Process for the production of a device for delivering an active substance, in particular a medicine, to an aqueous environment of use

(42) Date of commencement of the patent: 15. 1. 1992 (45) Date of issue: 27. 7.1992 (62) Elimination from application No: 880/84

<td>(30) Priority:</td><td>(73) Patent owner:</td>

<td>11. 5. 1983 US 493760 claims.</td><td>ALZA CORPORATION</td>

<td>(56) Documents:</td><td>94303 PALO ALTO (US).</td>

<td>DE-OS 2751587 EP-A2 0052917 GB-PS 2116842 U.S. Patent 3,995,632 U.S. Patent 4,2000,998 to U.S. Patent No. 4,327,725</td><td></td>

(54) METHOD FOR PRODUCING A DEVICE FOR DISPOSING AN ACTIVE AGENT, IN PARTICULAR A REMEDY, TO A WATER USE

CO (57) A process is described for producing a device for delivering an active ingredient, in particular a remedy, at a controlled release rate to an aqueous environment of use. The procedure is that the active ingredient with an osmotic agent and an osmopolymer, which absorbs an aqueous liquid, mixed into a first composition; an osmopolymer which absorbs an aqueous liquid and has a higher molecular weight than that in the first composition, mixed with an osmotic agent to form a second composition; bringing together the first composition and the second composition, and pressed into a two-layered core; a semipermeable polymer and a solvent thereof are mixed to form a wall-forming composition; coating the core with the wall-forming composition and forming an exit passage in the wall.

<img file="AT394944B_D0001.tif" />

AT 394,944

MR 0078318

AT394 944B

The present invention relates to a method for producing a device for delivering an active ingredient, in particular a remedy, at a controlled release rate to an aqueous environment of use, which is characterized in that

a) mixing the active ingredient with an osmotic agent and an osmopolymer which absorbs an aqueous liquid to provide a first composition;

b) an osmopolymer which absorbs an aqueous liquid and has a higher molecular weight than that present in the first composition, blended with an osmotic agent to provide a second composition;

c) bringing together the first composition and the second composition and pressing them into a two-layer core;

d) mixing a semipermeable polymer and a solvent therefor to provide a wall-forming composition;

e) coating the core with the wall-forming composition to create a wall surrounding the core; and

f) forming an exit passage in the wall connecting the first composition to the outside environment of the device to deliver the active agent from the device over time.

The device is useful for the delivery of remedies which due to their solubilities are difficult to administer in a known amount and controlled rate from an osmotic delivery system.

Already in the early antiquity both the pharmacy and the medicine looked for a delivery system for the administration of a cure. The first written reference to a dosage form is in the approximately 1552 BC. 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. It took about 2500 years without any progress in the development of the dosage form when the Arab physician Rhazes, 865-925 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. described Chr.,. These manuscripts describe a tablet formed by the hollow pressing in two opposed tablet forms. The 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 major leap in dosage forms came in 1972 with the invention of the osmotic dispenser by Theeuwes and Higuchi, described in U.S. Patent 3,845,770 and U.S. Patent 3,916,899. The osmotic devices described in these patents consist of a semipermeable wall surrounding a compartment containing an active agent. The wall is permeable to the passage of an external fluid and substantially impermeable to the passage of the drug. 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 this permeable 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 containing the active ingredient contains, which is then discharged through the passage from the device. These devices are particularly effective for delivery of an active agent which is soluble in the liquid and produces an osmotic pressure gradient through the semipermeable wall external fluid.

Pioneering performance on osmotic sequestration devices has been provided to the administration technique by the inventor Felix Theeuwes in U.S. Patent 4,111,202. 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 forming the osmotic device having a drug compartment and a film separated osmotic agent compartment. The film is movable from a rest position to an expanded position. The osmotic device delivers the drug by aspirating liquid into the osmotic agent chamber through the semipermeable wall, forming a solution which results in an increase in the volume of the chamber and acts as a driving force against the film Application passes. By this force, the film expands against the drug chamber, the volume of which consequently decreases accordingly, thereby delivering the drug 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 solutes of varying solubility, 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

In U.S. Patent 4,327,725, Richard Cortese and Felix Theeuwes, there is an osmotic delivery device for the

-2AT 394 944 B

However, because of their solubilities in aqueous and biological fluids, the latter are difficult to deliver in larger quantities at controlled release rates during time. The osmotic devices according to this patent have a semipermeable wall surrounding a chamber containing an active ingredient that 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-deliver remedies for the purpose intended for them. It has now been observed that the use of such a device is limited because the hydrogel lacks the ability to take up enough liquid for the drug to expel the drug from its maximum axial expansion.

For the skilled artisan, it is obvious that if an osmotic device could be created which would develop a high level of osmotic activity for delivery of a cure by generating in situ an expanding force sufficient to maximize the amount of drug at a controlled rate osmotic device, this would be a positive contribution and an advance in the delivery technique. Likewise, it is evident that in the field of pharmacy and medicine, an osmotic delivery device would find practical application having dual thermodynamic osmotic activity for delivery of increased amounts of a drug.

The inventively producible device is compared to the known devices another

Improvement and further advancement. It enables in vivo delivery of a curative which is difficult to administer and which can now be administered in therapeutically effective amounts over time.

The device of the present invention allows for higher loading with a water-insoluble or slightly water-soluble drug and delivery of the drug at a controlled rate and substantially continuously over time.

With the device of the present invention, a pH dependent remedy can be delivered by providing a neutral medium for delivery of the remedy in a finely disperse form for the purpose of enlarging the surface and maximizing the dissolution rate of the remedy.

Further, the delivery of a very low dissolution rate drug, ie, the rate limiting rate of delivery of the drug from the system, is enabled, however, which drug can now be administered using an osmotic composition which is in situ as a wetting agent and solvent for elevation the rate of dissolution and the solubility of the drug so that its delivery from the osmotic system is improved.

