DK163910B - OSMOTIC PREPARATION FOR DELIVERING A THERAPEUTIC ACTIVE CONNECTION WITH REGULATED SPEED - Google Patents

Description

in

DK 163910 B

The present invention relates to both an unknown and unique delivery system. More particularly, the invention relates to an osmotic composition for delivering a therapeutically active compound at a controlled rate comprising: a) a wall comprising a material permeable to the passage of an external fluid surrounding and forming a b, a compartment, 10 c a first material in the compartment comprising a therapeutically active compound, d) a second material in the compartment, and e) a passage in the wall which is in contact with the first material and the outer side of the osmotic preparation for delivery of the therapeutically active compound from the osmotic preparation.

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A passage through the wall connects the outer side of the osmotic composition with the first osmotic material containing the active compound for delivery of the first material from the osmotic composition. The osmotic composition is useful for the delivery of active compounds which, due to their solubility, are difficult to deliver in a known quantity at a controlled rate from an osmotic delivery system.

Since ancient times, both pharmacy and medical science have sought a delivery system for administering a beneficial drug. The first written reference to a dosage form is in Eber Papyrus, written ca. 1552 BC. In Eber Papyrus, dosage forms are mentioned such as anal suppositories, vaginal receptors, ointments, oral pill formulations and other dosage preparations. There were 35 approx. 2500 years without any progress in developing a dosage form when the Arab physician Rhazes, 865-925 AD, invented the coated pill. About a century later,

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2 Seren Avicenna, 980-1037 AD, pills with gold or silver to improve patient acceptance and to enhance the effect of the drug. Around this time, the first tablet was also described in Arabic manuscripts written by al-Zahrawi, 5 936-1009 AD. The manuscripts described a tablet formed from the hollow prints in two opposite tablet forms. Pharmacy and medicine waited about 800 years before the next renewal in dosage forms, when Mothes invented the capsule for the administration of drugs in 1883. The next major leap forward in dosage forms came in 1972 with the invention of the osmotic delivery preparation of the inventors Theeuwes and Higuchi, as described in U.S. Patent Nos. 3,845,770 and 3,916,899. The osmotic compositions disclosed in these patents comprise a semipermeable wall surrounding a compartment containing a useful agent. The wall is permeable to the passage of an outer fluid and it is substantially impermeable to the passage of useful agent. There is a passage through the wall for delivery of the useful agent from the osmotic device. These devices release useful agent by sucking liquid through the semipermeable wall of the room at a rate determined by the permeability of the semipermeable wall and the osmotic pressure gradient over the semipermeable wall to produce an aqueous solution containing useful agent which delivered through the passage from the preparation. These compositions are particularly effective in providing a useful agent which is soluble in the liquid and has an osmotic pressure gradient over the semipermeable wall against the outer liquid.

A groundbreaking advancement in osmotic delivery preparations 30 was presented within the delivery technique of the inventor.

Felix Theeuwes in U.S. Patent No. 4,111,202. In this patent, the delivery kinetics of the osmotic composition is improved to provide useful agents which are soluble to highly soluble in the liquid by preparing an osmotic composition having a space for useful agent and a space for an osmotic agent separated by a movie. The film is movable from a resting position to an extended position. The osmotic preparation le 3

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liquid is sucked in by liquid being sucked in through the semipermeable wall to the room with the osmotic agent, forming a solution which causes the space to grow in volume and act as a driving force applied to the film. This force forces the film to expand toward the useful agent space and correspondingly decrease the volume of the useful agent space, thereby providing the useful agent through the passage of the osmotic composition. While this composition works favorably for its intended use, and although it can provide several useful agents of varying solubilities, its use may be limited due to the manufacturing steps and costs required to manufacture and apply the moving film. in the space of the osmotic preparation.

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The state of the art is disclosed in U.S. Patent No. 4,327,725, which discloses an osmotic delivery composition for delivering beneficial agents which, due to their solubility in aqueous and biological fluids, are difficult to deliver in relevant quantities with regulated speeds over time. The osmotic compositions of this patent include a semipermeable wall surrounding a compartment containing a beneficial agent which is insoluble to highly soluble in aqueous and biological fluids, and an expandable hydrogel. Under 25, the hydrogel expands in the presence of an outer liquid entering the composition, thereby providing the beneficial agent delivered through the passage from the composition. This preparation works favorably for its intended use, and it provides many beneficial, difficult-to-deliver agents for their intended purpose. It has now been found that the utility is limited because the hydrogel lacks a present ability to absorb sufficient fluid for the maximum self-expansion needed to drive the beneficial agent from the composition.

It will be appreciated by those skilled in the art of delivery if an osmotic composition can be provided which has a high degree of

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4 of osmotic activity for delivering a beneficial agent by producing in situ an expanding force sufficient to deliver the maximum amount of agent at a controlled rate from an osmotic composition, such an osmotic composition having a positive value and signify a progress of 1 ever in the area. Similarly, it will be appreciated immediately by those skilled in the art of delivery if an osmotic composition possessing dual thermodynamic osmotic activity, i.e. the composition is capable of aspirating fluid and generating an expanding force to deliver increased amounts of a beneficial agent with controlled rate over time is made available, said osmotic preparation being of practical use in pharmacy and medicine.

Therefore, in view of the foregoing preparation, it is an immediate object of the present invention to provide an osmotic system which represents a further improvement and development in the field of delivery, which osmotic composition possesses a high degree of osmotic activity to provide therapeutically active compounds. , especially those which are difficult to deliver, in sufficiently effective therapeutic doses at a controlled rate continuously over time.

The object of the invention is further to provide an osmotic therapeutic composition capable of administering a complete pharmaceutical dosage regimen comprising poorly soluble to highly soluble agents at a controlled rate and continuously for a specified period of time, the use of which only requires intervention upon initiation and possible ending of the cure.

Thus, the present invention relates to an osmotic composition for delivery of a therapeutically active compound at a controlled rate comprising: (a) a wall comprising a material permeable to the passage of an external fluid which surrounds and forms:

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5 (b) a compartment, (c) a first material in the compartment comprising a therapeutically active compound, 5 (d) a second material in the compartment, and (e) a passage in the wall associated with the first material and the compartment. the outer side of the osmotic composition for delivery of the therapeutically active compound from the osmotic composition, said osmotic composition being characterized in that said first material in the space comprises, in addition to the therapeutically active compound, an osmotic polymer and said second material in the compartment, an osmotic agent and an osmotic polymer comprise which second material in function sucks fluid into the osmotic composition, expands and drives the first material out of the osmotic composition.

In the drawings, which are not drawn in the right conditions, but 20 are illustrated to illustrate various embodiments of the invention, the figures are as follows: FIG. 1 is an isometric view of an osmotic composition designed for oral administration of an active compound 25 to the gastrointestinal system; 2 is an opened view of the osmotic composition of FIG.

1 illustrating the structure of the osmotic composition of FIG.

1, 30 FIG. 3 is an opened view of the osmotic composition of FIG.

1 illustrating the osmotic composition during operation and delivery of an active compound from the osmotic composition; FIG. 4 is an opened view of the osmotic composition of FIG.

1, as viewed in FIG. 3 illustrating the osmotic composition during operation and delivery of a larger amount of an active compound from the osmotic composition,

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6 FIG. Figure 5 shows an osmotic therapeutic composition with its wall partially broken off, designed to deliver an active compound to a passage in the squirrel, such as rectal and vaginal passage; 6 shows the osmotic composition of FIG. 5 with a different wall structure; FIG. 7 shows the osmotic composition of FIG. 5, which depicts 10 a different wall structure than the wall structure depicted in FIG.

6, FIG. Figure 8 indicates the weight gain as a function of time for a polymer encapsulated in a semi-permeable membrane when the encapsulated polymer is placed in water; 9 depicts the cumulative amount of drug released from a composition comprising an osmotic polymer of two different molecular weights, i.e., wherein the therapeutically active agent is mixed with an osmopolymer of a given molecular weight and wherein an osmopolymer of a different molecular weight; usually a higher molecular weight, expanding and driving the second osmopolymer comprising the therapeutically active agent out of the osmotic composition; Figure 10 depicts the cumulative amount of drug released from a composition using a different set of osmotics in spoony polymers; 11 depicts the osmotic pressure curves for a number of osmotic agents and a number of osmotic polymer / osmotic agent compositions; FIG. Figure 12 depicts the cumulative release profile of an osmotic system using two different osmotic polymers; 13 depicts the release rate per hour for an osmotic system different from FIG. 9 containing two osmo-

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7, polymers having two different molecular weights; Figure 14 depicts the cumulative amount released from a single active compound preparation comprising only one layer; Fig. 15 illustrates in vivo and in vitro cumulative release of a drug supplied by the osmotic preparation, and 10 Fig. 16 illustrates in vivo and in vitro cumulative release of another drug supplied by an osmotic preparation.

