trihydroxyphenyl) -1-propanol and b- (4-hydroxyphenyl) -2,4,6-trihydroxypropiophenone ) Also protopin (eg C)₂₀H₁₉NO₅Cl), SKF-96365 (eg 1- [b- [3- (4-methoxyphenyl) propoxy] -4-methoxyphenethyl] -1H-imidazole, HC1), tetrandin (eg 6,6', 7,12- Tetramethoxy-2,2'-dimethylvelvaman), (. +-.)-Methoxybellapamil or (+)-bellapamil (eg 54N- (3,4-dimethoxyphenylethyl) methylamino] -2- (3, 4-Dimethoxyphenyl) -2-iso-propylvaleronitrile hydrochloride), and (R)-(+)-Bay K8644 (eg R-(+)-1,4-dihydro-2,6-dimethyl-5- Examples include, but are not limited to, nitro-4- (2- (trifluoromethyl) phenyl) -3-pyridinecarboxylic acid methyl ester). The above examples can be specific for L-type open-pot calcium channels or can inhibit a wider range of potential-opening calcium channels, such as N, P / Q, R and T-types.

According to some embodiments, the L-type voltage-gated calcium channel inhibitor is dihydropyridine. Typical dihydropyridines include amlodipine, alanidipine, azelnidipine, vanidipine, benidipine, sinardipin, ehonidipine, felodipine, islazipin, lasidipine, remildipine, relcanidipine, nicaldipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nisoldipine, nimodipine, nisoldipine, nimodipine, nisoldipine. However, it is not limited to these. According to one embodiment, the dihydropyridine is nimodipine. According to one embodiment, nimodipine has a half-life of 7-10 days when formulated as described herein and has adequate lipophilicity. According to some embodiments, the L-type voltage-gated calcium channel inhibitor is a phenylalkylamine. Examples of exemplary phenylalkylamines include, but are not limited to, gallopamil, verapamil and the like. According to some embodiments, the L-type voltage-gated calcium channel inhibitor is 1-4 benzothiazepines. According to one embodiment, 1-4 benzothiazepines are diltiazem. According to one embodiment, the L-type voltage-gated calcium channel inhibitor is bepridil. According to other embodiments, the at least one therapeutic agent is an endothelin antagonist. Exemplary endothelin antagonists include A-127722, ABT-627, BMS 182874, BQ-123, BQ-153, BQ-162, BQ-485, BQ-518, BQ-610, EMD-122946, FR 139317, IPI-725, L-744453, LU 127043, LU 135252, PABSA, PD 147953, PD 151242, PD 155080, PD 156707, RO 611790, SB-247083, Clazocentan, Atlascentan, Citaxsentan Sodium, TA-0201, TBC 11251, TTA-386, WS-7338B, ZD-1611, Aspirin, A-182086, CGS 27830, CP 170687, J-104132 , L-751281, L-754142, LU 224332, LU 302872, PD 142893, PD 145065, PD 160672, RO-470203, Bosentan, RO 462005, RO 470203, SB 209670, SB 217242, TAK-044, A-192621, Examples include, but are not limited to, A-308165, BQ-788, BQ-017, IRL 1038, IRL 2500, PD-161721, RES 701-1, RO 468443, etc. According to other embodiments, the at least one therapeutic agent is a transient receptor potential (TRP) protein antagonist. Exemplary transient receptor potential (TRP) protein antagonists include gadolinium chloride, lanthanum chloride, and SKF 96365. (1- (β- [3- (4-Methoxy-phenyl) propoxy] -4-methoxyphenethyl) -1H-imidazole hydrochloride), and LOE 908 ((RS)-(3,4-dihydro-6,7) -Dimethoxyisoquinoline-1-gamma 1) -2-phenyl-N, N-di- [2- (2,3,4-trimethoxyphenyl) ethyl] acetamide), but not limited to these. According to some embodiments, the at least one therapeutic agent is a separated molecule. According to some embodiments, the at least one therapeutic agent is substantially pure.

Microparticle Formulation According to one embodiment, the flowable sustained release microparticle composition comprises a plurality of microparticles containing at least one therapeutic agent. According to some embodiments, the at least one therapeutic agent is supplied in the form of particulates. According to other embodiments, the at least one therapeutic agent is located on or in the microparticles. According to one embodiment, at least one therapeutic agent is dispersed throughout each microparticle. According to some embodiments, at least one therapeutic agent is impregnated on the surface of each microparticle. According to other embodiments, the at least one therapeutic agent is contained within a fine particle core surrounded by a coating. According to other embodiments, at least one therapeutic agent is adsorbed on each of the microparticles. According to some such embodiments, the microparticles have a uniform particle size distribution. According to some embodiments, a uniform distribution of particle size is achieved by a homogenization process that forms a uniform emulsion containing the particles. According to some such embodiments, each microparticle contains a matrix. According to some embodiments, the matrix comprises at least one therapeutic agent. According to some embodiments, the microparticles may have an arbitrary order release kinetics including zero order release, primary release, secondary release, delayed release, sustained release, immediate release, and combinations thereof. Fine particles include, but are not limited to, erosive, non-erosive, biodegradable, or non-biodegradable substances or combinations thereof, in addition to therapeutic agents (one or more). Any of the substances routinely used in technology can be included.