With the device of the invention, a complete pharmaceutical dosage range consisting of sparingly soluble to highly soluble agents may be administered at a controlled rate and continuously for a given period of time, the use of the device requiring intervention only at the beginning and possibly at the end of the treatment area.

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 a perspective view of an osmotic device for the oral administration of a cure in the gastrointestinal tract; FIG. 2 a perspective sectional view of the osmotic device of FIG. 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 remedy from the osmotic device; FIG. 4 in a perspective sectional view of the device according to

Fig. 1 and seen in conjunction with Fig. 3, illustrating the osmotic device during use and delivery of a greater amount of remedy; Fig. 5 shows an osmotic therapeutic device with a partially fractured wall for delivery of a therapeutic agent into a body cavity, such as the anal space and the vaginal cavity; Fig. 6, the osmotic device of FIG. 5 with a

5θ other wall structure; Fig. 7, the osmotic device of FIG. 5 with a different wall structure than that of

Device according to Fig. 6; Figure 8 is an illustration 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; Figure 9 illustrates the total amount of drug released from a device consisting of an osmopolymer with two different molecular weights; Fig. 10 illustrates the total amount⁵⁵ Drug released from a device consisting of differently constructed osmopolymers;

Fig. 11 illustrates the osmotic pressure curves for a number of osmotic agents and a number of osmotic / osmotic agent compositions; Fig. 12 shows the overall release profile

-3AT394 944B for an osmotic system consisting of two different osmopolymers; FIG. 13 FIG. 4 illustrates the rate of release per hour for a portion different from that shown in FIG. 9 distinctive osmotic system containing an osmopolymer having two different molecular weights; FIG. 14 Fig. 10 shows the total amount released from a single composite device consisting of only one layer; FIG. 15 Figure 3 is a representation of the total release in vivo and in vitro for a drug substance delivered by the osmotic device;

Figure 16 illustrates the total release in vivo and in vitro for another drug delivered by an osmotic device.

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

The drawings describe various embodiments of osmotic devices that can be produced according to the invention. 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 remedy from the osmotic device (10).

In Fig. 2 is the osmotic device (10) according to FIG. 1 illustrated on average. According to FIG. 2 the osmotic device (10) comprises a body (11) and a semipermeable wall (12) forming and enclosing an internal chamber (14), which chamber communicates via the passageway (13) with the external environment of the osmotic device (10 ). The chamber (14) contains a first osmotic composition consisting of a remedy (15) which is shown dotted and in which liquid drawn into the chamber (14) may be insoluble to highly soluble, an osmotic agent (16) which is corrugated Lines is shown and soluble in the retracted into the chamber (14) liquid and through the semipermeable wall (12) against the outer

Liquid produces an osmotic pressure gradient, as well as from an osmopolymer (17) represented by horizontal dashes, which draws liquid into the chamber (14) and generates an osmotic pressure gradient through the semipermeable wall (12) against the external liquid present in the environment of use. The wall (12) is made of a semipermeable composition which is permeable to the passage of the external fluid and substantially impermeable to the passage of the agent (15), the osmotic agent (16) and the osmopolymer (17) The semipermeable wall (12 ) is non-toxic and maintains its physical and chemical integrity during the delivery time of the device (10).

In the chamber (14), further away from the passageway (13), is a second osmotic composition which is in touching contact with the first composition. The second composition is expandable and develops a driving force to which the first osmotic composition cooperates to deliver a maximum amount of remedy (15) from the osmotic device (10). The second osmotic composition consists of an osmotic agent (18), that is soluble in the liquid sucked into the chamber (14) and that anosmotic pressure gradient is generated against a liquid from the environment through the wall (12) and 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 capable 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 liquid aspirated into the chamber (14) by the osmotic suction of the osmopolymers (17 and 19) supplemented by the osmotic suction of the osmotic agents (16 and 18) for maximum expansion of the osmopolymer (17 and 19) to a larger mass.

During use of the device, delivery of the remedy (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 device

5θ suspension through the passage and simultaneously by (2) aspirating the fluid through the second composition to swell the first composition and to cause the first composition to co-express the drug suspension through the passageway. The osmotic device may be considered as a cylinder, 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 and 2 shown

Shape dermootic device is not exactly similar to a cylinder, but is so similar 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

-4AT394944B first composition F and the water intake rate by the second composition Q, wherein:

F_t = F + Q (1)

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

-2 = Q (2) dt

The total delivery rate from the osmotic device is then dm _ = F_t - C = (F + Q)_C (3) dt 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 , V_p (4) ^Λ ' ^Ja * A_p (5) where Vj and V_p are equal to the volumes of the first composition and the second composition respectively, and wherein A_d and are equal to the contact area with the wall of the first composition and the second composition, respectively. During use, both Vp and Ap) increase with ZLeit, whereas V_dand A_d over time as the device releases the remedy; lose weight:

The volume of the second composition, which expands over time as liquid is drawn into the chamber, is given by Equation 7:

v

<img file="AT394944B_D0002.tif" />

(7) wherein Wjj is the weight of the liquid sucked by the second composition, W_p the weight of the second composition initially present in the device, and Wjj / Wp is the ratio of liquid to solid originally present in the second composition, where Vp is the same

<img file="AT394944B_D0003.tif" />

where e is the density of the second composition corresponding to W_H/ W_p means. Thus, based on the geometry of a cylinder where r is the radius of the cylinder, the wicking area is related to the volume of the swollen second composition as follows:

A = r⁵P (8) (9)

AT394 944B

The liquid intake rates in each chamber are:

<img file="AT394944B_D0004.tif" />

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

<img file="AT394944B_D0005.tif" />

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 a solution containing the drug or a gel of the osmotic agent and the osmopolymer containing the drug in suspension, in each case releasing the solution or the suspension through the combined actions of the device (10). These modes of action include 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 FIG. 4 is illustrated. The last-mentioned swelling and increase in volume exerts pressure against the solution or suspension, acting on the first composition and at the same time causing the release of the remedy to the external environment of the device.

