Osmotic system with instant drug availability

The present invention relates to an osmotic device for the delivery of an active substance, except for drugs. The device provides the possibility of programmed release of an active agent which is initially delivered in an increased effective amount, followed by delivery of the active agent at a controlled rate during a certain period of time corresponding to the requirements.

Osmotic systems are known from U.S. Patents 3,845,770 and 3,916,899, both to the inventors Felix Theeuwes and Takem Higuchi. The osmotic systems disclosed in these pioneer patents consist of a semipermeable wall surrounding a container containing a drug. The wall is permeable to the passage of an external fluid and is impermeable to the passage of the drug and has a passageway through the semipermeable wall to deliver the drug from the osmotic system. These systems are exceptionally effective for delivering a drug which is soluble in the fluid, and the devices are also suitable for delivery of a drug having only limited solubility in the fluid, which drug is mixed with an osmotically active compound which in the liquid is soluble and produces an osmotic pressure gradient through the wall against the liquid. The osmotic systems release the drug by passing liquid through the semipermeable wall into the container. at a rate determined by the permeability of the semipermeable wall and by the osmotic pressure gradient across the wall to yield a solution of the soluble drug or a solution of a soluble compound containing the drug, which solution in each case is administered at a controlled rate a prolonged period of time.

Unexpected and surprising progress in the context of osmotic systems has been made by Felix Theeuwes and Atul D. Ayer in U.S. Patent 4,008,719; 4,014.334; 4,058.122; 4,116.241; 4,160.452; and 4,256,108. According to these patents, osmotic systems consisting of a two-layered wall are provided, and the like. tw. a semipermeable layer and a microporous layer, which walls cooperate in a controlled manner to deliver the drug in a controlled manner over a prolonged period of time. The two layers retain their physical and chemical cohesiveness during the controlled release of the drug, and the layering allows a broader control over the rate at which the drug is delivered to a drug receiving site for a prolonged period of time.

Although the above-mentioned osmotic systems consisting of a single layer of semipermeable wall and the osmotic systems consisting of the multi-layered wall consisting of a semipermeable layer and a microporous layer represent extraordinary and fundamental advances in osmotic delivery technology and, although these systems for the delivery of numerous drugs are useful to the treatment environment, has now been found that these osmotic systems can be further improved, to further increase the kinetics of delivery of an agent and the usefulness of the osmotic systems. Accordingly, it has surprisingly been found that osmotic systems can be provided which initially deliver an active ingredient in an increased amount, followed by delivery at a substantially constant rate and controlled rate over time. In this manner, the active ingredient is readily available and will become available often eliminates the startup time required for the delivery of some drugs by osmotic systems. The instant osmotic systems of the present invention, followed by the controlled and constant sustained release, operate according to a preselected optimal incorporation program of a drug composition.

Accordingly, the present invention relates to the provision of an osmotic device for the delivery of an active substance - except for drugs, characterized by a wall enclosing a chamber for containing an active substance, which wall, at least in part, consists of a material which is permeable to the passage of an ambient liquid present in the environment of use of the device and impermeable to the active substance in the chamber and is capable of receiving an active substance, which is released from the wall, when the device is in a fluid of the environment of use, and has a passage, which communicates with the chamber and with the outside environment of the device.

According to one embodiment of the invention, the wall is formed of a semipermeable material containing the active ingredient.

According to another embodiment of the invention, the wall is a laminate that surrounds the chamber and consists of a semipermeable layer and a microporous layer.

According to a further embodiment of the invention, the wall is a laminate surrounding the chamber, which consists of a semipermeable layer and a water-soluble layer, the latter containing an active substance.

According to a further embodiment of the invention, the wall is a laminate surrounding the chamber, which consists of a semipermeable layer, a microporous layer and an outer water-soluble layer containing an active ingredient.

According to a further embodiment of the invention, the wall is a chamber surrounding the chamber

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A laminate formed of a layer formed of a semi-permeable material, a layer formed of a microporous material containing an active agent and a layer formed of a material containing an active agent

The active ingredient is preferably a biocide that creates an osmotic pressure gradient through the wall against a liquid present in the environment of use.

In the drawings, which are not to scale, various embodiments of the invention are explained in more detail, wherein the figures have the following meaning:

FIG. 1 Figure 3 is an isometric view of an osmotic device for delivering an active agent to a use environment; FIG. 2 is an open view of an osmotic device of FIG. 1, wherein in FIG. 2 the construction of the osmotic device is shown; FIG. 3 Figure 10 is an open view of the osmotic device illustrating the semipermeable wall carrying an outer, fluid-soluble, drug-containing layer; FIG. 4 shows an osmotic device with a portion removed to illustrate the internal structure, the layered wall having an outer layer containing the active agent; 5 shows an osmotic device with a portion removed to illustrate the osmotic device receiving container with the coated wall coated with a water soluble drug-containing layer; FIG. 6 is an open-sectional osmotic device showing the device with a microporous drug-containing layer and an outermost drug-containing water-soluble layer; FIG. 7 shows an osmotic device for delivering the drug to a use environment; FIG. 8th shows the osmotic system of FIG. 7, the wall being partially broken off to highlight the structural details; FIG. 9 Figure 11 illustrates the profile of the delivery rate for an osmotic device according to the present invention; FIG. 10 shows a laminate consisting of a semipermeable layer, which is applied to a drug containing the rapid release layer.