According to some embodiments, the microparticles are microcapsules containing at least one therapeutic agent in solution or in a semi-solid state. According to some embodiments, the microparticles contain at least one therapeutic agent, in whole or in part. According to some embodiments, the microparticles are nanoparticles that contain at least one therapeutic agent in whole or in part. According to some embodiments, the microparticles can have substantially any shape. According to some embodiments, each microparticle is loaded with at least 40% by weight to at least 80% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 40% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 45% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 50% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 55% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 60% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 63% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 65% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 70% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 75% by weight of at least one therapeutic agent. According to one embodiment, each microparticle is loaded with at least 80% by weight of at least one therapeutic agent.

According to some embodiments, the particle size is from about 25 μm to about 100 μm. According to some embodiments, the particle size is from about 30 μm to about 80 μm. According to one embodiment, the particle size is at least about 25 μm. According to other embodiments, the particle size is at least about 30 μm. According to other embodiments, the particle size is at least about 35 μm. According to other embodiments, the particle size is at least about 40 μm. According to other embodiments, the particle size is at least about 45 μm. According to other embodiments, the particle size is at least about 50 μm. According to other embodiments, the particle size is at least about 55 μm. According to other embodiments, the particle size is at least about 60 μm. According to other embodiments, the particle size is at least about 65 μm. According to other embodiments, the particle size is at least about 70 μm. According to other embodiments, the particle size is at least about 75 μm. According to other embodiments, the particle size is at least about 80 μm. According to other embodiments, the particle size is at least about 85 μm. According to other embodiments, the particle size is at least about 90 μm. According to other embodiments, the particle size is at least about 95 μm. According to other embodiments, the particle size is at least about 100 μm. According to other embodiments, at least one therapeutic agent can be supplied in the string. The string may contain at least one therapeutic agent in a core surrounded by a coating, or at least one therapeutic agent may be dispersed throughout the string, or at least one therapeutic agent is absorbed by the string. May be good. Strings can have arbitrary order release kinetics, including zero order release, primary release, secondary release, delayed release, sustained release, immediate release, and combinations thereof. Strings include, but are not limited to, erosive, non-erodible, biodegradable, or non-biodegradable substances or combinations thereof, in addition to therapeutic agents (one or more). Any of the substances routinely used in technology can be included.

According to other embodiments, the at least one therapeutic agent may be supplied in at least one sheet. The sheet may contain at least one therapeutic agent and at least one additional therapeutic agent in a core surrounded by a coating, or at least one therapeutic agent and at least one additional therapeutic agent are dispersed throughout the sheet. Alternatively, at least one therapeutic agent may be absorbed into the sheet. Sheets can have arbitrary order release kinetics, including zero order release, primary release, secondary release, delayed release, sustained release, immediate release, and combinations thereof. Sheets include, but are limited to, erosive, non-erosive, biodegradable, or non-biodegradable substances or combinations thereof, in addition to at least one therapeutic agent and at least one additional therapeutic agent. Any of the substances routinely used in dispensing and pharmaceutical technology that are not used can be included. According to some embodiments, the microparticle formulation comprises a suspension of microparticles. According to one embodiment, the microparticle formulation comprises a suspension of microparticles. According to some embodiments, the microparticle formulation further comprises at least one of an anti-precipitation agent, a stabilizer and a dispersant. According to some such embodiments, the microparticle formulation exists as a suspension. According to some such embodiments, the microparticle formulation exists as a solution. According to some such embodiments, the microparticle formulation exists as an emulsion.

According to some embodiments, the microparticle formulation comprises at least one aqueous solution of a therapeutic agent in a water-soluble form. According to some embodiments, the microparticle formulation comprises an oily suspension of at least one therapeutic agent. An oily suspension of at least one therapeutic agent can be prepared with a suitable lipophilic solvent. Exemplary lipophilic solvents or excipients include, but are not limited to, fatty oils such as sesame oil or synthetic fatty acid esters such as ethyloleate or triglycerides. According to some embodiments, the microparticle formulation comprises an aqueous suspension of at least one therapeutic agent. Aqueous infusion suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxylmethyl cellulose, sorbitol, hyaluronic acid, or dextran. If desired, the suspension may also contain suitable stabilizers or substances that increase the solubility of the compound to allow the preparation of highly concentrated solutions. Alternatively, at least one therapeutic agent may be in powder form to form with a suitable excipient, eg, sterile water free of pyrogens, prior to use. The fine particle mixture is dispersed in an excipient to form a dispersion having fine particles as a dispersion phase and an excipient as a dispersion medium. The microparticle formulation is contained, for example, in a microcapsule encapsulating form, a liposome coated on microscopic gold particles, if appropriate, in a pellet for implantation in a tissue. Or may be included with one or more dried excipients on the object to be rubbed against the tissue. As used herein, the term "microencapsulated" means that very small droplets or particles are surrounded or coated with a continuous film of biocompatible, biodegradable polymer or non-polymeric material, non-pareil, pellets, crystals. , Aggregates, microspheres, or nanoparticles, but refers to the process of obtaining an integral structure. Microparticle formulations delayed the release of granules, beads, powders, tablets, coated tablets, (micro) capsules, suppositories, syrups, emulsions, suspensions, creams, drops or active compounds. In the formulation, excipients and additives and / or adjuvants such as disintegrants, binders, coatings, swelling agents, lubricants or solubilizers are usually in the form of formulations as described above. Used for. The microparticle formulation is suitable for use in a variety of drug delivery systems. For a brief review of drug delivery methods, see Langer (1990) Science 249, 1527-1533, which is incorporated herein by reference.

