Osmotic device

The present invention relates to a device for the controlled delivery of an active substance, except drug, to a use environment. The device is characterized by a) a wall, which consists at least in part of an impermeable material present in the environment of use for the passage of an external fluid, and b) a chamber, c) a first in the chamber, from an active ingredient, an osmotic agent and an osmopolymer composition; and d) a second chamber located in the chamber, consisting of an osmotic agent and an osmopolymer composition and e) a passage in the wall, which is in communication with the first composition and the external environment of the device for the purpose of delivering the active agent from the device

Already in the early antiquity both the pharmacy and the medicine searched for a dispensing system for the administration of a cure. The first written reference to a dosage form is in the approximately 1552 v. Chr. Chr. to find written boar-papyrus. The boar papyrus mentions dosage forms such as anal suppositories, vaginal pessaries, ointments, oral pill compositions and other dosage forms. Approximately 2500 years passed without any progress in the development of the dosage form when the Arab physician Rhazes, 865925 n. Chr. the coated pill invented. About a hundred years later, the Persian Avicenna, 980-1037 n. Chr., Pills with gold or silver, to improve the patient's tolerance and increase the effectiveness of the remedy. Around this time, the first tablet in Arabic manuscripts of Al-Zahrawi, 936-1009 n. Chr., Described. These manuscripts describe a tablet formed by the hollow pressing in two opposite tablet forms. Pharmacy and medicine had to wait about 800 years until the next innovation in the dosage forms, when in 1883 Mothes invented the capsule for the administration of remedies. The next big leap in the field of dosage forms came in 1972 with the invention of the osmotic delivery device by Theeuwes and Higuchi, U.S. Patent Nos. 3,845,770 and 3,916,899 describe the osmotic devices described in these patents as consisting of a semipermeable wall, which surrounds a chamber, containing an active substance The wall is permeable to the passage of an external fluid and substantially impermeable to the passage of the active substance. The wall has a passageway to deliver the active agent from the osmotic device. These devices release the active ingredient by sucking a liquid through the semipermeable wall into the chamber at a rate determined by the permeability of the semipermeable wall and by the osmotic pressure drop across the semipermeable wall to form an aqueous solution contains the active ingredient, which is then discharged through the passage from the device. These devices are particularly effective for delivering an active agent which is soluble in the liquid and which produces an osmotic pressure gradient across the semipermeable wall against the external fluid

A pioneering achievement in osmotic delivery devices has been provided by the inventor Felix Theeuwes in US Patent 4111202. In this patent, the delivery kinetics of the osmotic device are improved for the delivery of cures that are insoluble to highly soluble in the fluid, by: the osmotic device is formed with a drug chamber and a chamber separated by a film for the osmotic agent. The film is movable from a rest position to an expanded position. The osmotic device releases the drug, by sucking liquid into the osmotic agent chamber through the semipermeable wall, whereby a solution forms, which results in an increase in the volume of the chamber and acts as a driving force, which can be used against the film. By this force, the film is expanded toward the drug chamber, whose volume consequently decreases accordingly, whereby the drug is delivered through the passageway from the osmotic device. Although this device works successfully for its intended use, and although it can be used to deliver a variety of drugs of various solubilities, its use is limited due to the manufacturing steps and cost of producing and positioning the moveable film in the chamber of the osmotic device

U.S. Patent 4,327,725, Richard Cortese and Felix Theewes, describe an osmotic delivery device for remedies which, due to their solubilities in aqueous and biological fluids, can only be made difficult in larger quantities at controlled release rates during delivery. The osmotic devices of this patent have a semipermeable wall surrounding a chamber containing an active ingredient which is insoluble to highly soluble in aqueous and biological fluids and an expandable hydrogel. During use, the hydrogel expands in the presence of an external fluid entering the device, the drug being delivered through the port from the device. This device works satisfactorily for its intended use and is capable of delivering many difficult-to-dispense remedies for its intended use. It has now been observed that the use of such a device is limited because the hydrogel lacks the ability to accept enough fluid for the maximum self-expansion required to deliver the drug from the device.

For the skilled artisan of the art, it is obvious that when an osmotic device

It would be possible to develop a high level of osmotic activity for the delivery of an active agent by generating in situ an expanding force sufficient to pass the maximum amount of active agent out of an osmotic device at a controlled rate, a positive one Contribution and progress in the delivery technique. Likewise, it is obvious that in the field of

In the pharmaceutical and medical arts, an osmotic delivery device would find practical application having dual thermodynamic osmotic activity for delivery of increased amounts of an active agent.

Accordingly, it is an object of the present invention to provide an osmotic system which is a further improvement and progress over known devices.

Furthermore, an object of the present invention is to provide an osmotic system with dual osmotic activity, which system has a chamber, containing a first osmotic composition consisting of an active agent and preferably an osmotic agent and / or an osmopolymer and a second osmotic composition consisting of an osmotic agent and an osmopolymer, wherein the compositions for the delivery of the drug in the osmotic device cooperate.

Another object of the present invention is to provide an osmotic device with

Means for higher loading with a water-insoluble or slightly water-soluble active agent and means for delivery of the active ingredient at a controlled rate and substantially continuously over time.

Another object of the invention is to provide an osmotic device capable of delivering a pH dependent drug by providing a neutral medium for drug delivery in an anti-particulate form for the purpose of increasing the surface area and maximizing the rate of dissolution of the drug.

Further features and advantages of the invention will become more apparent from the following description with reference to the accompanying drawings.