For example, the various osmotic devices illustrated in the drawings represent embodiments of the invention only, without thereby limiting the invention. The in Fig. 1 The illustrated osmotic device (10) comprises a body (11) which may be appropriately shaped, sized, adapted and constructed for ease of placement and prolonged residence time in a use environment for the purpose of controlled delivery of an active agent to the latter. The osmotic device (10) has a wall (12) with a passage (13) through the wall (12) for connecting the inside of the osmotic device (10) to the outside environment of the osmotic device (10).

In Fig. 2 the osmotic device (10) according to FIG. 1 is illustrated in the open section. According to FIG. 2 For example, the osmotic device (10) comprises a body (11) and a semi-permeable wall (12) enclosing a chamber (14). The wall (12) is made of a semipermeable polymer which is permeable to the passage of the external fluid and substantially impermeable to the passage of active agents and osmotically active agents. The wall (12) contains an active agent (15) represented by dots, which is released from the wall (12) immediately or in a short time when the device (10) is in a use environment. The wall (12) of the device (10 ) is substantially inert and maintains its physical and chemical integrity during drug delivery. The wall is made of a semi-permeable material. The passage (13) in the wall (12) connects the chamber (14) to the external environment of the device (10). The chamber (14) serves to receive an active substance (16) which is soluble in an outer liquid (17) represented by dashes, which is fed through the semipermeable wall (12) into the chamber (14), and through the wall (14). 12) generates an osmotic pressure gradient against the external fluid. The chamber (14) optionally contains an osmotically effective dissolved additive substance (18), which is represented by wavy lines and is soluble in the liquid and generates an osmotic pressure gradient through the wall (12)

During use of the device (10) according to Figures 1 and 2, which is made in the form of an osmotic tablet, upon entry of a liquid of the environment of use, such as in a urine collection bag, initially the active agent (15) from the wall becomes the environment of use issued. This initial release of the active agent (15) makes it readily available to the environment of use and avoids the start-up time required before the drug can be delivered from the device (10). Delivery of the active ingredient (15), usually for a period of one or more hours, is independent of delivery of the active agent (16) by the device (10). The device (10) may release the active agent (16) during the period of time during which the active substance (15) is dispensed, or the device (10) causes the release of the active substance (16) only after the release of the active substance (15 ). The active ingredient (15) and the active ingredient (16) may optionally be the same or different active ingredients.

The osmotic device (10) sets the drug (16), which is contained in the chamber (14), by sucking liquid into the chamber (14), there is a tendency for osmotic equilibrium and release occurs at a rate which is controlled by the permeability of the semipermeable wall (12) and by the osmotic pressure gradient through the semipermeable wall (12), wherein a continuous solution of the active substance (16) takes place, which is osmotic from the chamber (14) through the passageway (13) at a controlled and continuous rate for a prolonged period of time

-3AT397 179B is pumped out. The osmotic device (10) is also suitable for the release of an active substance (16), which has only a limited solubility in the liquid (17) and is mixed with an osmotically active compound (18) through the liquid sucked into the chamber compartment (14) by the semipermeable wall (12), where there is a tendency to osmotic equilibrium and delivery occurs at a rate which is controlled by the permeability of the wall (12) and the osmotic pressure gradient through the wall (12), in order to continuously dissolve the osmotically active compound (18) and to form a solution containing the active substance (16) thereof, which is discharged from the device (10) through the passage (13) at a controlled and continuous rate for a prolonged period of time.

The Fig. 3 shows another osmotic device made in accordance with the present invention for the delivery of an active agent to a use environment. According to the drawing in which a part has been cut away from the device (10), the device consists of a body (11), a semipermeable wall (12), a passage (13) and a chamber (14) containing the active substance (16) ), in which liquid (17) has been sucked in, as well as from an osmotically active compound (18). The device (10) according to FIG. 3 further has a layer (19) which is applied to the outer surface of the semipermeable wall (12). The layer (19) is made of a water-soluble material, an aqueous disintegrant or the like. and contains the active substance (20). The layer (19) containing the active agent (20) is provided to immediately make the active agent (20) available. During use, when the device (10) is in a fluid environment, the layer (19) is dissolved or solubilized while concurrently delivering the active agent (20) to a use environment. The layer (19) containing the active agent (20), by causing an immediate release of the drug, allows to bridge the time necessary for delivery of the active agent (16) from the device. Often, it is necessary to draw in the liquid through the semipermeable wall (12) and to hydrate a fluid-entrained agent (17) which has lost its water of hydration during the drying or solvent evaporation processes used in the manufacture of the device (10). The layer (19) containing the active substance (20) operates independently of the device (10) which, as described in connection with FIG. 2 described, the drug (16) releases. Although Figs. 3 a layer (19) containing the active substance (20) and FIG. 2 a semipermeable wall (12) containing the active substance (15), it is obvious that the invention also comprises an osmotic device (10) consisting of a semipermeable wall containing the active substance (15) coated with an active substance (20). containing layer (19).

The Fig. 4 shows in an open view an osmotic device (10), which consists of a body (11) and a layered wall (21), which encloses the receiving chamber (14). The layered wall has a portal or passage (13) connecting the chamber (14) to the outside environment of the osmotic device (10). The chamber (14) contains an agent (16) which is soluble in the external fluid (17) which is aspirated through the layered wall (21), the agent (16) passing through the layered wall (21) against the exterior Optionally, the chamber (14) contains a drug (16) of limited solubility in the fluid and is present in the chamber (14) with an osmotic solute additive (18). The dissolved additive substance (18) is soluble in the liquid and creates an osmotic pressure gradient through the layered wall (21).