Microencapsulation process Microencapsulation process and product examples; Emulsion-based microparticle production method; Emulsion-based microparticle and its production method; Solvent extraction with adjustable extraction rate Microcapsulation encapsulation; Microcapsulation encapsulation with solvent and salt Process; Continuous double emulsion process to create fine particles; Drying method to adjust fine particle properties, emission control system from polymer blend; Polymer mixture containing polymers with different non-repetitive units and its production and use method; And the emulsion-based process for preparing microparticles and the workhead assembly used therein are described in US Pat. No. 5,407,609 (referred to as microencapsulation process and its products), US Patent Application Publication No. 10 / 553,003 (Emulsion). (Referred to as a method for producing base fine particles), US Patent Application Publication No. 11 / 799,700 (referred to as emulsion-based fine particles and a method for producing the same), US Patent Application Publication No. 12 / 557,946 (with variable extraction rate). US Patent Application Publication No. 12 / 779,138 (referred to as hyaluronic acid (HA) injectable excipient), US Patent Application Publication No. 12 / 562,455 (referred to as solvent and salt encapsulation). Microencapsulation process), US Patent Application Publication No. 12 / 338,488 (referred to as a method for preparing fine particles with a low residual solvent volume); US Patent Application Publication No. 12 / 692,027 (from a polymer blend). It is called an emission control system); U.S. Patent Application Publication No. 12 / 692,020 (referred to as a polymer mixture containing polymers with different non-repetitive units and its production and use); U.S. Patent Application Publication No. 10 / 565,401 ("Release Control Composition"). US Patent Application Publication No. 12 / 692,029 (referred to as "drying method for adjusting fine particle properties"); US Patent Application Publication No. 12 / 968,708 ("Emulsion-based process for preparing fine particles and It is referred to as the workhead used); and is disclosed and described in US Patent Publication No. 13/074542 (referred to as "compositions and methods that improve retention of the pharmaceutical composition at the site of topical administration"). .. The contents of each of these are incorporated herein by reference in their entirety. According to some embodiments, delivery of at least one therapeutic agent using microparticle technology requires bioreabsorbable polymer particles that enclose at least one therapeutic agent and at least one additional therapeutic agent.

Fine Particle Polymer Matrix According to one embodiment, the fine particles contain a matrix. According to some embodiments, the at least one therapeutic agent is impregnated in or on top of a naturally occurring biopolymer matrix, synthetic polymer matrix, or a combination thereof. According to one embodiment, the polymer is a sustained release polymer. According to one embodiment, the polymer is a biodegradable polymer. According to one embodiment, the polymer is poly (D, L-lactide-co-glycolide). According to another embodiment, the polymer is a poly (orthoester). According to another embodiment, the polymer is poly (anhydride). According to another embodiment, the polymer is polylactide-polyglycolide. Both non-biodegradable and biodegradable polymeric materials can be used in the production of particles to deliver therapeutic agents. Such polymers can be natural or synthetic polymers. The polymer is selected based on the desired duration of release. Bioadhesive polymers of particular interest include Sawhney et al in Macromolecules (1993) 26, Examples include, but are not limited to, the bioerosive hydrogels described by 581-587. The teachings of this document are incorporated herein by reference. Exemplary bioerodible hydrogels include polyhyaluronic acid, casein, gelatin, glutin, polyan anhydride, polyacrylic acid, arginate, chitosan, poly (methyl methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate). ), Poly (isobutyl methacrylate), poly (hexyl methacrylate), poly (isodecyl methacrylate), poly (lauryl methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate) , And poly (octadecyl acrylate), but are not limited thereto. According to one embodiment, the bioadhesive polymer is hyaluronic acid. In some such embodiments, the bioadhesive polymer contains less than about 2.3% hyaluronic acid.

