NO170834B - PROCEDURE FOR THE PREPARATION OF AN OSMOSE DEVICE FOR THE DELIVERY OF A USEFUL MEDICINE - Google Patents

Description

The present invention relates to a method

for the manufacture of an osmosis device for delivering a beneficial agent at a controlled rate to an application environment.

Since the beginning of ancient times, both pharmacy and

medicine tried to find a delivery system for the administration of a useful drug. The first written reference to a dosage form is in the Eber papyrus, which was written ca. year 1552 before Christ. In the Eber papyrus, dosage forms such as suppositories, pessaries, ointments, oral pill preparations and other dosage preparations are mentioned. About. 2,500 years passed without any progress in the development of dosage forms until the Arab physician Rhazes, 865-925 AD, invented the coated pill. About. 100 years later, the Persian Avicenna, 980-1037 AD, coated pills with gold or silver to make it easier for the patient to accept it and to increase the medicine's effectiveness. About this time the first tablets were described in Arabic manuscripts attributed to al-Zahrawi, 936-1009 AD. The manuscripts describe a tablet made from the hollow recesses in two tablet forms that face each other. Pharmacy and medicine waited approx. 800 years before the next innovation in dosage forms, when Mothes in 1883 invented the capsule for administering medicines. The next big leap in dosage forms came in 1972 with the invention of the osmosis delivery device according to US patents 3,845,770 and 3,916,899. The osmosis device according to these patents comprises a semi-permeable wall surrounding a chamber containing a useful agent. The wall is permeable for the passage of a liquid from the outside, and is largely impermeable for the passage of the useful agent. There is a channel through the wall for the release of the useful agent from the osmosis device. These devices release useful agent by allowing fluid to be drawn through the semipermeable wall into the chamber at a rate determined by the permeability of the semipermeable wall and the osmotic pressure gradient through

the semipermeable wall, so that an aqueous solution containing useful agent is formed which is released from the device through the channel. These devices are very effective for delivering a useful agent which is soluble in the liquid and exerts an osmotic pressure gradient through the semipermeable wall towards the liquid from the outside.

A pioneering advance in osmosis delivery devices was presented in the field of dispensing in US Patent 4,111,202. According to this patent document, the release kinetics of the osmosis device is increased for the release of useful agents that are from insoluble to highly soluble in the liquid by manufacturing the osmosis device with a chamber for the useful agent and an osmosis agent chamber separated by a film. The film can be moved from a rest position to an expanded position. The osmosis device releases agents by

in that liquid is sucked through the semi-permeable wall into the osmotic agent chamber so that a solution is formed which causes the volume of the chamber to increase and functions as a driving force exerted against the film. This force causes the film to expand towards the chamber for the beneficial agent and correspondingly reduces the volume of this chamber, whereby the beneficial agent is released through the channel from the osmosis device. Although this device functions well for its intended application, and although it can deliver numerous useful agents of varying solubility, its use may be limited due to the manufacturing steps and costs necessary to manufacture and place the moving film in the chamber. in the osmosis device.

From US patent 4,327,725, an osmosis dispensing device for dispensing useful agents is known which, due to

of their solubility in aqueous and biological fluids are difficult to release in meaningful amounts at controlled rates over time. The osmosis device according to said patent comprises a semi-permeable wall surrounding a chamber containing a useful agent which is from insoluble to highly soluble in aqueous and biological fluids, and an expandable hydrogel. In use, the hydrogel expands in the presence of the liquid from outside that enters the device and thereby causes the useful agent to be released through the channel from the device. This device works well for its intended use, and it releases many useful agents that are difficult to release for their intended purpose. It has been found that its use may be limited due to the hydrogel's lack of ability to absorb sufficient liquid for the

maximum seal expansion necessary to force the useful agent out of the device.

It will be understood by those skilled in the art that if an osmosis device can be produced which has a high degree of osmotic activity for delivering a useful agent by generating in situ an expansion force sufficient to deliver the maximum amount of agent at a controlled rate from the osmosis device, such an osmosis device would have a positive value and represent an advance in the dispensing area. Similarly, it will be immediately understood by professionals in this area that if an osmosis device is made available that has double thermodynamic osmotic activity for releasing larger amounts of useful agent, this osmosis device would find practical application in the fields of pharmacy and medicine.

Consequently, based on the presentation above, it is an object of the invention to produce an osmosis device which represents a further improvement and progress in the delivery area.

Thus, it is a primary object of the invention to produce a method for producing an osmosis device for in vivo release of a useful drug which is difficult to administer and which can be released in therapeutically effective amounts over time.

A further object of the invention is to produce

an osmosis system which has double osmotic activity and which comprises a chamber containing a first osmosis material containing a drug, and preferably an osmosis agent and/or an osmosis polymer, and a second osmosis material containing an osmosis agent and an osmosis polymer, where the materials function together for dispensing the medicine from the osmosis device.

Yet another object of the invention is to produce an osmosis device with the possibility of high uptake of a water-insoluble or slightly water-soluble drug and a device for releasing the drug in both cases at a controlled rate and continuously over time.

Yet another object of the invention is to produce an osmosis device which can release a pH-dependent beneficial agent by providing a neutral medium for the release of the beneficial agent in a finely dispersed form to increase its surface area and to maximize the dissolution rate of the beneficial agent medium.

With the device, the aim is to produce an osmosis system for the release of a drug which has a very low dissolution rate, which is the rate-limiting step for the release of the drug from the system, but which can be released by using an osmosis material that functions in situ as a wetting agent and a dissolving agent to increase the dissolution rate and solubility of the drug, thereby increasing its release from the osmosis system.

A further object of the invention is to produce an osmosis system which makes it possible to maintain a high level of osmotic activity of a polymer used for releasing a useful agent from the osmosis system.

Another object of the invention is to provide a therapeutic osmosis device which can administer a complete course of doses, comprising from poorly soluble to highly soluble agents, at a controlled rate and continuously for a particular period of time, necessitating intervention only for the start and possibly the end of the course.

The method according to the invention is characterized in that

a) a first material comprising an osmotic polymer is prepared for mixing with the useful agent, b) a second material comprising an osmotic agent and a hydrophilic swellable osmotic polymer is prepared, c) a body is produced, such as by pressing, from the first and second material, and the body is coated, preferably by air suspension coating, with a material which is at least partially permeable to the passage of a liquid present in the environment of use, to form a wall as the wall encloses and forms a chamber containing the body, and e) a channel is arranged in the wall, and preferably by laser drilling, to form a connection between the first

material and the outside of the device for releasing the useful agent from the device.

Further preferred embodiments of the method according to the invention appear from claims 2-10.

The invention will be explained in more detail below with reference to the accompanying drawings, where: Fig. 1 shows an isometric view of an osmosis device for oral administration of a useful agent to the gastrointestinal tract. Fig. 2 shows a perspective view, with parts cut away, of the osmosis device in fig. 1 and shows its structure. Fig. 3 shows a perspective view, with parts cut away, of the osmosis device in fig. 1 and shows this in use when releasing a useful agent from the osmosis device. Fig. 4 shows a perspective view, with parts cut away, of the osmosis device in fig. 1 and compared with fig. 3 and shows the osmosis device in use while releasing the majority of a useful agent from the osmosis device. Fig. 5 shows a therapeutic osmosis device with its wall partially cut away, designed to deliver a beneficial agent into a channel in the body, such as the rectum and vagina. Fig. 6 shows the osmosis device in fig. 5 with a different wall construction. Fig. 7 shows the osmosis device in fig. 5 with a different wall construction than the wall construction in fig. 6. Fig. 8 shows the weight gain as a function of time for a polymer encapsulated in a semipermeable membrane, when the encapsulated polymer is placed in water. Fig. 9 shows the cumulative amount of drug released from a device comprising an osmosis polymer having two different molecular weights. Fig. 10 shows the cumulative amount of drug released from a device using another set of osmosis polymers. Fig. 11 shows curves for osmotic pressure for a number of osmosis agents and a number of osmosis polymer/osmosis agent compositions. Fig. 12 shows the cumulative release profile for an osmosis system where two different osmosis polymers are used.

Fig. 13 shows the release rate per hour for one

different osmosis system than the one in fig. 9, containing an osmosis polymer having two different molecular weights.

Fig. 14 shows the cumulative amount released from a device containing only one preparation and comprising only one layer. Fig. 15 shows the cumulative release in vivo and in vitro of a drug delivered by the osmosis device. Fig. 16 shows the cumulative release in vivo and in vitro of another drug released by the osmosis device.