In the various embodiments of the invention, for example, illustrative drawings, FIG. 1 Fig. 2 is a perspective view of an osmotic device for the delivery of the material; 1, wherein the construction of the device is illustrated; FIG. 3 a perspective sectional view of the osmotic device of FIG. 1, wherein the osmotic device is shown in use and delivering a drug from the osmotic device; FIG. 4 in a perspective sectional view of the device of FIG. 1 and in connection with FIG. 3 seen, wherein the osmotic device is illustrated during use and delivery of a larger amount of active ingredient; FIG. 5 an osmotic device with a partially broken wall for the delivery of an active substance; FIG. 6 the osmotic device according to FIG. 5 with another wall structure; FIG. 7 the osmotic device according to FIG. 5 with a different wall structure than that of the device according to FIG. 6; FIG. 8th Figure 3 is a graph of weight gain as a function of time for a polymer encapsulated in a semipermeable membrane and when this encapsulated polymer is placed in water; FIG. 9 Figure 4 illustrates the total amount of drug released from a device consisting of an osmopolymer with two different molecular weights; FIG. 10 Figure 12 illustrates the osmotic pressure curves for a number of osmotic agents and a number of compositions consisting of osmopolymer / osmotic agent.

In the drawings, the same parts are designated by like reference numerals. The terms used in the preceding description and in the description of the drawings will be explained in more detail in the text.

In the drawings, various embodiments of osmotic devices according to the invention are described. Fig. 1 shows an osmotic device (10) consisting of a body part (11) with a wall (12), a passage (13) for the delivery of the active substance from the osmotic device (10).

In Fig. 2 is the osmotic device (10) according to FIG. 1 illustrated in section according to FIG. 2 the osmotic device (10) comprises a body (11) and a semi-permeable wall (12) forming and enclosing an internal chamber (14), which chamber communicates with the external environment of the osmotic device (10) via the passage (13). communicates. The chamber (14) contains a first osmotic composition consisting of an active substance (15), which is shown dotted and may be insoluble to highly soluble in the liquid drawn into the chamber (14); an osmotic agent (16), shown in wavy lines and soluble in the liquid drawn into the chamber (14) and creating an osmotic drag gradient through the semipermeable wall (12) against the external liquid; and an osmopolymer (17) represented by horizontal lines, aspirating the fluid into the chamber (14) and creating an osmotic pressure gradient through the semipermeable wall (12) against the external fluid added in the environment of use. The

Wall (12) consists of a semipermeable composition which is permeable to the passage of external fluid and substantially impermeable to the passage of active agent (15), osmotic agent (16) and osmopolymer (17). Semipermeable wall (12) is not toxic and keeps its physical and

-3AT397 180 B chemical integrity during the delivery time of the device (10).

In the chamber (14) is further housed, remote from the passage (13), a second osmotic composition in contact with the first composition. The second composition is expandable and develops a driving force which cooperates with the first osmotic composition to deliver a maximum amount of active agent (15) from the osmotic device (10). The second osmotic composition consists of an osmotic agent (18), which is soluble in the liquid sucked into the chamber (14) and generates an osmotic pressure gradient against a liquid from the environment through the wall (12) and is mixed with an osmopolymer (19), which draws liquid into the chamber (14) and generates an osmotic pressure gradient against a liquid from the environment through the wall (12). The osmopolymers (17) and (19) are hydrophilic water-soluble or slightly crosslinked water-insoluble polymers and have osmotic properties. by which they are capable Aspirate fluids from the outside environment and create an osmotic pressure gradient through the semipermeable wall against the fluid from the environment; Furthermore, they are able to swell or expand in the presence of the liquid. The osmopolymers (17) and (19) are mixed with the osmotic agents (16) and (18) to draw the maximum volume of liquid from the environment into the chamber (14). This liquid is available to the osmopolymers (17) and (19) to optimize the volumetric rate and bring about total expansion of the osmopolymers (17) and (19). D. e., the osmopolymers (17) and (19) absorb the into the chamber (14) sucked by the osmotic suction of the osmopolymer (17) and (19), supplemented by the osmotic suction of the osmotic agents (16) and (18) Liquid to provide maximum expansion of the osmopolymers (17) and (19) to a greater mass.

During use of the device, delivery of the active agent (15) from the osmotic device (10) according to a preferred embodiment of the invention is accomplished by (1) aspirating fluid from the outside environment through the first composition to form a suspension in situ and deliver the suspension through the passage and at the same time by (2) sucking the liquid through the second composition, to swell the first composition and to effect that the first composition is involved, to express the drug suspension through the passage. The osmotic device may be considered as a cylinder, with the second composition expanding in the manner of movement of a piston to deliver the drug suspension from the osmotic device. Although the in Figs. 1 2 and 2 does not exactly correspond to one cylinder, it is so far similar to this one that it can be characterized by the following physical analysis. In this analysis, the volume rate of the output achieved by the osmotic device is F_t composed of two sources; the water intake rate through the first composition F and the water intake rate through the second composition Q, wherein:

F_t = F + Q (1)

Since the interface between the first composition and the second composition hydrates very little during operation of the osmotic device, insignificant water migration occurs between these compositions. Thus, the water aspiration rate of the second composition, Q, equalizes the expansion of its volume

<img file="AT397180B_D0001.tif" />

dt (2)

The total delivery rate from the osmotic device is then dm - = F_tC = (F + Q) C dt (3) where C is the concentration of the drug in the dispensed slurry. The maintenance of the volume of the osmotic device, V, and the surface, A, give equations 4 and 5:

V = V_{d +} Vp (4)

A = A_d + A_p (5)

-4AT397 180 B where V_d and V_p are equal to the volumes of the first composition and the second composition respectively, and wherein Ajj and A_p are equal to the contact area with the wall of the first composition and the second composition. During use both V_p and Ap are larger with time, whereas V_dand A_d Over time, while the device delivers the drug, lose weight.