The layered wall consists of a semipermeable layer (22) forming the inner layer opposite the chamber (14) and a microporous layer (23) remote from the chamber (14), in the osmotic device of FIG. 4 the microporous layer (23) forms the outer layer which is exposed to the environment of use. The semipermeable layer (22) is permeable to the passage of an external fluid and substantially impermeable to the passage of active agent. The semipermeable layer (22) is made of a material which retains its physical and chemical integrity in the presence of the active agent, an osmotically active agent and the liquid, and is substantially non-erodible and inert. The layer may be thin to thick, at the same time permeability to liquid aspirated by the osmotic device (10) is controlled. The microporous layer (23) in one embodiment acts as a support or rigid structure for the semipermeable layer (22), especially when the latter layer (22) is thin. The microporous layer (23) may have preformed micropores or it may contain a micropore former, which will be described later. In this embodiment, the microporous layer (23) is generated in situ by wetting with the surrounding liquid and dissolving the pore-forming agent, the latter emerging and forming a microporous layer (23). The microporous layer (23) is permeable to the passage of liquid and the material forming the microporous layer (23) and containing the pore former maintains its physical and chemical integrity in the environment of use and is substantially non-erodible and inert in the environment of use. Furthermore, in the osmotic device (10) according to FIG. 4 the microporous layer (23) comprises an active agent (24) available for rapid initial delivery of the active agent to a use environment. The active substance (24) can serve as sole pore-forming agent for forming a microporous layer according to an embodiment of the invention, if the amount of active substance in the layer (23) is greater than 40%. The

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Active agent can co-act with a non-active pore-forming agent to form a microporous layer in the case of embodiments when the combined amount of active agent and pore-forming agent exceeds 25% by weight. The delivery of the active agent (24) from the microporous layer (23) is in addition to the delivery of the active substance (16) at a controlled and continuous rate by the osmotic device (10).

The Fig. 5 FIG. 3 shows an open view of an osmotic device (10) similar in construction to the osmotic device (10) according to FIG. 4 is. In Fig. 5 the osmotic device (10) additionally comprises the layer (25) containing the active substance (26). The layer (25) is applied to the outer surface of the device (10). This outermost layer (25) consists of a water-soluble material or a material which is soluble or disintegrates in the environment of use. The layer (25) contains a water-soluble active substance (26) which has only limited solubility in the surrounding liquid. The layer (25) gives the random substance (26) by erosion, solution od. like. from. The layer (25) achieves an initial burst or dosage of the active agent (26). The initial dosage of the active ingredient (26) may be an immediate total dosage of the active ingredient or it may be over a period of 15 to 75 minutes. The initial dosage of the active agent (26) reduces the time during which the active ingredient is unavailable to the environment of use by making the active ingredient available during the start-up time required for the osmotic device (10) to deliver the active ingredient. The initial dosage is done without affecting the delivery kinetics of the control properties of the delivery rate of the osmotic device (10).

The Fig. 6 shows an open osmotic device (10) as a further embodiment of the device (10). according to Figures 4 and 5. According to FIG. 6 the device (10) consists of an outermost layer (25) containing the active substance (26) and of the microporous layer containing the active substance (24). The layer (25) containing the active agent (26) gives off an instantaneous impulse or large burst of active agent (26) and is followed by the microporous layer (23), which releases an increased amount of active agent (24). The active ingredient (24) and the active ingredient (26) may be the same or different.

The Fig. 7 and Figure 8 illustrates another osmotic device (10). The device has a body (30) of elongate shape with a cord attached to it for removal of the device from the environment of use. The device (10) has a passage (13) and has a layered wall consisting of an outer semipermeable layer (32) and an inner microporous layer (33), both of which are shown in FIG. 7 are shown in dashed lines and in Fig. 8th made visible in open view. The semipermeable layer (32) contains the active substance (34). The amount of active agent (34) present in the semipermeable layer (32) is between 0.45% by weight in order to maintain the semipermeable properties of the layer. The layered wall surrounds the chamber (35) containing the agent (36). The osmotic device (10) operates in the manner described in connection with FIGS. 1 to 6 described way.

The various osmotic devices (10) of the present invention shown in Figs. 1-8 are not limited to the illustrations but may have a wide variety of shapes, sizes and dimensions for the delivery of agents to various environments of use. For example, environments such as rivers, aquariums, fields, factories, reservoirs, laboratories, greenhouses, hospitals, veterinary clinics, nursing homes, urine bags, chemical reactions and the like. like.

The device according to the invention may comprise 1 of a semipermeable wall containing an active substance, 2 a semipermeable wall containing an active substance, coated with a liquid-soluble layer containing an active substance, 3 a semipermeable wall, coated with a liquid-soluble layer containing an active substance, (4) a layered wall consisting of a semipermeable layer and a microporous layer, wherein the active ingredient is present in the microporous layer, 5 a layered wall consisting of a semipermeable layer and a microporous layer containing an active substance, coated with a liquid-soluble layer containing an active substance, 6 a layered wall consisting of a semipermeable layer and a microporous layer, coated with a liquid-soluble layer containing an active substance, 7 a microporous layer and a semipermeable, an active substance-containing layer, u. like. getting produced.

The semipermeable wall is formed of a material which does not damage the active agent, the osmotic agent and a living being, which is permeable to an external fluid such as water and substantially resistant to the passage of active agents, osmotic agents and the like. like. is impermeable. The selectively semipermeable materials are not erodible and insoluble in the liquids of interest. Typical materials for the formation of the wall (12) according to one embodiment of the invention are cellulose esters, cellulose ethers and cellulose ester ethers. These cellulose polymers have a degree of substitution, D. S., at the anhydroglucose unit of more than 0 and up to 3. By degree of substitution is meant the average number of hydroxyl group originally substituted on the cellulose polymer forming anhydroglucose unit and replaced by a substituting group.