The first composition and the second composition work together, to essentially ensure that the release of the remedy from the chamber over a longer period of time is accomplished by two methods. First, the first composition through the wall draws in fluid 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, because the driving force decreases with time. Second, the second composition works in the context of two simultaneous modes of operation: First, the second composition works to that she continuously concentrates remedies, by sucking liquid from the first composition, to contribute in this way that the concentration of the remedy 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 remedy is reduced, whereby the remedy is driven against the passage in the chamber. Further, as 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 associated with the second composition. The swelling and expansion of the second composition, and the associated increase in volume, along with the concomitant corresponding reduction in volume of the first composition, ensure delivery of the remedy at a controlled rate over time.

The device (10) according to FIGS. 1 4 may be formed in a variety of ways, including the presently preferred embodiment for oral use for delivering either a topical or a systemically acting drug in the gastrointestinal tract. The oral system (10) may have various known shapes and sizes, for example it may be formed round with a diameter of 4.7 to 12.7 mm. Among these forms, the system (10) is useful for administering the drug to a variety of animals including warm-blooded animals, humans, reptiles, and fish.

Figures 5, 6 and 7 show another embodiment of an osmotic device (10) for placement in body ducts, such as in the vagina or in the anorectal canal. The device (10) has a cylindrical

Self-supporting elongated shape with rounded insertion end (20) and hanger end (21) and is provided with cords (22) to easily remove the device (10) by hand from a biological channel. 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 semi-permeable wall (23), in FIG. 6 with a layered wall (24) consisting of an inner semipermeable layer (25) adjacent the chamber (14) and an outer microporous layer (26) remote from the chamber (14). 7 the device (10) consists of a layered wall (28) formed by 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 device (10) delivers a drug for absorption by the vaginal mucosa, or by the anorectal mucosa, to produce a local effect or system effect in vivo for a prolonged period of time.

The osmotic devices according to FIG. 1 7 can be used to deliver many agents, including medicines, at a controlled rate regardless of the pH dependence of the drug or when the solubility of the agent can vary between low and high in the liquid environment, such as in the gastric intestinal fluid, be used. Furthermore, the osmotic devices allow high loading of low solubility agents and their delivery in sufficient therapeutic amounts. The Fig. 1 Figures 7 to 7 show examples of various osmotic devices as may be constructed in accordance with the invention, but it will be apparent that these devices may also have a variety of other shapes, sizes and configurations for delivery of the beneficial agent to the environment intended for their use. Examples include devices for buccal use, implant devices, artificial glands, cervical devices, intrauterine devices, devices for use in the ear, nose, skin, subcutaneous devices and devices for delivery to the blood. The devices may also be sized, shaped and constructed to deliver drug in rivers, aquariums, fields, factories, reservoirs, laboratory equipment, greenhouses, transportation facilities, shipping facilities, military facilities, hospitals, veterinary clinics, nursing homes, farms Zoos and sick rooms, as well as in chemical reactions and on others.

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 which is the remedy, 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 is made of a material which does not harm an animal or a host and the selectively semipermeable 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, DS, at the anhydroglucose unit of greater than 0 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-, di- and tricellulose alkanylates, mono-, di- and tricellulose anroylates, and the like. like. Examples of such polymers are cellulose acetate with a DS from 1 to 2 and an acetyl content of 21 to 35%; Cellulose acetate with a DS 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 DS 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 DS 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 acetylate with a DS from 2.9 to 3, such as cellulose trivalerate, cellulose trilaurate, cellulose tripalmitate, cellulose trisuccinate and cellulose trioctanoate; Cellulose diacylates with a DS from 2.2 to 2.6 such as cellulose disuccinate, cellulose dipaimitate, cellulose dioctanoate, cellulose dipental, cellulose co-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, U.S. Patent No. 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; light

-7AT394944B crosslinked polystyrene derivatives; crosslinked poly (sodium styrenesulfonate), crosslinked poly (vinylbenzyltrimethylammonium chloride), semipermeable polymers having a liquid permeability of 10 to 10 '¹ cm³.0.025 mm / cm², h.bar (cc.mil/cm².hr.atm), expressed per bar 10 '^ hydrostatic or osmotic pressure difference through the semipermeable wall. The polymers are disclosed in U.S. Patent Nos. 3,845,770; 3,916,899 and 4,160,020 and from the Handbook of Common Polymers, by Scott. J ^ .undRoff.WJ · 1971. published by CRC Press. Cleveland. Ohio, known.

In the laminated wall consisting of a semipermeable layer and a microporous layer are the

Layers are in a laminar arrangement and cooperate to form a unitary laminated wall which retains its physical and chemical integrity and does not break down into its layers throughout the process of release of the drug from an osmotic device. 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. In both embodiments, the microporous materials are laminated to form the 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 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 both sides 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 with other microscopically detectable paths. 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 having a pore size of 10 '' can be used.⁹ to lO ^ m, are used. The pore size and other parameters characterizing the microporous structure can also be obtained in the course of flow measurements wherein 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 relationship 13:

<img file="AT394944B_D0006.tif" />

(13) where J is the volume transported per unit time and layer area containing a number N of pores of radius r, η represents the viscosity of the liquid, and Δ P is the pressure difference across the layer of Δx thickness. For this type of layer, the number of pores N can be calculated from the relationship 14, 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 (14).

The pore radius is then calculated from the relationship 15:

<img file="AT394944B_D0007.tif" />

(15) 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 the diffusion path length in the Layer to layer thickness, stands the relationships given above

-8AT394 944B are in transport Phenomena In Membranes. by Lakshminatayaniah, N, chapter 6,1969, published by Academic Press, Inc., New Yoik.