In the drawings and in the description, the same parts in related figures are identified by the same parts. The terms that appeared 15 earlier in the description and description of the drawings, as well as embodiments thereof, are more clearly set forth in detail elsewhere in the disclosure.

By looking at the drawings in detail, which are examples 20 of various osmotic devices according to the invention, an example of an osmotic composition of FIG. 1. In FIG. 1, an osmotic composition 10 is shown comprising a part of a body 11 having a wall 12 and a passage 13 for releasing an active compound from the osmotic composition 10.

In FIG. 2, the osmotic composition 10 of FIG. 1 in the opened section. In FIG. 2, the osmotic composition 10, a spokes 11, comprises a semipermeable wall 12 surrounding and forming an inner space 14 which, through a passage 13, communicates with the exterior 30 of the osmotic composition 10. The space 14 contains a first osmotic material comprising an active compound 15 represented by dots, and it may be from insoluble to highly soluble in a liquid sucked into space 14 and an osmotic polymer 17 represented by horizontal strokes which suck liquid to the space 14 and has an osmotic pressure gradient over the semipermeable wall 12 against an outer liquid present in the environment used. The wall 12 is 8

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formed of a semipermeable material which is substantially permeable to the passage of the outer liquid, and which is substantially impermeable to the passage of the active compound 15, osmotic agent 16 and osmotic polymer 17. The semipermeable wall 12 is non-toxic and retains its physical and chemical integrity during preparation 101 s 1 ever for life.

Room 14 contains another osmotic material which is distant from passage 13 and in contact with the first material.

The second material is an expandable driving force which acts with the first osmotic material to deliver the maximum amount of an active compound 15 from the osmotic composition 10. The second osmotic material comprises an osmotic agent 18, which is soluble in liquid 15 which is sucked into space 14 and which has an osmotic pressure gradient across the wall 12 towards an outer liquid and which is mixed with an osmotic polymer 19 which sucks liquid into the space 14 and has a osmotic pressure gradient across the wall 12 to external fluid.

The osmotic polymers 17 and 19 are hydrophilic, water-soluble 20 or slightly crosslinked vanu-soluble polymers, and have osmotic properties, such as the ability to absorb outer liquid, exhibit an osmotic pressure gradient across the semipermeable wall to the outer liquid, and swell or expand. oneself in the presence of the liquid. The osmotic polymers 17 and 19 are mixed with the 25 osmotic agents 16 and 18 to absorb the maximum volume of outer fluid into compartment 14. This fluid is available for the osmotic polymers 17 and 19 to optimize the volumetric velocity and for total expansion. That is, osmotic polymers 17 and 19 absorb 30 fluid sucked into space 14 by the osmotic suction action of osmotic polymers 17 and 19, supplemented by the osmotic suction effect of the osmotic agents. 16 and 18 to effect the maximum expansion of the osmotic polymers 17 and 19 to an enlarged state.

During operation, the delivery of the active compound 15 from an osmotic preparation 10 is carried out in an immediately preferred embodiment.

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9, in (1) suction of liquid of the first material to form a suspension in situ and delivery of the suspension through the passage, and in parallel by (2) suction of liquid of the second material receiving the second material. to swell and cooperate with the first material to drive the suspension of the active compound through the passage. In accordance with the described operation, the osmotic composition may be construed as a cylinder in which the second material expands as the movement of a piston to assist in the delivery of the suspension of the active compound from the osmotic composition. Although the shape of the osmotic composition as depicted in FIG. 1 and 2 is a genuine cylinder, it is sufficiently approximated for the following physical analysis. In this analysis, the volume velocity provided by the osmotic composition Ft is composed of two sources; the water suction rate of the first material F and the water suction rate of the second material Q, wherein:

Ft = F + Q (1) 20

Since the boundary between the first material and the second material hydrates very little while the osmotic composition works, there is a negligible water movement between the materials. The water suction rate of the second material Q is equal to the expansion of its volume dvP = Q (2) dt 30 The total delivery rate from the osmotic composition is then _dm_ = Ft. C = (F + Q) C (3) dt 35 wherein C is the concentration of active compound in the delivered sludge. Preserving the volume of osmotic preparation V and surface area A gives equations 4 and 5 10

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v = Vd + Vp (4) A = Ad + Ap (5) 5 wherein Vd and Vp are the volumes of the first material and the second material, respectively, and wherein Ad and Ap are the surface area1, respectively, in contact with the wall of the first material and the other material. During use, both Vp and Ap increase with time, while Vd and Ad decrease with time as the preparation delivers an active compound.

The volume of the second material that expands over time as liquid is sucked into space is given by Equation 7: 15 V -f / V \ (7) P} Iwp) wherein Wg is the weight of liquid sucked in by the other material, is the weight of the other material initially present in the composition, W 2 / w is the ratio of M p liquid to initial solid of the second material, V is

P

equals (> 50? 25 \ P / where e is the density of the second material corresponding to Wr / W. Calculated on the geometry of a cylinder where r is the radius of the cylinder, the relationship between the suction area and the volume of the swollen other material is therefore as follows: 30 35

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11

Ap + -Τ '~ f (l + ”/ ^ p) 181 A, = A - A (9) 5 dp The liquid suction rates for each compartment are: 10 F = (l-XAd ΔΧ (10> Q = (4-)) CP Δ "ρ) (11)

where k is equal to the osmotic permeability of the wall, h is equal to the wall thickness, Δπ and Δπ are the osmotic gradients for respectively 15 d P

show the first material and the second material. The total delivery rate is therefore: -IS- -4 <{[»- -2 - 4- -4- (1 + -¾)] ^ 20 + 142 + ~ 4e_ (i + (12)

FIG. 3 and 4 illustrate the osmotic composition in use as described in FIG. 1 and 2. In FIG. 3 and 4, for an osmotic composition ^ 10, liquid of the first material is sucked in at a rate determined by the permeability of the wall and the osmotic pressure gradient across the wall. The suction fluid continuously forms a solution containing active compound or a solution or of osmotic agent such as gel and osmotic polymer containing the active compound in suspension, which solution or suspension in each operation is released by the combined operations of preparation 10. These operations include that the solution or suspension is delivered osmotically through the passage as a result of the continuous formation of solution or suspension, and by the swelling and growing volume but of the other material represented by the increase in

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12 height of the vertical lines of FIG. 3 and 4. This latter swelling and volume increase apply pressure to the solution or suspension, thus aiding the first material and simultaneously providing active compound to the outer 5 of the composition.

The first material and the second material work together to substantially ensure that the delivery of the active compound from space is constant over a longer period of time by two methods. First method, the first material sucks outer liquid through the wall, thereby forming either a solution or a suspension, the latter of which will be substantially delivered in non-zero order (without the second material being present) as the driving power decreases with time.

Second method, the second material works in two parallel operations: First, the second material works to continuously concentrate the active compound by sucking in some liquid from the first material to help prevent the concentration of the active compound from falling below Second, continuously increasing the volume of the second material by suctioning external liquid through the wall, thereby exerting a force on the first material and reducing the volume of the active compound, thereby passing the active compound to the passage. in space. Furthermore, as the extra solution or suspension formed in the first compartment is pressed out, the osmotic material is in close contact with the inner wall and produces a constant osmotic pressure and therefore a constant rate of delivery with the second material. The swelling and expansion of the second material with the accompanying volume increase along with the simultaneous corresponding reduction in the volume of the first material results in the delivery of active compound at a controlled rate with time.

Composition 10 of FIG. 1-4 can be made in many embodiments including the presently preferred embodiments for oral use to release either a local or

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13 systemic therapeutic agent in a gastrointestinal tract1.

The oral system 10 may have various common shapes and sizes, such as rounds having a diameter of 4.8 mm (3/16 ") to 12.7 mm (%"). In these forms, composition 10 can be adapted to administer an active compound to a variety of animals including warm-blooded animals, humans, birds, reptiles and fish.

FIG. 5, 6 and 7 show another embodiment, an osmotic composition 10 designed for placement in a passage in the body, such as a vagina, or the rectal duct. The composition 10 has an elongated cylindrical, self-standing shape with a rounded end 20, a rear end 21, and it is provided with manually controlled threads 22 for easy removal of the composition 10 from a biological passage. The composition 10 is structurally identical to the composition 1510 as described above and acts in a similar manner. In FIG.

5, the composition 10 is depicted with a semi-permeable wall 23, in FIG. 6 with a layered wall 24 comprising an inner semipermeable layer 25 adjacent to space 14 and an outer microporous layer 26 distant from space 14. In FIG. 7, composition 10 comprises a 20 layered wall 28 formed of a microporous layer 29 adjacent to space 14, and a semi-permeable layer 30 facing the environment in which it is used, and in layered connection with a microporous layer 29. The composition 10 provides an active compound for absorption of the vaginal mucosa or rectal mucosa to produce an in vivo local or systemic effect over an extended period of time.

