Pharmaceutical composition for the treatment of psychotic diseases

The present invention relates to a pharmaceutical composition for the treatment of psychotic disorders and its use.

US 4804663 discloses 3-piperidinyl-1,2-benzizothiazoles and 3-piperidinyl-1,2-benzizoxazoles having antipsychotic properties. In particular, 3- [2- [4- (6-fluoro-1,2-benzisoxazol3-yl) -1-piperidinyl] ethyl] -6,7,8,9-tetrahydro-2-methyl-4H- pyrido [1,2-a] pyrimidin-4-one ( "risperidone"). U.S. Patent 5,158,952 discloses 3-pyrimidinyl-1,2-benzizoxazoles having long-acting antipsychotic properties. In particular, 3- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -6,7,8,9-tetrahydro-9-hydroxy is described -2-methyl-4H-pyrido] [1,2-a] pyrimidin-4-one ("9-hydroxy-risperidone").

A number of methods by which the compounds can be encapsulated as particles are known. In many processes, the encapsulation material is dispersed in a solvent containing a coating forming material. In a single step of the process, the solvent is removed from the microparticles and the product is then obtained as microparticles.

US 3737337 describes the preparation of a wall or shell polymeric material in a solvent that is only partially miscible with water. A solid or core material is dissolved or dispersed in the solution containing the polymer and thereafter, the solution containing the core material is dispersed in an aqueous liquid which is not miscible with the organic solvent to remove the solvent from the microparticles.

Another example of a process in which the solvent is removed from microparticles containing a substance is described in US Pat. No. 3523906. In this process an encapsulating material is emulsified in a solution of polymeric material in a solvent which is not miscible with water and then the emulsion is emulsified in an aqueous solution containing a hydrophilic colloid. Removal of the solvent from the microparticles is then performed by evaporation and the product is obtained.

In US 3691090, the organic solvent is evaporated from a dispersion of microparticles in an aqueous medium, preferably under reduced pressure.

Similarly, U.S. Patent No. 3891570 discloses a method wherein the solvent in a dispersion of microparticles in a polyhydric alcohol medium is evaporated from microparticles by heat application or by subjecting the microparticles to reduced pressure. Another example of a solvent removal process is shown in US 3960757.

US 4389840 describes the preparation of microparticles containing an active agent by a method comprising: (a) dissolving or dispersing an active agent in a solvent and dissolving a wall-forming material in a solvent, (b) dispersing the solvent containing the active agent and of the wall forming material in a continuous processing environment; (c) evaporation of a portion of the solvent from the dispersion of step (b), thereby forming microparticles containing the active agent in suspension; and (d) extracting the remaining solvent from the microparticles.

The problem to be solved by the invention is to establish the relationship between the components and their nature.

The invention relates to a composition containing biodegradable and biocompatible microparticles containing a 1,2-benzazole of formula (I):

<img file="RO119224B1_D0001.tif" />

or a pharmaceutically acceptable acid addition salt thereof, wherein:

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R is hydrogen or C 1-6 alkyl: R¹ and R² are independently hydrogen, halogen, hydroxy, alkyloxy and C 1-4 alkyl; X is O or S; Alk is CM diyl alloy; and R³ is hydrogen or C 50 -alkyl; Z is -S-, -CH2-, or -CR⁴= CR⁵-; where R⁴ and R⁵ are independently hydrogen or C 1-4 alkyl; A is a bivalent radical -CH₂CH₂-, -CHj-dȚ-CH, - or -CR⁶= CR⁷-; wherein R⁶ and R⁷ are hydrogen, halogen, amino or C 1-6 alkyl; and R⁸ are hydrogen or hydroxyl.

In the above definitions, the term "halo" is generic for fluorine, chlorine, bromine and iodine; "C 1-4 alkyl is intended to include straight or branched saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, and isomers thereof. . Alkandyl C 1 is intended to include linear or branched chain bivalent alkanediyl radicals having 1 to 4 carbon atoms, such as, for example, methylene, ethylene, propylene, butylene, and isomers thereof.

The advantage of the invention is that a composition is obtained which releases an efficient amount needed for treatment.

The composition of the present invention offers the advantage of having a duration of action ranging from 7 to more than 200 days, depending on the type of microparticle selected, in a preferred embodiment, the microparticles are designed so as to provide patients with a treatment. over a period of 14 to more than 100 days, in particular 14 to 50 65 or 60, or 30 to 60 days. The duration of the action can be controlled by manipulating the polymer composition, the polymer-drug ratio and the size of the microparticle. Another important advantage of the present invention is that practically all the active agent is released to the patient because the polymer used is degradable, thus allowing all the captured agent to be released to the patient. Within the invention, compounds are preferred wherein R³ is alkyl and in particular is methyl and A is a bivalent radical -CH₂CH₂-, -CH₂CH₂CH₂- or -CR⁶= CR⁷-; wherein R⁶ and R⁷ are independently hydrogen or C 1-4 alkyl. Particularly preferred compounds are those compounds in which X is oxygen, R¹ is halo or in particular hydrogen, and R²is hydrogen, halo, hydroxy or C 1-4 alkyloxy. 75

Particularly preferred are compounds in which -ZA- is -CH₂CH₂CH₂-CH2-, -S-CH ^ CH, -, -S- (CH&gt; V, S-CR⁶= CR⁷- or -CH = CH-CR⁶= CR⁷-, wherein R⁶ and R⁷ are independently hydrogen or methyl and R⁸ is hydrogen or 9-hydroxy.