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 less than 0.3, the layer becomes substantially microporous, as expressed by the osmotic reflection factor σ, which falls below 0.5. Microporous layers having a reflectivity σ 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 16:

osmotic volume flow * ------ (16) hydrostatic volume flow

The properties of microporous materials are in Science. Vol. 170, pages 1302 to 1305, 1970: Nature. Band 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 Leav RE and Loeb, Sidney. Pages 131 to 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 of making microporous materials are in silicone polymer membranes. from RE 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, Polv Be .. Volume 15, pages 811 to 829, 1979; and in U.S. Patent 3,565,259; 3,615,024; 3,751,536; 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 dihydroxy laromene, like bisphenol A, microporous polyvinyl chloride, microporous polyamide, such as polyhexamethylene adipamide, microporous modacrylic copolymers, including the copolymers formed from polyvinylchloride 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, 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 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 intermediate polymers of reduced bulk density and materials, as disclosed in U.S. Patents 3,597,752; 3 643 178; 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, Dist., Volume 714274F, 22572F, 22573F, 1969 are described.

Other microporous materials are polyurethanes, crosslinked polyurethanes with extended chain, microporous polyurethanes according to US Pat. No. 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; 3,541,055; 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; 3,646,178 and 3,852,224 are microporous

-9AT394944B

Materials.

An example of another microporous material that can be used for the purposes of the present invention is that which forms the microporous layer in situ, wherein a pore former is removed by causing it to leach or leach to the microporous layer during use of the system to build. 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 include 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, and the like. etc .; water-soluble cellulosic polymers such as hydroxy (lower) alkylcellulose, hydroxypropylmethylcellulose, methylcellulose, methylethylcellulose, hydroxyethylcellulose and the like; etc .; water-soluble polymers such as poly venylpyrrolidone, sodium carboxymethyl cellulose 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 consisting of inorganic and organic salts, carbohydrates, polyalkylene glycols, poly (am) -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 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) draw fluid into the osmotic device, using the in situ fluid for impregnation of an osmopolymer to expand it and / or to form a solution or suspension which is a cure for the osmotic agent Delivery from the osmotic device contains, make available. The osmotically active compounds are also known as osmotically effective dissolved adjunct substances or osmotic agents. The osmotically effective compounds are employed by mixing them with a curative and the osmopolymer to form a solution or suspension containing the curative, 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 solubilized adjunct substances are processed by mixing them homogeneously or heterogeneously with the drug 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, ad lactose monohydrate and mixtures thereof. The amount of in-chamber

The osmotic agent 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 substance is initially in excess and may be in any physical form that is compatible with the remedy and the osmotic agent. The osmotic pressure of saturated solutions of various osmotically active compounds and mixtures of

<td colspan="2">Compounds at 37 ° C in water are 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 understood that the invention also encompasses 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.</td>

<td>Deeds? 1</td><td></td>

<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>

The osmopolymers suitable for the formation of the first and osmotic compositions are those which are capable of absorbing the liquid. These osmopolymers 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 a preferred embodiment, wherein these 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 produced by forming a dispersion of a finely divided copolymer of maleic anhydride with styrene, ethylene, propylene, Butylene or isobutylene, crosslinking from 0.001 to 0.5 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

<img file="AT394944B_D0008.tif" />

Molecular weight of 450,000 to 4,000,000 (Carbopol); Polyacrylamides (cyanamer); crosslinked, water-swellable indene-maleic anhydride polymers; Polyacrylic acid having a molecular weight of 8,000 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 US Pat. No. 3,865,108 (Hartop); U.S. Patent 4,002,173 (Manning); U.S. Patent 4,207,893 (Michaels); and the Handbook 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%. In 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 and equipped with 12.7 mm diameter dies is charged with a known amount of a polymer, with the press pins projecting away from both ends of the hole pattern. 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 dies were pressurized at 690 to 1035 bar. After heating for 10 to 20 minutes and applying pressure, the plates were electrically heated and water was circulated through the plates. The resulting disks, 12.7 mm in diameter, were placed in an air-suspension coater. charged with 1.8 kg of saccharide kernels, introduced and with cellulose acetate having an acetyl content of 39.8%, dissolved in 94: 6 w / w, CH2Cl2 / CH3OH, which gave 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 purpose of giavimetric determination of the aspirated water. The initial suction pressure was determined using the water transfer constant for cellulose acetate after normalizing the membrane surface aspiration values and the membrane thickness calculated The polymer used in this determination was the sodium derivative of the polymer Carbopol-934, manufactured according to the procedures according to BFGoodrich Service Bulletin GC-36, "Carbopol Water-Soluble Resins", Page 5, published by BF Goodrich, Akron, Ohio.

The values ​​of cumulative weight gain, y, as function, currently, for the cellulose acetate-coated disk of water-soluble polymer were used to obtain 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 given time is equal to the slope of the curve according to the following equations 18 and 19:

dy ₌ &lt;3 (0.359 + 0.665t - 0.00106t ') (18) dt dt = 0.665 - 0.00212t dt (19)

To determine the initial rate of water flow, the derivative at t = 0, and dy / dt = 0.665 μϊ / 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:

"1

60-K Ti = 0.665 μϊ / min x (

<img file="AT394944B_D0009.tif" />

, 0.008 cn '' 0 or

2.86 cm '(20) where K = 1.13 x IO²¹ cm²/H. The π value for NaCl was calculated using a Hewlett-Packard vapor pressure osmometer from the NaCl suction values ​​and was 1.9 times<img file="AT394944B_D0010.tif" />10 '¹ cm²/has.