The osmotic compositions of FIG. 1 to 7 can be used to deliver numerous active compounds including drugs 30 at a controlled rate, regardless of the drug's pH value dependency, or where the solubility rate of the active compound may vary between low and high in liquid environments such as gastric juice and intestinal juice. The osmotic compositions also provide for the high supply of low-solubility active compounds and their delivery in relevant therapeutic amounts. And although FIG. 1-7 are illustrative of various osmotic compositions, the compositions may assume

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14 many different shapes, sizes and shapes for the delivery of active compounds to the environment in which they are used. Eg. The compositions include buccal, implanted, artificial gland, cervical, intrauterine, ear, nose, skin, subcutaneous and blood delivery preparations.

In accordance with the practice of the present invention, it has now been found that the osmotic delivery preparation 10 can be prepared with a first osmotic material and a second osmotic material interposed in cooperative conditions in the composition space. The compartment is formed of a wall comprising a material which does not adversely affect the active compound, the osmotic agent, the osmotic polymer and the like. The wall is permeable to the passage of an outer fluid such as water and biological fluids and is substantially impermeable to the passage of active compounds, osmotic agents, osmotic polymers and the like. The wall is formed of a material which does not adversely affect an animal or a host, and the selectively semipermeable materials used to form the wall are non-degradable and are insoluble in liquids. Typical materials for forming the wall are in one embodiment cellulose esters, cellulose ethers and cellulose ester ethers. These cellulose polymers have a degree of substitution D.S. on the anhydroglucose unit, from 25 greater than 0 up to and including 3. By degree of substitution is meant the average number of hydroxy groups initially found on the anhydrous glucose unit comprising cellulose polymers replaced by a substituting group. Representative materials include an element selected from the group consisting of cellulose acylate, cellulose diacylate, cellulose triacylate, e.g. cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di- and tricellulose alcanates, i.e. cellulose substituted with 1, 2 or 3 alkanyl groups, respectively, mono-, di- and tricellulose arylates, i.e. cellulose which is substituted 1, 2 or 3 times, respectively, with aromatic hydrocarbons such as aryl or arylene and the like. Examples of polymers include cellulose acetate with a D.S. up to 1 and

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An acetyl content up to 21%; cellulose acetate having an acetyl content of 32 to 39.8%; cellulose with a D.S. of 1 to 2 and an acetyl content of 21 to 35%; cellulose acetate with a D.S. of 2 to 3 and an acetyl content of 35 to 44.8%, and the like. More 5 special cellulose polymers include cellulose propionate with a D.S. of 1.8 and a propionyl content of 39.2 to 45% and a hydroxyl content of 2.8 to 5.4%; ce11u1ose acetate butyrate with a D.S. of 1.8, an acetyl content of 13 to 15% and a butyryl content of 34 to 39%; cellulose acetate butyrate having an acetyl content of 2 to 29%, a butyryl content of 17 to 53% and a hydroxyl content of 0.5 to 4.7%; ce11u1osetriacy1 ater with a D.S. of 2.9 to 3, such as cellulose trivalent, cellulose triaurate, cellulose tripalmate, cellulose trisuccinate and cellulose trioclanoate; cellulose diacylates with a D.S. of 2.2 to 2.6, such as cellulose disuccinate, cellulose dipalmitate, cellulose disioclanoate, 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 dimethyl cellulose acetate, cellulose acetate ethyl carbamate, cellulose acetate methyl carbamate, in the US Patent Nos. 3,173,876, Nos. 3,276,586, Nos. 3,541,005, Nos. 3,541,006, and Nos. 3,546,142; semipermeable polymers as described in U.S. Pat. U.S. Patent No. 3,133,132; slightly crosslinked polystyrene derivatives; cross-linked poly (sodium styrene sulfonate), cross-linked poly (vinylbenzyltrimethylammonium chloride), semipermeable polymers having a liquid permeability of 10 ^ to 10 ^ (2.54.10 ^ mm) 'cm'. h. atm) expressed per at -8 atmosphere 10 of hydrostatic or osmotic pressure difference over the semipermeable wall The polymers are known in the art in the US

35 Patent Nos. 3,845,770, 3,916,899 and 4,160,020, and in the Handbook of Common Polymers by Scott, J.R. and Roff, W.J. , 1971, published by CRC Fress, Cleveland, Ohio.

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The layered wall comprising a semi-permeable layer and a microporous layer is in layered arrangement and they work together to form a complete layered wall that retains its physical and chemical integrity and is not separated into layers during the release period. of active compound from an osmotic preparation. The semi-permeable layer is made from the semi-permeable polymeric materials listed above, the semi-permeable homopolymers, semi-permeable copolymers and the like.

Microporous layers suitable for making an osmotic device usually comprise pre-formed microporous polymeric materials and polymeric materials capable of forming a microporous layer in the environment employed. The microporous materials in both embodiments are layered to form the layered wall. The preformed materials suitable for forming the microporous layer are substantially inert, retaining their physical and chemical integrity during the release agent period, and may be described generically as having a fungal-like appearance which provides a supportive structure for a semipermeable layer and also provides a supportive structure for interconnected microscopic pores or voids. The materials may be isotropic in which the structure is homogeneous over a cross-sectional area or they may be anisotropic in which the structure is inhomogeneous over a cross-sectional area. The pores may be continuous pores having an aperture on both faces of a microporous layer, pores interconnected through curved paths of regular and irregular shape including curved, curvilinear, randomly oriented continuous pores, obstructed connected pores and other porous pathways distinguishable by microscopic examination. Usually, microporous layers are defined by the pore size, the number of pores, the twist of the microporous path, and the porosity associated with the size and the number of pores. The pore size travel of a microporous layer is readily ascertained by painting the observed pore diameter at the surface of the material.

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17 there the electron microscope. In general, materials having from 5 to 95% pores and having a pore size of 10 Angstroms to 100 microns can be used to prepare a microporous layer. The pore size and other parameters characterizing the microporous structure can also be obtained by flow measurements where a wash flow J is produced by a pressure difference ΔΡ over the layer. The flow of the liquid through a layer of pores of uniform radius extending across the membrane and perpendicular to its surface with an area A is given by Equation 13: j = N.7r.r4.AP j13j

8rjAX

wherein J is the volume transported per. time unit and area of the layer containing N number of pores with radius r, η is the viscosity of the wash, and ΔΡ is the pressure difference over the layer of thickness ΔΧ. For this type of layer, the number of pores N can be calculated from Equation 14, where ε is the porosity defined as the ratio of the void volume to the total volume of layer and A is the cross-sectional area of the layer containing N pores.

N = - ^ 2 (14) itr 25

Pore radius is then calculated from Equation 15: r 2 = 817. AlAllI (15 A · ΔΡ · ε where J is the volume flow through the layer per unit area, produced by the pressure difference ΔΡ over the layer, η, ε and ΔΧ has the above defined and τ is the twist defined as the relationship between the diffusion path length in the layer and the layer thickness. Relationships of the above type are discussed in Transport Phenomena In Membranes, by Lakshmina-35 tayanaiah, N, Chapter 6, 1969, published by Academic Press,

Inc., Nev .; York.

18

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As discussed in this reference on page 336 of Table 6.13, the porosity of the layer with pores with radius r can be expressed in relation to the size of the transported molecule with a radius a, and when the ratio of molecular radius to pore radius a / r decreases. , is made porous with respect to this molecule. That is, when the ratio a / r is less than 0.3, the layer becomes substantially microporous as expressed by the osmotic reflection coefficient cr decreasing below 0.5. Microporous layers having a coefficient of reflection o 10 in the range of less than 1, usually from 0 to 0.5, and preferably less than 0.1 with respect to the active agent, are suitable for preparing the system. The coefficient of reflection is determined by designing the material in the form of a 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 compound. The osmotic pressure difference forms a hydrostatic volume flow and the reflection coefficient is expressed by Equation 16: 20 = osmotic volume flow Qgj σ hydrostatic volume flow.

Properties of microporous materials are described in Science, Vol. 170, pages 1302 to 1305, 1970; Nature, Vol. 214, pp. 285, 1967; Polymer Engineering and Science, Vol. 11, pp. 254-288, 1971; U.S. U.S. Patent Nos. 3,567,809 and 3,751,536; and in Industrial Processing With Membranes, by Lacey R.E., and Loeb, Sidney, pages 131 to 134, 1972, published by Wiley, Interscience, New York.

Thirty microporous materials having a preformed structure are commercially available and can be prepared by prior art.

The microporous materials can be prepared by etching, core tracing, by cooling a solution of liquid polymer to below freezing point, whereby the solvent evaporates 35 from the solution in the form of crystals dispersed in the polymer and then storage of the polymer followed by removal of the polymer.