According to another embodiment, the polymer enhances the water solubility of the microparticle formulation. Examples of suitable polymers are polyethylene glycol, poly- (d-glutamic acid), poly- (1-glutamic acid), poly- (1-glutamic acid), poly- (d-aspartic acid), poly- (1-aspartic acid). Acids), poly- (1-aspartic acid) and copolymers thereof, but not limited to these. Polyglutamic acid having a molecular weight of about 5,000 to about 100,000, a molecular weight of about 20,000 to about 80,000 can be used, and a molecular weight of about 30,000 to about 60,000 can also be used. The polymer is ester-bonded to one or more hydroxyls of the epothilones of the invention using the protocol essentially described by US Pat. No. 5,977,163, which is incorporated herein by reference. Specific binding sites include the hydroxyl of carbon-21 in the case of the 21-hydroxy derivative of the invention. Other binding sites include, but are not limited to, carbon 3 hydroxyl and / or carbon 7 hydroxyl. According to some embodiments, the at least one therapeutic agent is impregnated in or on the polyglycolide (PGA) matrix. PGA is a linear aliphatic polyester developed for use in suturing. Studies have reported PGA copolymers formed with trimethylene carbonate, polylactic acid (PLA), and polycaprolactone. Some of these copolymers can be formulated as microparticles for sustained drug release. According to some embodiments, the at least one therapeutic agent is impregnated in the polyester-polyethylene glycol matrix or on the polyester-polyethylene glycol matrix. Polyester-polyethylene glycol compounds can be synthesized; they are soft and can be used for drug delivery.

According to some embodiments, the at least one therapeutic agent is impregnated in or on a poly (amino) -derived biopolymer matrix. Examples of poly (amino) -derived biopolymers include those containing lactic acid and lysine as aliphatic diamines (see, for example, US Pat. No. 5,399,665), and tyrosine-derived polycarbonates and polyacrylates. Not limited to. Modification of polycarbonate can change the length of the alkyl chain of the ester (ethyl to octyl), and modification of polyarylate can further include changing the length of the alkyl chain of the diacid (eg). , Succinic acid to sebacic acid), which allows for greater substitution of the polymer and greater flexibility of the polymer properties. According to some embodiments, the at least one therapeutic agent is impregnated in or on the polyanhydride matrix. Polyanhydrides are prepared by dehydration of two diacid molecules by melt polymerization (see, eg, US Pat. No. 4,757,128). These polymers decompose by surface erosion (compared to polyester, which decomposes by total erosion). The release of the drug can be controlled by the hydrophilicity of the monomer selected. According to some embodiments, the at least one therapeutic agent is impregnated in or on the photopolymerizable biopolymer matrix. Photopolymerizable biopolymers include, but are not limited to, lactic acid / polyethylene glycol / acrylate copolymers. According to some embodiments, the at least one therapeutic agent is impregnated in or on the hydrogel matrix. The term "hydrogel" means a substance that provides a solid, semi-solid, pseudoplastic or plastic structure containing the aqueous components necessary to form a gelatinous or jelly-like mass. Hydrogels generally include various polymers including hydrophilic polymers, acrylic acid, acrylamide and 2-hydroxyethyl methacrylate (HEMA).

According to some embodiments, the at least one therapeutic agent is impregnated in or on a naturally occurring biopolymer matrix. Naturally occurring biopolymers include, but are not limited to, protein polymers, collagen, polysaccharides and photopolymerizable compounds. According to some embodiments, the at least one therapeutic agent is impregnated in or on the protein polymer matrix. Protein polymers are synthesized from self-assembled protein polymers such as silk fibroin, elastin, collagen, and combinations thereof. According to some embodiments, the at least one therapeutic agent is impregnated in or on a naturally occurring polysaccharide matrix. Naturally occurring polysaccharides include chitin and its derivatives, hyaluronic acid, dextran and cellulosic (generally non-denaturing and non-biodegradable), and sucrose acetate isobutyrate (SAIB). Not limited to. According to some embodiments, the at least one therapeutic agent is impregnated in or on the chitin matrix. Chitin is mainly composed of 2-acetamido-2-deoxy-D-glucose groups and is found in yeast, fungi and marine invertebrates (shrimp, crustaceans), which are the main components of the exoskeleton. Chitin is not water-soluble, and only deacetylated chitin and chitosan are soluble in acidic solutions (eg, acetic acid). Studies have shown that it is water-soluble, very high molecular weight (greater than 2,000,000 daltons), viscoelastic, non-toxic, biocompatible and cross-linked with peroxides, glutaraldehyde, glyoxal and other aldehydes and carbodiamides. A chitin derivative capable of forming a gel has been reported. According to some embodiments, the at least one therapeutic agent is impregnated in or on the hyaluronic acid (HA) matrix. Hyaluronic acid (HA) found in mammalian extracellular matrix, synovial fluid, umbilical cord and comb, which is composed of alternating glucuronide and glucosaminide bonds and is separated and purified, can also be produced by the fermentation process.

Pharmaceutically Acceptable Carriers According to some embodiments, the flowable sustained release microparticle composition comprises (ii) a pharmaceutically acceptable carrier. According to one embodiment, the pharmaceutically acceptable carrier is a solid carrier or an excipient. According to other embodiments, the pharmaceutically acceptable carrier is a gel phase carrier or an excipient. Examples of carriers or excipients include, but are limited to, calcium carbonate, calcium phosphate, various monosaccharides and polysaccharides (including but not limited to hyaluronic acid), starches, cellulose derivatives, gelatin, and polymers. Not done. An exemplary carrier may also include a saline excipient such as hydroxylpropyl methylcellulose (HPMC) in phosphate buffered saline (PBS). According to other embodiments, the pharmaceutically acceptable carrier is a buffer solution. An exemplary buffer may include, but is not limited to, phosphate buffered saline (PBS).