Most preferred compounds are 3- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinylethyl] 6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidine-4-one ("Risperidone") and pharmaceutically acceptable acid addition salts 80 thereof.

The compounds of formula (I) may be prepared by the methods described in the patents

US 4804663 or 5158952.

The compounds of formula (I) have basic properties and, consequently, can be transformed into their non-toxic, therapeutically active addition salts by treatment with 85 suitable acids, such as, for example, inorganic acids, such as halohydric acid, for example hydrochloric acid, hydrobromic acid, and the like, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids, for example acetic acid, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanioic, propandioic, butandioic, (Z) -2 / butandioic, (E) -2-butandioic, 2-hydroxybutandioic, 2, 3-dihydroxybutandioic, 2-hydroxy-1,2,3-propantricarboxylic, methanesulfonic, 90 ethanesulfonic, benzenesulfonic, toluenesulfonic, cyclohexansulfamic, 2-hydroxybenzoic, 4-amino2-hydroxybenzoic, and other such acids.

The compounds of formula (I) are potential antagonists of several neurotransmitters and therefore have useful pharmacological properties. In particular, the compounds of formula (I) are mixed antagonists of serotonin and dopamine. consequently, they are useful as antipsychotics and 95 in the treatment of several conditions in which serotonin release is of predominant importance such as, for example, blocking serotonin-induced contractions in the level.

RO 119224 Β1 of bronchial tissue and blood vessels, arteries and veins. The therapeutic indications for the use of the present compounds are mainly in the CNS sphere, that is, as antipsychotic agents and therefore can be used to combat psychosis, in particular schizophrenia, aggressive behavior, anxiety, depression and migraine. In addition, the compounds of formula (I) are also useful as sedative, anxiolytic, anti-aggressive, anti-stress and muscle protective agents.

In the present, there is also provided a method of treating warm-blooded animals suffering from psychotic disorders, the respective method comprising systemic administration of an effective amount of a compound of formula (I) or an addition salt of acid, pharmaceutically acceptable thereof, microencapsulated in admixture with a pharmaceutical carrier. Alternatively, it is shown the use for the manufacture of a drug of the compound of formula (I) microencapsulated for the treatment of psychotic disorders. Or in another alternative, use of the micro-brushed formula (I) compound or a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutical carrier thereof in admixture with a pharmaceutical carrier for the treatment of the conditions psychotic. In general, it is considered that an effective amount of the active ingredient itself will be from 0.01 mg / kg to 4 mg / kg body weight, in particular, from 0.04 mg / kg to 2 mg / kg body weight. .

By the term "administered" as used herein, is meant any method of delivering the microparticles of the invention to a warm-blooded animal, such as, for example, parenteral administration (intravenously, intramuscularly or subcutaneously). By "microparticles" we mean solid particles containing an ingredient, here 1,2-benzazole, either in solution or in crystalline form. The active agent is dispersed or dissolved in the polymer that serves as a particle matrix.

In another aspect, the present invention relates to a method of inhibiting serotonergic or dopaminergic over-stimulation in warm-blooded animals, wherein the method comprises administering a biodegradable and biocompatible microparticle composition comprising a 1,2-benzazole of formula (I). ) in a polymeric matrix. Alternatively, the use of a drug, a biodegradable and biocompatible microparticle composition comprising a 1,2-benzazole of formula (I) in a polymeric matrix, for inhibiting serotonergic and dopaminergic over-stimulation in warm-blooded animals is described. Or use a biodegradable and biocompatible microparticle composition comprising a 1,2-benzazole of formula (I) in a polymeric matrix to inhibit serotonergic and dopaminergic over-stimulation in warm-blooded animals.

In another aspect, the invention relates to microparticles obtained from a biocompatible and biodegradable matrix containing a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof.

The compositions of this invention are useful for the treatment of mental illness in warm-blooded animals, preferably in mammals, especially in humans, (hereinafter referred to collectively as "patients") which comprises administering to such patients a of biodegradable microparticles loaded with a 1,2-benzazole, as described above.

The compositions of the present invention comprise microparticles intended for controlled release from a biocompatible, biodegradable matrix over an extended period of time of an effective amount of 1,2-benzazole of formula (I). They provide advantages over the compositions known in the art, such advantages comprising, among other things, that it is a biodegradable system, an injection system that prevents dose loss during treatment, the ability to mix particles containing different drugs and the ability to program release (multiphase release models) to give higher or lower drug delivery rates as needed.