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Solvation crystals, by cold or hot stretching at low or high temperatures until pores are formed, by leaching from a polymer of a soluble component with a suitable solvent, by ion exchange reaction 5 and by polyelectrolyte processes. Methods for preparing microporous materials are described in Synthetic Polymer Membranes, by R.E. Resting, Chapters 4 and 5, 1971, published by McGraw Hiil, Inc.; Chemical Reviev; s, Ultrafiltration, Vol. 18, pages 373 to 455, 1934; Polymer Eng. and Sci., Vol. 11, No. 10, pages 284 to 288, 1971; J. Appl. Poly. Sci., Vol. 15, pages 811 to 829, 1971, and in U.S.A. U.S. Patent No. 3,565,259, No. 3,615,024, No. 3,751,536, No. 3,801,692, No. 3,852,224, and No. 3,849,528.

Microporous materials useful in preparing the layer include microporous polycarbonates constituted by linear polyesters of carbonic acid in which carbonate groups are repeated in the polymer chain, microporous materials prepared by phosgenation of an aromatic dihydroxyl such as 20 bisphenol A, microporous poly ( vinyl chloride), microporous polyamides such as polyhexamethylene adipamide, microporous modacrylic copolymers including those formed from poly (vinyl chloride) 60% and acrylonitrile, styrene-acrylic and its copolymers, porous polysulfones characterized by diphenylene sulfone a linear chain thereof, halogenated poly (vinylidene), polychloroethers, acetal polymers, polyesters prepared by esterification of a dicarboxylic acid or anhydride with an alkylene polyol, poly (alkylene sulfides), phenol polyesters, microporous poly (saccharides), microporous poly (saccharides) with substituted and unsubstituted anhydroglucose units, and as for stepwise has an increased permeability for passage of water and biological fluids than semipermeable layers, asymmetrically porous polymers, cross-linked olefin polymers, hydrophobic or hydrophilic microporous homopolymers, copolymers or interpolymers having a reduced bulk weight and materials described 20

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in the U.S. U.S. Patent Nos. 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, to British Patent Nos. 1,126,849 and in Chem. .

Abst., Vol. 71, 4274F, 22572F, 22573F, 1969.

5

Additional microporous materials include poly (urethanes), cross-linked, chain-extended poly (urethanes), microporous poly (urethanes) in the U.S. Patent No. 3,524,753, poly (imides), poly (benzimidazoles), collodion (cellulose nitrate with 11% nitrogen), regenerated proteins, semi-solid crosslinked poly (vinyl pyrrolidone), microporous materials made by diffusion of polyvalent cations into polyelectrolyte sols, such as in the US U.S. Patent No. 3,565,259, anisotropic permeable microporous materials of ionically associated polyelectrolytes, porous polymers formed by the simultaneous precipitation of a polycation and a polyanion as described in U.S. Pat. U.S. Patent Nos. 3,276,589, 3,541,055, 3,541,066 and 3,546,142, poly (styrene) derivatives such as poly (sodium styrene sulfonate) and poly (vinylbenzyltrimethyl aromonium chloride), the microporous materials described in US U.S. Patent No. 3,615,024 and U.S. Pat. U.S. Patent 3,646,178 and 3,852,224.

The microporous forming material used for the purpose of the invention includes the embodiment in which the microporous layer is formed in situ by means of a pore former which is removed by dissolution or leaching to form the microporous layer during use of the system. The pore former may be a solid or a liquid. The term liquid comprises in the present invention semi-solids and viscous liquids. The pore formers may be inorganic or organic. The pore formers suitable according to the invention include pore formers which can be extracted without any chemical change in the polymer. The pore forming solids have a size 35 of approx. 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,

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21 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 ferric chloride, ferrous sulfate,

zinc sulphate, cuprichloride, manganese fluoride, manganese fluorosilicate S

and the like. The pore forming agents include organic compounds such as polysaccharides. The polysaccharides include the sucrose sucrose, glucose, fructose, mannitol, mannose, galactose, aldohexose, altrose, talose, sorbitol, lactose, monosaccharides and disaccharides. In addition, organic aliphatic and aromatic oils and solids including diols and polyols, as exemplified by polyhydric alcohols, poly (alkylene glycols), polyglycols, alkylene glycols, poly (a-oj) alkylene diol esters or alkylene glycols and the like; water-soluble cellulose polymers such as hydroxy lower alkyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, methyl ethyl cellulose, hydroxyethyl cellulose and the like; water-soluble polymers such as polyvinylpyrrolidone, sodium carboxymethyl cellulose and the like. The pore forming agents are 2Q non-toxic, and upon removal from the layer, channels form through the layer. In a preferred embodiment, the non-toxic pore forming agents are selected from the group consisting of inorganic and organic salts, carbohydrates, polyalkylene glycols, poly (au>) alkylene diols, esters of alkylene glycols, glycols and water-soluble cellulose polymers useful for formation. of a microporous layer in biological environments.

When the polymer forming the layer contains more than 25% by weight of a pore forming agent, the polymer is usually for the purpose of the present invention a precursor microporous layer which, upon removal of the pore forming agent, provides a layer which is substantially microporously, at concentrations less than this, the layer behaves like a semipermeable layer or membrane.

The term passage as used herein encompasses agents and methods suitable for releasing the agent or drug.

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the agent from the osmotic system. The term includes opening, orifice, hole or bore through the semipermeable wall or the layered wall. The passage may be formed by mechanical piercing, laser piercing or by decomposition of a degradable element such as a gelatin plug in the area in which it is used. A detailed description of osmotic passages and the maximum and minimum dimensions of a passageway are described in U.S. Pat. U.S. Patent 3,845,770 and 3,916,899.

The osmotically active compounds which can be used for the purpose of the present invention include inorganic and organic compounds having an osmotic pressure gradient over a semipermeable wall, or over a semipermeable microporous layered wall, against an outer liquid. The osmotically active compounds (together with the osmotic polymers) suck liquid into the osmotic composition and thereby make available in situ liquid for suctioning an osmotic polymer to enhance its expansion and / or available to form a solution or suspension containing a 20 active compound for delivery thereof from the osmotic preparation. The osmotically active compounds are also known as osmotically effective solutes or osmagents (osmotic agents).

The osmotically active compounds are used by mixing them with an active compound and an osmotic polymer to form a solution or suspension containing the active compound that is osmotically delivered from the composition. The term limited solubility, as used herein, means that the active compound has a solubility of approx. less than 5% by weight in the aqueous liquid present in the environment. The 30 osmotic solutes are used by homogeneous or heterogeneous mixing of the solute with the active compound or osmotic polymer and then by introducing them into the vessel. The solutes and osmotic polymers draw liquid into the vessel to form a solution of solute in a gel supplied from the system which simultaneously transports unresolved and dissolved active compound to the exterior of the system. Osmotic 23

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effective solutes used for the latter purpose include magnesium sulfate, magnesium chloride, sodium chloride, potassium chloride, 1 in thium chloride, potassium sulfate, sodium sulfate, 1 in thium sulfate, potassium phosphate, d-mannitol, urea, inositol, magnesium, 5 raffinose, sucrose, glucose, α-d-lactose monohydrate and mixtures thereof. The amount of osmotic agent in the compartment will usually be from 0.01% to 30% or more in the first agent and usually from 0.01 to 40% or more in the second compartment.

10

The solute is initially found in excess, and it can be in any physical form compatible with the active compound and the osmotic agent. The osmotic pressure of saturated solutions of various osmotically effective compounds and 15 of mixtures of compounds at 37 ° C in water are given in Table I. In the table, the osmotic pressure is n 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 rules, the vapor pressure ratio is converted to osmotic pressure difference. Table I lists osmotic pressures from 20 ATM to 500 ATM; of course, the invention includes the use of lower zero osmotic pressures and higher osmotic pressures than those listed in Example I. The osmometer used for the present measurements is known as Model 320B, Vapor Pressure Osmometer which manufactured by Hewlett Packard Co., Avonadale, Penna.

30 35 24

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Table I.