Examples of such representative materials are those of the group cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono- and tricellulose alkanylates, mono-, di- and tricellulosearoylates, and the like. Examples of polymers are cellulose acetate having a DS up to 1 and an acetyl content up to 21%; Cellulose acetate having an acetyl content of 32 to 39.8%;

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Cellulose diacetate with a D. S. from 1 to 2 and an acetyl content of 21 to 35%; Cellulose triacetate with a D. S. from 2 to 3 and an acetyl content of 35 to 44.8% u. like. Examples of particular cellulosic polymers are cellulose propionate with a D. S. of 1.8 and a propionyl content of 39.2 to 45% and a hydroxyl content of 2.8 to 5.4%; Cellulose acetate butyrate with a D. S. from 1.8, an acetyl content of 13 to 15% and a butyryl content of 34 to 39%; Cellulose acetate butyrate having an acetyl content of 2 to 29%, a butyryl content of 17 to 53% and a hydroxyl content of 0.5 to 4.7%; Cell nonsetriacylates with a D. S. from 2.9 to 3 such as cellulose trivaleiate, cellulose trilaurate, cellulose tripalmitate, cellulose trisuccinate and cellulose trioctanoate; Cellulose diacylates with a D. S. from 2.2 to 2.6%, such as cellulose disuccinate, cellulose dipalmitate, cellulose dioctanoate, cellulose dipental, and the like. like.

Examples of other semipermeable polymers are acetaldehyde dimethyl acetate, Zelluloseacetatäthylcarbamat, Cellulose acetate phthalate for use in low pH environments, Zelluloseacetatmethylcarbamat, Zelluloseacetatdimethylaminoacetat, semipermeable polyamides, semipermeable polyurethanes, semipermeable sulfonated polystyrenes, crosslinked selectively semipermeable polymers formed by coprecipitation of a polyanion and a polycation, such as U.S. Patent 3,173,876; 3,276.586; 3,541.005; 3,541.006; and 3,546,142; Semipermeable polymers according to Loeb and Sourirajan in US Patent 3,133,132; lightly crosslinked polystyrene derivatives; crosslinked polysodium styrenesulfonate, crosslinked polyvinylbenzyltrimethylammonium chloride, semipermeable polymers having a liquid permeability of 105 to 10¹ cm ^ · 0.025 mm / cm² · Hbar (cc · mil / cm² Hr · atm), expressed per bar · 10 8 hydrostatic or osmotic pressure differential across the semipermeable wall. The polymers are disclosed in US Pat. Nos. 3,845,770; 3,916,899 and 4,160,020 and from the Handbook of Common Polymers by Scott, JR and Roff, WJ 1971, published by CRC Press, Cleveland, Ohio.

In the laminated wall consisting of a semipermeable layer and a microporous layer, the layers are in a laminar arrangement and cooperate to form a unitary laminated wall which retains its physical and chemical integrity and throughout the process of release of the active substance from an osmotic device does not fall into their layers. The semipermeable layer consists of the above-mentioned semipermeable polymeric materials, the semipermeable homopolymers, the semipermeable copolymers, and the like. like.

Microporous layers suitable for the preparation of an osmotic device usually consist of preformed microporous polymeric materials and polymeric materials which are capable of forming a microporous layer in the environment of use. The microporous materials are layered in both embodiments to form a laminated wall.

The preformed materials suitable for forming the microporous layer are substantially inert, maintain their physical and chemical integrity throughout the release period of the active agent, and may generally be referred to as sponge-like, providing a support structure for a semipermeable layer as well as a support structure for the microscopically large, interconnected pores or cavities. The materials can be isotropic the structure being homogeneous throughout the cross-sectional area, or they are anisotropic, the structure is not homogeneous throughout the cross-sectional area. The pores can be contiguous pores, which have an opening on both sides of a microporous layer, pores which are connected by winding paths, like regular or irregular shaped, including curved, curved linear, arbitrarily oriented continuous and impaired connected pores, as well as pores with other microscopically recognizable ways. Usually, the microporous layer is defined by the pore size, the number of pores, the entanglement of the microporous paths, and the porosity based on the size and number of pores. The pore size of a microporous layer can be easily determined by measuring the observed pore diameter at the surface of the material under the electron microscope. Usually, for the production of a microporous layer, materials containing 5 to 95% pores with a pore size of 10 * 9 to 10⁴ m be used. The pore size and other parameters characterizing the microporous structure can also be obtained in the course of flow measurements whereby a liquid flow, J, through a pressure difference (Δ P), is produced by the layer. The liquid flow through the layer of pores of uniform radius extending through the membrane and perpendicular to its surface of size A is given by the relationship 1:

Νρ⁴ΔΡ J = 8ηΔχ (1) wherein J is the volume transported per unit time and layer area containing a number N of pores of radius r, η is the viscosity of the liquid and Δ P is the pressure difference across the layer of thickness Δx For this type of layer, the number of pores N can be calculated from relationship 2, where ε is the porosity defined by the ratio of void volume to total volume of the layer and A is the cross-sectional area of ​​the n-pore containing layer

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Α

Ν = εχπι² (2)

The pore radius is then calculated from the relationship:

J Δγτ

Γ = 8ηΑρε (3) where J is the volume flow through the layer per unit area produced by the pressure difference ΔP through the layer, η, ε and Δ x have the meanings given above and τ for the entanglement, defined as the ratio of Diffusionsweglänge in the layer to the layer thickness, is. The above relationships are in transport Phenomena In Membranes. by Lakshminatayaniah, N, Chapter 6, 1969, published by Academic Press, Inc., New York.