^σ ° Τ ') -Α Ί

If one puts these values ​​into the calculated K expression (1.9 x 10 '/ cm / h.atm) π = 1.13 x 10 cm / h, one obtains 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

-12AT394944B y = 0.665t + 0.359. In order to determine when the sum value of the water absorption is 90% below the initial rate, the following expression is resolved after t.

0,9 = at '+ bt + c = Λ w bt + cw (21) (22) (23)

-0.00106 t '+ 0.665 t + 0.359 = 0.9 and

0,665t + .359

Solution after t,

-0.00106t '+ 0.0665t + 0.0359 = 0 _{t =} -0.0665 ± £ (0.665) '- 4 (-0.00106) (0.0359) 7 (-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 examining the hydrogel solution interface include theological analysis, viscometric analysis, ellipsometry, contact angle measurements, electrokinetic determinations, infrared spectroscopy, optical microscopy, interfacial morphology, and microscopic examination of a functional device. The term "active ingredient" as used herein includes any remedy that can be released from the device to achieve a curative effect. 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, Microorganisms - debilitating agents and other means for the environment, in which the device is to be applied, are beneficial.

In the context of the present invention, the term drug drug and the term drug includes any physiologically or pharmacologically active substances present in animals, including warm-blooded animals, humans and primates, birds, pets, sport animals and farm animals, laboratory animals, fish, reptiles and zoo animals , lead to a local or systemic effect. The term "physiological" used in the context of the present invention refers to the administration of a drug for the purpose of obtaining normal levels and functions.

The term "pharmacological" refers to variants in which the ingestion organism is responsive to the amount of ampoule administered. See Stedman's Medical Dictionary: 1966, published by Williams and Wilkins, Baltimore, Md.

The term "drug preparation" means that the drug in the chamber is mixed with an osmotic additive and / or an osmopolymer and, if applicable, with a binder and lubricant. The active substance, which can be administered includes medicines, on the peripheral nerves, adrenergic receptors, cholinergic receptors, the nervous system, the skeletal muscle, cardiovascular system, smooth musculature, Blood circulation system, synoptischeStellen, neuroeffector joints on the endocrine system, on hormone systems, the immonological system, organic systems, the reproductive system, Skeletal system, autokoid systems, on the embryo and excretory systems, inhibiting autokoid and histamine systems, Act. Examples of active ingredients, which can be administered to affect these living systems, are depressants, hypnotics, sedatives, mental stimulants, Tranquilizers, antispasmodic, Muscle relaxants, Anti-Parkinson drugs, analgesics, anti-inflammatory agents, local anesthetics, Muscle relaxants contract, antimicrobial agents, Antimalarials, hormonal agents, contraceptives, sympathomimetic, diuretics, antiparasitic agents, neoplastic agents, hypoglycemic agents, ophthalmic agents, electrolytes diagnostic and cardiovascular drugs.

Examples of drugs which are highly soluble in water and by means of the devices according to the invention

Can be administered prochlorazine disylate, Iron (II) sulfate, Aminocapronsäuie, Potassium chloride, mecamylamine, procainamide, Aphetaminsulfat, Benzphetaminhydrochlorid, Isoproternolsulfat, methamphetamine hydrochloride, Phenmetrazinhydrochlorid, bethanechol, methacholine chloride, pilocarpine hydrochloride, atropine sulfate, Methascopolaminbromid, isopropamide, Tridihexäthylchlorid, phenformin, methylphenidate hydrochloride, oxprenolol hydrochloride, metoprolol tartrate, Cimetindinhydrochlorid, Theophyllincholinat, Cephalexin hydrochloride and the like like.

Examples of drugs which are poorly soluble in water and which can be administered by the devices of the invention are diphenidol, meclizine hydrochloride, prochlorperazine, phenoxybenzamine, Thiäthylperazinmaleat, anisindone, Diphenadionerythrityl, Dizoxin, Isofurophat, reserpine, acetazolamide, Methazolamide, bendroflumethiazide, chlorpropamide, tolazamide, chlormadinone, phenaglycodol, allopurinol, Aluminum aspirin, methotrexate, Acetylsulfisoxazol, erythromycin, progestins, estrogenic progestational, corticosteroids, Hydrocortisone, hydrocorticosterone, cortisone acetate, Triaminolon, methyltesterone, 17ßÖstradiol, ethinyl estradiol, prazosin hydrochloride, Ethinyl estradiol 3-methyl ether, prednisolone, 17-hydroxyprogesterone, 19-nor-progesterone, Norgestrel, norethindrone, Progesterone, norgesterone, Norethynodrel u. like.

Examples of other medicines, which can be administered by the osmotic device, are aspirin, indomethacin, naproxen, fenoprofen, sulindac, diclofenac, indoprofen, Nitroglycerin, propranolol, metoprolol, valproate, oxprenolol, timolol, atenolol, alprenolol, cimetidine, clonidine, imipramine, levodopa, chloropromazine, reserpine, Methyl-dopa, dihydroxyphenylalanine, Pivaloyloxyäthyl, Esters of methyldopahydrochloride, theophylline, calcium gluconate, ketoprofen, ibuprofen, cephalexin, erythromycin, prazosin, haloperidol, Zomepirac, iron (II) lactate, vincamine, diazepam, phenoxybenzamine, α-blocking agents, Calcium channel blocking drugs such as nifedipine, diltiazem, verapamil, Beta-Blocker u. like. The remedies are from the Pharmaceutical Sciences, edited by Remington.14. Output. 1979, published by MackPublishing Co..Easton.Penna .: The Drug.The Nurse. The patient. Including CurrentDrugHandbook. 1974-1976, by Falconer et al., Published by Saunder Company, Philadelphia, Penna .; and Medicinal Chemistry. Third Edition, Volumes 1 and 2, by Burger, published by Wiley-Interscience, New York