Compound Osmotic pressure or mixture _ATM___ ® lactose-fructose 500 dextrose-fructose 450 sucrose-fructose 430 mannitol-fructose 415 sodium chloride 356 fructose 355 lactose-sucrose 250 potassium chloride 245 lactose-dextrose 225 mannitol-dextrose 225 dextrose 225 dextrose 82 potassium sulfate 39.,. mannitol 38 sodium phosphate tribasic · 12 ^ 0 36 sodium phosphate dibasic-7H-C; 31 Sodium Phosphate Dibasic · 12Η20 31 Sodium Phosphate Dibasic Vanity 29 Sodium Phosphate Monobasic · Η20 28 20 The osmotic polymers suitable for forming the first osmotic material / and also suitable for forming the second osmotic material are osmotic polymers which have liquid oak suction which has liquid oak. The osmotic polymers are swellable, hydrophilic polymers that interact with water and aqueous biological fluids and swells or even in an equilibrium state. The osmotic polymers have the ability to swell in water and retain a noticeable amount of the absorbed water in the polymer structure. The osmotic polymers swell or expand to a very high degree, usually exhibiting a 2 to 50 times volume increase. The swellable hydrophilic polymers in a presently preferred embodiment are readily crosslinked, such crosslinks being formed by covalent or ionic bonds. The osmotic polymers may be of plant, animal or synthetic origin. The osmotic polymers are hydrophilic polymers. Hydrophilic polymers suitable for the present purpose include poly (hydroxyalkyl methacrylate) having a molecular weight of 30,000 to 5,000,000;

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25 poly (vinylpyrrolidone) having a molecular weight of 10,000 to 360,000; anionic and cationic hydrogels; polyelectrolytkomplekser; poly (vinyl alcohol) having a low acetate residue, cross-linked with glyoxal, formaldehyde or glutaraldehyde and having a degree of polymerization from 200 to 30,000; a mixture of methyl cellulose, cross-linked agar and carboxymethyl cellulose; a water-insoluble, water-swell copolymer prepared by forming a dispersion of finely distributed copolymer of maleic anhydride with styrene, ethylene, propylene, butylene or isobutyl crosslinked with from 0.001 to about 100 0.5 mole of polyunsaturated crosslinking agent per moles of maleic anhydride in the copolymer; water-swollen polymers of N-vinyl lactams and the like.

Other osmotic polymers include polymers that form hydrogels such as Carbopol® acidic carboxy polymers having a molecular weight of 450,000 to 4,000,000; Cyanamer® polyacrylamides; crosslinked water-swelling-suitable intravenous maleic anhydride polymers; Good-rite® polyacrylic acid having a molecular weight of 20,000 to 200,000; Polyox® polyethylene oxide polymers having a molecular weight of 100,000 to 5,000,000; starch graft copolymer-lymere; Aqua-Keeps® acrylate polymer; diester crosslinked PClyglucan and the like. Representative polymers forming hydrogels are known. from the U.S. patent specification no.

No. 3,865,108, U.S. U.S. Patent No. 4,002,173 and U.S. Pat. U.S. Patent No. 4,207,893 and in the Handbook of Common Polymers, by Scott and Roff, published by the Chemical Rubber Company, Cleveland, Ohio. The amount of osmotic polymer in the first osmotic material is approx. 0.01 to 90% and the amount of osmotic polymer in the second osmotic reactor is 15 to 95%. In a presently preferred embodiment, the molecular weight of the osmotic polymer in the second osmotic neighbor is greater than the molecular weight of the osmotic polymer in the first osmotic material.

Determination of liquid suction of osmotic polymer for a given polymer can be carried out by the method described below.

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26 way. A 12.7 mm (1/2 ") round disc equipped with a 12.7 mm diameter stainless steel plug is charged with a known amount of polymer with the plugs projecting at both ends. The plugs and die was placed in a Carver-5 press with plates between 200 and 300 ° F. A pressure of 10,000 to 15,000 psi was applied to the plugs. After 10 to 20 minutes of heat and pressure, the electrical heating of the plates was switched off and tap water was passed through the plates The resulting 12.7 mm slices were placed in an air-bed coating apparatus loaded with 1.8 kg of saccharide cores and coated with cellulose acetate having an acetyl content of 39.8% dissolved in 94: 6 w / w, CH 2 Cl 2 / CH 3 OH to give The coated systems were dried overnight at 50 [deg.] C. The coated disks were immersed in water at 37 [deg.] C. and periodically removed for a gravimetric determination of aspirated water. calculated by using the water transfer constant f or cellulose acetate after normalization of membrane surface area suction values and thickness. The polymer used in this assay was the sodium derivative of Carbopol® 934 polymer prepared according to the method of B.F. Goodrich Service Bulletin GC-36, "Car-bopol® Water-Soluble Resins", page 5, published by B.F. Goodrich, Akron, Ohio.

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

(R) The weight gain for Na Carbopol ^ 934 is given by Equation 1 as follows: The weight gain is equal to 0.359 + 0.665t -2 0.00106t, where t is the elapsed time in minutes. The velocity of the water flux at any time will be equal to the slope of the 35 line given by the following equations 18 and 19:

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27 dy _ d (0f 359 + 0.665t - 0.00106t2) / lnl dt dt 5 ft = ° '665 "0.00212t (19)

To determine the initial velocity of the water flux, the derivative is determined at t-0 and dy / dt = 0.665 µΐ / hr, which is equal to the coefficient b. Then normalize the suction rate for time, membrane surface area and thickness, and the membrane permeability constant for water, K , π can be determined according to the following equation 20: Κπ = 0.665 μΐ / min. x <—-) x (fooo µ1) (-1 —-?> (20) 2. foo cm 15 4 2 with K = 1.13 x 10 cm / hr. The value (π) of NaCl was determined with a Hewlett -Packard vapor pressure osmometer to 345 atm + 10%, and the K value of cellulose acetate used in 2Q this experiment, calculated from NaCl aspiration values, was determined at 1.9 x 10 7 cm 2 / h * atm.

By inserting these values into the calculated Κπ expression (1.9 x 10 7 / cm2 / h'atm) (i) = 1.13 x 10 4 cm2 / hour, π = 600 gives atmosphere at t = 0. As a method of assessing ef-

& O

For the efficiency of a polymer for the duration of the zero-order 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 starting from the axis with percent weight gain will be equal to the initial value of dy / dt calculated at t = 0, with the y-intercept c defining the linear swell time with (dy / dt) ^ = 0.665, and the y cut = 0.359, giving y = 0.665t + 0.359. To determine when the value of the cumulative water uptake is 90% below the initial rate, the following expression for t 28 is solved.

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0.9 = atlj_bt_Lc_ = ΔΜ_ 0.9 (21) 'bt + c w 5 -0.00106 t2 + 0.665 t + 0.359 _ n n _

-07665t "0.359" "" ϋ '*' ° 9 1 J

of which is obtained for t -0.00106t2 + 0.0665t + 0.0359 = 0 10. -0 -0.0665 + Γ (0.0665) 2 - 4 (-0.00106) (0.0359)] 1/2 (23) r '2 (-0.00106), resulting in t = 62 min. and the weight gain is 15 -0.00106 (62) 2 + (0.655) (62) + 0.359 = 38 µΐ, and with the sample weight initially = 100 mg, obtain (Aw / w) 0.9 x 100 = 38 %. The results are shown in FIG. 8 as a graphical representation of the values. Other methods available for examining the hydrogen-solution interface include rheological 2o analysis, viscomosimetric analysis, elliptical geometry, contact angle measurements, electrokinetic determinations, infrared spectroscopy, optical microscopy, interface charge morphology and microscopic examination of an effective composition.

The term active compound as used herein includes any beneficial agent or compound which may be delivered from the composition to provide a beneficial and useful result. The active compound can be insoluble to highly soluble in the outer liquid entering the composition and it can be mixed with an osmotically active compound and an osmotic polymer. The term active compound includes pesticides, herbicides, germicides, biocides, algicides, rodenticides, fungicides, insecticides, antioxidants, plant growth promoters, plant growth inhibitors, preservatives, disinfectants, sterilizers, catalysts, chemical reactants, chemical reactants,

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sterilizing agents, fertility inhibitors, fertility promoters, air purifiers, microorganisms attenuators and other compounds that benefit the environment being used.

In the specification and accompanying claims, the term active compound includes a drug, and the term drug includes any physiologically or pharmacologically active substance that produces a local or systemic effect in animals, including warm-blooded mammals, humans and primates, birds, domestic animals. , animals for sports and on farms, laboratory animals, fish, reptiles and animals in zoos. The term physiological, as used herein, denotes the administration of a drug to produce normal states and functions. The term pharmacologically refers to 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. The term drug formulation as used herein means that the drug is in the room mixed with an osmotic solute or an osmotic polymer and, if applicable, with a binder and a lubricant. The active drug that can be delivered includes inorganic and organic compounds including drugs acting on the peripheral nerves, adrenergic receptors, cholinergic receptors, nervous system, skeletal muscles, cardiovascular system, smooth muscle, blood circulation system, synoptic sites, neuroeffector junction sites, the endocrine system, hormone systems, the immune system, the organ system, the reproductive system, the skeletal system, the autocoid systems, digestive and excretion systems, autocoids and histamine inhibition systems. The active drug that can be delivered to act on these animal systems includes reducing agents, insomnia, sedatives, psychosuppressants, sedatives, anticonvulsants, muscle relaxants, antiparkinson agents, painkillers, anti-inflammatory agents, local office

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anesthetics, muscle contraceptives, anti-microbial agents, antimalarial agents, hormonal agents, contraceptives, sympathomimetic agents, diuretics, anti-parasite agents, neo-plasma, hypoglycemics, eye drugs, electrolytes, diagnostic agents and cardiovascular drugs.