As stated on page 336 in Table 6.13 of this reference, the porosity of the layer having pores of radius r can be expressed relative to the size of the molecules being transported having a radius a and to the extent that the molar radius to pore radius a / r, the layer becomes porous with respect to this molecule. D. that is, when the ratio a / r is smaller than 0.3, the layer becomes substantially microporous, as expressed by the osmotic reflection factor υ, which falls below 0.5. Microporous layers having a reflectance υ in the range of less than 1, usually from 0 to 0.5, and preferably less than 0.1, in terms of the active ingredient are suitable for the preparation of the system. The reflection factor is determined by shaping the material into a plate-shaped layer and performing the water flow measurements as a function of the hydrostatic pressure difference and as a function of the osmotic pressure difference caused by the active ingredient. The osmotic pressure difference causes a hydrostatic volume flow and the reflection factor is expressed by the relationship 4:

hydrostatic pressure difference x osmotic volume flow υ = osmotic pressure difference x hydrostatic volume flow (4)

The properties of microporous materials are in Science. Volume 170, pages 1302 to 1305, 1970; Nature. Volume 214, page 285, 1967; Polymer Engineering and Science. Volume 11, pages 284 to 288.1971; U.S. Patents 3,567,809 and 3,751,536 and Industrial Processing With Membranes. by Lacey RE and Loeb, Sidney, pp. 131-134, 1972, published by Wiley, Interscience, New York.

Microporous materials having a preformed structure are commercially available and can be prepared by methods known per se. The preparation of the microporous materials can be carried out by etching, Nuclear Tracking ", by cooling a solution of a flowable polymer below the glass transition point, whereby solvent evaporates from the solution in the form of crystals distributed in the polymer, and subsequently curing the polymer followed by removal of the solvent crystals, by cold or hot stretching at low or high temperatures until the formation of pores, by leaching a soluble component from a polymer by means of a suitable solvent, through an ion exchange reaction and through polyelectrolytic processes, respectively. Methods for making microporous materials are in svnthetic polymer membranes. from R. E. Kesting, Chapters 4 and 5, 1971, published by McGraw Hill, Inc., Chemical Reviews. Ultrafiltration, Vol. 18, pp. 373-455, 1934; Polymer Eng, and Be .. Volume 11, Number 4, pages 284 to 288, 1979; J, Appl, Poly Sei .. Volume 15, pages 811 to 829, 1979; and in U.S. Patent 3,565,259; 3,615,024; 3 751536; 3,801,692; 3,852,224 and 3,849,528.

Examples of microporous materials, which can be used for the production of the plate-shaped layers, are microporous polycarbonates consisting of linear polyesters of carboxylic acids, in which the carbonate groups in the polymeric chain occur repeatedly, microporous materials prepared by phosgenation of a dihydroxylaromete, like bisphenol A, microporous polyvinyl chloride, microporous polyamide, such as polyhexamethylene adipamide, microporous modacrylic copolymers, including the copolymers formed from polyvinyl chloride 60% and acrylonitrile, Styrene-acrylic polymer and its copolymers, porous polysulfones, which are characterized by diphenylsulfone groups in one of their linear chains, halogenated polyvinylidene, Polychloräther, Acetalpoiymere, Polyester prepared by esterification of a dicarboxylic acid or an anhydride with an alkylene polyol, polyalkylene sulfides, phenolic polyesters, microporous polysaccharides, microporous polysaccharides with substituted and unsubstituted anhydroglucose units, which preferentially develop greater permeability to the passage of water and biological fluids as semi-permeable layers, asymmetric porous polymers, crosslinked olefin polymers, hydrophobic or hydrophilic microporous homopolymers, Copolymers or

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Reduced bulk weight interpolymers and materials such as those disclosed in U.S. Patents 3,597,752; 3 643 178; 3,654,066; 3,709,774; 3,718,532; 3,803,061; 3,852,224; 3,853,601 and 3,852,388, British Patent 1,126,849 and Chem. Abst. Vol. 714274F, 22572F, 22573F, 1969.

Other microporous materials are polyurethanes, crosslinked polyurethanes with extended chain, microporous polyurethanes according to US Pat. No. 3,524,753, polyimides, polybenzimidazole, Collodium (cellulose nitrate with 11% nitrogen), regenerated proteins, semi-solid cross-linked polyvinylpyrrolidone, microporous materials made by diffusing polyvalent cations into polyelectrolyte sols, as described in U.S. Patent 3,565,259, anisotropic permeable microporous materials of ionically associated polyelectrolytes, porous polymers formed by coprecipitation of a polycation and a polyanion, as disclosed in US Pat. Nos. 3,276,589; 3,541,055; 3,541,066 and 3,546,142, are described Polystyrene derivatives, such as polysodium styrenesulfonate and polyvinylbenzyltrimethylammonium chloride, as well as those disclosed in US Pat. Nos. 3,615,024; 3 646178 and 3 852 224, to microporous materials.

An example of another micropore-forming material that can be used for the purposes of the invention is that which forms the microporous layer in situ, wherein a pore-forming agent is removed by causing it to leach or leach to the microporous layer during use of the microporous layer To form systems. The pore-forming agent may be a solid or a liquid. The term liquid in the context of the present invention includes semi-solids and viscous liquids. The pore former may be an inorganic or an organic material. The pore formers useful for the purposes of this invention include those which can be extracted without any chemical conversion and in the polymer. The pore builder solids are from about 0.1 to 200 microns in size and include alkali metal salts such as sodium chloride, sodium bromide, potassium chloride, potassium sulfate, potassium phosphate, sodium benzoate, sodium acetate, sodium citrate, potassium nitrate, and the like. like.