The volume of the second composition which expands over time while liquid in the

Chamber is sucked, is given by the equation 7:

<img file="AT397180B_D0002.tif" />

where Wjj is the weight of the liquid sucked through the second composition, W_p the weight of the second composition originally present in the device, and Wjj / Wp is the ratio of liquid to solid originally present in the second composition, where V is_p equal

W_H W_p(1 + -) W_p e is where e is the density of the second composition corresponding to Wjj / W_p means. Accordingly, based on the

Geometry of a cylinder, where r is the radius of the cylinder, the binsug area related to the volume of the swollen second composition as follows:

W

A_p = r² + - Li _{+ WH}Wp (8) r

A = A_d-A_p (9)

The liquid intake rates in each chamber are:

k _F = (.-) (A_dOn_d) (10) h

k

Q = (-) (ΑρΔπ_ρ) (11) h

where k is the osmotic permeability of the wall and h is the wall thickness and Apd and App are the osmotic gradients for the first and second compositions, respectively. The total delivery rate is therefore:

dm k 2 W_p W_H 2 W_p W_H

- = - C {[A-jtr²--- 1 (+ -)] Δπΰ + [πτ² + - (1 + -)] Δπρ} (12) dt hrp W_p rp W_p

FIGS. 3 and 4 show the osmotic device according to FIG. 1 and 2 in the functional state. According to FIGS. 3 and 4, in the osmotic device (10), the liquid is aspirated by the first composition at a rate determined by the permeability of the wall and the osmotic pressure gradient across the wall. The aspirated fluid continuously forms an active agent-containing solution or gel of the osmotic agent and the osmopolymer which releases the active ingredient in suspension, in each case releasing the solution or suspension through the combined actions of the device (10). These modes of action include the osmotic delivery of the solution or suspension through the passageway due to the continued formation of solution or suspension and the swelling and increase in volume of the second composition resulting from the enlargement of the vertical lines in Figs. 3 and Figure 4 illustrates. The last-mentioned swelling and volume increase exerts pressure against the solution or suspension, acting on the first composition while simultaneously delivering the drug to the outside environment

-5AT397 180 B of the device.

The first composition and the second composition work together, to essentially ensure that the delivery of the active substance from the chamber takes place over a longer period of time by two methods. First, the first composition sucks through the wall liquid from the environment and forms either a solution or a suspension, the last part of which (in the absence of the second composition) would practically no longer be released, Secondly, the second composition acts in the course of two simultaneous modes of operation: First, the second composition acts to that it continuously concentrates active ingredient, by sucking liquid from the first composition, so as to contribute that the concentration of the active ingredient does not fall below the saturation value, secondly, the second composition sucks in liquid from the outside environment through the wall and continuously increases its volume, so that a force is exerted against the first composition and the volume of the active ingredient is reduced, whereby the drug is driven against the passage in the chamber. Further, because the separate solution or suspension formed in the first chamber is squeezed out, the osmotic composition is in intimate contact with the inner wall and produces a constant osmotic pressure and thus a constant delivery rate in conjunction with the second composition. The swelling and expansion of the second composition and the associated increase in volume, along with the concomitant corresponding volume reduction of the first composition, ensure delivery of the drug at a controlled rate over time

The device (10) according to FIGS. 1 to 4 can be designed in various ways.

The system (10) may have various known shapes and sizes, for example, it may be formed around a diameter of 4.7 to 12.7 mm.

The Fig. Figs. 5, 6 and 7 show another embodiment of an osmotic device (10). The device (10) has a cylindrical self-supporting elongated shape with a rounded insertion end (20) and attachment end (21) and is provided with cords (22) to easily remove the device (10) by hand from their environment of effect. The device (10) is structurally identical to the device (10) described above and operates in the same way. In FIG. 5, the device (10) is formed with a semipermeable wall (23), as shown in FIG. 6 layered wall (24) comprising an inner semipermeable layer (25) adjacent the chamber (14) and an outer microporous layer (26) remote from the chamber (14). In Fig. 7 the device (10) consists of a layered wall (28) formed of a microporous layer (29) near the chamber (14) and a semi-permeable layer (30) exposed to the environment in which the device is applied and is present as a layer on the microporous layer (29).

The osmotic devices according to FIG. 1 to 7 may be used to deliver many drugs at a controlled rate regardless of the pH dependence of the drug, or where the solubility of the drug may vary between low and high in the liquid environment. Furthermore, the osmotic devices allow high loading of low solubility drugs and their delivery in sufficient quantities. The Fig. 1 Figures 7 to 7 show examples of various osmotic devices as may be constructed according to the invention, but it will be apparent that these devices may also have a variety of other shapes, sizes and configurations for delivering the active agent to the environment intended for its use. The devices may also be sized, shaped and constructed to deliver an active agent to rivers, aquariums, fields, factories, reservoirs, laboratory equipment, greenhouses, transport facilities, shipping facilities, military facilities, hospitals, tectal clinics, nursing homes, farms , Zoos and sick rooms, as well as in chemical reactions and the like. suitable.