Examples of highly water-soluble drugs that can be provided by the compositions of the present invention include prochlorperazine disylate, ferrous sulfate, 10 aminocaproic acid, potassium chloride, mecamylamine hydrochloride, procainamide hydrochloride, amphetamine hydrochloride, amphetamine sulfate, benzene sulfate -metrazine hydrochloride, bethanechol chloride, methacholine chloride, pilocarpine hydrochloride, atropine sulphate, methascopolamine bromide, isopropamide iodide, tridihexethyl chloride, phenformin hydrochloride, methylphenidate hydrochloride, oxprenolol hydrochloride, me

Examples of drugs that are poorly soluble in water and which can be delivered by the compositions of the present invention include diphenidol, meclizine hydrochloride, prochlorperazine maleate, phenoxybenzamine, thiethyl-perazine maleate, anisindone, diphenadione etheritrite, diphenadione etherthritite, titrate , acetazolamide, methazolamide, bendroflumethiazide, chlorpropamide, tolazamide, chloromadinone acetate, phenaglycodol, allopurinol, aluminum aspirin, methetrexate, acetylsulphisoxazole, erythromycin, progestins, ester estrogen acetate, corticosteroids, corticosteroids testerone, 170-estradiol, ethinylestradiol, prazosine hydrochloride, ethinylestradiol-3-methyl ether, prednisolone, 17β-hydroxy-progesterone acetate, 19-nor-progesterone, norgestrel, norethinone, norethiderone, progesterone, norgesterone, norethester .

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31

Examples of other drugs that may be provided by the osmotic preparation include aspirin, indomethacin, naproxen, phenoprofen, sulidac, dichlofenac, indoprofen, nitroglycerin, propranolol, metoprolol, valproate, oxprenolol, timolol, alinolene, ethanolol, athenolol imipramine, levodopa, chlorpromazine, reserpine, methyl-dopa, dihydroxyphenylalanine, pivaloyloxyethyl, ester of α-methyldopa hydrochloride, theophylline, calcium gluconate, ketoprofen, ibuprofen, cephalexin, erythromycol, procine, procine , phenoxybenzamine, α-blocking agents, calcium channel blocking drugs such as nifedipine, diliazene, verapamil, β-blockers and the like. The beneficial drugs are known in the field of Pharmaceutical Sciences, edited by Remington 14th Edition, 1979, published by Mack Publis-15 hing Co., Easton, Penna; The Drug, The Nurse, The Patient,

Including Current Drug Handbook, 1974-1976, by Falconer et al., Published by Saunder Company, Philadelphia, Penna .; and Medicinal Chemistry, 3rd Edition, Vols 1 and 2, by Burger, published by Wiley-Interscience, New York.

The drug may be in various forms such as uncharged 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, e.g. quaternary ammonium is used. Derivatives of drugs such as esters, ethers and amides can be used. A drug which is insoluble in water can be used in a form which is a water-soluble derivative thereof, to serve as a dissolved product and upon its release from the composition, it is converted by enzymes, hydrolyzed by the pH of the body. value or other metabolic processes to the original biologically active form. The active compound including drug may be present in compartment 35 together with a binder, dispersant, wetting agent, suspending agent, lubricant and dye. Repre- 32

DK 163910B

Sentents thereof include suspending agents such as acacia, agar, calcium carrageenan, alginic acid, algin, agarose powder, collagen, colloidal magnesium silicate, colloidal silica, hydroxyethyl cellulose, pectin, gelatin and calcium silicate, magnesium sulfate, intermediate agents such as polyvinyl acid, intermediates such as polyvinyl acid fatty amines, fatty quaternary ammonium salts and the like. The term drug formulation indicates that the drug is present in the compartment accompanied by an osmotic agent, an osmotic polymer, a binder, and the like. The amount of active compound in a preparation is usually from 0.05 ng to 5 g or more, with single compositions containing e.g. 25 ng, 1 mg, 5 mg, 125 mg, 250 mg, 500 mg, 750 mg, 1.5 and the like. The compositions can be administered once, twice or three times daily.

15

The solubility of an active compound in the liquid can be determined by known techniques. One method consists in preparing a saturated solution comprising the liquid plus the active compound as determined by analyzing the amount of active compound present in a certain amount of the liquid. A simple apparatus for this purpose consists of a medium-sized test tube fixed in an upright position in a water bath maintained at constant temperature and pressure in which the liquid and the agent are placed and agitated by means of a rotating glass coil.

After a given stirring period, a weighed amount of the liquid is analyzed and stirring is continued for a further period of time. If the assay shows no increase in dissolved active compound after successive stirring periods, in the presence of excess solid active compound in the liquid, the solution is saturated and the results taken as the product's solubility in the liquid. If the active compound is soluble, an added osmotically effective compound may not be necessary; if the agent has limited solubility in the liquid, an osmotically effective compound can be incorporated into the composition.

Several other methods are available for determining the solubility of an active compound in a liquid. Typical methods,

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33 used for the measurement of solubility is chemical and electrically specific conductivity. Details of various solubility determination methods are described in United States Public Health Service Bulletin, No. 67 of the Hygenic Laboratory; 5 Encyclopedia of Science and Technology, Vol. 12, pages 542 to 556, 1971, published by McGraw-Hill, Inc., and Encyclopedia Dictionary of Physics, Vol. 6, pages 547 to 557, 1962, published in Pergamon Press, Inc.

The osmotic composition of the invention is prepared by standard techniques. Eg. in one embodiment, the active compound is mixed with an osmotic agent and an osmotic polymer and pressed into a solid having dimensions corresponding to the internal dimensions of the space adjacent to the passage; 15 or the active compound and other ingredients to form the formulation and a solvent are mixed into a solid or a semi-solid by conventional methods such as ball milling, calendering, stirring or milling, and then pressed into a preselected form. Then, a layer of a material comprising an osmotic agent and an osmotic polymer is contacted with the active compound composition layer, and the two layers are surrounded by a semipermeable wall. The layering of the composition of the active compound and the osmotic agent / osmotic polymer can be performed by conventional two-layer plate pressing techniques. The wall can be applied by casting, spraying or by dipping the pressed molds into wall forming material. Another and presently preferred technique which can be used for wall application is the air-laying procedure. This procedure consists in suspending and tumbling the pressed compositions in an air stream and a wall-forming agent until the wall surrounds and coats the two pressed compositions. The procedure is repeated with a different layer forming agent to form a layered wall. The air bed procedure is described in U.S. Patent No. 2,799,241; J.

35 Am. Pharm. Assoc., Volume 48, pages 451-459, 1979, and Volume 49 of the same site, pages 82-84, 1960. Other standard manufacturing methods

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34 is described in Modern Plastics Encyclopedia, Volume 46, pages 62-70, 1969, and in Pharmaceutical Sciences, by Remington, 14th Edition, pages 1626-1678, 1970, published by Mack Publishing Co., Easton, Penna.

5

Examples of solvents suitable for preparing the laminates and layers include inert inorganic and organic solvents which do not adversely affect the materials and the finished layered wick. The solvents 2o broadly include elements selected from the group consisting of aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic compounds, aromatic compounds, heterocyclic solvents and mixtures thereof. Typical solvents include 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, ethyl ethylene dichloride, propylene dichloride, carbon tetrachloride, chloroform, nitroethane, nitropropane, tetrachloroethane, ethyl ether, isopropyl ether, cyclohexane, cyclooctane, benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, diethylene glycol and diethylene glycol water, acetone and methanol, acetone and ethyl alcohol, methylene dichloride and methanol and ethylene dichloride and methanol.

The following examples are illustrative of the present invention only.

30

Example 1

An osmotic delivery preparation prepared as a certain size osmotic shaped tablet and adapted for oral access to the gastrointestinal tract is prepared as follows: A first osmotic drug composition is prepared by aiming 355 g of poly (ethylene oxide) with an approximate 35

DK 163910B

200,000 molecular weight through a 40 mesh stainless steel screen, then 100 g of nifedipine is passed through the 40 mesh screen, 25 g of hydroxypropyl methyl cellulose is passed through the 40 mesh screen, and finally 10 g of potassium chloride is passed through the 40 mesh screen.

Then add all the sieved ingredients to the bowl of a laboratory mixer and mix the ingredients dry for 15-20 minutes to form a homogeneous mixture. Then a granulating liquid comprising 250 ml of ethanol and 250 ml of isopropyl alcohol is prepared and the granulating liquid is added to the mixing bowl; initially, 50 ml is sprayed into the bowl under constant mixing, then 350 ml of the granulation liquid is slowly added to the bowl and the moist mass is mixed for an additional 15-20 minutes. Then, the moist granules are passed through a 16 mesh screen and dried at room temperature for 24 hours, and the dry 15 granules are passed through a 16 mesh screen. Then, 10 g of magnesium stearate is added to the dried granules and the ingredients are blended for 20-30 minutes on a standard two-roll mill.

