DE3509743A1 - DELIVERING DEVICE FOR RELEASING AN ACTIVE SUBSTANCE - Google Patents

Description

PATENTANWÄLTE d * -ing. pramz vjestbopf

WUESTHOFF - ν. PECHMANN - BEHRENS - GOETZ ^{DR FH} ' ^L " ^rDA ™ ^{ESTH0FI <}

DIPL.-ING. GERHARD PULS (l95i'I97l) EUROPEAN PATENTATTORNEYS d.pl.-cheu. _D r., Fke, he _R r from pechmann DR.-ING. DIETER BEHRENS DIPL.-ING .; DIPL ₁ -VIRTSCH ₁ -INp. RUPERT GOETZ

LA-58 960 3509743 D-8000 MUNICH 90

Note: Alza Corp. Schweigerstrasse 2

phone: (089) 66 20 ji

TELEGRAM: PROTECTPATENT TELEX: 5HO7O

fax; via (089) 2 71 60 63 (in)

description Dispensing device for releasing an active ingredient

The invention relates to a new and inexpensive dispenser (drug dispenser). The dispenser comprises a semipermeable wall which at least partially surrounds (a) an inner chamber or (b) an inner one Capsule shell, wherein in (a) or (b) in each case an active substance preparation which responds to the temperature and an expandable one Driving agent is included. The parts forming the delivery device work together to release the active ingredient Substance to an application environment at a controlled rate over time.

Dispensing devices or drug dispensers for release an active ingredient to an application environment are known. For example, U.S. Patent No. 3,760,984 describes a dispenser that consisting of a container that shrinks when heated and has an osmotically soluble on its outside A fabric and a layer facing away from the container made of a liquid permeable polymer. The levy * device has a stopper for filling the container.

The dispensing device is powered by drawing liquid into the device, causing the soluble Substance dissolves and forms a solution that exerts pressure on the shrinkable container and causes the-r

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water shrinks and releases active ingredient from the device. In US-PS 3,865,108 a dispensing device is described, Consists of an inner piece of pipe or tube that can collapse and contains a drug and is arranged in a part made of a swellable material. The device releases the active ingredient or the drug free in that the base part and other parts suck in liquid from the environment, thereby expanding and compress the piece of tubing, thereby releasing the medicine. in U.S. Patent 3,971,376 discloses a delivery device consisting of a capsule with uniform walls of a cross-linked gel which swells in liquids. A textile material is embedded in the material to give it strength and the To largely reduce problems caused by the poor mechanical properties of the materials and which show up when the liquid is aspirated to drive the dispensing device. U.S. Patent 3,887,790 relates to one Improvement of an osmotic delivery device comprising a conduit for filling a pouch in the device.

The device is powered by an osmotically active solute, the liquid in the device sucked in, which in turn exerts a hydraulic pressure against the bag and causes it to be pressed inward 5 and thereby releases active ingredient from the device. In US-PS 3,995,631 a pouch is described which on on the outside a layer of an osmotically soluble substance and on the side facing away from the bag a wall which partly consists of a material controlling the liquid passage. When used, a solution of the soluble forms Substance that compresses the bag and thereby causes the active substance to be released from the bag. US Pat. No. 4,320,758 discloses a dispensing device consisting of a flexible bag of a casing from a

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Dispersion of an osmotically active soluble substance in a soluble polymer and an outer wall permeable to liquid. The dispenser deploys drug freely, in that the casing draws water into the space between the outer wall and the bag and thereby hydraulic pressure exerts on the bag which causes the bag to be compressed and active ingredient releases. U.S. Patent 4,350,271 relates to a liquid dispenser which operates so that water is in ο a mass is sucked in, which is opposite to a lipophilic Expands fluid that is released through an outlet port.

While the above delivery devices are suitable to release numerous active ingredients to the application environment and while making an economic advance represent in the field of the release of active ingredients, it is clear to those skilled in the art that this Vorrichr can be improved even further. For example, if a dispenser were available, the first consists of an inner capsule which makes the dispensing device easier and better and cheaper to manufacture becomes possible and if such a device did not include a flexible bag and fabric and thereby the The number of steps to manufacture such a capsule and the number of parts required would be reduced such a dispenser was immediately adopted and represents a significant advance. If further possible would be to provide a device in which it is no longer necessary to only use the active ingredient in the form of To release solutions or suspensions, such a dispenser would also be based on scientific, medical and economic area are accepted immediately.