According to the invention, it has been found that the osmotic delivery device (10) can be made by co-contacting a first osmotic composition and a second osmotic composition in the chamber of the device. The chamber is defined by a wall of material containing the active agent, the osmotic agent, the osmopolymer u. like. not adversely affected. The wall is permeable to the passage of an external fluid, such as water and biological fluids, and permeable to the passage of agents, osmotic agents, osmopolymers and the like. like. essentially impermeable. The wall consists of a material that does not harm the environment of use and that selectively resists materials used to form the wall are not erodible and insoluble in liquids. Typical materials for the formation of the walls 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 from more than 0 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,

-6AT397 180 B

Cellulose triacetate, mono-, di- and Trizellulosealkanylate, mono-, di- and Trizellulosearoylate u. like. Examples of such polymers are cellulose acetate with a D. S. from 1 to 2 and an acetyl content of 21 to 35%; Cellulose acetate with a D. S. from 2 to 3 and an acetyl content of 35 to 44.8%; u. like. Examples of specific cellulosic polymers are cellulose propionate with a D. S. of 1.8 and a propioyl content of 39.2 to 45% and a hydroxyl content of 2.8 to 5%, 4%; cellulose acetate butyrate with a D. S. of 1.8 and 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%; cellulose tetracycylate having a D. S. from 2.9 to 3, such as cellulose trivalerate, cellulose trilaural cellulose tripalmitate, cellulose trisuccinate and cellulose trioctanoate; cellulose diacylate with a D.S. from 2.2 to 2.6, such as cellulose disuccinate, cellulose dipaimitate, cellulose dioctanoate, cellulose dipental, cellulose esters, such as cellulose acetate, butyrate, and cellulose acetate propionate, and the like. like.

Examples of other semipermeable polymers are ethyl cellulose, Cellulose nitrate, Acetaldehyddimethylacetat, 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 541005; 3 541006 and 3 546142; Semipermeable polymers according to Loeb and Sourirajan in US Pat. No. 3,133,132; slightly&gt; bar (cc · mil / cm² Hr · atm), expressed per bar 10'8 hydrostatic or osmotic pressure differential across the semipermeable wall. The polymers are known from U.S. Patent 3,845,770; 3,916,899 and 4160,020 and in 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 disintegrate into its 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 fully formed microporous polymeric materials and polymeric materials which are capable of forming a microporous layer in the environment of use. In both embodiments, the microporous materials are laminated to form the laminated wall. The preformed materials suitable for the formation of 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 may be isotropic, the structure being homogeneous throughout the cross-sectional area, or anisotropic, the structure being non-homogeneous throughout the cross-sectional area. The pores may be contiguous pores having an opening on either side of a microporous layer, pores interconnected by entangled paths, such as regular or irregularly shaped, including curved, curved, linear, randomly oriented continuous and hindered pores, as well as pores having other microscopic 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 '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 the pressure difference ΔΡ, is generated through the sheets. The fluid flow through the layer of even radius pores extending through the membrane and perpendicular to its surface of size A is given by the relationship (13):

Ν ^ ΔΡ

J = - (13)

8ηΔχ in which J transported per unit time and layer area containing a number N of pores of radius r

-7AT397 180 B

Volume is, η is the viscosity of the liquid and Δ P is the pressure difference through the layer with the thickness Δ x For this type of layer, the number of pores N from the relationship (14) can be calculated, where ε from the ratio of Void volume to the total volume of the layer is defined porosity and A is the cross-sectional area of ​​the n-pore containing layer means ε A

N = - (14) πτ²

The pore radius is then calculated from the relationship 15:

ΙΔχτ _Γ = 8η- (15)

Δρε where J is the volume flow through the layer per unit area produced by the pressure difference Δ P through the layer is η, ε and Δ x have the meanings given above and τ for the entanglement, defined as the ratio of the diffusion path length in the layer to the layer thickness, The relationships given above 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-like 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 drug. The osmotic pressure difference causes a hydrostatic volume flow and the reflection factor is expressed by the relationship 16:

osmotic volume flow υ = - (16) hydrostatic volume flow

The properties of microporous materials are described in Science, Vol. 170, pages 1302 to 1305, 1970; Nature. Volume 214, page 285, 1967; Polymer Engineering and Science, Vol. 11, pp. 284-288, 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, wherein solvent evaporates from the solution in the form of crystals dispersed in the polymer and subsequent curing of 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 of making microporous materials are described in Svnthetic Polymer Membranes of R. E. Kesting, Chapters 4 and 5, 1971, published by McGraw Hill, Inc., Chemical Reviews. Ultrafiltration Volume 18 pages 373 to 455.1934; Polymer Eng, and Sci., Vol. 11, Number 4, pages 284 to 288, 1979; J. APPI. Polv SeLBand 15, pages 811 to 829,1971; and in U.S. Patent 3,565,255; 3,615,024; 3,751,536; 3 801692; 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, Milaoporous materials prepared by phosgenation of a dihydroxylaromete, such as bisphenol A, microporous polyvinyl chloride, microporous polyamide, such as polyhexamethylene adipamide, microporous modacrylic copolymers, including those of polyvinylchloride 60%

-8AT397 180 B and acrylonitrile-formed copolymers, Styrene-acrylic polymer and its copolymers, porous polysulfones, which are characterized by diphenylsulfone groups in one of their linear chains, halogenated polyvinylidene, Polychloräther, acetal polymers, 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 preferably develop greater permeability to the passage of water and biological fluids into semi-permeable layers, asymmetric porous polymers, crosslinked olefin polymers, hydrophobic or hydrophilic microporous homopolymers, Copolymers or intermediate polymers of reduced bulk density and materials, as disclosed in U.S. Patents 3,597,752; 3 643178; 3,654,066; 3,709,774; 3718 532; 3,803,061; 3,852,224; 3,853,601 and 3,852,388, in GB-PS 1,126,849 and in Chem, Abst .. Vol. 7142742F, 2257F, 22573F, 1969.