In preferred embodiment, administration of 1,2-benzazoles to patients is accomplished by a single administration of drug-loaded microparticles, which deliver the drug constantly or intermittently in the patient and eliminates the need for repeated 150 injections.

The polymeric matrix material of the microparticles of the present invention is biocompatible and biodegradable polymeric material. The term "biocompatible" is defined as a polymeric material that is not toxic to the human body, is not carcinogenic and does not induce significant inflammation of body tissues. The matrix material must be biodegradable in the sense that the polymeric material must degrade through bodily processes into products that are readily removed from the body and do not accumulate in the body. Biodegradation products must also be biocompatible with the body in the sense that the polymeric matrix is ​​biocompatible with the body.

Suitable examples of polymeric matrix materials include polyglycolic acid, 160 poly-D, L-lactic acid, poly-L-lactic acid, their copolymers, aliphatic carboxylic acid polymers, copolioxalates, polycaprolactone, polydioxone, poly (ortho carbonates), polyacetals, lactic acid polymers and caprolactone, polyorthoesters, glycolic acid and caprolactone polymers, polyanhydrides, and natural polymers including albumin, casein and waxes such as mono- and glycerol distearate and the like. The preferred polymer for use in the practice of this invention is d / - (polylactide-co-glycolide), i.e. a copolymer of polyglycolic acid and polyD, L-lactic acid. It is preferred that the molar ratio of lactide to glycolide in such a polymer be in the range of about 85:15 to about 35:65, especially from about 75:25 to about 50:50, for example 85 : 15, 75:25, 65:35 or 50:50.

The amount of active ingredient incorporated into the microparticles is typically 170 from about 1% by weight to about 90% by weight, preferably 30 to 50% by weight, especially 35 to 40% by weight. By% by weight we mean parts of the agent relative to the total weight of the particle. For example, 10% by weight of agent would mean 10 parts of agent and 90 parts of polymer by weight.

The molecular weight of the polymeric matrix material is of some importance. The molecular weight must be large enough to allow the formation of satisfactory, polymeric coatings, that is, the polymer must be a good film maker. Usually, a satisfactory molecular weight is in the range of 5000 to 500,000 daltons, preferably from 50,000 to 400,000, especially from 100,000 to 300,000, in particular from 100,000 to 200,000, and in particular about 150,000 daltons. However, because the properties of the film 180 are also partially dependent on the particular polymeric material being used, it is very difficult to specify a suitable molecular weight range for all polymers. The molecular weight of the polymer is also important in terms of its influence on the biodegradation rate of the polymer. For a diffusion mechanism to release the drug, the polymer must remain intact until all 185 the drug is released from the microparticles and then degraded. The drug may also be released from the microparticles as the polymeric excipient erodes. By an appropriate choice of polymeric materials, a microparticle formulation can be obtained in which the resulting microparticles exhibit both diffusion release and biodegradation release properties. This is useful for obtaining multifaceted release models.

The particulate product of the present invention can be prepared by any method by which microparticles of acceptable size range can be produced for use in an injectable composition such as the methods described in US Pat. Nos. 4389330 and 4530840. A preferred method of preparation is the one described in the preceding patent and involves dissolving or dispersing the active agent in a suitable solvent. In the environment

Containing the agent, the polymeric matrix material is added in an amount relative to the active ingredient, which provides a product having the desired loading of the active ingredient. Optionally, all the ingredients of the microparticle product can be mixed together in the solvent medium.

Solvents for the agent and polymeric matrix material that can be used in the practice of this invention include solvents such as acetone; halogenated hydrocarbons, such as chloroform, methylene chloride and the like; halogenated aromatic hydrocarbon compounds; cyclic ethers; alcohols, such as benzyl alcohol; ethyl acetate and the like. A preferred solvent is a mixture of benzyl alcohol and ethyl acetate.

The mixture of ingredients in the solvent is emulsified in a continuous-phase processing medium, the continuous-phase medium being such that a microparticle dispersion containing the indicated ingredients is formed therein. Of course, the continuous processing environment and the organic phase must be as immiscible as possible. The most commonly used continuous processing medium is water, although non-aqueous media such as xylene, toluene and synthetic and natural oils can also be used.

Usually, a surface active agent is added to the continuous processing medium to prevent agglomeration and to control the size of solvent micropications in the emulsion. A preferred combination of surface-active dispersing medium is a solution of 0.1 to 10% by weight, especially 0.5 to 2% by weight polyvinyl alcohol in water. The dispersion is formed by mechanical agitation of the mixed materials. An emulsion can also be formed by adding small drops of solution of active agent - coating forming material to the continuous processing medium.

The temperature during the emulsion formation is not particularly critical, but it can influence the size and quality of the microparticles and the solubility of the agent in the continuous phase. Of course, it is desirable that in the continuous phase there is as little agent as possible. Moreover, depending on the solvent and the continuous-phase processing medium used, the temperature should not be too low, because otherwise the processing medium will solidify or become too viscous for practical purposes. On the other hand, it must not be so large that the processing medium evaporates or that the fluid of the processing medium is not maintained. Moreover, the ambient temperature cannot be so high that the stability of the particular active agent that is incorporated into the environment is adversely affected. Accordingly, the dispersion process can be conducted at any temperature that maintains stable operating conditions, preferably from about 20 ° C to about 60 ° C, depending on the selected agent and excipient.