In the drawings and in the description, like parts in related figures are indicated by like reference numbers. The term given earlier in the description and with the description of the drawings is discussed in more detail elsewhere in the description.

The drawings show examples of different embodiments of the osmosis device manufactured according to the invention. Such an example is shown in fig. 1 where an osmosis device 10 comprises a body 11, which has a wall 12 and a channel 13 for releasing a useful agent from the osmosis device 10.

Fig. 2 shows the osmosis device in fig. 1 partly on average.

In fig. 2, the osmosis device 10 comprises the body 11, the semipermeable wall 12 which encloses and forms an inner chamber 14, which via a channel 13 communicates with the outside of the osmosis device.

The chamber 14 contains a first osmotic material, which comprises a useful agent 15 indicated by dots, and it can be from insoluble to very soluble in liquid that is sucked into the chamber 14,

an osmosis agent 16, indicated by wavy lines, which is soluble

in the liquid in the chamber 14 and exerts an osmotic pressure gradient across the semipermeable wall 12 towards an external liquid, as well as an osmosis polymer 17, indicated by horizontal dashed lines,

which sucks liquid into the chamber 14 and exerts an osmotic pressure gradient across the semi-permeable wall 12 against an external liquid present in the application environment. The wall 12 is formed of a semipermeable material which is largely permeable to the passage of the liquid from the outside and which is largely impermeable to the passage of the liquid from the outside and largely impermeable to the passage of the useful agent 15, the osmosis agent 16 and the osmosis polymer 17. The semipermeable wall 12 is non-toxic and it maintains its physical and chemical integrity during the life of the device

10 delivery time.

The chamber 14 also contains a second osmotic material

which is located at a distance from the channel 13 and which is in connection with the first material. The second material exerts a driving force by expansion and cooperates with the first osmotic material to release the maximum amount of useful agent from the osmosis device 10. The second osmotic material comprises an osmotic agent 18, which is soluble in the liquid in the chamber 14 and exerts an osmotic pressure gradient across the wall 12 towards an external liquid, mixed with an osmosis polymer 19 which absorbs liquid in the chamber 14 and exerts an osmotic pressure gradient across the wall 12 towards the external liquid. The osmosis polymers 17 and 19 are hydrophilic, water-soluble, weakly cross-linked water-insoluble polymers, and they have osmotic properties such that their ability to absorb liquid from the outside, exert an osmotic pressure gradient across the semipermeable wall towards the external liquid, and swell or expand in the presence of the liquid . The osmosis polymers 17 and 19 are mixed with the osmosis agents 16 and 18 for the absorption of the maximum volume of external liquid in the chamber 14. This liquid is available to the osmosis polymers 17 and 19 for the optimization of the volume and for the total expansion of the osmosis polymers 17 and 19, i.e. that the osmosis polymers 17 and 19 absorbs liquid that is sucked into the chamber 14 by means of the osmotic action of the osmosis polymers 17 and 19 and is supplemented by the osmotic suction action of the osmosis agents 16 and 18, so that maximum expansion of the osmosis polymers 17 and 19 to a larger state is achieved.

In a preferred embodiment, the release of useful agent 15 from the osmosis device 10 is carried out by (1) liquid being absorbed by the first material to form a suspension in situ and release of the suspension through the channel, and by (2) the second material simultaneously absorbs liquid, causing the second material to swell and cooperate with the first material to propel the suspension of the beneficial agent out through the channel. In the described mode of operation, the osmosis device can be considered as a cylinder, while the other material expands as with the movement of a piston to assist in the delivery of the suspension of the useful agent from the osmosis device. Although the form of the osmosis device shown in fig. 1 and 2 is not an exact cylinder, it is approximate enough for the subsequent physical analysis. In this analysis, the volume released from the osmosis device is Ffc per time unit of two factors: the water absorption rate of the first material F and the water absorption rate of the second material

Q,

As the boundary layer between the first material and the second material is very little hydrated when using the osmosis device, there is negligible water migration between the two materials. The rate of water absorption of the second material, Q, is thus equal to the expansion of its volume:

The total discharge rate from the osmosis device is therefore: where C is the concentration of the "useful" medium in the discharged slurry. The volume of the osmosis device and its surface area A give equations 4 and 5:

where Vd , and ^ V p are the volumes of the first material and the second material, respectively, and A, and A^ are the surface area against the wall for the first material and the second material, respectively. IN

use increases both V and A with time, while V and A decrease with time

p p d 3 d

when the device emits a useful agent.

The volume of the second material that expands with time as liquid is absorbed into the chamber is given by equation 7:

where Wr„ i is the weight of the liquid absorbed by the other material, W p is the weight of the other material at the beginning, WTH T/W p is the ratio between the weight of the liquid and the initial weight of the

other material, V is equal

P

where e is the other

P

the material's density and corresponds to WH/Wp- Based on the geometry of a cylinder, where r is the radius of the cylinder, the absorption area is thus connected to the volume of the swollen second material as follows:

The liquid absorption rates into each chamber are: where k is the osmotic permeability of the wall, h is the wall thickness, Au^ and ATTp are the osmotic gradients for the first material and the second material, respectively. The total release rate is therefore:

Fig. 3 and 4 show the osmosis devices in fig. 1 and 2 in use. For the osmosis device 10, according to fig. 3 and 4 liquid in

of the first material at a rate determined by the permeability of the wall and the osmotic pressure gradient across the wall.

The absorbed liquid continuously forms a solution containing a useful agent, or a solution or gel of osmotic agent and osmotic polymer containing a useful agent in suspension. This solution or suspension is released by combined use of the device 10. This combined use comprises that the solution or suspension is released osmotically through the channel due to the continuous formation of solution or suspension and by the swelling of the other material and its volume being increased, which is indicated by the increase in the height of the vertical lines in fig. 3 and 4. This latter swelling and increase in volume causes pressure to be exerted against the solution or suspension, and thereby helps the first material and at the same time causes release of useful agent to the outside of the device.

The first material and the second material cooperate so that it is largely ensured that the release of useful agent from the chamber is constant over a longer period of time in two ways. First, the first material absorbs liquid from the outside through the wall, thereby forming either a solution or a suspension, the last fraction of which will be emitted in a non-zero degree (without the presence of the second material) as the driving force decreases with time. Secondly, the second material works in two ways at the same time: Firstly, the second material works by continuously concentrating the useful agent by absorbing some liquid from the first material so that it contributes to the concentration of the useful agent not falling below saturation, and secondly, the second material's volume is continuously increased by absorption of liquid from the outside across the wall, whereby a force is exerted against the first material and the volume of useful agent decreases, so that useful agent is led to the channel in the chamber. Furthermore, because the extra solution or suspension formed in the first chamber is forced out, the osmotic material is in close contact with the inner wall and exerts a constant osmotic pressure and thereby a constant release rate together with the second material. The swelling and expansion of the second material with the associated increase in volume, together with the simultaneous, corresponding decrease in the volume of the first material ensures the release of the beneficial agent at a controlled rate with time.

The device 10 in fig. 1-4 can be prepared in many embodiments, such as the currently preferred embodiments for oral use, for the release of either locally or systemically acting therapeutic agents in the gastrointestinal tract. The oral device 10 can have various conventional shapes and sizes, such as round with a diameter of 5-12.7 mm. With such forms, the device 10 can be adapted to administer useful agents to many animals, such as warm-blooded animals, humans, reptiles and fish.

Fig. 5, 6 and 7 show another embodiment where the osmosis device 10 is designed for placement in a channel in the body, such as the vagina or the rectum. The device 10 has an elongated, cylindrical, self-supporting shape with a rounded front end 20 and a rear end 21, and it is equipped with manually operated cords 20 for easy removal of the device 10 from a biological channel. The device 10 is structurally identical to the device

10 which is described above and it functions in a similar way. In fig. 5, the device 10 is equipped with a semi-permeable wall

23, and in fig. 6 with a laminated wall 24 comprising an internal, semi-permeable laminate wall 25 up to the chamber 14 and an external, microporous laminate layer 26 away from the chamber 14. In fig. 7, the device 10 comprises a laminated wall 28 formed by a micro-porous laminate layer 29 up to the chamber 14 and a semi-permeable laminate wall 30 which faces the surroundings and which is laminated to the microporous laminate layer 29. The device 10 emits a useful agent which is absorbed by the mucous membrane in the vagina or of the mucous membrane of the rectum, so that a local or systemic effect is achieved in vivo over a longer period of time.