The agent may be administered in various forms such as charged molecules, molecular complexes, pharmacologically acceptable salts such as the hydrochloride, hydrobromide, sulfate, laurylate, palmitate, phosphate, nitrite, borate, acetate maleate, tartrate, oleate and salicylate. For acidic drugs, salts of metals, amines or organic cations may be used, such as quaternary ammonium salts. Derivatives of drugs such as esters, ethers and amides can be used. It may also be a water-insoluble drug in the form of a water-soluble derivative used and serve as a dissolved additive, wherein they are converted in their release from the device to its original biologically active form by enzymes, hydrolyzed by the pH of the body or in the course other metabolic processes is transferred. The drug-containing agent may be present in the chamber along with a binder, dispersant, wetting agent, suspending agent, lubricant and a dye. Examples of such substances are suspending agents such as acacia, agar, calcium carrageenan, alginic acid, algin, agarose powder, collagen, colloidal magnesium silicate, colloidal silicic acid, hydroxyethyl cellulose, pectin, gelatin and calcium silicate; Examples of binders are polyvinyl pyrrolidone, of lubricants are magnesium stearate, of wetting agents are fatty amines, fatty quaternary ammonium salts u. like. The term drug composition refers to having the drug in the chamber together with an osmotic agent, an osmopolymer, a binder, and the like. like. is present. The amount of curative present in the device is usually 0.05 ng to 5 ng or more, with individual devices containing, for example, 25 ng, 1 mg, 5 mg, 125 mg, 250 mg, 500 mg, 750 mg, 1.5 g u. like. contain. The device may be administered once, twice, or three times a day.

The solubility of a drug in the fluid can be determined by known methods. One method is to prepare a saturated solution consisting of the liquid plus the remedy, determined by analyzing the amount of remedy present in a defined amount of the liquid. A simple apparatus to accomplish this purpose consists in 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 syringe. 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 agent 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 agent is soluble, an added osmotically effective compound may not be required; however, if the agent has limited solubility in the fluid, an osmotically active compound may be added to the device

Become -14AT394 944B. There are a number of other methods for determining the solubility of an agent in a liquid. Typical methods for measuring solubility are the 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 to 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.

According to one embodiment, the remedy 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 remedy or other formulation of ingredients and a solvent become a solid or semi-solid post-conventional methods, such as by ball milling, calendering, Stir, or grinding on a roller mill, mixed and then brought into a preselected form. Then a layer of a composition consisting of an osmotic agent and an osmopolymer is brought into contact with the layer of the curative formulation and the two layers are surrounded by a semipermeable wall. Layering of the curative 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. Patent 2,799,241; in the J.Am.Pharm.Assoc .. Volume 48, pages 451-459, 1979; undibid.Band49. Pages 82bis84.1960. Other standard manufacturing processes are in Modem Plastics Encyclopedia. Volume 46, pages 62 to 70, 1969; and in Pharmaceutical Sciences, by 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 the following examples

example 1

An osmotic waste device, manufactured as an osmotic tablet with a shape and size suitable for oral administration to the gastrointestinal tract, is prepared as follows: A first osmotic drug composition is prepared by sieving 355 g of polyethylene oxide having an approximate molecular weight of 200,000 through a 40 mesh stainless steel screen, after which 100 g of nifedipine passed through the 40-mesh sieve, 25 g of hydroxypropyl methylcellulose through the 40 mesh screen and finally 10 g of potassium chloride through the 40 mesh screen. Then all sieved ingredients are placed in the bowl of a laboratory mixer and the ingredients mixed for 15 to 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. Then 10 grams of magnesium stearate are added to the dry granules and the ingredients are milled for 20 to 30 minutes on a standard two-roll mill.

Then, a second osmotic composition is prepared as follows: First, 170 g of polyethylene oxide having a molecular weight of 5,000,000 are sieved through a 40-mesh sieve, followed by 72.5 g of sodium chloride

Sift the 40 mesh sieve and mix the ingredients in a mixing bowl for 10 to 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 granulating liquid is sprayed into the dish with constant stirring, after which 350 ml of the granulating liquid is added slowly to the dish and the moist mixture is mixed for 15 to 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 milled with 5 g of magnesium stearate for 20 to 30 minutes on a two-roll mill.

By compressing the two compositions on a Manesty ply press, a number of drug kemes are prepared. The drug-containing composition is introduced into the mold cavity of the press and compressed to a solid layer. Then, the cavity above the compressed layer is charged with the second osmotic composition and also pressed into a solid layer, so that a two-layer drug core is obtained.

The Aizneimittelkeme 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 1160 ml of methylene chloride and 820 ml of methanol The Aizneimittelkeme as long as with the semipermeable wall forming mass coats until the wall surrounds the Aizneimittelkem. 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 circulation oven at 50 ° C for 65 hours. After cooling to room temperature, a 0.26 mm diameter passageway is drilled through the semipermeable wall connecting the exterior environment of the osmotic device to the drug-containing mass by laser beam. The osmotic device weighed 262 mg and contained 30 mg of drug in the first , 150 mg composition, the second composition weighed 75 mg and the semipermeable wall weighed 37 mg. The first osmotic composition of the osmotic device consists of 30 mg of nifedipine, 106 mg of polyethylene oxide, 3 mg of potassium chloride, 7.5 mg of hydroxypropylmethylcellulose and 3 mg of magnesium stearate. The second osmotic composition consists of 51 mg polyethylene oxide, 22 mg sodium chloride and 1.5 mg magnesium stearate Device has a diameter of 8 mm, a surface of 1.8 cm, the semipermeable wall is 0.17 mm thick. The delivered sum quantity of the drug substance is shown in FIG. 9 shown