According to some embodiments, the pharmaceutically acceptable carrier imparts stickiness to the composition. According to one embodiment, the pharmaceutically acceptable carrier comprises hyaluronic acid. According to some embodiments, the pharmaceutically acceptable carrier contains 0% -5% hyaluronic acid. According to one embodiment, the pharmaceutically acceptable carrier contains less than 0.05% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.1% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.2% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.3% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.4% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.5% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.6% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.7% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.8% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 0.9% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.0% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.1% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.2% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.3% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.4% hyaluronic acid. According to other embodiments, pharmaceutically acceptable carriers are: 1. Contains less than 5% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.6% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.7% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.8% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 1.9% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.0% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.1% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.2% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.3% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.4% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.5% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.6% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.7% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.8% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 2.9% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 3.0% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 3.5% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 4.0% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier contains less than 4.5% hyaluronic acid. According to other embodiments, the pharmaceutically acceptable carrier is 5.

In some embodiments, pharmaceutically acceptable carriers include, but are not limited to, gels, sustained release solids or semi-solid compounds, and may optionally be sustained release gels. In some such embodiments, the at least one therapeutic agent is embedded in a pharmaceutically acceptable carrier. In some embodiments, the at least one therapeutic agent is coated on a pharmaceutically acceptable carrier. The coating can be any desired material, preferably a polymer or a mixture of different polymers. If desired, the polymer may be used during the granulation step to form a matrix with the active ingredient to obtain the desired release pattern of the active ingredient. The gel, sustained release solid or semi-solid compound can release the activator over a desired period of time. Gels, sustained release solids or semi-solid compounds can be implanted in tissues within the parenchyma of the human brain, including, but not limited to, blood vessels, eg, in close proximity to the cerebral arteries. According to other embodiments, the pharmaceutically acceptable carrier comprises a sustained release solid compound. According to one such embodiment, the at least one therapeutic agent is embedded in a sustained release solid compound or coated with a sustained release solid compound. According to yet another embodiment, the pharmaceutically acceptable carrier comprises sustained release microparticles containing at least one therapeutic agent. According to other embodiments, the pharmaceutically acceptable carrier is a gel compound, such as a biodegradable hydrogel.

Additional Ingredients According to some embodiments, the flowable sustained release microparticle composition further comprises a preservative. According to some such embodiments, the flowable sustained release microparticle delivery composition is present in unit dosage form. Exemplary unit dosage forms include, but are not limited to, ampoules or multi-dose containers. A fluid sustained-release microparticle composition for parenteral (including, but not limited to, subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intrathecal, intraventricular and intra-articular) administration. Aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, bacteriostats and solutes to make the formulation isotonic with the blood or CSF of the intended recipient; And aqueous and non-aqueous sterile suspensions which may contain anti-precipitation agents and thickeners. According to some embodiments, the flowable sustained release microparticle composition is formulated for parenteral infusion, surgical transplantation, or a combination thereof. According to some such embodiments, the flowable sustained release microparticle composition is a pharmaceutically acceptable aqueous or non-aqueous sterile solution, dispersion, suspension or emulsion or sterile solution for injection. Alternatively, it is in the form of a sterilized powder reconstituted into a dispersion. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, dichloromethane, acetonitrile, ethyl acetate, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, Examples include, but are not limited to, vegetable oils (eg olive oil) and organic esters for injection, such as ethyloleate. Appropriate fluidity can be maintained, for example, by the use of coatings such as lecithin, the maintenance of particle size required in the case of dispersions, and the use of surfactants. The suspension further contains anti-precipitation agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, polyoxyethylene sorbitan ester, microcrystan cellulose, aluminum metahydroxydo, bentonite, agar, tragacant, and mixtures thereof. May contain.

According to some embodiments, the flowable sustained release microparticle composition is formulated in the form of an injectable depot. The injectable depot form is produced by forming a microencapsulated matrix of therapeutic agent in a biodegradable polymer. The rate of drug release can be controlled by the ratio of drug to polymer and the specific type of polymer used. Such long-acting formulations can be used with suitable polymeric or hydrophobic materials (eg, as emulsions in acceptable oils) or ion exchange resins, or as slightly sparing derivatives, eg, slightly sparingly soluble. Can be formulated as a salt. Examples of biodegradable polymers include, but are not limited to, polylactide-polyglycolide, poly (orthoester) and poly (anhydride). Depot formulations for injection are also prepared by encapsulating the drug in liposomes or microemulsions that are compatible with body tissue. According to some embodiments, the flowable sustained release microparticle composition further comprises an adjuvant. Exemplary adjuvants include, but are not limited to, preservatives, wetting agents, emulsifying agents, and dispersants. Blocking the action of microorganisms can be ensured by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid and the like. Isotonic agents such as sugar, sodium chloride and the like may also be included. Long-term absorption of the injectable pharmaceutical form can be brought about by the use of substances that delay absorption, such as aluminum monostearate or gelatin. The flowable sustained release microparticle composition is a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile medium for injection, eg, by final gamma irradiation, filtration through a bacterial retention filter, or shortly before use. It can be sterilized by incorporating a sterilizing agent in the form. Injectable formulations, such as sterile aqueous or oily suspensions for injection, can be formulated according to known techniques with suitable dispersants or wetting agents and anti-precipitation agents. Injectable sterile formulations also include injectable sterile solutions, suspensions or emulsions in non-toxic parenterally acceptable diluents or solvents such as 1,3-butanediol, dichloromethane, ethyl acetate, acetonitrile. It can be dissolved in or the like. Water, Ringer's solution, USP and isotonic saline can be used in acceptable excipients and solvents. In addition, sterile fixed oils are typically used as solvents or suspension media. For this purpose, non-irritating fixed oils containing synthetic monoglycerides or diglycerides can be used. In addition, fatty acids such as oleic acid are used in the preparation of injections.