The osmosis device in fig. 1-7 can be used for releasing numerous agents, such as drugs, at a controlled rate that is independent of the drug's pH dependence or that the agent's dissolution rate can vary between low and high in liquid environments, such as gastric juice or liquid in the intestines. The osmosis device can also absorb larger amounts of agents with low solubility and deliver these in meaningful, therapeutic amounts. Fig. 1-7 show different embodiments of the osmosis device according to the invention, which can otherwise have many different shapes, sizes for releasing the useful agents into a use environment. E.g. the devices include delivery to the cheek, for implantation in artificial glands, in the throat, in the uterus, in the ear, the nose, the intestine, subcutaneously and in the blood. These devices can also have

a size, shape and structure which is arranged for the release of an active agent in rivers, aquariums, fields, factories, reservoirs, laboratory facilities, greenhouses, transport devices, marine installations, military installations, hospitals, veterinary clinics, clinics, farms, zoos, sick rooms, for chemical reactions and other applications.

In use, it has been shown that the osmosis device

10 can be produced with the first osmotic material and the second osmotic material placed in the chamber of the device and arranged to cooperate. The chamber is formed by a wall consisting of a material which does not adversely affect the useful agent, the osmosis agent, the osmosis polymer and the like. The wall is permeable to the passage of a liquid from the outside, such as water and biological fluids, and it is largely impermeable to the passage of the useful agents, osmosis agents, osmosis polymers and the like. The wall is formed from a material that does not adversely affect an animal or a host, and the selectively semipermeable materials used to make the wall are non-erodible, and they are insoluble in liquids. Typical materials for making the wall are, according to one embodiment, cellulose esters, cellulose ethers and cellulose ester ethers. The cellulose polymers have a degree of substitution, D.S., in the anhydroglucose unit of more than 0 and up to 3. By degree of substitution is meant the average number of hydroxyl groups originally present in the anhydroglucose unit of the cellulose polymer, which has been replaced by a substituent. Representative materials include cellulose acylate, cellulose cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di- and tricellulose alkanylates, mono-, di- and tricellulose aroylates and the like. Examples of polymers are cellulose acetate which has a degree of substitution of up to 1 and an acetyl content of up to 21%, cellulose acetate which has an acetyl content of 32-39.8, cellulose acetate which has a degree of substitution of 1-2 and an acetyl content of 21-35%, cellulose acetate which has a degree of substitution of 2-3 and an acetyl content of 35-44.8%,

and similar. More specific cellulose polymers are cellulose propionate which has a degree of substitution of 1.8 and a propionyl content of 39.2-45% and a hydroxyl content of 2.8-5.4%, cellulose acetate butyrate which has a degree of substitution of 1.8, an acetyl content

of 13-15% and a butyryl content of 34-39%, cellulose acetate butyrate having an acetyl content of 2-29%, a butyryl content of 17-53%

and a hydroxyl content of 0.5-4.7%, cellulose triacylates having a degree of substitution of 2.9-3, such as cellulose trivalerate, cellulose trilaurate, cellulose tripamitate, cellulose trisuccinate as well as cellulose trioclanoate, cellulose diacylates having a degree of substitution of 2.2-2.6, such as cellulose disuccinate, cellulose dipalmitate, cellulose dioclanoate, cellulose dipental, coesters of cellulose such as cellulose acetate butyrate and cellulose acetate propionate, and the like.

Additional semipermeable polymers include ethyl cellulose, cellulose nitrate, acetaldehyde dimethylacetate, cellulose acetate ethyl carbamate, cellulose acetate methylcarbamate, cellulose acetate dimethylaminoacetate, semipermeable polyamides, semipermeable polyurethanes, semipermeable sulfonated polystyrenes, crosslinked, selectively semipermeable polymers formed by co-precipitation of a polyanion and a polycation as known from US Patents 3,173,876, 3,276,586, 3,541,005, 3,541,006 and 3,546,142, semipermeable polymers according to US Patent 3,133,132, weakly cross-linked polystyrene derivatives, cross-linked poly(sodium styrene sulfonates), cross-linked poly(vinylbenzyltrimethylammonium chloride) , semipermeable polymers that have a liquid permeability of 10 5-10 — 1 (mm <3> /cm <2> .h.atm) expressed per atmospheres x 10 —<8>hydrostatic or osmotic pressure difference across the semipermeable wall. Polymers are known in the art from US Patents 3,845,770, 3,916,899 and 4,160,020 as well as in the Handbook of Common Polymers by J.R. Scott and W.J. Roff, published by CRC Press, Cleveland, Ohio, 1971.

The laminated wall comprising a semipermeable laminate layer and a microporous laminate layer which cooperate to form a uniform laminated wall which maintains its physical and chemical integrity and does not split into laminate layers when using the osmosis device for delivering the beneficial agent. The semi-permeable laminate layer is made from the above-mentioned semi-permeable polymeric materials, semi-permeable homopolymers, semi-permeable copolymers and the like.

Microporous laminate layers which are suitable for the manufacture of the osmosis device usually comprise microporous polymeric materials and polymeric materials which can form a microporous laminate layer in the application environment. In both embodiments, the microporous materials are laminated to form the laminated wall. The materials suitable for the production of the microporous laminate layers are largely inert, they retain their physical and chemical integrity during the time the agent is released, and they can be generically described as having a sponge-like appearance that provides a supporting structure for a semipermeable laminate layer and also provides a supporting structure for interconnected pores or cavities of microscopic size. The materials can be isotropic, where the structure is homogeneous in the entire cross-sectional area, or they can be anisotropic, where the structure is inhomogeneous in a cross-sectional area. The pores may be continuous pores that have an opening on both surfaces of a microporous laminate layer, pores that are connected to each other through tortuous paths of regular or irregular shape, such as curved, curved-linear, randomly oriented continuous pores, pores that are connected to each other via obstacles as well as other porous paths that can be detected by microscopic examination. In general, microporous laminate layers are determined by pore size, the number of pores, the tortuosity of the microporous webs, and the porosity associated with the size and number of pores. The pore size in a microporous laminate layer can easily be determined by measuring the observed pore diameter on the material's surface under an electron microscope. In general, materials that have from 5 to 95% pores and a pore size of from 10 Å to 100 (im) can be used to produce a microporous laminate layer. The pore size and other parameters that are characteristic of the microporous structure can also be obtained from flow measurements, where a liquid flow . laminate layer area containing a number of N pores with radius r, is the viscosity of the liquid and AP is the pressure difference through the laminate layer of thickness Ax. For this type of laminate layer, the number of pores N can be calculated using the equation 14 below, where e is the porosity defined as the ratio between void volume and the total volume of the laminate layer and A is the cross-sectional area of the laminate layer containing N pores r:

The pore radius is then calculated by the following equation 15:

where J is the volume flow through the laminate layer per unit of time caused by the pressure difference AP through the laminate layer,*), e and Ax have the above-mentioned meaning and t is the tortuosity defined as the ratio between the path length in the laminate layer and the thickness of the laminate layer. Conditions of the above type are discussed in Transport Phenomena In Membranes, by N. Lakshminataya-naiah, 1969, Chapter 6, published by Academic Press, Inc., New York.

As discussed in the aforementioned publication on page 336 in Table 6.13, the porosity in laminate layers having pores of radius r can be expressed in relation to the size of the transported molecule having a radius a, and as the ratio between molecular radius and pore radius, a/r, decreases , the laminate layer becomes porous to this molecule, i.e. that when the ratio a/r is less than 0.3, the laminate layer is largely microporous expressed with the osmotic reflection coefficient a decreasing to below 0.5. Microporous laminate layers with a reflection coefficient a in the range below 1, usually from 0 to 0.5, preferably below 0.1 for the active agent are suitable for manufacturing the device. The reflection coefficient is determined by forming materials as a laminate layer and performing water flow measurements as a function of hydrostatic pressure difference and as a function of the osmotic pressure difference caused by the active agent. The osmotic pressure difference produces a hydrostatic volume flow, and the reflection coefficient is expressed using the following equation 16:

The properties of microporous materials are described in Science, vol 170, 1970, p. 1302-1305, Nature, vol 214, 1967, p. 285, Polymer Engineering and Science, vol 11, 1971, p. 284-288, US Pat. 3,567,809 and 3,751,536 and in Industrial Processing With Membranes, by R.E. Lacey and Sidney Loeb, 1972,

pp. 131-134, published by Wiley, Interscience, New York.