Example 1A

There are prepared osmotic Abgäbesysteme consisting of a first composition of 25 to 100 mg of nifedipine, 100 to 325 mg of polyethylene oxide having a molecular weight of 200,000, 2 to 10 mg of potassium chloride, 5 to 30 mg hydroxypropylmethylcellulose and 2 to 10 mg of magnesium stearate and from a second composition of 30 to 175 mg of polyethylene glycol having a molecular weight of 5,000,000 to 75 mg of sodium chloride and 1 to 5 mg of magnesium stearate. For the preparation of the osmotic devices having the following compositions, the procedure of Example 1 was repeated (a) an osmotic device having a first composition consisting of 60 mg nifedipine, 212 mg of polyethylene oxide, 6 mg of potassium chloride, 15 mg of hydroxypropyl methylcellulose and 6 mg of magnesium stearate; and a second composition consisting of 102 mg of polyethylene oxide, 44 mg sodium chloride and 3 mg magnesium stearate; and (b) an osmotic device of a first composition consisting of 90 mg of nifedipine, 318 mg of polyethylene oxide, 9 mg of potassium chloride, 22.5 mg of hydroxypropyl methylcellulose and 9 mg of magnesium stearate, and a second composition consisting of 102 mg of polyethylene oxide, 66 mg sodium chloride and 4.5 mg magnesium stearate. In one embodiment, the osmotic devices described in (a) and (b) additionally comprise an enclosure applied to the outer semipermeable wall. The wrapper is 30mg of nifedipine and hydroxypropyl methylcellulose. During use, the wrapper immediately provides a drug for the instant drug treatment in the surrounding fluid.

Example 2

The procedure of Example 1 is repeated under all the conditions indicated therein, except that the drug in the chamber is constituted by a substance selected from the group comprising a beta-blocker, an anti-inflammatory agent, an analgesic, a sympathomimetic agent, an antiparkinsonian Means or a diuretic agent is replaced,

Example 3

An osmotic therapeutic device for the controlled and continuous oral release of the calcium channel blocker drug verapamil is prepared in the following manner: 90 mg

-16AT394 944B

Verapamil, 50 mg of sodium carboxyvinyl polymer having a molecular weight of 200,000, sold under the trade name Carbopol polymer (BF Goodrich Chemical Comp.), 3 mg sodium chloride, 7.5 mg of hydroxypropylmethylcellulose and 3 mg of magnesium stearate are well mixed together as described in Example 1 and compressed in a Manesty press with a 7.9 mm die using a pressure of 211 bar (11/2 tons) to a layer of excipient composition Thereupon, 51 mg of carboxyvinyl polymer having a molecular weight of 3,000,000, sold under the trade name Carbopol Polymer, 22 mg of sodium chloride and 2 mg of magnesium stearate were well mixed together and placed in the Manesty press and pressed into a layer of an expandable osmotic composition in contact with the osmotic drug composition layer

A semipermeable wall was then made by mixing 170g of cellulose acetate having an acetyl content of 39.8% with 900 ml of methylene chloride and 400 ml of methanol and spray coating the bilayered chamber forming member in an air-suspension machine until a 0.13 mm (5.1 mils ) thick semipermeable wall surrounding the chamber is formed. The coated device was dried at 50 ° C for 72 hours, after which a 0.2^mm (8 mils) large bore was laser drilled through the semipermeable wall to connect the drug-containing layer to the outside environment of the device for delivery of the drug for a prolonged period of time.

Example 4

The procedure of Example 3 is repeated in compliance with all conditions specified therein, except that the drug in the osmotic device is fendiline, diazoxide, prenylamine or diltiazem.

Example 5

An osmotic therapeutic device for delivering the drug sodium diclofenac for use as an anti-inflammatory agent is prepared by first administering in a Manesty press an osmotic drug composition containing 75 mg sodium diclofenac, 300 mg sorbitol, 30 mg narium bicarbonate, 26 mg pectin, 10 mg polyvinylpyrrolidone and 5 mg stearic acid compressed in the cavity of the mold into a solid layer. The mold cavity is then charged with a second and larger force generating composition consisting of 122 mg of pectin having a molecular weight of 90,000 to 130,000, 32 mg of mannitol, 20 mg of polyvinylpyrrolidone and 2 mg of magnesium stearate and pressed into a second layer in first contact with the first layer. The second layer has a density of 1.28 g / cm³ and a hardness score of more than 12 kg. The two-layer core was then formed with a semipermeable wall consisting of 85 g of cellulose acetate having an acetyl content of 39.8% and 15 g of polyethylene glycol 4000, w / w% solids, in a wall-forming solvent consisting of 1960 ml of methylene chloride and 819 ml of methanol , surround. The coated device is dried at 50 ° C for 72 hours, after which a passage of 0.26 mm is laser drilled into the wall. This semi-permeable wall is 0.1 mm thick, the device has a surface of 3.3 cm², the average release rate of the drug is 5.6 mg per hour during a 12-hour period. The total amount dispensed is illustrated in Figure 10. The small vertical bars refer to the minimum and maximum drug release for five systems measured at that time.

Example 5A

It was worked as described in Example 5 to provide an osmotic device, in which the chamber contained a mixture of osmopolymers. The chamber contained a first composition of 312 mg consisting of 48% sodium diclofenac drug, 38% polyethylene oxide osmopolymer having a molecular weight of 200,000.10% polyethylene glycol osmopolymer having a molecular weight of 20,000.2% sodium chloride and 2%. magnesium stearate; and a second composition of 150 mg consisting of 93% polyethylene oxide having a molecular weight of 5,000,000.5% sodium chloride and 2% magnesium stearate.

Example 6

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 use advantage 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%. The measurements are made by measuring the dry components of the semipermeable bag and then the bag in a 37 ° C water bath for various lengths of time. The weight gain is due to the suction of water through the semipermeable wall caused by the

-17AT394 944B osmotic pressure gradients through 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 = A (ΚΔπ) / 1, where dw / dt is the ratio of water uptake over time, A is the area of ​​the semipermeable wall, and K is the permeability coefficient. Further, in Figure 1, Wjj / Wp is the amount of water absorbed divided by the weight of the osmopolymer plus osmotic agent.