Other microporous materials are polyurethanes, crosslinked polyurethanes with extended chain, microporous polyurethanes according to US-PS 3,524,753, polyimides, polybenzimidazoles, 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 541055; 3 541066 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; 3,646,178 and 3,852,224 are 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 former 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 the transition metals are iron (III) chloride, iron (II) 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, soibitol, lactose, monosaccharides and disaccharides. Other useful pore-forming agents are organic aliphatic and aromatic oils and solids including diols and polyols such as polyhydric alcohols, polyalkylene glycols, polyglycols, alkylene glycols, poly (am) -alkylene diols, esters of alkylene glycols. the like; water-soluble cellulosic polymers such as hydroxy (lower) alkylcellulose, hydroxypiopylmethylcellulose, methylcellulose, methylethylcellulose, hydroxyethylcellulose and the like; etc .; water-soluble polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose and the like; 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 consisting of inorganic and organic salts, carbohydrates, polyalkylene glycols, poly (ao) -alkylenediols, esters of alkylene glycols, glycols and water-soluble cellulosic polymers which are materials for forming a microporous layer are useful in a biological environment. When the layer-forming polymer contains more than 25% by weight of a pore-forming agent, for the purposes of this invention, the polymer is usually a precursor of the microporous layer which, after removal of the pore-forming agent, forms a layer which is substantially microporous, with Layer behaves like a semipermeable layer or membrane.

The term passageway used in the context of the present invention refers to devices and methods by which the drug or drug can be released from the osmotic system. The term includes holes, openings or bores through the semipermeable wall or through the layered wall. The passage may be by mechanical drilling, by laser drilling, or by erosion of an erordierbaren element such. 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 this invention include inorganic and organic compounds which produce an osmotic pressure gradient through a semipermeable wall or through a semi-permeable microporous layered wall against an external fluid. The osmotically active compounds (together with the osmopolymers) suck liquid into the

Osmotic device, wherein it provides the in-situ fluid for impregnation of an osmopolymer for the purpose of its expansion and / or to form a solution or suspension containing an active ingredient for delivery from the osmotic device do. The osmotically active compounds are also known as osmotically effective dissolved adjunct substances or osmotic agents. The osmotically active compounds are used by mixing them with an active ingredient and the osmopolymer to form a solution or suspension containing the active ingredient, the latter being delivered osmotically from the device. The term limited solubility used in the context of the present invention means that the agent has a solubility of less than 5% by weight in the surrounding aqueous liquid. The osmotic dissolved adjunct substances are processed by mixing them homogeneously or heterogeneously with the active ingredient or osmopolymer and then introducing them into the chamber. The dissolved additive substances and osmopolymers draw liquid into the chamber and form a solution of the dissolved additive in a gel 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, potassium chloride, lithium chloride, potassium sulfate, sodium sulfate, potassium acid phosphate, potassium sulfate, sodium sulfate, lithium sulfate, d-mannitol, urea, inositol, magnesium succinate, tartaric acid, carbohydrates, such as Raffinose, sucrose, glucose, α-d-lactose monohydrate and mixtures thereof. The amount of the osmotic agent in the chamber is usually 0.01 to 30% or higher in the first composition, and usually 0.01 to 40% or higher in the second composition.

The osmotic solubilized additive is initially present in excess and may be in any physical form that is compatible with the drug and the osmotic agent. 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 difference in vapor pressure 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 1. 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>

-10AT397 180 B

The osmopolymers suitable for the formation of the first and osmotic compositions are those which are capable of absorbing the liquid. These osmopoly mers are swellable hydrophilic polymers which react with water and aqueous biological fluids and swell or expand to an equilibrium state. These osmopolymers have the ability to swell in water and to store a significant portion of the absorbed water in the polymer structure. The osmopolymers swell or expand to a very high degree, u. tw. usually up to an increase in volume by two to fifty times. The swellable hydrophilic polymers are weakly crosslinked according to one preferred embodiment, which crosslinks are formed by covalent bonds or ionic bonds. The osmopolymers may be of vegetable, animal or synthetic origin. The osmopolymers are hydrophilic polymers. Hydrophilic polymers, which are suitable for the purposes of the invention, are polyhydroxyalkyl methacrylate having a molecular weight of from 30,000 to 5,000,000; Polyvinylpyrrolidone having a molecular weight of 10,000 to 360,000; anionic and cationic hydrogels; polyelectrolyte complexes; Polyvinyl alcohol with a small amount of acetate, crosslinked with glyoxal, Formaldehyde or glutaraldehyde and having a degree of polymerization of from 200 to 30,000; a mixture of methyl cellulose, cross-linked agar and carboxymethyl cellulose; a water-insoluble, water swellable copolymer formed by forming a dispersion of a finely divided copolymer of maleic anhydride with styrene, ethylene, propylene, butylene or isobutylene. crosslinked with O, 001 to 50, 5 moles of polyunsaturated crosslinking agent per mole of maleic anhydride in the copolymer; water-swellable polymers of N-vinyl lactams and the like; like.