Suitable buffers include acetic acid and salt (1-2% w / v); citric acid and salt (1-3% w / v); boric acid and salt (0.5-2.5% w / v); and phosphorus. Acids and salts (0.8-2% w / v) can be mentioned. Suitable preservatives include benzalkonium chloride (0.003-0.03% w / v); chlorobutanol (0.3-0.9% w / v); Parabens (0.01-0.25% w / v) and thimerosal (0.004-0.02% w / v) can be mentioned. As used herein, the singular forms "a," "an," and "the" include the plural, unless the context specifically dictates otherwise. For example, referring to a "polypeptide" means one or more polypeptides. Where values in a range are indicated, each intervening value between the upper and lower bounds of the range, and any other specified or intervening value within that specified range, unless the context specifically dictates otherwise. It is understood that up to one tenth of the lower limit unit is included in the present invention. Upper and lower limits of these smaller ranges, which may be independently included in the smaller ranges, are also included in the invention in accordance with any clearly excluded limits within the defined range. If the specified scope includes one or both of its limitations, the scope of the invention also includes excluding any of those included limits. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which the present invention belongs. Any method and material similar to or equivalent to the methods and materials described herein may be used in the practice or testing of the present invention, but preferred methods and materials are described herein. All references referred to herein are incorporated herein by reference to disclose and describe the methods and / or materials in which the literature is cited. The publications referred to herein are merely presented for their disclosure prior to the filing date of this application. In the present specification, the present invention should not be construed as acknowledging that the prior invention does not have the right to precede such publications. In addition, the dates of publications shown may differ from the actual publication dates and may need to be confirmed independently.