Examples of alkaline earth metal salts are calcium phosphate, calcium nitrate and the like. like. Examples of salts of transition metals are ferric chloride, ferrous sulfate, zinc sulfate, copper chloride, manganese fluoride, manganese fluorosilicate, and the like. like. Further examples of pore-forming agents are organic compounds, such as polysaccharides. Examples of polysaccharides are the sugars sucrose, glucose, fructose, mannitol, mannose, galactose, aldohexose, altrose, talose, sorbitol, lactose, monosaccharides and disaccharides. Other useful pore formers are organic aliphatic and aromatic oils, including diols and polyols, such as polyhydric alcohols, polyalkylene glycols, polyglycols, alkylene glycols, poly (aa) alkylene diols, esters of alkylene glycols, and the like. the like; water-soluble cellulosic polymers such as hydroxy (lower) alkylcellulose, hydroxypropylmethylcellulose, methylcellulose, methylethylcellulose, hydroxyethylcellulose and the like; etc .; water-soluble polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose and the like; Like., And water-soluble drugs usually in the form of their addition salts, such as procainamide hydrochloride, propoxyphene hydrochloride u. like. The pore formers are non-toxic and as they are removed from the layer channels are formed through the layer. According to a preferred embodiment of the invention, the non-toxic pore-forming agents are selected from the group comprising inorganic and organic salts, carbohydrates, polyalkylene glycols, poly (a-co) -alkylenediols, esters of alkylene glycols, glycols and water-soluble cellulosic polymers, which are materials for forming a Microporous layer in a biological environment are useful.

When the laminate-forming polymer contains more than 40% by weight of the pore-forming agent or a mixture consisting of pore-forming agent and a drug, usually the polymer is a precursor of a microporous layer which, after removal of the pore-forming agent or the pore-forming agent and the drug, produces a essential microporous layer results; At concentrations less than that stated above, the layer behaves similar to a semipermeable layer or membrane. In the latter embodiment, the semipermeable layer contains 0.5 to 40% by weight of active ingredient or a mixture of active ingredient and pore-forming agent in an amount of 0.5 to 40% by weight.

Examples of materials for forming a layer containing an immediately available active ingredient are water-soluble polysaccharide gums such as carrageenan, fucoidan, ghatti gum, tragacanthine, arbalinogalactan, pectin, xanthan, and the like. etc .; water-soluble salts of polysaccharide gum such as sodium alginate, sodium tragacanthine, sodium ghattate gum, and the like; etc .; water-soluble hydroxyalkyl cellulose, wherein the alkyl portion is straight or branched chain and contains 1 to 7 carbon atoms, such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc .; cellulose-based synthetic water-soluble layer formers, such as methyl cellulose and hydroxyalkylmethyl cellulose thereof, derivatives such as, for example, from the group comprising hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose and the like. etc .; and other cellulosic polymers such as sodium carboxymethylcellulose. Other film-forming materials which can be used for these purposes are polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene oxide, a mixture of gelatin and polyvinylpyrrolidone, gelatin, glucose, saccharides and the like. like.

The term passageway used in the context of the present invention refers to devices and methods by which the active agent can be released from the osmotic system. The term includes holes, openings or bores through the semipermeable wall or through the

-8AT397 179B layered wall. The passage can be made by mechanical drilling, by laser drilling, or by erosion of an erodible element, such as ζ. B. a gelatin plug, are formed in the user environment . A detailed description of osmotic passages and their maximum and minimum dimensions is given in U.S. Patent Nos. 3,845,770 and 3,916,899. The osmotically effective compounds which can be used for the purposes of the invention include inorganic and organic compounds which produce an osmotic pressure gradient through a semi-permeable wall or through a layered wall against an external fluid. The osmotically active compounds are also referred to as osmotically effective dissolved additional substances. The compounds are used by mixing them with a drug or drug having limited solubility in the ambient fluid, which compounds form a solution containing the drug and which is delivered osmotically from the system. The term limited solubility used in the context of the present invention means that the active ingredient has a solubility of less than 1% by weight in the surrounding aqueous liquid. The osmotic dissolved additive substances are processed by mixing them homogeneously or heterogeneously with the active ingredient and then introducing a single operation into the chamber. The dissolved additive substances draw liquid into the chamber and form a solution of the dissolved additive substance which is released from the system and at the same time transports the undissolved and dissolved remedies to the outside environment of the system. Examples of osmotically effective dissolved adjunct substances used for the aforementioned purpose are magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, acid potassium sulfate, calcium lactate, calcium acid phosphate, d-mannitol, urea, inositol, magnesium succinate, tartaric acid, carbohydrates such as raffinose, sucrose, Glucose, α-d-lactose monohydrate and mixtures thereof.

The osmotic solubilized additive is initially present in excess and may be in any physical form, such as particles, crystals, pellets, tablets, strips, films or granules. The osmotic pressure of saturated solutions of various osmotically active compounds and mixtures of compounds at 37 ° C. in water is given in Table 1. Table 1 shows the osmotic pressure π, in bar. The osmotic pressure is measured in a commercial osmometer, which measures the vapor pressure difference between pure water and the solution to be analyzed, the vapor pressure being converted into the osmotic pressure difference in accordance with standard thermodynamic principles. In Table 1, pressures of 20 to 500 bar are given. It will be appreciated that the invention also contemplates the use of lower osmotic pressures above zero and higher osmotic pressures than those exemplified in Table 2. The osmometer used for the measurements is a Model 320B Osmometer, Vapor Pressure Osmometer, Hewlett Packard Co. , Avonadale, Penna.