Other osmopolymers are polymers which form hydrogels, such as acidic carboxy polymers having a molecular weight of from 450,000 to 4,000,000 (Carbopol); Polyacrylamides (cyanamer); crosslinked, water-swellable indene-maleic anhydride polymers; Bolyaranic acid having a molecular weight of 8000 to 200,000 (Good-rite), polyethylene oxide polymers having a molecular weight of 100,000 to 5,000,000 (Polyox); starch graft; Acrylate polymer (Aqua-Keeps); with diester - crosslinked polyglucan u. like. Examples of polymers which form hydrogels are known in the art from U.S. Patent 3,865,108 (Hartop); U.S. Patent 4,002,173 (Manning); U.S. Patent 4,207,893 (Michaels); and the Handhook of Common Polymers. Scott and Roff, published by the Chemical Rubber Company, Cleveland, Ohio. The amount of osmopolymer in the first composition is about 0.01 to 90%, that of the osmopolymer in the second osmotic composition is 15 to 95%. According to a preferred embodiment, the molecular weight of the osmopolymer in the second osmotic composition is greater than the molecular weight of the osmopolymer in the first osmotic composition. The determination of the liquid uptake of an osmopolymer for a selected polymer can be carried out according to the procedure described below. A hole mold having a round opening of 12.7 mm, equipped with 12.7 mm diameter dies, is charged with a known amount of a polymer with the caulking pins at both ends of the hole form. The press pins and hole form were placed in a Carver press whose plates were heated to a temperature between 93 and 140 ° C. The Preßstifte were subjected to a pressure of 690 to 1035 bar. After heating for 10 to 20 minutes and applying pressure, the electric heating of the plates was stopped and tap water circulated through the plates. The resulting 12.7 mm diameter discs were placed in an air suspension coater loaded with 1.8 kg saccharide kernels and with cellulose acetate an acetyl content of 39.8%, dissolved in 94: 6 w / w, CH 2 Cl 2 / CH 3 OH, giving a 3% w / w solution. The coated systems were dried overnight at 50 ° C. The dried slices were immersed in 37 ° C water and periodically removed for the gravimetric determination of the aspirated water. The initial suction pressure was determined using the water transfer constant for cellulose acetate after normalizing the suction values ​​for the Membrane Surface Area and Membrane Thickness Calculated The polymer used in this determination was the sodium derivative of Carbopol-934 polymer. prepared according to the methods according to B. F. Goodrich Service Bulletin GC-36, Carbopol Water-Soluble Resins, page 5, published by B. F. Goodrich, Akron, Ohio. The sum weight gain values, y, as a function of t for the cellulose acetate-coated water-soluble polymer disk, were used around the equation of the curve y = c + bt + at passing through these points² to determine the least squares method. The weight gain for Na Carbopol-934 is given by the following equation 17: Weight gain equal to 0.359 + 0.665t - 0.00106t²where t is the time in minutes The rate of water flow at any one time is equal to the slope of the curve according to the following equations 18 and 19:

dy d (0.359 + 0.665t-0.00106t²) - = - (18) dt dt

-11AT397 180 B dy - = 0.665 - 0.00212t (19) dt

To determine the initial rate of water flow, the derivative at t = 0, and dy / dt = 0.665 μΐ ​​/ min, which is equal to the coefficient b, is assumed. The normalization of the time, membrane surface and thickness, as well as the membrane permeability constant against water, K π can then be determined according to the following equation 20:

min 1 ml 0.008 cm K π = 0.665 μΐ ​​/ min x (-) x (-) (-) (20) h 1000 μΐ 2.86 cm² where K = 1.13x10⁴ cm²/H. The (π) value for NaCl was determined with a Hewlett-Packard vapor pressure osmometer and was 345 bar ± 10%, the K value for the cellulose acetate used in this experiment was calculated from the NaCl suction values ​​and was 1.9 x 10 '² cm²/has.

Taking these values ​​into the calculated K expression (1.9 x 10²/cm²/ h · atm) (π) = 1.13 x IO⁴ cm²/ h, we obtain π = 600 atm at t = 0. For the method of evaluating the effectiveness of a polymer with respect to the duration of the O-magnitude driving force, the percentage of water uptake was selected before the water flow values ​​dropped to 90% of their initial values. The value of the slope for the equation of a straight line originating from the axis of the percent weight gain equals the initial value of dy / dt, estimated at t = 0, where the y-section c is the linear swelling time, at (dy / dt) 0 = 0.665 and the y-section = 0 which gives y = 0.665t + 0.359. To determine when the cumulative water absorption value is 90% below the initial rate, the following expression is resolved after t² + bt + c aw

0.9 = - = - 0.9 (21) bt + cw

-0,00106t² + 0,665t + 0359

- = 0.9 and (22)

0,665t + 0.359

Solution after t,

-0,00106t² + 0.0665t + 0.0359 = 0 (23)

-0.0665 ± [(0.665)² - 4 (-0.00106) (0.0359)] t = 2 (-0.00106) where t = 62 min, the weight gain is -0.00106 (62)² + (0.665) (62) + 0.359 = 38 μΐ, where, at the initial sample weight = 100 mg, (Δ w / w) 0.9 × 100 = 38%. The results are shown in FIG. 8th illustrated in the form of a graphical representation of the values. Other methods of assaying the hydrogel solution interface include rheological analysis, viscometric analysis, ellipsometry, contact angle measurements, electrokinetic determinations, infrared spectroscopy, optical microscopy, interfacial morphology, and microscopic examination of a functional device. The active ingredient may be insoluble to highly soluble in the surrounding fluid entering the device and may be mixed with an osmotically effective compound and an osmopolymer. The term active ingredient includes herbicides, pesticides, germicides, biocides, algaecides, Rodenticide, fungicides, Insecticides, antioxidants Accelerators and inhibitors for plant growth, Preservatives, Disinfectants, Sterilants, catalysts chemical reactants, Fermentation agents, Sexualsterilisantien, fertility inhibiting agents, fertility enhancing agents, Air cleaners, Micro-organism-awakening agents and other means for the environment, in which the device is to be applied, especially biocides, are beneficial. Examples of biocides are paraformaldehyde and MethenaminmendelaL

The solubility of an active ingredient in the liquid can be determined by known methods. One method is to use a saturated solution consisting of the liquid plus the active ingredient, determined by

-12AT397 180 B

Analysis of the amount of active ingredient in a defined amount of the liquid to produce. A simple apparatus to accomplish this purpose is a medium-sized sample tube mounted upright in a water bath maintained at a constant temperature and pressure, the liquid and the agent being introduced into the sample tube 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 a further period of time. If the analysis shows no increase in dissolved agent after successive stirring periods in the presence of excess solid in the liquid, the solution is saturated and can give the results as 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 an agent in a fluid.