2 0

Then another osmotic material is prepared as follows:

Initially, 170 g of poly (ethylene oxide) having a molecular weight of 5,000,000 is sieved through a 40 mesh sieve, then 72.5 g of sodium chloride is passed through the 40 mesh sieve and the ingredients are added to a mixing bowl and mixed for 10-15 minutes . On it, a granulation liquid is prepared by mixing 350 ml of methanol and 150 ml of isopropyl alcohol, and the granulating liquid is added to the mixing bowl in two steps. First, 50 ml of the granulation liquid is sprayed into the bowl under constant mixing, then 350 ml of the granulation liquid is slowly added to the bowl, and the moist mixture is mixed for 15-20 minutes for a homogeneous mixture. Then, the moist mixture is passed through a 16 mesh screen, spread on a stainless steel tray and dried at room temperature at 22.5 ° C for 24 hours. The dried mixture is passed through a 16 mesh sieve, then rolled with 5 g of magnesium stearate on a two-roll mill for 20-30 minutes.

36

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A number of drug cores are prepared by pressing the two compositions onto a Manesty Layer press. The drug-containing material is fed to the mold casting hole and pressed into a solid layer. Then the second osmotic material is introduced into the cavity over the compressed layer and pressed into a solid layer to form a two-layered drug core.

The drug cores are then coated with a semipermeable wall-forming material comprising 95 g of cellulose acetate with an acetyl content of 39.8% and 5 g of poly (ethylene glycol) 4000 in a solvent comprising 1960 ml of methylene chloride and 820 ml of methanol. The drug cores are coated with the semipermeable wall-forming material until the wall surrounds the drug core. A Wurster air bearing coating apparatus is used to form the semi-permeable wall. The coated cores are then spread on a tray and the solvent is evaporated in a circulating air oven at 50 ° C for 65 hours. After cooling to room temperature, a 0.26 mm diameter passage is laser drilled through the semipermeable wall and connects the exterior of the osmotic composition to the drug-containing material.

The osmotic preparation weighed 262 mg and contained 30 mg of drug in the first material weighing 150 mg, the second material weighing 75 mg, and the semipermeable wall weighing 37 mg. The first osmotic material in the osmotic composition comprises 25 mg of nifedipine, 106 mg of poly (ethylene oxide), 3 mg of potassium chloride, 7.5 mg of hydroxypropyl methylcellulose and 3 mg of magnesium stearate. The other osmotic material comprises 51 mg of poly (ethylene oxide), 22 mg of sodium chloride and 1.5 mg of magnesium stearate. The device has a diameter of 8 mm, a surface area of 1.8 cm, and the semi-permeable wall is 0.17 mm thick. The cumulative amount of released drug agent is given in FIG. 9th

Example 1A.

Osmotic delivery systems are prepared with a first material comprising 25-100 mg of nifedipine, 100-325 mg of poly (ethylene oxide) having a molecular weight of 200,000, 2-10 mg of potassium chloride, 37

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5-30 mg of hydroxypropyl methylcellulose and 2-10 mg of magnesium stearate, and another material comprising 30-175 mg of poly (ethylene oxide) having a molecular weight of 5,000,000, 20-75 mg of sodium chloride and 1-5 mg of magnesium stearate . The procedure of Example 5 1 is repeated to prepare osmotic compositions having the following compositions: (a) an osmotic composition having a first material. comprising 60 mg of nifedipine, 212 mg of poly (ethylene oxide), 6 mg of potassium chloride, 15 mg of hydroxypropylmethyl cellulose and 6 mg of magnesium stearate, and another material comprising 102 mg of poly (ethylene oxide), 44 mg of sodium chloride and 60 mg of magnesium stearate, and (b) an osmotic composition with a first material comprising 90 mg of nifedipine, 318 mg of poly (ethylene oxide), 9 mg of potassium chloride, 22.5 mg of hydroxypropyl methylcellulose and 9 mg of magnesium stearate, and a second material comprising 102 mg poly (ethylene oxide), 66 mg sodium chloride and 4.5 mg magnesium stearate. In one embodiment, the osmotic composition described in (a) and (b) further comprises a pulse coating on the outer semipermeable wall. The pulse coating comprises 30 mg of nifedipine and hydroxypropylmethyl cellulose. I work; in the liquid environment employed, the pulse coating provides immediate drug availability for immediate drug therapy.

Example 2.

25

The procedure of Example 1 is repeated under all conditions as previously described except that the drug in the room is replaced with etelarot selected from the group consisting of a / 3 blocker, anti-inflammatory, analgesic, sympathomimetic, antiparkinsonian or a diuretic drug.

Example 3

An osmotic therapeutic preparation controlled and continuous oral release of the beneficial calcium channel blocking drug verapamil is prepared as follows: 90 mg verapamil,

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38 50 mg sodium carboxyvinyl polymer having a molecular weight of 200,000 and sold under the trade name Carbopo® polymer, 3 mg sodium chloride, 7.5 mg hydroxypropylmethylcellulose and 3 mg magnesium stearate are thoroughly mixed as described in Example 1 and pressed 5 in a Manesty press with a 7.9 mm (5/16 ") piston, using a 1-1 / 2 ton press head to prepare a layer of the drug composition. Then 51 mg of the carboxy-vinyl polymer with a molecular weight of 3,000 is mixed. 000, sold under the trade name Carbopol® polymer, 22 mg sodium chloride 10 and 2 mg magnesium stearate thoroughly and added to the Manesty press and pressed to form a layer of expandable osmotic material - in contact with the osmotic drug composition layer.

Then, a semi-permeable wall is formed by mixing 170 g of cellulose acetate with an acetyl content of 39.8% with 900 ml of methylene chloride and 400 ml of methanol, and spray coating the double-layered space-forming element in an air bearing machine until a 0.13 mm (5.1 mil) thick semipermeable wall surrounds the room · The 20 coated composition is dried, for 72 hours at 50 ° C, and then a 0.2 mm (8 mil) passage is drilled through the semipermeable wall to connect the layer, containing the drug, with the exterior of the composition for releasing drug over a long period of time.

25

Example 4

The procedure of Example 3 is repeated under all conditions as described except that the drug in the osmotic preparation is fendiline, diazoxide, prenylamine or diltiazene.

Example 5

An osmotic therapeutic composition for delivery of the drug sodium diclofenac for use as an anti-inflammatory agent is prepared by first pressing in an Manesty press an osmotic agent.

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39 pharmaceutical drug composition containing 75 mg of sodium diclofenac, 300 mg of sorbitol, 30 mg of sodium bicarbonate, 26 mg of pectin, 10 mg of polyvinylpyrrolidone and 5 mg of stearic acid and to press the composition into a solid layer cavity. Then, the cavity is filled with another material which produces greater strength comprising 122 mg of pectin with 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 to form a second layer in contact with the first layer . The second layer 1 ° had a density of 1.28 g / cm and a hardness of more than 12 kg. Next, the core is surrounded by the two layers with a semi-permeable wall comprising 85 g of cellulose acetate having an acetyl content of 39.8% and 15 g of polyethylene glycol 4000, 3 w / w% solids in a wall-forming solvent comprising 1960 15 ml of methylene chloride and 819 ml of methanol. The coated composition is dried for 72 hours at 50 ° C and then a 0.26 mm diameter passage is laser drilled through the wall. The semipermeable 2 wall is 0.1 mm thick, the composition has an area of 3.3 cm, and it has an average drug release rate of 5.6 mg per day. hour over a 12 hour period. The cumulative released amount is illustrated in FIG. 10. The small vertical lines denote the minimum and maximum drug release for five systems measured at that time.

25

Example 5A.

The procedure of Example 5 is followed to provide an osmotic composition wherein the compartment contains a mixture of 30 osmotic polymers. The compartment contained a first material weighing 312 mg and comprised of 48% sodium diclofenac drug, 38% poly (ethylene oxide) osmotic polymer having a molecular weight of 200,000, 10% poly (ethylene glycol) osmotic polymer having a molecular weight of 20,000, 2% sodium chloride and 2% magnesium stearate; and another material weighing 150 mg and consisting of 93% poly (ethylene oxide) having a molecular weight of 5,000,000, 5% sodium chloride and 2% magnesium stearate.