The dispersion formed is stable and from this dispersion the fluid of the organic phase can be easily removed by ordinary techniques, such as heating, low pressure application, or a combination of the two. The temperature used to evaporate the solvent from the microparticles is not critical, but must not be so high that it degrades the agent used in the preparation of a particular microparticle or to evaporate the solvent at a rate sufficiently high to cause defects in the forming material. covering. Generally, in the first step it is removed from 10 to 90%, preferably 40 to 60% of the solvent. After the first step, the microparticles dispersed in the immiscible solvent in the fluid medium are isolated from the fluid medium by any convenient separation methods. Thus, for example, the fluid may be decanted from the microparticles or the microparticle suspension may be filtered. Various other combinations of separation techniques can be used, if desired.

After isolation of the microparticles from the continuous processing medium, the remaining solvent from the microparticles is removed by extraction. In this step, the microparticles may be suspended in the same continuous-phase processing medium used in step one, with or without surface active agent, or in another liquid. The extraction medium removes the solvent

RO 119224 Β1 from the microparticles, but does not dissolve them. During extraction, the extraction medium containing dissolved solvent should be removed and replaced with fresh extraction medium. This is best done on a continuous basis, in which the rate of completion of the extraction medium is critical. If the velocity is too low, crystals of the agent may emerge from the particles or increase in the extraction medium. Obviously, the rate of completion of the extraction medium for 250 for a given process is a variable that can be easily determined at the time the process is performed and therefore precise speed limits cannot be predetermined. After the remaining solvent has been removed, the microparticles are dried by exposure to air or other conventional drying techniques, such as, vacuum drying, drying on a desiccant, or the like. This process is very effective for encapsulating the agent, 255 because core loads of up to 80% by weight, preferably up to 50% by weight, can be obtained.

A more preferred method for encapsulating the active agent to form controlled-release microparticles of the present invention involves the use of static mixtures. Static or stationary mixers consist of a pipe or tube in which a number of static mixing elements are housed. Static mixers provide homogeneous mixing over a relatively short length of pipeline and in a relatively short period of time. In static mixers, it is the fluid that moves through the mixer and does not move any part of the mixer, such as a pallet, through the fluid. A static mixer is further described in US Pat. No. 4,511,258. 265

When, to form an emulsion, a static mixer is used, the size of the emulsion particle is determined by a variety of factors. These factors include the density and viscosity of the various mixing solutions or phases, the volume ratio of the phases, the interfacial tension between the phases, the parameters of the static mixer (pipe diameter, the length of the mixing element, the number of mixing elements) and the linear velocity 270 through the static mixer. Temperature is a variable because it affects density, viscosity and interfacial tension. The control variables are the linear speed, the shear rate and the pressure drop per unit length of the static mixer. In particular, the droplet size decreases as the linear velocity increases and the droplet size increases as the pressure drop decreases. The drops will reach a 275 dimension balance after a set number of elements for a given flow velocity. The higher the flow velocity, the fewer elements are required. Because of this relationship, switching from batches to lab scale to batches to industrial scale is safe and accurate, and the same equipment can be used for both lab and industrial batches. 280

To create microparticles containing an active agent, an organic phase and an aqueous phase are combined. The organic and aqueous phases are largely or substantially immiscible with the aqueous phase which constitutes the continuous phase of the emulsion. The organic phase includes an active agent as well as a polymer or polymeric matrix material, coating maker. The organic phase may be prepared by dissolving an active agent in an organic solvent or other suitable solvent 285, or by forming a dispersion or an emulsion containing the active agent. Preferably, the organic phase and the aqueous phase are pumped such that the two phases flow simultaneously through the static mixer, thus forming an emulsion comprising the microparticles containing the active agent encapsulated in the polymer matrix material. The organic and aqueous phases are pumped through the static mixer into a large volume of coolant. Coolant 290 may be plain water or a solution in water or other suitable liquid. The organic solvent can be "removed from the microparticles while they are washed or stirred in the coolant. After the particles are washed in the coolant to extract or remove the organic solvent, they are isolated, for example by a sieve and dried.

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A laboratory assembly for performing a static mixing process is illustrated in fig.1. An organic or oily phase 30 is prepared by dissolution and, optionally, by heating an active agent and a matrix polymer material or a polymer in a stirred vessel 32 on a hot plate. However, the process of the present invention is not limited to the preparation of the organic phase 30 by dissolving an active agent. Alternatively, the organic phase 30 may be prepared by dispersing an active agent in a solution containing a polymeric matrix material. In such a matrix, the active agent is only readily soluble in organic phase 30. Alternatively, organic phase 30 may be prepared by preparing an emulsion containing an active agent and a matrix polymeric material (double emulsion process). In a double emulsion process, a primary emulsion containing an active agent and a polymeric matrix material (organic phase 30) is prepared. The primary emulsion can be a water-in-oil emulsion, an oil-in-water emulsion or any suitable emulsion. The primary emulsion (organic phase 30) and an organic phase are then pumped through a static mixer to form a second emulsion comprising microparticles containing the active agent encapsulated in the polymeric matrix material.