Microporous materials having a preformed structure are commercially available, and they can be produced according to known methods. The microporous materials can be produced by etching, radioactive tracing, by cooling a solution of a flowable polymer to below freezing, whereby solvent evaporates from the solution in the form of crystals dispersed in the polymer, and then curing the polymer followed by removal of the solvent the solvent crystals, by cold or hot stretching at low or higher temperatures until pores are formed, by leaching a soluble component from a polymer with the help of a suitable solvent, by ion exchange reaction and by poly-electrolyte processes. Methods of making micro-porous materials are described in Synthetic Polymer Membranes by R. E. Resting, Chapters 4 and 5, 1971, published by McGraw Hill, Inc., Chemical Reviews, Ultrafiltration, vol 18, 1934, pages 373-455, Polymer Eng. . and Sei., vol. 11, no. 4, 1971, p. 284-288, J. Appl. Poly. Sei., vol 15, 1971, p. 811-829 as well as in US patents 3,565,259, 3,615,024, 3,751,536, 3,801,692, 3,852,224 and 3,849,528.

Microporous materials which are useful for producing the laminate layer include microporous polycarbonates which are formed from linear polyesters of carbonic acid, where carbonate groups appear in the polymer chain, microporous materials produced by phosgenation of a dihydroxyaromatic, such as bisphenol A, microporous polyvinyl chloride, microporous polyamides which polyhexamethylene adipamide, microporous modacrylic copolymers, such as those made from 60% polyvinyl chloride and acrylonitrile, styrenacryl and its copolymers, porous polysulfones characterized by diphenylene sulfone groups in an unbranched chain, halogenated polyvinylidene, polychloroether, acetal polymers, polyesters made by esterification of a dicarboxylic acid or anhydride with an alkylene polyol, polyalkylene sulfides, phenolic polyesters, microporous polysaccharides, microporous polysaccharides containing substituted and unsubstituted anhydroglucose units and preferably having greater permeability to the passage of water and biological liquids other than semipermeable laminate layers, asymmetric porous polymers, crosslinked olefin polymers, hydrophobic or hydrophilic microporous homopolymers, copolymers or interpolymers with a lower bulk density, as well as the materials according to US Patents 3,597,752, 3,643,178, 3,654,066, 3,709,774, 3,718,532 , 3,803,061, 3,852,224, 3,853,601 and 3,852,388, and in British patent specification 1,126,849 and in Chem. Abst., vol 71, 4274F, 22572F, 22573F, 1969 .

Additional microporous materials are polyurethanes, cross-linked polyurethanes with extended chain, microporous polyurethanes according to US patent 3,524,753, polyimides, polybenzimida-sols, collodion (cellulose nitrate with 11% nitrogen), regenerated proteins, semi-solid, cross-linked polyvinylpyrrolidone, microporous materials prepared by diffusion of multivalent cations into polyelectrolyte sols, according to US patent 3,565,259, anisotropic, permeable microporous materials of ionically related polyelectrolytes, porous polymers formed by simultaneous precipitation of a polycation and a polyanion as described in US patents 3,276,589, 3,541. 055, 3,541,066 and 3,546,142, derivatives of polystyrene, such as poly(sodium styrene sulfonate) and poly(vinyl-benzyltrimethylammonium chloride), as well as the microporous materials known from US patents 3,615,024, 3,646,178 and 3,852. 224 .

Moreover, the microporous material used in the device manufactured according to the invention includes the embodiment where the microporous laminate layer is formed in situ by a pore former being removed by dissolving or leaching out to form the microporous laminate layer when using the device. The pore former can be a solid or a liquid. Liquid here also means semi-solid substances and viscous liquids. The pore formers can be inorganic or organic. Pore formers suitable for the invention include pore formers which can be extracted without any chemical change

of the polymer. The pore-forming solids have a size

of from 0.1 to 200 microns, and they 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. The alkaline earth metal salts include calcium phosphate, calcium nitrate and the like. The transition metal salts include iron III chloride, iron II sulfate, zinc sulfate, copper II chloride, manganese fluoride, manganese fluorosilicate and the like. The pore formers include organic compounds such as polysaccharides. The polysaccharides include the sugars sucrose, glucose, fructose, mannitol, mannose, galactose, aldohexose, altrose, talose, sorbitol, lactose, monosaccharides and disaccharides. Also organic

aliphatic and aromatic oils and solids, such as diols

and polyols, e.g. polyols, polyalkylene glycols, polyglycols, alkylene glycols, poly (a-o>)-alkylene diol esters or alkylene glycols and similar water-soluble cellulose polymers such as hydroxy-lower alkyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, methyl ethyl cellulose, hydroxyethyl cellulose and similar water-soluble polymers such as polyvinylpyrrolidone, sodium carboxymethyl cellulose and the like. The pore formers are non-toxic, and when they are removed from the laminate layer, channels are formed through this. In a preferred embodiment, the non-toxic pore-forming agents are selected from the following: inorganic and organic salts, carbohydrates, polyalkylene glycols, poly(a-to)-alkylene diols, esters of alkylene glycols, glycols and water-soluble cellulosic polymers and usable for the production of a microporous laminate layer in a biological environment. For the purpose of the invention, when the polymer forming the laminate layer contains more than 25% by weight of pores, the polymer forms a precursor for the microporous laminate layer, which upon removal of the pore former produces a laminate layer which is largely microporous, while at lower concentrations than this it behaves as a semipermeable laminate layer or membrane.

The term channel as used here means devices and methods which are suitable for releasing the agent or medicine from the osmosis device. The term includes opening, outlet, hole or bore through the semipermeable wall or the laminated wall. The channel can be formed by mechanical drilling, laser drilling or by eroding an erodible element, such as a gelatin plug, in the application environment. A detailed description of osmotic channels and the largest and smallest dimensions for such a channel are described in US Patents 3,845,770 and 3,916. 899.

The osmotically effective compounds which can be used for the purpose of this invention include inorganic and organic compounds which exert an osmotic pressure gradient across a semi-permeable wall or across a semi-permeable, microporous laminated wall, against a liquid from the outside. The osmotically effective compounds (together with the osmosis polymers) absorb liquid into the osmosis device and thereby make in situ liquid available so that it can be absorbed by an osmosis polymer so that the expansion of this increases and/or so that a solution or suspension containing it is formed useful agent so that this can be released from the osmosis device. The osmotically effective compounds are also known as osmotically effective materials in solution, or osmotic agents. The osmotically effective compounds are used by mixing them with a useful agent and with an osmosis polymer to form a solution or suspension containing the useful agent which is released osmotically from the device. The term limited solubility as used here means that the agent has a solubility of less than approx. 5% by weight in the aqueous liquid present in the environment. The osmotic materials in solution are used by homogeneous or heterogeneous mixing of these with the agent or the osmosis polymer and then placing them in the reservoir. The materials in solution and the osmosis polymers draw liquid into the reservoir to form a solution of the material in a gel which is released from the device accompanied by transport of undissolved and dissolved beneficial agent to the outside of the device. Osmotically effective materials used for this purpose include magnesium phosphate, magnesium chloride, sodium chloride, potassium chloride, lithium chloride, potassium sulfate, sodium sulfate, lithium chloride, potassium sulfate, lithium sulfate, potassium hydrogen phosphate, d-mannitol, urea, inositol, magnesium succinate, succinic acid, carbohydrates such as raffinose, sucrose , glucose, a-d-lactose monohydrate and mixtures thereof. The amount of osmotic agent in the chamber will usually be from 0.01 to 30% or more in the first material and usually from 0.01 to 40% or more in the second chamber.

The osmotic material is initially present in excess and it can be in any physical form that is compatible with the useful agent and the osmosis agent. The osmotic pressure for saturated solutions of various osmotically effective compounds and for mixtures of compounds at 37°C in water is given in Table 1 below. In the table, the osmotic pressure tt is in atmospheres, atm. The osmotic pressure is measured in a commercially available osmometer that measures the vapor pressure difference between pure water and the solution to be analyzed, and in accordance with standard thermodynamic principles, the vapor pressure ratio is transformed into an osmotic pressure difference. In Table 1, osmotic pressures are from 20 to 500 atm. indicated. It is clear that the invention encompasses the use of lower osmotic pressures, from 0, and higher osmotic pressures than those indicated in table 1. The osmometer that has been used for the measurements is designated as model 320B, Vapor Pressure

Osmometer, manufactured by Hewlett Packard Co., Avondale, Penna.