<p> The following examples are shown to provide those skilled in the art with full disclosure and description of how the invention is manufactured and used, and may also limit the scope of what we consider to be the invention. It is also not intended to represent that the following experiments are all or only experiments performed. Efforts have been made to ensure accuracy with respect to the numbers used (eg, quantity, temperature, etc.), but some experimental errors and deviations should be considered. Unless otherwise indicated, parts are parts by mass, molecular weight is mass average molecular weight, temperature is degrees Celsius, and pressure is atmospheric pressure or near atmospheric pressure.</p><p>Example 1. Action of nimodipine formulation on angiographic cerebral vasospasm in a canine model of subarachnoid hemorrhage (SAH) Treatment group A total of 24 hybrid dogs were assigned to one of three groups as shown in Table 1.</p><p><img file="JP2014515744A_D0001.tif" /></p><p>Formulation A test formulation of a fine particle nimodipine formulation containing a uniform particle size distribution of fine particles was prepared by combining a polymer solution (eg, a 50-50 glycolide-lactide blend) with a solvent in the presence of nimodipine. .. The mixture was added to a surfactant-containing aqueous solution to form an emulsion and solvent-extracted to produce a fluidable microparticle nimodipine formulation. The particle size distributions for 63% nimodipine (wt%) and 1.3% water were 66 μm (mean), 95 μm (95th percentile) and 39 μm (10th percentile). The initial drug load was 65% nimodipine (mass per volume). A placebo microparticle formulation containing a uniform particle size distribution of microparticles was prepared by combining a polymer solution (eg, a 50-50 glycolide-lactide blend) with a solvent in the absence of nimodipine. FIG. 12 is a scanning electron micrograph (SEM) image showing the fine particle nimodipine formulation of the present invention. FIG. 13 is a graph showing the in vitro cumulative release of an exemplary fine particle nimodipine formulation expressed as% by weight over time. Nimodipine by high performance liquid chromatography (HPLC) at specific time points (1 hour, 2 hours, 6 hours, 24 hours and 14 days daily) for samples of the fine particle nimodipin formulation to measure the in vitro release profile. The content was analyzed. An exemplary microparticle formulation is capable of releasing approximately 50% to 100% of nimodipine in vitro within a 6-14 day time frame. According to some embodiments, the microparticle formulation for intracapsular administration is mixed with a pharmaceutically acceptable carrier.</p><p>Administration Figure 14 is an exemplary diagram showing the application of a microparticle composition of the invention containing a calcium channel blocker, endothelin receptor antagonist, or TRP protein antagonist into the ventricles through an intraventricular catheter (Figure 14). Source: Mccomb JG: Techniques of CSF diversion. In: Scott RM (ed). Hydrocephalus. Vol. 3. Williams &amp; Wilkins: Baltimore. 1990. page 48, pp. 128). FIG. 15 shows a microparticle composition of the invention comprising a calcium channel blocker, an endoserine receptor antagonist, or a TRP protein antagonist, or a combination thereof, in or on the microparticles from the ventricles to the subarachnoid space. It is a schematic diagram showing that it is carried to the artery of the cavity (Pollay M: Cerebrospinal fluid. In: Tindall GT, Cooper PR, Barrow DL (eds). The Practice of Neurosurgery. Vol. 1. Williams &amp; Wilkins: Baltimore. 1996. page 36, pp. 1381). A microparticle nimodipine formulation (100 mg ventricle) was administered to treatment group 3 by syringe through a catheter (14 gauge to 18-ji) into the ventricles. The microparticle placebo composition was administered to Treatment Group 1 (placebo) and Treatment Group 2 (oral nimodipine) with excipients (eg, hyaluronic acid) by surgical injection into the cisterna magna of the subarachnoid space. Treatment group 2 (oral nimodipine) was administered the fine particle placebo composition on day 1 and then oral nimodipine capsules (0.86 mg / kg) 6 times daily until day 21. The syringe was loaded taking into account the overfill required to fill the dead volume in the delivery system. Controls were administered to the oral control and placebo groups as in the treated group. The dose of oral nimodipine is equal to 30 mg every 4 hours in humans when converting the dose based on body surface area, or 60 mg every 4 hours when converting the dose based on body weight (Reagan-Shaw, S. et al. et al., "Dose translation from animal to human studies revisited", FASEB J., 22: 659-661 (2008)). This dose was selected because it is associated with decreased blood pressure in dogs (Zabramski, J. et al., "Chronic cerebral vasospasm: effect of calcium antagonists", Neurosurgery, 18: 129-135 (1986)). For reconstitution / injection, a syringe containing the diluent was attached via a connector to the syringe containing the fine particle nimodipine formulation. For treatment groups 1 and 2, i.e., for intracisterna magna administration, the plunger is reciprocated to draw the excipient into the microparticle formulation. The resulting fine particle composition is then pushed into the left syringe and separated from the connector. For delivery, all compositions can be injected through a surgical needle or can be attached or injected by a suitable arbitrary size cannula or catheter.</p><p>Surgical procedure On day 1, all dogs were baseline evaluated, followed by angiography and infusion of autologous blood, 0.5 ml / g, into the cisterna magna. After blood injection, the microparticle placebo composition is injected into the cisterna magna of treatment group 1 animals (placebo) and treatment group 2 animals (oral nimodipine), and the microparticle nimodipine formulation is applied to treatment group 3 animals (ventricular nimodipine). It was injected into the right ventricle. After the infusion was complete, the animal was laid face down and its head tilted 30 ° down for 15 minutes. The animal was raised and returned to its cage. On day 3, blood injections (05 ml / kg) into the animal cisterna were repeated.</p><p>End points On days 8 and 15, animals were anesthetized, angiographically photographed, CSF removed from the cisterna magna and plasma collection repeated. Other end points included daily blood pressure measurements, behavioral assessments, and brain and spinal cord pathology. After angiography on day 15, the animals did not return from anesthesia. Animals were euthanized by anesthesia, perfused with phosphate buffered saline and then neutral buffered formalin, and the brain was subjected to histological analysis.</p><p>Angiography Angiographic spasms were evaluated by comparing the diameters of the basilar arteries on days 1, 8 and 15. Angiography was measured by a blind evaluator and analyzed by analysis of variance (ANOVA) between groups at each time and within time groups. Pairing with Kruskal-Wallis ANOVA by rank if the values were not distributed properly (Dunn's posttest method). For normally distributed data, pair comparisons were performed by the Holm-Sidak method for multiple comparisons. Equation (1) was used to quantify individual vascular spasm percentages in each animal on days 8 and 15.