Organic phase 30 is pumped out of the vessel 32 by a magnetically driven gear pump 34. Discharging the pump 34 feeds a în ”connection 36, a branch

361 of connection Ύ ”36 returns to vessel 32 through a recirculation flow. The other branch

362 feeds a static static mixer 10. The aqueous or water phase 40 is prepared in a similar manner, with a stirred vessel 42, a magnetically driven gear pump 44 and a pipe in Ύ ”46. A branch 461 of the pipe 46 returns to vessel for recirculation flow. The other branch 462 feeds to a static mixer 10 mounted in parallel. Organic phase 30 and aqueous phase 40 are practically immiscible.

Branches 362 and 462 of each solution which feeds the static mixer 10 mounted in parallel are joined by another connection in Ύ 50 and feed through the inlet pipe 51 of the mixer, the static mixer 10. The static mixer 10 is discharged through the outlet pipe 52 a mixer in the washing tank 60. In the system illustrated in fig. 1, silicone pipes and polypropylene gaskets are used. For all pipes, silicone tubes with Dl 9.53 mm are used, except for the drain pipe 52. For the drain pipe 52, a smaller diameter tube (Dl 4.76 mm) is used to prevent the emulsion from breaking in both the pipe. mixer outlet 52 as well as after entering the wash tank 60.

In a embodiment of the process, the pumps 34 and 44 are recirculated and the desired flow rates for the organic phase 30 and the water phase 40 are matched. Preferably the flow rate of the aqueous phase 40 is greater than the flow rate of the organic phase. However, the two flow rates can be substantially the same. The ratio of the flow rate of the aqueous phase 40 to the flow rate of the organic phase 30 is preferably in the range of 1: 1 to 10: 1. Then, the connection Ύ ”46 is switched so that the aqueous phase flows through the branch 462 to the static mixer 10. Once the aqueous phase 40 fills the inlet pipe 51, the static mixer 10 and the outlet pipe 52, the connection Ύ” 36 is switched so that the phase organic 30 flows through the branch 362 of the static mixer 10. Organic phase 30 and the aqueous phase 40 now flow simultaneously through the static mixer 10. When the desired volume of organic phase has been pumped into the static mixer 10, the connection to "Y", 36 is switched to recirculation through the branch 361. The aqueous phase 40 continues to flow for a short period of time to clean any remaining organic phase. which remains in the mixer inlet 51, in the static mixer 10 and in the mixer outlet 52. The "Y" connection 46 is then switched to recirculation through the branch 461.

Organic phase 30 and aqueous phase 40 are mixed in the static mixer 10 to form an emulsion. The emulsion formed comprises microparticles containing the active agent encapsulated in the polymeric material of the matrix.

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The microparticles produced by the method of the present invention are usually of spherical shape 345, although they may also have an irregular shape. The microparticles produced by the method of the present invention may vary in size, ranging in diameter from submicron to millimeter. In a preferred embodiment of the present invention, the static mixing elements 14 of the static mixer 10 are selected such that the size range of the microparticles is from 1 to 500 μ (μηι), preferably 25 to 180 μ, in particular 60 350 to 120 μ, for example 90 μ. The microparticles can be agitated in the wash tank 60 which contains a coolant. The microparticles can be isolated from the coolant using a sieve column. The microparticles can be dried using standard drying techniques and additional dimensional insulation can be made.

The microparticles carrying the active agent are obtained and stored as dry magterial. Prior to administration to a patient, dried microparticles may be suspended in a pharmaceutically acceptable liquid carrier, preferably a 2.5 wt% carboxymethylcellulose solution, after which the suspension is injected into the desired body portion. The microparticles may be mixed according to size or type to release the active agent in a multi-phase manner and / or in a manner that gives the patient different agents at different times or a 360 mixture of agents at the same time.

In vitro measurement studies that measure the release of risperidone from the microparticles of this invention show an almost constant release of risperidone over a long period of time. Similarly, in vivo studies in dogs in which the microparticle formulation of the invention is dosed intramuscularly, in particular the formulation described in the following examples, show near-constant and long-lasting plasma concentrations of the active agent.