The osmosis polymers which are suitable for the production of the first osmotic material, and also suitable for the production of the second osmotic material, are osmosis polymers which exhibit liquid absorption properties. The reverse osmosis polymers are swellable, hydrophilic polymers that interact with water and aqueous biological fluids and swell or expand to an equilibrium state. The osmosis polymers have the ability to swell in water and retain a significant proportion of the absorbed water inside the polymer structure. The osmosis polymers swell or expand to a very high degree, usually showing an increase in volume of from 2 to 50 times. According to a currently preferred embodiment, the swellable, hydrophilic polymers are weakly crosslinked, whereby the crosslinks are formed by covalent or ionic bonds. The osmosis polymers can be of vegetable, animal or synthetic origin. The osmosis polymers are hydrophilic polymers. Hydrophilic polymers suitable for the present invention include poly(hydroxyalkyl methacrylate) having a molecular weight of from 30,000 to 5,000,000, polyvinylpyrrolidone having a molecular weight of from 10,000 to 360,000, anionic and cationic hydrogels, polyelectrolyte complexes, polyvinyl alcohol which has a low acetate content, cross-linked with glyoxal, formaldehyde or glutaraldehyde and with a degree of polymerization from 200 to 30,000, a mixture of methyl cellulose, cross-linked agar-agar and carboxymethyl cellulose, a water-insoluble, water-swellable copolymer produced by forming a dispersion of finely divided copolymer of maleic anhydride and styrene, ethylene, propylene, butylene or isobutylene cross-linked with 0.001-0.5 mol polyunsaturated cross-linking agent per moles of maleic anhydride in the copolymer, water-swellable polymers of N-vinyl lactams, and the like.

Other osmosis polymers are polymers that form hydrogels, such as "Carbopol" carboxylic acid polymers having a molecular weight of 450,000-4,000,000, "Cyanamer", polyacrylamides, cross-linked, water-swellable indenmaleic anhydride polymers, "Good-rite" polyacrylic acid having a molecular weight of from 80,000 to 200,000, "Polyox" polyethylene oxide polymers having a molecular weight of from

100,000 to 5,000,000, starch graft copolymers, "Aqua-Keeps" acrylate polymer, diester cross-linked polyglucan, and the like. Representative polymers that form hydrogels are known from US Patents 3,865,108, 4,002,173, 4,207,893 and from the Handbook of Common Polymers by Scott and Roff, published by Chemical Rubber Company, Cleveland, Ohio. The amount of osmosis polymer in the first osmotic material is from 0.01 to 90%, and the amount of osmosis polymer in the second osmotic material is from 15 to 95%. According to a currently preferred embodiment, the molecular weight of the osmosis polymer in the second osmotic material is greater than the molecular weight of the osmosis polymer in the first osmotic material.

Determination of the osmosis polymer liquid absorption for a selected polymer can be done as follows: A 12.7 mm round disk, fitted with a 12.7 mm diameter stainless steel plug is charged with a known amount of polymer with the plugs protruding at both ends. The plugs and sinker were placed in a Carver press with plates between 93 and 149°C. 703 and 1055 kg/cm 2 were exerted against the plugs. After 10-20 minutes of heat and pressure, the electrical heating of the plates was turned off, and tap water was circulated through the plates. The resulting 12.7 mm disks were placed in an air suspension coater loaded with 1.8 kg of saccharide cores coated with cellulose acetate with an acetyl content of 39.8% dissolved in a mixture of CH2Cl2/CH3OH in a 94:6 weight ratio to a 3 weight percent solution. The coated systems were dried overnight at 50°C. The coated discs were immersed in water at 37°C and periodically removed for gravimetric determination of absorbed water. The initial absorption pressure was calculated using a water transfer constant for the cellulose acetate, after normalizing absorption values for membrane surface area and thickness. The polymer used in this determination was the sodium derivative of the polymer "Carbopol-934", prepared by the method according to B.F. Goodrich Service Bulletin GC-36, "Carbopol" Water-Soluble Resins, page 5, published by B.F. Goodrich, Akron, Ohio.

The cumulative weight gain values, y, as a function of time, t, of the water-soluble polymer disc coated with the cellulose acetate were used to determine the equation of the line y=c + bt + at 2, which passed through these points according to the least squares method.

The weight increase for N-"Carbopol-934" is given by equation 17: Weight increase = 0.359 + 0.665t - 0.00106t<2>, where t is elapsed time

in minutes. The water flow rate at any time will be equal to the slope of the line, which is given by the following equations 18 and 19:

To determine the initial velocity of the water flow, the derivative is determined at t=0 and dy/dt = 0.665 ^1/min., which is equal to the coefficient b. Then, after normalizing the absorption rate for time, the membrane surface area and thickness as well as the membrane permeability constant to water K , ir is determined using the following equation 20:

-4 2 where K = 1.13 x 10 cm /h. The value of v for NaCl was determined with a Hewlett-Packard vapor pressure osmometer to be 345 atm. + 10%, and the value of K for cellulose acetate used in this experiment was calculated from NaCl absorption values to -7 2

be 1.9 x 10 cm/h atm.

By inserting these values into the calculated expression Ktt (1.9 x 10~<7> cm<2>/h atm) (ir) = 1.13 x IO<-4> cm<2>/h gives v = 600 atm. at t=0. As a method of determining a polymer's efficiency in relation to the duration of zero-order driving force, the percentage water uptake was chosen before the water flow values decreased to 90% of their initial values. The value of the slope of the equation for a straight line from the percent weight gain axis will be equal to the initial value of dy/dt determined at t=0, where the point where y intercepts c defines the linear swelling time, with (dy/dt) 0 = 0.665 and y intercept = 0, giving y = 0.665t + 0.359. To determine when the value of the cumulative water uptake is 90% below the initial rate, the following equation is solved for t: solved for t:

t = 62 minutes, and the weight gain is -0.00106(62) 2 + (0.665)(62)

+ 0.359 = 38 µl at initial sample weight = 100 mg, whereby (Aw/w) 0.9 x 100 = 38%. The results are graphically reproduced in fig. 8. Other methods available for studying the hydrogel solution interface include rheological analyses, viscometric analyses, ellipsometry, contact angle measurements, electrokinetic determinations, infrared spectroscopy, optical microscopy, interface morphology and microscopic examination of a device in use.

By the term active agent is meant here any useful agent or any useful compound that can be emitted from the device and cause a useful and applicable result. The agent can be from insoluble to very soluble in the external liquid entering the device, and it can be mixed with an osmotically effective compound and an osmotic polymer. The term active agent includes pesticides, herbicides, germicides, biocides, algicides, rat poisons, fungicides, insecticides, antioxidants, plant growth promoters, plant growth inhibitors, preservatives, disinfectants, sterilizing agents, catalysts, chemical reactants, fermenting agents, fertility preventing agents, fertilization enhancing agents, air purifiers, microorganism-weakening agents and other agents that affect the working environment.

The useful agent includes drugs, and by drug is meant any physiologically or pharmacologically active substance that produces a local or systemic effect in animals that include warm-blooded mammals, humans and primates, birds, domestic animals, animals for sport and on farms, laboratory animals, fish, reptiles and animals in zoos. With the term physiological here is meant the administration of a drug to produce normal concentrations and functions. By pharmacological is meant variations in response to the amount of drug administered to the host, see Stedman's Medical Dictionary, 1966, published by Williams and Wilkins, Baltimore, Md. By drug preparation is meant that the drug is in the chamber mixed with an osmotic solution and/or an osmosis polymer and possibly with a binder and lubricant. The active drug that can be released includes inorganic and organic compounds without limitation, also drugs that act on the peripheral nerves, adrenergic receptors, cholinergic receptors, the nervous system, skeletal muscles, the blood circulation system, synoptic sites, nerve action connection sites,

the endocrine system, hormonal systems, the immunological system, the organic system, the reproductive system, the skeletal system, autocoid systems, nutritional and excretory systems, inhibition of autocoid and histamine systems. The active drug that can be released so that it affects these animal systems includes preparations that reduce functions, sleeping aids, sedatives, mental stimulants, tranquilizers, antiparkinsonian agents, analgesics, anti-inflammatory agents, local anesthetics, muscle astringents, antimicrobials agents, antimalarial agents, hormone preparations, contraceptives,

astringents, sympathomimetic agents, diuretics, agents against parasites, agents against tumours, agents against eye inflammation, electrolytes, diagnostic agents and cardiovascular drugs.

Examples of drugs which are highly soluble in water and which can be delivered with the device manufactured according to the invention include per-chloroperazine disylate, iron II sulphate, aminocaproic acid, potassium chloride, mecamylamine hydrochloride, procainamide hydrochloride, amphetamine sulphate, benzphetamine hydrochloride, isoproternol sulphate, methamphetamine hydrochloride, phenmetrazine hydrochloride , bethanechol chloride, methacholine chloride, pilocarbine hydrochloride, atropine sulfate, metascopolamin bromide, isopropamide iodide, tridihexethyl chloride, phenformin hydrochloride, methylphenidate hydrochloride, oxprenolol hydrochloride, metoprolol tartrate, cimetidine hydrochloride, theophylline cholinate, cephalexin hydrochloride and the like.