Example 7

An osmotic therapeutic device for the delivery of sodium diclofenac is prepared by sieving through a 40 mesh screen a composition consisting of 49% sodium diclofenac, 44% 100,000 molecular weight polyethylene oxide, 2% sodium chloride and 3% hydroxypropyl methylcellulose after which the sieved composition is mixed with an alcohol solvent which is used in a ratio of 75 ml of solvent to 100 g of granules. The wet granules are sieved through a 16 mesh sieve, dried under vacuum at room temperature for 48 hours, sieved through a 16 mesh sieve and with 2% magnesium stearate passed through an 80 mesh sieve (80 th sieve) mesh) was screened, mixed. The composition is compressed in the manner described above

Then, a composition consisting of 73.9% pectin having a molecular weight of 90,000 to 130,000,5,8% of microcrystalline cellulose, 5.8% polyvinylpyrrolidone, 14.3% sodium chloride and 2% sucrose sieved through a 40 mesh screen (40 mesh), mixed with an organic solvent in the ratio of 100 ml of solvent to 100 g of granules for 25 minutes, sieved through a 16 mesh sieve (16mesh), dried under vacuum at room temperature for 48 h, again sieved through a 16 mesh sieve (16 mesh), mixed with 2% magnesium stearate and then pressed onto the pressed layer described in the preceding paragraph. The bilayer drug core is coated by dipping it into a wall-forming composition consisting of 80% cellulose acetate having an acetyl content of 39.8%, 10% polyethylene glycol 4000 and 10% hydroxypropyl methylcellulose. A passage is drilled through the wall communicating with the composition containing the drug. The diameter of the passage is 0.38 mm. The theoretical total delivery profile for the device is shown in FIG. 12 illustrated. The Fig. 13 shows the theoretical delivery rate in mg per hour for the osmotic device.

Example 8

The procedure of Example 7 is repeated using all of the conditions described therein, except that the osmopolymer in the drug composition is a polyoxyethylene-polyoxypropylene block copolymer having a molecular weight of about 12,500.

Example 9

An osmotic device is made according to the procedures described above. The device according to this example consists of a single composition consisting of 50% sodium diclofenac, 46% polyethylene oxide having a molecular weight of 100,000.2% sodium chloride and 2% magnesium stearate. The device has a semipermeable wall consisting of 90% cellulose acetate with 39.8% acetyl content, and 10% polyethylene glycol 4000. The amount of sums dispensed for this device consisting of the single composition is 40% of the device consisting of two compositions. The amount of money delivered is shown in FIG. 14 illustrates

Example 10

The amount of sum delivered in vivo and in vitro of diclofenac sodium from an osmotic device consisting of a first osmotic composition consisting of 75 mg diclofenac sodium, 67 mg of polyethylene oxide having a molecular weight of 100,000, 3.0 mg sodium chloride, 4.5 mg of hydroxypropyl methylcellulose and 3.0 mg of magnesium stearate and a second osmotic composition, which was located at a distance from the discharge passage, consisting of 51 mg of polyethylene oxide having a molecular weight of 5,000,000,22,5 mg of sodium chloride and 1,5 mg of magnesium stearate, which through a semipermeable wall

Consisting of 90% cellulose acetate with an acetyl content of 39.8% and 10% polyethyleneglycol 4000 was measured in vivo and in vitro in laboratory dogs. The amounts of drug delivered at different times in vivo were determined by administering to the animal a series of devices and detecting the amount released from the device concerned after the appropriate residence time.

The results are shown in Fig. 15, in which the circles with the bars represent the average amount of the delivered sums and the triangles with the bars represent the amounts of sums delivered in vivo.

The in vivo and in vitro released average sum amounts for a nifedipine-containing device were measured as indicated immediately above. The osmotic device consisted of a composition in the vicinity of the passageway consisting of 30 mg of nifedipine, 106.5 mgpolyethylene oxide with a molecular weight of 200,000.3 mg potassium chloride, 7.5 mg hydroxypropyl methylcellulose and 3 mg magnesium stearate; a composition, which was arranged at a distance from said passage, consisting of 52 mg of polyethylene oxide with a molecular weight of 5,000,000, 22 mg sodium chloride and 1.5 mg magnesium stearate; and a semipermeable wall consisting of 95% cellulose acetate having an acetyl content of 39.8% and 5% hydroxypropyl cellulose. From Fig. 16 the release from this system is evident. The circles in FIG. 16 represent the sum quantities delivered in vivo, and the triangles represent the amount of the released quantity in vitro.

Example 11

The method of Example 10 was repeated for the purpose of preparing a therapeutic delivery system containing the following ingredients. A first or drug composition having a 638 mg mass consisting of 96% cephalexin hydrochloride. 2 % Povidone (polyvinylpyrrolidone) and 2% magnesium stearate a second osmotic composition having a mass of 200 mg consisting of 68.5% polyethylene oxide having a molecular weight of 5x10 ^, 29.5% sodium chloride and 2% magnesium stearate; a semipermeable wall with a mass of 55.8 mg consisting of 80% cellulose acetate with an acetyl content of 39.8%, 14 % Polyethyleneglycol 4000 and 14% hydroxypropyl methylcellulose; and an osmotic port with a diameter of 0.039 mm. The device has an average delivery rate of about 54 mg per hour for a period of 9 hours.

The novel osmotic system of the invention utilizes a dual means of achieving a precise delivery rate of drugs which are difficult to deliver to the environment while maintaining the integrity and character of the system. The invention has been explained in more detail with reference to the preceding embodiments and it is obvious that various changes of the described system are possible for the person skilled in the art without thereby exceeding the scope of the invention.