Typical methods for measuring solubility are chemical and electrical conductivity. Details of various methods for determining solubilities are disclosed in the United States Public Health Service Buletin, No. 67, the Hygenic Laboratory; in the Encyclopedia of Science and Technology, Vol. 12, pp. 542-556, 1971, published by McGraw-Hill, Inc. and in the Encyclopedia Dictionary of Physics, Vol. 6, pp. 547-557, 1962, published in Pergamon Press, Inc.

The osmotic device according to the invention is produced by standard methods. For example, according to one embodiment, the active ingredient is mixed with an osmotic agent and an osmopolymer and pressed into a solid of such dimensions, that it corresponds to the internal dimensions of the chamber next to the passage; or the active ingredient or ingredients and, optionally, a solvent become a solid or semi-solid by conventional methods, such as by milling in a ball mill, calendering, Stir, or grinding on a roller mill, Then, a layer of a composition consisting of an osmotic agent and an osmopolymer is brought into contact with the layer of the drug formulation and the two layers are surrounded with a semipermeable wall. Layering of the drug composition and the osmotic agent / osmopolymer can be accomplished by conventional bilayer tablet squeezing. The wall may be applied by molding and spraying or dipping the pressed shapes into the wall-forming material. Another and currently preferred technique that can be used to apply the wall is coating in air suspension. In this process, the pressed compositions are suspended in a stream of air and wall-forming mass and agitated until the wall surrounds and coats the two compressed compositions. The process is repeated with another layering mass to obtain a layered wall. The air suspension process is disclosed in U.S. Patents 2,799,241; in the year Am, Pharm. Assoc .. Volume 48, pages 451-459, 1979; and ibid, volume 49, pages 82-84, 1960. Other standard methods of preparation are described in Modem Plastics Encyclopedia, Vol. 46, pp. 62-70, 1969; and in Pharmaceutical Sciences. from Remington, 14. Edition, pages 1626 to 1678, 1970, published by Mack Publishing Co., Easton, Penna.

Examples of suitable 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 walls. Examples of such general purpose solvents are those selected from the group consisting of aqueous solvents, alcohols, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic hydrocarbons, aromatics, heterocyclic solvents, and mixtures thereof. Typical solvents are 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-heptane, n-heptane, ethylene glycol monoethyl, Äthylenglykolmonoäthylacetat, methylene dichloride, ethylene dichloride, propylene dichloride, Carbon tetrachloride, Chloroformnitroäthan, Nitropropane, tetrachloroethane, Chloroformnitroäthan, Nitropropane, tetrachloroethane, ethyl ether, isopropyl ether, cyclohexane, Cyclooctane, Benzene, Toluene, naphtha, 1,4-dioxane, tetrahydrofuran, diglyme, Water, and mixtures thereof, like acetone and water, Acetone and methanol, Acetone and ethyl alcohol, Dichloromethylene and methanol, and dichloroethylene and methanol.

The invention is further illustrated by, but not limited to, the following examples.

example 1

A device for the controlled release of an active substance, their shape and dimensions allow their introduction into a urine bag, is prepared as follows: A first biocidal osmotic device is prepared, by sieving 355 g of polyethylene oxide having an approximate molecular weight of 200,000 through a 40 mesh sieve of stainless steel, then 100 g of paraformaldehyde through the 40-mesh sieve, 25 g of hydroxypropyl-13AT 397 180 B methylcellulose through the 40-mesh sieve and finally 10 g of potassium chloride through the 40-mesh sieve. Then all sieved ingredients were placed in the bowl of a laboratory mixer and the ingredients mixed for 15-20 minutes to form a homogeneous mixture. Then a granulation liquid consisting of 250 ml of ethanol and 250 ml of isopropyl alcohol is prepared and added to the mixing bowl; First, 50 ml are sprayed into the dish with constant mixing, whereupon 350 ml of the granulating liquid are slowly added to the dish and the wet mass is mixed for a further 15 to 20 minutes. The wet granules are then screened through a 16 mesh screen and dried at room temperature for 24 hours, after which the dry granules are screened through a 16 mesh screen. Thereafter, 10 grams of magnesium stearate are added to the dry granules and the ingredients are milled for 20-30 minutes on a standard two-roll mill.

A second osmotic composition is then prepared as follows. First, 170g of 5,000,000 molecular weight polyethylene oxide are screened through a 40 mesh screen, then 72.5 grams of sodium chloride are sieved through the 40 mesh screen and the ingredients mixed in a mixing bowl for 10-15 minutes. Then, a granulation liquid is prepared by mixing 350 ml of methanol and 150 ml of isopropyl alcohol and added to the mixing bowl in two stages. First, 50 ml of the granulation liquid is sprayed into the dish with constant stirring, after which 350 ml of the granulation liquid are added slowly to the dish and the moist mixture is mixed for 15-20 minutes until a homogeneous mixture is obtained. The wet mixture is then sieved through a 16 mesh sieve, spread on a stainless steel plate and dried at room temperature of 22.5 ° C for 24 hours. The dry mixture is then sieved through a 16-mesh sieve and ground with 5 g of magnesium sulfate for 20-30 minutes on a two-roll mill.