Examples of drugs that are poorly soluble in water and

that can be delivered with the device include diphenidol, meclizine hydrochloride, prochlorperazine maleate, phenoxybenzamine, thiethylperazine maleate, anisindone, diphenadioneerythritol tetranitrate, dizoxin, isofurophate, reserpine, acetazolamide, methazolamide, bendroflumethiazide, chlorpropamide, tolazamide, chlormadinone acetate, phenaglycodol, allopurinol, aluminum aspirin, methotrexate, acetylsulfisoxazole, erythromycin, progestins, estrogen progestational, corticosteroids, hydrocortisone, hydrocorticosterone acetate, cortisone acetate, triamquinolone, methyltesterone, 17-8-estra-diol, ethinylestradiol, prazosin hydrochloride-ethinylestradiol-3-methylether, pednisolone, 17 -B-hydroxyprogesterone acetate, 19-nor-progesterone, norgestrel, norethindone, noretiderone, progesterone, norgesreron, noretynodrel and the like.

Examples of other medicines that can be dispensed with

the device includes aspirin, indomethacin, naproxen, fenoprofen, sulidac, diclofenac, indoprofen, nitroglycerol, propranolol, metoprolol, valproate, oxprenolol, timolol, atenolol, alprenolol, cimetidine, clonidine, imipramine, levodopa, chlorpromazine, reserpine, methyldopa, dihydroxyphenylalanine, pivaloyloxyethyl ester of α-methyldopa hydrochloride, theophylline, calcium gluconate, ketoprofen, ibuprofen, cephalexin, erythromycin, proszine, halo-peridol, zomepirak, iron II lactate, vincamine, diazepam, phenoxybenzamine, α-blocking agents, calcium channel blockers drugs such as nifedipine, diliazen, verapamil, beta blockers and similar

nende. The drugs are known in the art from Pharmaceutical Sciences, published by Remington, 14th ed., 1979, published by Mack Publishing Co., Easton, Penna., The Drug, The Nurse, The Patient, Including Current Drug Handbook, by Falconer et al ., 1974-1976, published by the Saunder Company, Philadelphia, Penna., as well as Medicinal Chemistry, 3rd ed., vol. 1 and 2, by Burger, published by Wiley-Interscience, New York.

The drug may exist in various forms, such as pure molecules, molecular complexes, pharmacologically acceptable salts, such as hydrochloride, hydrobromide, sulfate, laurylate, palmitate, phosphate, nitrite, borate, acetate, maleate, tartrate, oleate and salicylate. For acidic drugs, salts of metals, amines or organic cations can be used, e.g. quaternary ammonium. Derivatives of drugs, such as esters, ethers and amides can be used. A drug that is insoluble in water can also be used,

in a form which is a water-soluble derivative thereof to form a solution, and upon release from the device it is converted by means of enzymes, hydrolysed by the body's pH or in another metabolic way into the original, biologically active form.

The useful agent, also as a medicine, can be present in the chamber together with a binder, dispersant, wetting agent, suspending agent, lubricant and dye. Examples of these include suspending agents such as acacia, agar-agar, calcium carrageenan, alginic acid, algin, agarose powder, collagen, colloidal magnesium silicate, colloidal silicon dioxide, hydroxyethyl cellulose, pectin, gelatin and calcium silicate, binders such as polyvinylpyrrolidone, lubricants such as magnesium stearate, wetting agents such as fatty amines, quaternary ammonium salts of fatty acids and the like. The term drug preparation indicates that the drug is present in the chamber together with an osmosis agent, an osmosis polymer, a binder and the like. The amount of useful agent in the device is usually from 0.05 ng to 5 g or more, where individual devices contain e.g. 25 ng, 1 mg, 5 mg, 125 mg, 250 mg, 500 mg, 750 mg, 1.5 g and similar. The devices can be administered once, twice or three times daily.

The solubility of a useful agent in the liquid can be determined in a known manner. One method consists in preparing a saturated solution containing the liquid plus the agent determined by analyzing the amount of agent present in a specific quantity of the liquid. A simple apparatus for this purpose consists of a test tube of medium size fixed upright in a water bath maintained at constant pressure and temperature, in which the liquid and the agent are placed and stirred by means of a rotating glass spiral. After a given period of stirring, a quantity of the liquid is analyzed, and the stirring is continued for a further period of time. If the analysis does not show an increase in solute after successive periods of stirring in the presence of excess solids in the liquid, the solution is saturated and the results are considered the solubility of the agent in the liquid. If the agent is soluble, an added, osmotically effective compound may not be necessary. If the remedy

have limited solubility in the liquid, an osmotically effective compound can be introduced into the device. Numerous other methods are available for the determination of an agent's solubility in a liquid. Typical methods used for the measurement of solubility are chemical and electrical conductivity. Details of various methods for determining solubility are described in the United States Public Health Service Bulletin, No. 67 of the Hygenic Laboratory, Encyclopedia of Science and Technology, vol. 12, 1971, pp. 542-556, published by McGraw-Hill, Inc., and Encyclopedia Dictionary of Physics, vol. 6, 1962, pp. 547-557, published by Pergamon Press, Inc.

The osmosis device can be produced by e.g. to

mixing the beneficial agent with an osmosis agent and an osmosis polymer and pressing the mixture into a solid

which have dimensions corresponding to the internal dimensions of the chamber at the channel, or the useful agent or other preparation constituents and a solvent are mixed to a solid or a semi-solid in a known manner, such as grinding in a ball mill, calendering, stirring or grinding in rolling mill and then pressed into a predetermined shape. A layer of a material containing an osmosis agent and an osmosis polymer is then placed in contact with the layer of the preparation with the useful agent, and the two layers are enclosed with a semi-permeable wall. The formation of the layers of the preparation with the useful agent and the osmosis agent/osmosis polymer can be carried out by means of conventional two-layer tablet pressing technique. The wall can be placed by casting, spraying or dipping the pressed forms into the wall-forming material. Another and currently preferred method that can be used for placing the wall is the air suspension coating method. This method consists in suspending and slinging them

Pressed materials are passed around in a stream of air and a wall-forming material until the wall encloses and covers the two pressed materials. The process is repeated with another laminate layer-forming material, whereby a laminated wall is formed. The air suspension method is known from US patent 2,799,241, J. Am. Pharm. Assoc., vol. 48, 1979, p. 451-459 and in the same journal vol.

49, 1969, pp. 82-84. Another standard manufacturing method is described in Modern Plastics Encyclopedia, vol. 46, 1969, pp. 62-70, and in Pharmaceutical Sciences, by Remington, 14th ed., 1970, pp. 1626-1678, published by Mack Publishing Co., Easton, Penna.

Examples of solvents that are suitable for manufacturing. of the laminates and laminate layers include inert inorganic and organic solvents that do not adversely affect the materials and the finished laminated wall. The solvents are generally selected from aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic hydrocarbons, aromatic hydrocarbons, 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-hexane, n-heptane, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene dichloride, ethylene dichloride, propylene dichloride, carbon tetrachloride -chloride, chloroform, nitroethane, nitropropane, tetrachloroethane, ethyl ether, isopropyl ether, cyclohexane, cyclooctane, benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, diglyme, water and mixtures thereof, such as acetone and water, acetone and methanol, acetone and ethyl alcohol, methylene dichloride and methanol as well as ethylene dichloride and methanol.

The invention will be further explained by means of

the following examples.

Example 1

An osmosis delivery device prepared as an osmosis tablet, shaped and sized and adapted for oral introduction into the gastrointestinal tract was prepared as follows: A first osmotic drug material was prepared by sieving 355 g of polyethylene oxide, which had a molecular weight of about 200,000 through a 40 mesh stainless steel sieve, after which 100 g of nifedipine was sieved through the 40 mesh sieve, 25 g of hydroxypropyl methylcellulose was sieved through the 40 mesh sieve, and finally 10 g of potassium chloride was sieved through the sieve. All sieved ingredients were then placed in the bowl of a laboratory mixer and the ingredients were dry mixed for 15-20 minutes, whereby a homogeneous mixture was formed. A granulation liquid containing 250 ml of ethanol and 250 ml of isopropyl alcohol was then prepared, and the granulation liquid was introduced into the mixing bowl. First, 50 ml was injected into the bowl with constant mixing, then 350 ml of granulating liquid was slowly added to the bowl, and the wet mass was mixed for a further 15-20 minutes. Then, wet granules were passed through a 60 mesh sieve and dried at room temperature for 24 hours, and the dry granules were passed through a 16 mesh sieve. Then 10 g of magnesium stearate was added to the dry granules, and the ingredients were mixed for 20-30 minutes in a standard roller mill.