Table 1

<td>Compound or mixture</td><td>Osmotic pressure bar</td>

<td>Lactose-Fructose</td><td>500</td>

<td>Dextrose-fructose</td><td>450</td>

<td>Sucrose-fructose</td><td>430</td>

<td>Mannitol-fructose</td><td>415</td>

<td>sodium chloride</td><td>356</td>

<td>fructose</td><td>355</td>

<td>Lactose, sucrose</td><td>250</td>

<td>potassium chloride</td><td>245</td>

<td>Lactose dextrose</td><td>225</td>

<td>Mannitol dextrose</td><td>225</td>

<td>Dextrose-Sucrose</td><td>190</td>

<td>Mannitol-sucrose</td><td>170</td>

<td>dextrose</td><td>82</td>

<td>potassium sulphate</td><td>39</td>

<td>mannitol</td><td>38</td>

<td>Tertiary sodium phosphate · 12H₂O</td><td>36</td>

<td>Secondary sodium phosphate · 7H₂O</td><td>31</td>

<td>Secondary sodium phosphate · 12H₂O</td><td>31</td>

<td>Secondary sodium phosphate anhydrous</td><td>29</td>

<td>Primary sodium phosphate · H₂O</td><td>28</td>

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The term active ingredient as used herein includes any compound or compound mixture that can be delivered from the device, except for remedies. The active ingredient may be soluble in the surrounding fluid entering the device and act as an osmotically-active dissolved additive, or it may have limited solubility in the fluid and with an osmotically-active, liquid-soluble additive resulting from the system is dispensed, mixed. The term drug also refers to compounds released from the wall for immediate release. Examples of active substances are herbicides, pesticides, germicides, biocides, algaecides, rodenticides, fungicides, Insecticides, antioxidants Accelerators and inhibitors for plant growth, Preservatives, Disinfectants, Sterilants, catalysts chemical reactants, Fermentation agents, Food additives Nutrient, Cosmetics, drugs vitamins, Sexualsterilisantien, fertility inhibiting agents, fertility enhancing agents, Air cleaners, Micro-organism debilitating agents and other means for the environment, in which the device is to be applied, are beneficial.

The solubility of an active ingredient in a liquid can be determined by known methods. One method is a saturated solution consisting of the liquid plus the active ingredient, determined by analyzing the amount of active ingredient present in a defined amount of the liquid, manufacture, a simple apparatus, to achieve this purpose, consists in a test tube of medium size, which is mounted upright in a water bath maintained at a constant temperature and pressure, is wherein in the test tube, the liquids and the active ingredient are introduced and stirred by means of a rotating glass spiral. After a given stirring period, a weight sample of the liquid is analyzed and stirring continued for another period of time. If the analysis shows no increase in dissolved material after successive stirring periods in the presence of excess solid in the liquid, the solution is saturated and the results can be used as the solubility of the product in the liquid. If the active ingredient is soluble, an added osmotically active compound may not be required; however, if the active ingredient has a limited solubility in the liquid, an osmotically active compound may be added to the device. There are a number of other methods for determining the solubility of a substance in a liquid. Typical methods for measuring solubility are chemical and electrical conductivity. Details regarding the different methods for determining the solubilities are available in United States Public Health Service Bulletin. No. 67, by Hygenic Laboratory; Encyclopedia of Science and Technology. Volume 12, pages 542 to 556, 1971, published by McGraw-Hill, Inc.; and Encvclopedia Dictionary of Phsics. Vol. 6, pp. 547-557, 1962, published by Pergamon Press, Inc..

The devices of the invention are prepared by standard methods. For example, according to one embodiment, the active ingredient and the other ingredients to be incorporated into the chamber and a solvent become a solid, semi-solid or gel-like fabric by conventional methods such as ball milling, calendering, stirring or roll mill processing , are mixed, after which they are pressed to a preselected shape. The system-forming layers can be formed by casting, spraying or dipping the pressed shape into wall-forming materials. In another embodiment, the layers are cast into films, formed into the desired dimensions, and an outer layer is applied to an inner layer to thereby define a chamber which is filled with the active agent and then sealed. Furthermore, the system can be made and the chamber left empty, which is then filled through the passage. If the system is formed of more than one layer, the connection may be by various joining techniques, such as electronic high frequency sealing, with clean edges and a tightly sealed system. Another and currently preferred procedure that can be used to apply the laminate to a chamber is the air suspension technique. This method consists in suspending and vortexing the pressed active substance in a stream of air as well as a layer composition until the layer has been applied to the active substance. The process is repeated with another layer to form the laminate. The air suspension process is described in U.S. Patent 2,799,241; J. At the. Pharm. Assoc., Vol. 48, pp. 451-459, 1979 and ibid, Vol. 49, pp. 82-84, I960. Other standard manufacturing processes are in Modem Plastics Encvclopedia. Volume 46, pages 62 to 70, 1969; and in Pharmaceutical Sciences, by Remington, 14. Edition, pages 1626-1678, 1970, published by Mack Publishing Co., Easton, Penna.