</p><p><img file="JP2014515744A_D0002.tif" /></p><p> The mean percentage of vascular spasms on days 8 and 15 compared to the diameter on day 1 of each group was also quantified. FIG. 16 shows dogs treated with placebo microparticle composition (placebo, n = 8), oral nimodipine plus placebo microparticle composition (oral nimodipine, n = 8), or 100 mg intraventricular nimodipine microparticles (n = 8). It is a bar graph showing the percentage change of the angiographic diameter of the basilar artery on the 8th and 15th days after subarachnoid hemorrhage (SAH) in. Analysis of variance showed little angiographic vasospasm on days 8 and 15 after SAH in dogs treated with intraventricular nimodipine microparticles (P &lt;0.05, values are mean ± standard error of mean). A comparison of the percentage changes in basilar artery diameter between the groups on day 8 showed significant differences (n = 8, P = 0.006 per group, Figure 16). By comparison, the group treated with 100 mg of intraventricular nimodipine microparticles compared to oral nimodipine (P &lt;0.05) or placebo microparticles alone (P &lt;0.05) showed angiographic vasospasm. There was also a significant difference between groups on day 15 (P = 0.001) and nimodipine (P &lt; There was little angiographic vasospasm in the placebo group that did not receive 0.05) and in the group treated with 100 mg of intraventricular nimodipine microparticles compared to oral nimodipine (P = 0.05). Significant angiographic vasospasm on days 8 and 15 in the group not receiving oral nimodipine (P = 0.001) and in the group treated with oral nimodipine (P &lt;0.001) However, there was no significant difference in the group treated with intraventricular nimodipine microparticles. Therefore, these data indicate that (1) sustained-release nimodipine microparticles in the ventricle reduce angiographic vasospasm and (2) there is no toxicity associated with intraventricular nimodipine microparticles containing 100 mg of nimodipine. ing.</p><p>Behavioral Observation Cahill, J. et al., "Vasospasm and p53-induced apoptosis in an experimental model of subarachnoid hemorrhage", Stroke, 37: 1868-1874 (2006). Behavior was assessed on a 3-component scale used to quantify drug treatment for. Observations on morbidity, mortality, injury, and food and water availability were made twice daily for all animals. Body weights were measured and recorded weekly before randomization and during the study. A complete physical examination was performed on all animals daily. Daily behavioral observations were performed on each animal recorded in the study. The behavior of each animal was examined daily. Behavioral scores related to behavioral classification of appetite, activity and neurological deficits were shown according to Table 2-4. Table 2 shows the behavioral scores shown for appetite.</p><p>Table 2. Behavioral scores for appetite<img file="JP2014515744A_D0003.tif" /></p><p> Table 3 shows the behavioral scores for the activity.</p><p>Table 3. Behavioral scores for activities<img file="JP2014515744A_D0004.tif" /></p><p> Table 4 shows the behavioral scores for neurological defects. The neurological defect recorded due to ataxia or paresis was the ability to walk.</p><p>Table 4. Behavioral scores for neurological deficits<img file="JP2014515744A_D0005.tif" /></p><p> Figure 17 shows dogs treated with placebo microparticle composition (placebo, n = 8), oral nimodipine plus placebo microparticle composition (oral nimodipine, n = 8), or 100 mg ventricular nimodipine microparticles (n = 8). It is a graph which shows the plot line of the averaged behavior score of the dog subjected to subarachnoid hemorrhage (SAH) in. The value is the mean ± standard error of the mean (n = 8 per measurement). There was no significant difference in behavior between groups in the time after SAH (Fig. 17, ANOVA).</p><p>Plasma and Cerebrospinal Fluid (CSF) Analysis Figure 18 plots plasma concentrations of nimodipine (ng / ml) in two groups treated with oral nimodipine (administered for 21 days [504 hours]) or intraventricular nimodipine microparticles. It is a graph which shows. Both groups had similar plasma concentrations and showed systemic exposure to nimodipine after intraventricular microparticle injection (values are mean ± standard error of mean [n = 8 per measurement]). FIG. 19 is a graph showing plot lines of CSF concentrations in cerebrospinal fluid (CSF) of nimodipine obtained from the cisterna magna in two groups treated with oral nimodipine or intraventricular nimodipine microparticles. The value is the mean ± standard error of the mean (n = 8 per measurement). Plasma and CSF concentrations of nimodipine demonstrated sustained release of nimodipine at higher concentrations in CSF than in plasma of the group treated with intraventricular nimodipine microparticles. CSF nimodipine levels were high and maintained in the therapeutic range for up to 15 days after SAH, but were low or undetectable when oral nimodipine was administered (FIGS. 18 and 19).</p><p>Histological observation FIG. 20 is a diagram showing a cross-sectional view used in a dog model experiment. Table 5 shows subarachnoid hemorrhage (SAH) in dogs treated with placebo microparticles (placebo), oral nimodipine plus placebo microparticles (oral nimodipine), or 100 mg intraventricular nimodipine microparticles recovered on day 28 or 49. It shows a summary of the macroscopic observations of the dogs that were used in the above. Animals are categorized according to whether the animal died or was euthanized (DOS) or the animal underwent scheduled autopsy (SNC).</p><p>Table 5: Summary of macroscopic observations<img file="JP2014515744A_D0006.tif" /></p><p> Table 6 shows subarachnoid hemorrhage (SAH) in dogs treated with placebo microparticles (placebo), oral nimodipine plus placebo microparticles (oral nimodipine), or 100 mg intraventricular nimodipine microparticles recovered on day 28 or 49. It shows a summary of the microscopic observations of the dogs used in the above. Animals are classified according to whether the animal died or was euthanized (DOS) or the animal underwent scheduled autopsy (SNC).</p><p>Table 6: Summary of microscopic observations<img file="JP2014515744A_D0007.tif" /><img file="JP2014515744A_D0008.tif" /><img file="JP2014515744A_D0009.tif" /><img file="JP2014515744A_D0010.tif" /></p><p>Equivalents Although the invention has been described with respect to its individual embodiments, it will be appreciated by those skilled in the art that various modifications can be made and that the equivalents can be replaced without departing from the true spirit and scope of the invention. It should be. In addition, many modifications may be made to use specific situations, materials, compositions, processes, process steps (one or more) for the objective spirit and scope of the invention. All such amendments are within the scope of the claims attached herein.</p>