The following are examples of embodiments of the invention:

Example 1. Preparation of Microparticles theoretically charged with 35% risperidone (Prodex Country 2). 370

First, the aqueous phase (solution A) is prepared by weighing and mixing 906.1g 1% polyvinyl alcohol (Vinyl 205 ™, Air Products and Chemical Inc.), 29.7 g benzyl alcohol and 65.3 g ethyl acetate. . Then the organic phase (solution B) is prepared by dissolving 29.3 g dl (polylactide-co-glycolide), 75: 25 high viscosity in 108.7 g of ethyl acetate and 108.7 g of benzyl alcohol. Once the polymer is completely dissolved, 15.7 g of risperidone base is added and 375 is dissolved in the polymer solution. The exposure time of risperidone dissolved with the polymer is kept to a minimum (&lt;10 min). Then solutions A and B are then pumped through a static mixer with a diameter of 6.35 mm through a pump with gear wheels and head. L07002-16) with flow rates of 198 and 24 ml / minute respectively, in a cooling mixture composed of 55 liters of water for injection containing 1276.0 g of ethyl acetate, 92.3 g (0.02 molar ) bicarbo- 380 nat anhydrous sodium and 116.2 g (0.02 molar) anhydrous sodium carbonate at 11 ° C. The microparticles are allowed to stir in the first wash water for 1.75 h, then isolated by sieve with a 25 μ sieve. The retained product is transferred into a 25 liter washing solution at 13 ° C. After stirring in the washing solution of the citrate for 2.25 h, the microparticles are isolated and fractionally dimensioned by sifting through a column with stainless steel mesh with 385 25- and 180-μ mesh dimensions. The microparticles are dried overnight, then collected and weighed.

Example 2. Preparation of theoretically charged microparticles with 40% risperidone (Prodex Country 3)

The aqueous phase (solution A) is first prepared by weighing and mixing 904.4g 390 of 1% polyvinyl alcohol (Vinyl 205 ™, Air Products and Chemical Inc), 30.1 g of benzyl alcohol and 65.8 ethyl acetate. Then, the organic phase (solution B) is prepared by dissolving 27.1 g dl (polylactide-co-glycolide) 75:25 of high viscosity in 99.3 g of ethyl acetate and 99.1 g of

RO 119224 Β1 benzyl alcohol. Once the polymer is completely dissolved, 18.1 g of risperidone base is added and dissolved in the polymer solution. The exposure time of risperidone dissolved with the polymer is kept to a minimum (&lt;10 min). Solutions A and B are then pumped through a static mixer with a diameter of 6.35 mm, a pump with gear wheels and a head with a flow rate of 198 and 24 ml / minute respectively and in a cooling solution composed of 55 liters of water for injection containing 1375.6 g of ethyl acetate, 92.4 g (0.02 molar) anhydrous sodium bicarbonate and 116.6 g (0.02 molar) anhydrous sodium carbonate at 12 ° C. The microparticles are allowed to stir in the first wash water for 2 h, then isolated by sieve with a 25-μm sieve. Then the product retained on the screen is transferred into 20 liters of washing water at 12 ° C. After stirring in the solution with the seating for 3 hours, the microparticles are isolated and fractionated by sifting through a stainless steel sieve column composed of 25- and 180mesh dimensions. The microparticles are dried overnight, then collected and weighed.

Gamma-ray lyophilization and irradiation of the microparticles in the Prodex 2 and Prodex 3 batches (Prodex 4A, Prodex 4B and Prodex 4C samples)

The microparticles in the Prodex 2 and Prodex 3 batches are lyophilized. The microparticles are weighed in 5 cm serum vials³. Then an aqueous vehicle consisting of 0.75% CMC, 5% Manitol and 0.1% Tween 80 ™ is added to the vials. The microparticles are suspended in the vehicle by shaking, then quickly frozen in a dry ice / acetone bath. The vials are then lyophilized in a pilot-scale lyophilizer using a graded cycle at a maximum temperature of 30 ° C for 50 hours. Prodex 4A and Prodex 4C samples are lyophilized samples from Prodex 2 and Prodex 3 respectively. The Prodex 4B sample is lyophilized from Prodex 2 which was subsequently sterilized by irradiation with 2.2 Mrad Gamma from a 60 Co. source.

In vivo study

The duration of action of formulations based on risperidone microparticles is studied in the test in dogs who were induced with apomorphine. Neuroleptics are known to antagonize apomorphine-induced emesis by blocking dopamine D2 receptors in the posterior area of ​​the fourth ventricle. The test is generally used to demonstrate the timing of action and the duration of antipsychotic action of neuroleptics in humans. (Janssen et al., Arzneim-Forsh./Drug /? Es. 15: 1196-1206 (1979)).

9-OH-risperidone has a pharmaceutical profile that is virtually identical to that of risperidone.

Both together constitute the "active radical" that determines the biological activity of risperidone.

Apomorphine is administered subcutaneously at a dose of 0.31 mg / kg in dogs twice weekly throughout the experiment. In dogs, vomiting is observed for a period of 1 hour after administration of apomorphine. The complete absence of emesis for 1 hour after apomorphine administration is considered to reflect significant antiemetic activity. The duration of the antiemetic action is defined as the time interval during which 2 out of 3 dogs are protected from emesis.

The formulations are injected in a volume of 0.5 ml into the femur of the biceps of one of the hind legs at the thigh level. At various intervals after intramuscular injection, blood samples are taken and immediately afterwards, the dogs are given a dose of apomorphine. The complete absence of emesis for 1 hour after administration of apomorphine (which is never observed in control animals; n&gt; 1000) is considered to reflect significant antiemetic activity.