Then a second osmotic material was prepared in the following way: First, 170 g of polyethylene oxide, which had a molecular weight of 5,000,000, was sieved through a 40 mesh sieve, after which 72.5

g of sodium chloride was passed through the same sieve, and the ingredients were mixed in a mixing bowl for 10-15 minutes. A granulating liquid was then prepared by mixing 350 ml of methanol and 150 ml of isopropyl alcohol, and the granulating liquid was added to the mixing bowl in two stages. First, 50 ml of the granulating liquid was injected into the bowl under constant mixing, and then 350 ml of the granulating liquid was slowly added to the bowl and the wet mixture mixed for 15-20 minutes to a homogeneous mixture. Then the wet mixture was passed through a 16 mesh sieve, distributed in a stainless steel trough and dried at room temperature at 22.5°C for 24 hours. The dried mixture was passed through a 16 mesh sieve and then mixed with 5 g of magnesium stearate in a two roll roller mill for 20-30 minutes.

A number of drug cores were produced by pressing

the two materials in a Manesty Layer press. The drug containing the first material was fed into the press and compressed into a solid layer. Next, the second osmotic material was fed into the mold space on top of the compressed layer and pressed into a solid layer, thereby forming a two-layer drug core.

The drug cores were then coated with a material which was to form the semipermeable wall and which contained 95 g of cellulose acetate with 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 drug cores were coated with the material forming the semipermeable wall until the wall enclosed the drug core. A Wurster air suspension coating device was used to produce the semipermeable wall. The coated cores were then distributed in a trough and the solvent evaporated in a circulating air oven at 50°C

for 65 hours. After cooling to room temperature, a channel of 0.26 mm diameter was laser drilled through the semipermeable wall and connected the outside of the osmosis device to the material containing the drug. The osmosis device weighed 262 mg, and it contained 30 mg of drug in the first material weighing 150 mg, while the second material weighed 75 mg and the semipermeable wall 37 mg. The first osmotic material in the osmosis device comprised 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 material contained 51 mg of polyethylene oxide, 22 mg of sodium chloride and 1.5 mg of magnesium stearate. The device had a diameter of 8 mm, a surface area of 1.8 cm 2 ,

and the semipermeable wall was 0.17 mm thick. The cumulative amount of drug that was released is shown in fig. 9.

Example IA

Osmosis delivery devices were prepared comprising a first material containing 25-100 mg of nifedipine, 100-325

mg of polyethylene oxide with a molecular weight of 200,000, 2-10 mg of calcium chloride, 5-30 mg of hydroxypropyl methylcellulose and 2-10 mg of magnesium stearate, and a second material containing 30-175 mg of polyethylene oxide with a molecular weight of 5,000,000, 20-75 mg sodium chloride

and 1-5 mg of magnesium stearate. The procedure in Example 1 was repeated to prepare reverse osmosis devices having the following compositions: (a) a first reverse osmosis device comprising a first material containing 60 mg of nifedipine, 212 mg of polyethylene oxide, 6 mg of potassium chloride, 15 mg of hydroxypropylmethylcellulose and 6 mg magnesium stearate, and a second material containing 102 mg polyethylene oxide, 44 mg sodium chloride and 3 mg magnesium stearate, and (b) an osmosis device comprising a first material containing 90 mg nifedipine, 318 mg polyethylene oxide,

9 mg potassium chloride, 22.5 mg hydroxypropylmethylcellulose and 9

mg magnesium stearate, and a second material containing 102

mg polyethylene oxide, 66 mg sodium chloride and 4.5 mg magnesium stearate. In one embodiment, the osmosis devices (a) and (b) also included a cover coated on the outer semipermeable wall. The coating comprised 30 mg of nifedipine and hydroxypropylmethylcellulose. In use in the liquid environment, the overcoat provided immediate availability of the drug for immediate drug therapy.

Example 2

The procedure in Example 1 was repeated with all the conditions stated there, with the exception that the drug in the chamber was replaced with one of the following: a beta-blocker, an anti-inflammatory, an analgesic, a sympathomimetic, an antiparkinsonian or a diuretic drug.

Example 3

A therapeutic osmosis device for controlled and continuous oral delivery of the useful calcium channel blocking drug verapamil was prepared as follows: 90 mg verapamil, 50 mg sodium carboxyvinyl polymer with a molecular weight of 200,000 (Carbopol<w>), 3 mg sodium chloride , 7.5 mg of hydroxypropyl methylcellulose and 3 mg of magnesium stearate were mixed thoroughly as described in example 1 and pressed in a Manesty press with a piston of approx. 8 mm and a pressure height of lh tonnes so that a layer of the medicinal material was formed. Next, 51 mg of the carboxyvinyl polymer Carbopol w with a molecular weight of 3,000,000, 22 mg of sodium chloride and 2 mg of magnesium stearate were thoroughly mixed and introduced into the Manesty press and pressed into a layer of expandable osmotic material in contact with the layer of osmotic drug material.

Next, a semipermeable wall was formed by mixing 170 g of cellulose acetate, which had an acetyl content of 39.8%, with 900 ml of methylene chloride and 400 ml of methanol, after which the element forming the two-layer chamber was spray-coated in an air suspension machine until a 13 0 |im thick semipermeable wall enclosed the chamber. The coated device was dried for 72 hours at 50°C

and then a 203 µm channel was laser-drilled through the semipermeable wall to connect the layer containing the drug to the outside of the drug release device over an extended period of time.

Example 4

The procedure in example 3 was repeated with all the described conditions, with the exception that the drug in the osmosis device was fendiline, diazoxide, prenylamine or diltiazen.

Example 5

A therapeutic osmosis device for delivering the drug sodium dichlorfenac for use as an anti-inflammatory was prepared by first pressing in a Manesty press an osmotic drug material containing 75 mg sodium dichlorfenac, 300 mg sorbitol, 30 mg sodium bicarbonate, 26

mg pectin, 10 mg polyvinylpyrrolidone and 5 mg stearic acid. This material was pressed into a solid layer in a cavity. Then the cavity was charged with a second material which caused greater force and which contained 122 mg of pectin with a molecular weight of 90,000-130,000, 32 mg of mannitol, 20 mg of polyvinylpyrrolidone and 2 mg of magnesium stearate, which was pressed to form a second layer in contact with the first layer. The second layer had a density of 1.28 g/cm and a hardness of over 12 kg. The bilayer core was then enclosed with a semipermeable wall consisting of 85 g of cellulose acetate with an acetyl content of 39.8% and 15 g of polyethylene glycol 4000, as a 3% by weight solution in a solvent mixture of 1960 ml of methylene chloride and 819 ml of methanol. The coated device was dried for 72 hours at 50°C, after which a 0.26 mm diameter channel was laser drilled through the wall. The semipermeable wall was 0.1 mm thick, the device had an area of o 3.3 cm 2 and its average drug release rate was 5.6

mg per hour over a period of 12 hours. The cumulative amount released is shown in fig. 10. The small, vertical bars represent the smallest and largest drug release for five systems measured over that period of time.

Example 5A

The procedure in Example 5 was followed for preparation

of an osmosis device where the chamber contained a mixture of osmose polymers. The chamber contained a first material weighing 312 mg consisting of 48% sodium dichlorfenac drug, 38% polyethylene oxide reverse osmosis polymer with a molecular weight of 200,000,

10% polyethylene glycol reverse osmosis polymer with a molecular weight of 20,000, 2% sodium chloride and 2% magnesium stearate, and a second material

which weighed 150 mg and consisted of 93% polyethylene oxide with a molecular weight of 5,000,000, 5% sodium chloride and 2% magnesium stearate.