Examples of solvents suitable for the preparation of the laminates and the individual layers are inert inorganic and organic solvents which do not adversely affect the materials and the finished layered wall. Examples of solvents are generally those of the group comprising aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic solvents, aromatic solvents, heterocyclic solvents and mixtures thereof. Typical solvents are, for example, acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane, n-heptane, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, dichloromethylene, dichloroethylene, dichloropropylene, carbon tetrachloride, Nitroethane, nitropropane,

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Tetrachloroethane, ethyl ether, isopropyl ether, cyclohexane, cyclooctane, benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, diglyme, water and mixtures thereof, such as acetone and water, acetone and methanol, acetone and ethyl alcohol, dichloromethylene and methanol, dichloroethylene and methanol.

The invention is further illustrated by the following examples.

Example 1:

An osmotic delivery system is prepared, sized and fitted as an osmotic device, so osmotic tablet for incorporation into a urine bag to prevent bacterial growth therein as follows: First, 53 g of methenamine are mixed with 47 g of mannitol and 33 g of water to form a homogeneous mixture , The ingredients are mixed in a small laboratory mixer for 30 minutes, after which the mixture is sieved through a 20 mesh sieve. The sieved homogeneous mixture is then dried in an oven at 50 ° C for 2 hours, removed from the oven and sieved through a 10 mesh screen. The last sieved granules are returned to the oven and dried at 50 ° C. for a further 2 hours. Thereafter, the dried granules are mixed with 2% by weight of magnesium stearate and pressed into a number of biocide cores in a standard tablet press. The pressed drug cells have a diameter of about 6.5 mm and a weight of 190 mg. Thereafter, the drug cells are coated with a semipermeable wall-forming composition comprising methenamine mandelate. The composition consists of 13 g of methenamine mandelate and 117 g of cellulose acetate with an acetyl content of 32%. The wall is formed from a solvent system consisting of 260 ml of water and 2900 ml of acetone. To form the semi-permeable biocide-containing wall, a Wurster air-suspension coater is used. The solvent is evaporated for 65 hours in an air circulation oven at 50 ° C and, after cooling to room temperature, a 0.25 mm diameter passage is drilled through the semipermeable wall with a laser beam. The passage connects the outside environment of the osmotic device to the biocide for delivery of the biocide. The final osmotic device contained 52% methenamine mandelate, 46% mannitol and 2% magnesium stearate in the chamber and the semipermeable wall is 90% cellulose acetate with acetyl content of 32% and 10% methenamine mandelate. The percentages are based on the weight.

Example 2:

An osmotic device for the immediate release and controlled and continuous delivery of a biocide is prepared as follows: First, 2284.8 g of the biocide bronopol (2-bromo-2-nitropropane-1,3-diol) is passed through a 30 mesh screen (30 mesh). sieved and placed in a mixing crucible. Then 91.2 g of hydroxypropyl methylcellulose are added to 510 ml of a 84:16 volume of ethanol water in a separate mixer and mixed until a clear solution is obtained. Thereafter, the solution consisting of hydroxypropylmethylcellulose-ethanol-water is added to the bronopol and is stirred for the purpose of obtaining a uniform consistency for 1 h. The wet granules are then sieved through a 30 mesh stainless steel screen and the granules are spread on a tray and dried in an air circulation oven at 50 ° C ± 2 ° C for 20 to 25 hours. After cooling to room temperature of 22.2 ° C, the dried granules are sieved through a 20 mesh stainless steel mesh screen. The granules are returned to the mixing crucible and treated with 24 grams of stearic acid, previously sieved through a 80 mesh stainless steel sieve, after which all ingredients are mixed at low speed for 10 minutes. Finally, a number of bronopol formulations forming the bronopol reservoirs of the osmotic device are prepared by pressing the formulation containing all the ingredients into a 6 mm mold cavity under a 900 kg pressure load. The finished bronopole composition consists essentially of Bronopol 55 mg, hydroxypropylmethylcellulose 2.5 mg and stearic acid 0.6 mg.

Next, a semipermeable wall is formed around the bronopolekes by mixing 150 g of 39.8% acetyl acetate with 2493 ml of methylene chloride and 456 ml of methanol and spraying the semipermeable wall-forming composition around the bronopoleks in a conventional air-suspension coater. The wall-forming coating is sprayed on until the entire coating solution is consumed, usually for a period of 1 to 2 hours. A second layer-forming composition consisting of 352 g of dry bronopol and 88 g of dry hydroxypropymethylcellulose in a solvent system consisting of 2842 ml of methylene chloride and 2578 ml of methanol is then prepared by adding the dry ingredients to the solvent system, stirring continuously for 30 minutes to obtain a to obtain a clear laminate-forming solution. The solution is added to the air suspension coater and a layer is formed on the semipermeable wall. Finally, the coated osmotic devices are placed on stainless steel trays and dried at 50 ° C for 48 hours, after which an osmotic passage is drilled through the layered wall with laser beam. The osmotic passage has a diameter of about 0.25 mm. The Fig. 9 the profile of the delivery rate for osmotic devices according to this example can be seen. The osmotic

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Devices initially provide an initial dose of drug during a short delivery period accompanied by an effective amount of drug delivered at a controlled rate and continuously over a longer period of time. The Fig. 10 shows a layer structure prepared according to the example. The laminate could also be made by solvent casting the layers. The laminate or laminate consists of a semipermeable layer (37) formed of cellulose acylate which retains its physical integrity in aqueous and biological environments, the layer (37) being in a layered arrangement with a layer (38) formed of a material, which loses its physical integrity in an aqueous or biological environment. The layer (38) contains the active substance (39), which is released from the layer (38) when it loses its cohesion.