By pressing the two compositions together on a Manesty press, a number of biocide kernels are prepared. The biocide-containing composition is introduced into the mold cavity of the press and pressed into a solid layer. Then the cavity above the pressed layer is charged with the second osmotic composition and also pressed into a solid layer, so that a ZweischichtenBiocidkem is obtained.

The biocidal nuclei are then coated with a semipermeable, wall-forming mass consisting of 95 g of cellulose acetate having an acetyl content of 39.8% and 5 g of polyethylene glycol 4000 in a solvent consisting of 1960 ml of methylene chloride and 820 ml of methanol. The biocidal nuclei are coated with the semipermeable wall forming mass, until the wall surrounds the biocidal core A Wurster air-suspension coater is used to form the semipermeable wall. The coated cores are then spread on a plate and the solvent is evaporated in an air-licking oven at 50 ° C for 65 hours. After cooling to room temperature, laser beam is introduced Passage of 0.26 mm diameter through the semipermeable wall, which drilled the external environment of the osmotic device with the compound containing the biocide. The osmotic device weighed 262 mg and contained 30 mg of biocide in the first 150 mg composition, the second composition weighed 75 mg and the semipermeable wall 37 mg. The first osmotic composition of the osmotic device consists of 30 mg biocide, 106 mg polyethylene oxide, 3 mg potassium chloride, 7.5 mg hydroxypropyl methylcellulose and 3 mg magnesium stearate. The second osmotic composition consists of 51 mg polyethylene oxide, 22 mg sodium chloride and 1.5 mg magnesium stearate The device has a diameter of 8 mm, an area of ​​1.8 cm², this wall is 0.17mm thick. Upon introduction of the device into a urine bag, the paraformaldehyde depolymerizes to formaldehyde due to the presence of the urine and thus prevents the growth of unwanted bacteria in the urine bag. The delivered sum effect of the drug is shown in Figure 9. The use of paraformaldehyde as a biocide is described in U.S. Patent 4,144,309 (ALZA Corporation).

Example 2

An osmotic device for the controlled and continuous release of the biocide methenamine mendelate is prepared as follows: 90 mg methenamine mendelate, 50 mg of sodium carboxy vinyl polymer having a molecular weight of 200,000, 3 mg sodium chloride, 7.5 mg of hydroxypropyl methylcellulose and 3 mg of magnesium stearate, as described in Example 1, mixed well and compressed in a Manesty press with a 7.9 mm punch using a pressure of 211 bar to a layer of the biocide composition. Thereupon, 51 mg of carboxyvinyl polymer having a molecular weight of 3,000,000,22 mg of sodium chloride and 2 mg of magnesium stearate are well mixed and introduced into the Manesty press and pressed into a layer of an expandable biocidal osmotic composition.

A semipermeable wall was then made by mixing 170g of cellulose acetate having an acetyl content of 39.8% with 900ml of methylene chloride and 400ml of methanol and spray coating the bilayered chamber forming member in an air-suspension machine until a 0.13mm thick semipermeable wall is the chamber The coated device was dried for 72 hours at 50 ° C, after which a 0.2 mm

In order to connect the biocide-containing layer to the outside environment of the device for delivery of the biocide during a prolonged period of time, the laser beam was bored through the semipermeable wall. The use of methenamine mendelate as a biocide in a fluid containment vessel is described in U.S. Patent 4,445,889 (ALZA Corporation, Palo Alto).

Example 3

In this example, the increase in osmotic pressure for a number of compositions consisting of an osmotic agent and an osmopolymer is demonstrated to demonstrate the utility afforded by the present invention. The measurements are made by measuring the amount of water that is drawn in through the semipermeable wall of a pouch containing an osmotic agent, or an osmopolymer, or a composition consisting of an osmotic agent and an osmopolymer. The semipermeable wall of the bag is made of cellulose acetate with an acetyl content of 39.8%. Measurements are made by placing the dry components of the semipermeable bag and then the bag in a water bath of 37 ^eC is measured during different lengths of time. The increase in weight is due to the suction of water through the semipermeable wall caused by the osmotic pressure gradient across the wall. The osmotic pressure curves are shown in FIG. 11 refer to. In Fig. 11 the curve with the triangles shows the osmotic pressure for polyethylene oxide having a molecular weight of 5,000,000; the curve with the circles the osmotic pressure for a composition consisting of polyethylene oxide with a molecular weight of 5,000,000 and sodium chloride, the ingredients in the composition being present in the ratio of 9.5 parts osmopolymer to 0.5 part osmotic agent; the curve with the squares has a composition consisting of the same osmopolymer and osmotic agent in the ratio of 9 parts of osmopolymer and one part of osmotic agent; the curve with the hexagons same composition consisting of the osmopolymer and the osmotic agent in the ratio of 8 parts to 2 parts and the dashed curve the osmotic agent sodium chloride. The mathematical calculations were based on the formula dw / dt = Α (K Δ 7t) / h, where dw / dt is the ratio of water absorption over time, A is the area of ​​the semipermeable wall and K is the permeability coefficient. Furthermore, it is necessary. The amount of water absorbed per ounce and osmotic agent is divided by the weight of the osmopolymer.