Example 6

DK 163910B

In this example, measurements of the increase in osmotic pressure are made for a variety of materials comprising an osmotic agent 5 and an osmotic polymer to show the advantage of the use provided by the invention. The measurements are made by measuring the amount of water sucked in through the semipermeable wall of a bag containing an osmotic agent or osmotic polymer or material comprising an osmotic agent and an osmotic polymer. The semipermeable wall of the bag is formed of cellulose acetate with an acetyl content of 39.8%. The measurements are made by weighing the dry components of the semipermeable bag, followed by a weighing of the semipermeable bag after aspiration, after the bag is in a water bath 15 at 37 ° C for various periods of time. The increase in weight is due to water suction through the semipermeable wall caused by the osmotic pressure gradient across the wall. The osmotic pressure curves are illustrated in FIG. 11. In FIG. 11, the curved line of the triangles represents the osmotic pressure of poly (ethylene) oxide having a molecular weight of 5,000,000? the curved line of the circles represents the osmotic pressure of a material comprising poly (ethylene) oxide having a molecular weight of 5,000,000 and sodium chloride, the constituents being present in the composition of 9.5 parts osmotic polymer to 0.5 parts osmotic agent; the curved line of squares represents a material comprising the same osmotic polymer and osmotic agent in the ratio of 9 parts osmotic polymer to one part osmotic agent; the curved line of hexagons represents the same material comprising the osmotic polymer and osmotic agent in the 8 parts to 2 parts ratio; and the dotted line represents the osmotic agent sodium chloride. The mathematical calculations are made using the formula dw / dt = A (ΚΔπ) / h, where dw / dt is the rate of water suction with time, A is the area of the semipermeable wall, and K is the coefficient of permeability. In addition, W 2 / W in FIG. 11 the amount of suction n p water divided by the weight of osmotic polymer plus osmotic agent.

Example 7

41

DK 163910 B

An osmotic therapeutic composition for delivery of sodium di-clofenac is prepared by sieving through a 40 mesh sieve a material comprising 49% sodium diclofenac, 44% poly (ethylene) oxide having a molecular weight of 100,000, 2% sodium chloride and 3% hydroxypropylmethyl cellulose and then mixing the sieved material with an alcohol solvent used in the ratio of 75 ml of solvent to 100 g of granulation.

The moist granulation is sieved through a 16 mesh screen, dried at room temperature for 48 hours under vacuum, passed through a 16 mesh screen and mixed with 2% 80 mesh screened magnesium stearate. The material is pressed as described above.

Then, a material comprising 73.9% pectin having a molecular weight of 90,000 to 130,000, 5.8% microcrystalline cellulose, 5.8% polyvinylpyrrolidone, 14.3% sodium chloride and 2% sucrose is passed through a 40 mesh screen, mixed with a organic solvent in 100 ml solvent to 100 g granulation 20 for 25 minutes, passed through a 16 mesh sieve, dried for 48 hours at room temperature under vacuum and again passed through a 16 mesh sieve, mixed with 2% magnesium stearate and then pressed onto it. compressed layers, described in the previous section. The bilayered drug core is coated by immersion in a wall-forming composition comprising 80% cellulose acetate having an acetyl content of 39.8%, 10% polyethylene glycol 4000 and 10% hydroxypropylmethylcellulose. A passage is drilled through the wall associated with the drug-containing material. The diameter of the passenger is 0.38 mm. The theoretical cumulative release profile of the composition is depicted in FIG. 12. FIG. 13 depicts the theoretical release rate in mg per ml. hour for the osmotic preparation.

35

Example 8.

42

DK 163910 B

The procedure of Example 7 is repeated under all conditions as described except that the osmotic polymer 5 in the drug composition is a polyoxyethylene-polyoxypropylene block copolymer having a molecular weight of approx. 12,500.

Example 9

An osmotic composition is prepared by the above procedures. The composition of this example comprises a single material comprising 50% sodium diclofenac, 46% poly (ethylene) oxide having a molecular weight of 100,000, 2% sodium chloride and 2% magnesium stearate. The composition has a semipermeable wall comprising 90% cellulose acetate comprising 39.8% acetyl and 10% polyethylene glycol 4000. The cumulative released amount for this composition comprising the individual material is 40% of the composition. which includes two materials. The cumulative released amount is illustrated in FIG. 14th

20

Example 10.

The average in vivo and in vitro cumulative release of diclofenac sodium from an osmotic composition comprising a first osmotic material comprising 75 mg of diclofenac sodium, 67 mg of poly (ethylene) oxide having a molecular weight of 100,000, 3.0 mg of sodium chloride, 4.5 mg of hydroxypropyl methylcellulose and 3.0 mg of magnesium stearate; another osmotic material distant from the release passage comprising 51 mg of poly (ethylene) oxide having a molecular weight of 5,000,000, 22.5 mg of sodium chloride and 1.5 mg of magnesium stearate, and surrounded by a semipermeable wall comprising 90 % cellulose acetate with an acetyl content of 39.8% and 10% polyethylene glycol 4000 was measured 3g in vivo and in vitro in laboratory dogs. The amount of drug released at various times in vivo was determined by administering a series of preparations to the animal and by

DK 163910 B

43 measure the released amount from the corresponding composition at the appropriate residence time. The results are depicted in FIG. 15, in which the circles with the line pieces are the average cumulative releases in vitro, and the triangles with the line 5s are the average cumulative releases in vivo.

The average cumulative in vivo and in vitro releases of a nifedipine-containing preparation were measured as described immediately above. The osmotic composition comprising a material adjacent to the passage comprising 30 mg of nifedipine, 106.5 mg of poly (ethylene) oxide with a molecular weight of 200,000, 3 mg of potassium chloride, 7.5 mg of hydroxypropylmethyl cellulose and 3 mg of magnesium stearate; a material removed from the passage comprising 52 mg of poly (ethylene) oxide having a molecular weight of 15,000,000, 22 mg of sodium chloride and 1.5 mg of magnesium stearate, and a semipermeable wall comprising 95% cellulose acetate having an acetyl content of 39.8% and 5 % hydroxypropyl methyl cellulose.

FIG. 16 depicts the release from the system. In FIG. 16, the circles represent the cumulative release in vivo, and the tri-20 edges represent the average cumulative release in vitro.

Example 11.

The process of Example 10 is followed for the preparation of an osmotic therapeutic delivery system comprising: a first or a drug composition weighing 638 mg and consisting of 96% cephalexinium chloride, 2% Poviclon (polyvinylpyrrolidone) and 2% magnesium stearate; a second or osmotically derived material weighing 200 mg and consisting of 68.5% poly (ethylene oxide) having a molecular weight of 5 x 10,, 29.5% sodium chloride and 2% magnesium stearate; a semipermeable wall weighing 55.8 mg, consisting of 80% cellulose acetate having an acetyl content of 39.8%, 14% polyethylene glycol 4000 and 14% hydroxypropylmethylcellulose; 35 and an osmotic orifice having a diameter of 0.039 mm. The composition has an average release rate of ca. 54 mg per hour over a period of 9 hours.

Claims (10)

An osmotic composition for delivering a therapeutically active compound at a controlled rate comprising: a) a wall comprising a material permeable to the passage of an outer fluid surrounding said wall forming and b) a compartment, c) a first material in the compartment comprising a therapeutically active compound, d) a second material in the compartment, and e) a passage in the wall which is in contact with the first material and the exterior side of the osmotic composition for delivery of the therapeutically active compound from the osmotic composition. , characterized in that said first material in the room comprises, in addition to the therapeutically active compound, an osmotic polymer and said second material in the room comprises an osmotic agent and an osmotic polymer, which second in function absorbs liquid in the osmotic polymer. preparation, expands and drives the first material out of the osmotic composition. DK 163910 B Osmotic composition according to claim 1, characterized in that the wall forming material comprises a component selected from the group consisting of cellulose acetate, cellulose diacetate, cellulose triacetate, ethyl cellulose, cellulose acetate butyrate, cellulose acetate cellulose propylate, hydroxypropylate, hydroxypropylate, hydroxypropylate, hydroxypropylate, hydroxypropylate methyl ethyl cellulose and mixtures thereof. 3. An osmotic composition according to claim 1, characterized in that the first material is in space as a layer and the second material is in space as a layer. Osmotic composition according to claim 1, characterized in that the first material is adapted to suck outer liquid through the wall into the compartment and the second material is adapted to simultaneously suck external fluid through the wall into the compartment. 5. An osmotic composition according to claim 1, characterized in that the osmotic polymer contained in the second material has a molecular weight greater than the molecular weight of the osmotic polymer contained in the first material. An osmotic composition according to claim 1, characterized in that the wall is a laminate comprising a semipermeable layer and a microporous layer. Osmotic composition according to claim 1, characterized in that the material forming the wall contains polyethylene glycol. Osmotic composition according to claim 1, characterized in that the osmotic polymer in the first material is poly (ethylene oxide). 3 8 DK 163910 B An osmotic composition according to claim 1, characterized in that the osmotic polymer in the second material is poly (ethylene oxide). 5 Osmotic preparation according to claim 1, characterized in that the active compound is drugs selected from non-fedipine, verapamil, diltiazem, diclofenac, propranolol, proszine, prazosin, ibuprofen, ketoprofen, haloperidol, indomethacin and cephalexin. 15 20 25 30 35