Example 6

In this example, the increase in osmotic pressure from a number of materials comprising an osmosis agent and an osmosis polymer was determined to demonstrate the benefit of the osmosis device in use. The measurements were carried out by measuring the amount of water that was sucked in through the semipermeable wall in a bag containing an osmosis agent, or an osmosis polymer, or a material that contained an osmosis agent and an osmosis polymer. The semipermeable wall of the bag was made from cellulose acetate which had an acetyl content of 39.8%. The measurements were carried out by weighing the dry ingredients in the semipermeable bag, followed by weighing the dried semipermeable bag after the bag had been in a water bath at 37°C for varying lengths of time. The increase in weight is due to the absorption of water through the semipermeable wall caused by the osmotic pressure gradient through the wall. Curves for the osmotic pressure are shown in fig. 11. In fig. 11, the curve with the triangles represents the osmotic pressure for polyethylene oxide with a molecular weight of 5,000,000, the curve with the circles represents the osmotic pressure for a material that comprised polyethylene oxide with a molecular weight of 5,000,000 and sodium chloride, where the components were present in the material in the ratio 9, 5 parts osmosis polymer and 0.5 parts osmosis agent. The curve with the squares represents a material that included the same osmosis polymer and osmosis agent in the ratio of 9 parts osmosis poly to 1 part osmosis agent. The curve with the hexagons represents the material with the same osmosis polymer and osmosis agent in a ratio of 8 parts to 2 parts, and the dashed line represents the osmosis agent sodium chloride. The mathematical calculations were carried out using the formula dw/dt=A (KAir)/h, where dw/dt is the water absorption rate over time, A

is the area of the semipermeable wall and K is the permeability

the coefficient. In fig. 11 is also WTT/W the amount of water that is

3 H p

absorbed divided by the weight of osmosis polymer plus osmosis agent.

Example 7

A therapeutic osmosis device for the release of sodium dichlorfenac was produced by sifting through a 40 mesh sieve a material comprising 49% sodium dichlorfenac,

I to \^ I

44% polyethylene oxide with a molecular weight of 100,000, 2% sodium chloride and 3% hydroxypropylmethylcellulose. The sieved material was then mixed with an alcohol solvent which was used in a ratio of 75 ml of solvent to 100 g of granules.

The wet granules were sieved through a 16 mesh sieve, dried

at room temperature for 48 hours under vacuum, passed through a 16 mesh sieve and mixed with 2% magnesium stearate which was sieved through an 80 mesh sieve. The material was compacted as described above.

Then a material comprising 73.9% pectin was added

a molecular weight of from 90,000 to 130,000, 5.8% microcrystalline cellulose, 5.8% polyvinylpyrrolidone, 14.3% sodium chloride and 2% sucrose sieved through a 40 mesh sieve, mixed with an organic solvent in the ratio of 100 ml solvent to 100 g granulated for 25 minutes, passed through a 16 mesh screen, dried for 48 hours at room temperature under vacuum, again passed through a 16 mesh screen, mixed with 2% magnesium stearate and then compacted into the compacted layer described in the paragraph above. The two-layer drug core was coated by dipping it in a wall-forming material comprising 80% cellulose acetate with an acetyl content of 39.8%, 10% polyethylene glycol 4000 and 10% hydroxypropylmethylcellulose. A channel was drilled through the wall. The diameter of the channel was 0.38 mm. The theoretical, cumulative emission profile for the device is shown in fig. 12. Fig. 13 shows the theoretical release rate in mg per hour for the osmosis device.

Example 8

The procedure in example 7 was repeated with all the described conditions, with the exception that the osmosis polymer in the drug material was polyoxyethylene-polyoxypropylene block copolymer with a molecular weight of approx. 12,500.

Example 9

An osmosis device was prepared by following the methods described above. The device in this example comprised a single material consisting of 50% sodium dichlorfenac, 46% polyethylene oxide with a molecular weight of 100,000, 2% sodium chloride and 2% magnesium stearate. The device had a semipermeable wall of 90% cellulose acetate with 39.8% acetyl, and 10% polyethylene glycol 4000. The cumulative dispensed amount for this device, which comprised only one material, was 40% of the amount for the device that comprised two materials. The dispensed amount is shown in fig. 14.

Example 10

The average releases of dichlorfenac sodium in vivo and in vitro from an osmosis device comprising a first osmotic material containing 75 mg dichlorfenac sodium, 67

mg of polyethylene oxide with a molecular weight of 100,000, 3.0 mg of sodium chloride, 4.5 mg of hydroxypropylmethylcellulose and 3.0 mg of magnesium stearate, a second osmotic material at a distance from the delivery channel and comprising 51 mg of polyethylene oxide with a molecular weight of 5,000,000, 22 .5 mg sodium chloride and 1.5 mg magnesium stearate and, enclosed by a semipermeable wall of 90% cellulose acetate with an acetyl content of 39.8%, and 10% polyethylene glycol 4000 were measured in vivo and in vitro in laboratory dogs. The amounts of drug released at different times in vivo were determined by administering a series of the devices to the animal and measuring the amount released from the relevant device after the appropriate dwell time. The results are shown in fig. 15, where the circles with the sticks are the mean cumulative release in vitro and the triangles with the sticks are the mean cumulative release in vivo.

The average cumulative release in vivo and in vitro for a device containing nifedipine was measured as described just above. The osmosis device comprised a material which was placed at the channel and which comprised 30 mg of nifedipine, 106.5 mg of polyethylene oxide with a molecular weight of 200,000,

3 mg potassium chloride, 7.5 mg hydroxypropylmethylcellulose and 3

mg of magnesium stearate, a material which was located at a distance from the channel and which comprised 52 mg of polyethylene oxide with a molecular weight of 5,000,000, 22 mg of sodium chloride and 1.5 mg of magnesium stearate, as well as a semipermeable wall of 95% cellulose acetate with an acetyl content of 39, 8% and 5% hydroxypropyl methylcellulose. Fig. 16 shows the output from the device. In fig. 16, the circles represent the release in vivo, and the triangles represent the average cumulative release in vitro.

Example 11

The procedure in Example 10 was followed for preparation

of a therapeutic osmosis delivery device comprising: a first or drug material weighing 638 mg and consisting of 96% cephalexin hydrochloride, 2% "Poviclone" (polyvinylpyrrolidone) and 2% magnesium stearate, a second or osmotic material weighing 200 mg and consisting of 68 .5% polyethylene oxide with a molecular weight of 5x10^, 29.5% sodium chloride and 2% magnesium stearate, a semipermeable wall weighing 55.8 mg and consisting of 80% cellulose acetate with an acetyl content of 39.8%, 14% polyethylene glycol 4000 and 14% hydroxypropylmethylcellulose, as well as an osmotic mouth with a diameter of 0.039 mm. The device had an average release rate of approx. 54 mg per hour over a period of 9 hours.

In the osmosis device produced by the method according to the invention, a double material is used to achieve an accurate release rate of drugs that are difficult to deliver in the application environment, while at the same time maintaining the integrity and character of the device.

Claims (10)

1. Method for producing an osmosis device (10) for releasing a useful agent (15) at a controlled rate into an application environment, characterized in that a) a first material comprising an osmosis polymer is produced for mixing with the useful agent, b) the a second material comprising an osmosis agent and a hydrophilic swellable osmosis polymer is prepared, c) a body is produced, such as by pressing, from the first and second material, and the body is coated, preferably by air suspension coating, with a material that is at least partially permeable for the passage of a liquid that is in the application environment, for the formation of a wall (12) as the wall (12) encloses and forms a chamber (14) that accommodates the body, and e) a channel is arranged in the wall (12), and preferably by laser drilling, to form a connection between the first material and the outside of the device for releasing the useful agent from the device. 2. Method in accordance with claim 1, characterized in that one of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, ethyl cellulose, cellulose acetate butyrate, cellulose acetate propionate, hydroxypropyl methyl cellulose, hydroxy-lower alkyl cellulose, methyl cellulose, methyl ethyl cellulose or mixtures of these is used as the wall-forming material . 3. Method in accordance with claim 1, characterized in that the first and the second material are produced as separate layers. 4. Method in accordance with claim 1, characterized in that the first and second materials used are arranged to suck in liquid from the outside of the device through the wall (13) into the chamber (14). 5. Method in accordance with claim 1, characterized in that the osmosis polymer used in the second material has a higher molecular weight than the molecular weight of the osmosis polymer used in the first material. 6. Method in accordance with claim 1, characterized in that the wall (12) is produced in the form of a laminate comprising a semi-permeable laminate layer and a microporous laminate layer. 7. Method in accordance with claim 1, characterized in that a wall-forming material containing polyethylene glycol is used. 8. Method in accordance with claim 1, characterized in that the osmosis polymer used in the first material is polyethylene oxide. 9. Method in accordance with claim 1, characterized in that the osmosis polymer used in the second material is polyethylene oxide. 10. Method in accordance with claim 1, characterized in that a first material containing an osmosis agent is used.