Table 1 indicates whether dogs are protected (+) or unprotected (-) by apomorphine-induced emesis at various time intervals after intramuscular injection of dhr formulations of this invention. All the formulations show an immediate installation of the antiemetic action.

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RO 119224 Β1

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<td>Prodex 4C</td><td> 13,2 16,4 16,2</td><td>rt I o rt IO o ' «I o *</td><td> 2,4 2,4 2,5</td><td>im im im</td><td> + + +</td><td> + + +</td><td> + + +</td><td> + + +</td><td> + + +</td><td> + + +</td><td> + + +</td><td> + + +</td><td> + + +</td><td> + + +</td><td> + + +</td>

<td>that</td><td>co¹ a</td><td>rt IO A*</td><td>IO CM *</td><td>E</td><td> +</td><td> +</td><td> +</td><td> +</td><td> +</td><td> +</td><td> +</td><td> +</td><td> +</td><td> + -</td><td> +</td>

<td>X φ T&gt;</td><td>co 00</td><td>IO o '</td><td>ΜCM *</td><td>E</td><td> +</td><td> (</td><td> +</td><td> 1</td><td></td><td> 1</td><td> +</td><td> +</td><td> +</td><td> +</td><td> +</td>

<td>IT- Q.</td><td>bσ&gt;</td><td>rt IO o '</td><td>MCM</td><td>E</td><td></td><td> +</td><td> +</td><td> 1</td><td></td><td></td><td> 1</td><td> +</td><td> +</td><td> +</td><td> +</td>

<td></td><td>CM</td><td>&lt;a</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> &lt;</td><td>the CO</td><td>• oo '</td><td>IO CM *</td><td>E</td><td> +</td><td> +</td><td> +</td><td>and</td><td> 4</td><td> *</td><td> +</td><td> +</td><td> +</td><td> +</td><td> +</td>

<td>X Φ</td><td>CM *</td><td>IO</td><td> 5.</td><td>E</td><td> +</td><td> +</td><td> +</td><td> +</td><td> 1</td><td> +</td><td> +</td><td> +</td><td> +</td><td> +</td><td> +</td>

<td>•a</td><td>T</td><td>a</td><td>CM</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>or ία.</td><td>oo</td><td>or in</td><td>Φ cm</td><td>E</td><td> +</td><td> +</td><td> +</td><td> +</td><td>t</td><td> +</td><td> +</td><td> +</td><td> +</td><td> +</td><td> +</td>

<td></td><td></td><td>a'</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>M</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>CO</td><td>CO *</td><td>IO o '</td><td>IO CM *</td><td>E</td><td> +</td><td> +</td><td> +</td><td> +</td><td> +</td><td> +</td><td> +</td><td> +</td><td> +</td><td> +</td><td> +</td>

<td>φ n 2</td><td>M CM</td><td>CO IO o '</td><td>vr CM *</td><td>E</td><td> +</td><td> +</td><td> +</td><td></td><td> +</td><td> +</td><td> +</td><td> +</td><td> +</td><td> +</td><td> +</td>

<td>CL</td><td>CD</td><td>CO in</td><td rowspan="2">CM</td><td>E</td><td> +</td><td> +</td><td> +</td><td> +</td><td> 1</td><td> +</td><td> +</td><td> +</td><td> +</td><td> +</td><td> +</td>

<td></td><td>CM</td><td>a'</td><td> *</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> 00</td><td>co</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>CM X</td><td>CD* IO</td><td>mo</td><td>IO CM *</td><td>E</td><td> 1</td><td> +</td><td> +</td><td> +</td><td></td><td></td><td></td><td></td><td></td><td> +</td><td> +</td>

<td>Φ σ o</td><td></td><td>IO o '</td><td>cm</td><td>E</td><td> +</td><td> +</td><td> +</td><td> 4</td><td>I</td><td> 4</td><td></td><td></td><td></td><td> +.</td><td> +</td>

<td> 0-</td><td>CM M^-</td><td>&lt;0 in</td><td>M CM *</td><td>E</td><td> +</td><td> +</td><td> +</td><td> 1</td><td> 4</td><td> 4</td><td></td><td></td><td></td><td> +</td><td> +</td>

<td></td><td>T ~</td><td>a*</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>CD</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>Φ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>c</td><td>A)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>Φ</td><td>&lt;ro</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>E ιΟ LL</td><td>C A Φ</td><td>A £</td><td>A) • ra</td><td>O</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>Inquiry</td><td>E</td><td>N</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>A</td><td>a</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>Φ</td><td>a</td><td>Q</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> 0</td><td> &gt;</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Ό</td><td>Ί3</td><td> 73</td><td> 73</td><td> 73</td><td> 73</td>

<td></td><td></td><td></td><td></td><td></td><td>_c</td><td>--C</td><td>TJ</td><td>A</td><td>Π</td><td>V</td><td>M *</td><td>co</td><td></td><td>IO</td><td>CD</td>

<td></td><td></td><td></td><td></td><td></td><td>T "</td><td>IO</td><td></td><td>M *</td><td>b-</td><td>v-</td><td></td><td></td><td>CM</td><td>CM</td><td>CM</td>

OD 't

CN CN O

The gold

<img file="RO119224B1_D0004.tif" />

LO &lt;o

<td>Prodex 4C</td><td> 13,2 16,4 16,2</td><td>(0 IO θ ' &lt;a IO O there I am</td><td> 2,4 2,4 2,5</td><td>im im im</td><td> + + +</td><td> + + +</td><td> + + +</td><td> + +</td><td> 1 + +</td><td>1 «D + + +</td><td> 1 + 1</td><td>t 1</td><td>Stop</td>

<td></td><td rowspan="2"> 10,6</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>4B</td><td>IO o '</td><td> 2,5</td><td>E</td><td> +</td><td> +</td><td> 1</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>ex</td><td>co</td><td>IO</td><td></td><td>E</td><td> +</td><td> +</td><td> 1</td><td>and</td><td> 1</td><td></td><td></td><td></td><td></td>

<td>Ό</td><td>oo '</td><td>a'</td><td>CM</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>2 CL</td><td>rσ&gt;</td><td>« I o</td><td>T cm '</td><td>E</td><td> +</td><td> +</td><td> 1</td><td> 1</td><td> 1</td><td>CL</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>A</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>• 4-J</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>co</td><td></td><td></td><td></td>

<td></td><td>CM</td><td>"a</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>4A</td><td>σΓ co</td><td>in o</td><td> 2,5</td><td>E</td><td> +</td><td> +</td><td> 1</td><td> 1</td><td> 1</td><td></td><td></td><td></td><td></td>

<td>ex</td><td>CM</td><td>IO</td><td></td><td>E</td><td> +</td><td> +</td><td> +</td><td> 1</td><td> «</td><td></td><td></td><td></td><td></td>

<td>TJ</td><td></td><td>a</td><td>CM</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>A L_ CL</td><td> 10,0</td><td>n IO a'</td><td> 2,4</td><td>E</td><td> +</td><td> +</td><td> +</td><td> +</td><td> 1</td><td>and 1</td><td>top</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> 1</td><td>co</td><td></td><td></td>

<td></td><td>M</td><td>&lt;a</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td rowspan="2">odex 3</td><td>CD</td><td> 0,5</td><td> 2,5</td><td>E</td><td> +</td><td> +</td><td> +</td><td> +</td><td> 1</td><td></td><td></td><td></td><td></td>

<td> 12,4</td><td>co IO_ o '</td><td> 2,4</td><td>E</td><td> +</td><td> +</td><td> 1</td><td></td><td> 1</td><td></td><td></td><td></td><td></td>

<td>CL</td><td>CD</td><td>co IO</td><td rowspan="2"> 2,4</td><td>E</td><td> +</td><td> +</td><td> +</td><td> +</td><td> +</td><td>¹</td><td></td><td></td><td></td>

<td></td><td>CM</td><td>a'</td><td> *</td><td></td><td></td><td></td><td></td><td></td><td></td><td>CL</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>a</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>co</td><td></td><td></td>

<td></td><td> 00</td><td>co</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>CM X</td><td>σί IO</td><td>IO o</td><td> 2,5</td><td>E</td><td> +</td><td> +</td><td> +</td><td> 1</td><td> 1</td><td></td><td></td><td></td><td></td>

<td>ode</td><td></td><td>IO o '</td><td> 2,4</td><td>E</td><td> +</td><td> +</td><td> +</td><td> 1</td><td> 1</td><td></td><td></td><td></td><td></td>

<td>IT. 0.</td><td> 14,2</td><td>ro IO o</td><td> 2,4</td><td>E</td><td> +</td><td> +</td><td> 1</td><td>¹</td><td>¹</td><td>CL</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>A</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>co</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>A)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> &lt;1)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>c.</td><td>A)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>&lt;D</td><td>&lt;ffi</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>c</td><td>Q</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Form.</td><td>how about you</td><td> £</td><td>I have G</td><td>way</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> 05</td><td>c</td><td>N</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> ♦-»</td><td>D</td><td>A</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>ZJ 0)</td><td>a</td><td>Q</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>k_</td><td> &gt;</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> 0</td><td></td><td></td><td></td><td>Ό</td><td>T5</td><td>Ό</td><td>TS</td><td>T5</td><td>Ό</td><td>Ό</td><td>Ό</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>CM</td><td>IO</td><td>CD</td><td>CM</td><td>(A</td><td>CD</td><td>CO</td><td>CO</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>CO</td><td>CO</td><td>CO</td><td>tut</td><td>T</td><td>tut</td><td>IO</td><td>IO</td><td></td>

o 'cr I

<img file="RO119224B1_D0005.tif" />

a

RO 119224 Β1