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It is therefore an object of the invention to provide a dispensing device for the release of active ingredients to all possible environments. This device aims to provide all of the necessary Components contained in the liquid environment start releasing by themselves and propel themselves, easily be manufactured and be able to deliver active substances to animals, including humans, and other 'biological' and non-biological application environments. The dispensing device may contain a temperature sensitive hydrophobic mass, comprising insoluble to soluble drugs, wherein the temperature sensitive composition is responsive to temperature the biological environment changes its shape and becomes liquid, semi-solid or the like, whereby it is easily removed from the Device is delivered. The device initially has an inner capsule arrangement which facilitates its manufacture and cheaper, thereby increasing the applicability of the device. The dispensing device of the invention comprises a Lumen or a cavity containing a temperature-sensitive mass, an expandable part or. Means that with the temperature-0 sensitive mass is arranged in parallel, an inner capsule containing the mass and the part in the cavity of the Capsule, an outer semipermeable wall surrounding at least a portion of the capsule and a passage through which the device the mass gives off through a combination of physicochemical processes, in that the mass melts and becomes liquid or semi-solid or the like and a (immiscible) interface between the mass and the expanding Part is retained and the expanding part swells and expands into the space occupied by the mass and dispensing a corresponding amount of the mass from the device. The device is initially empty until it is filled with a solid mass is filled, which liquefies at elevated temperatures. It can then increase the mass over a period of time

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Space in a complete pharmaceutical dosing program, with intervention only to start and stop the program. The delivery device may contain active ingredients contained in a temperature sensitive lipophilic pharmaceutically acceptable carrier which, in the presence of energy absorbed from the biological environment of use, melts into a releasable mass which is harmless, thereby substantially avoiding irritation to mammalian tissue and interaction with mammalian proteins will. The osmotic delivery device can contain a eutectic agent of at least two components and at least one drug, the melting point of which corresponds essentially to the body temperature of a warm-blooded animal, and which can be delivered from the device to the organism of the animal at this temperature. The device can also contain a temperature-sensitive hydrophilic mass in the inner capsule, comprising insoluble to soluble medicaments, the temperature-sensitive mass also changing its shape as a reaction to the absorbed energy and being able to be released from the device. The thermoplastic composition may also contain an active ingredient which is chemically unstable in an aqueous environment and which is dispersed in the device in a non-aqueous carrier and is protected by this during release from the device. The delivery device comprises a semipermeable wall that surrounds at least a part of a chamber in which a temperature-responsive drug-containing composition is contained and means by which the ground through a Durchgangj of the chamber to the exterior of the device connects may be pressed out _f.

In the accompanying drawings, which are not true to scale, but merely show various embodiments

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To illustrate the invention, the individual figures show the following:
1 is a view of a one-piece dispenser made for the oral administration of a drug to a warm-blooded animal;

Fig. 2 is a cutaway view of the dispenser of Fig. 1 in the vertical direction showing the inner chamber containing a thermodynamically effective temperature-sensitive part and an expandable one Parts which, when taken together, form the dispenser,

Fig. 3 is a cut away view of the delivery device of Figs. 1 and 2 showing that device comprising a semi-permeable wall surrounding a chamber in which the temperature sensitive agent and a driving member are located during application and release of the active ingredient ₍

Fig. 4 shows a dispensing device made of two telescopically nested parts which have been manufactured is about the release of an active substance over time

Fig. 5 is a cutaway view of the device of Fig. 4 showing the main part of the dispenser shows without the telescopically engaging cap part,

Fig. 6 is a cutaway view of the device according to Fig. 4, showing the main part, to the telescopically a cap member is slid ₁ and wherein an active substance-containing temperature-sensitive mass, and an expandable driving member located in the cavity of the device

Figure 7 is a cut away view of the dispenser of Figures 4 and 6 illustrating the dispenser comprising a semipermeable wall which

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a chamber surrounds during the delivery of a drug over time shows

Fig. 8 is a cutaway view of the main part of a capsule comprising an expandable swellable Stopper in the opening of the capsule

Fig. 9 is a cut away view of the capsule body as in Fig. 8 including an expandable swellable plug parallel to an active substance-containing temperature-sensitive mass and Fig. 10 shows the delivery pattern for a drug preparation from a device over a longer period of time.

Exemplary embodiments of the device according to the invention for dispensing an active ingredient are described in the drawings. An example of such a device is indicated as 10 in FIG. The device 10 of FIG. 1 comprises a body 11 of a wall 12 which surrounds and defines an internal cavity or lumen ( _{not shown in FIG.} 1) and a passageway 18 which is indicated by dotted lines.

2 is a cut away view of the device 10 of Fig. 1. The device 10 of Fig. 2 comprises a body 11 and a wall 12. The wall 12 consists of a semi-5 permeable polymeric wall-forming mass that is substantially permeable to the passage of external fluid and essentially impermeable to the passage of active ingredient and other components contained in the device is. The wall 12 is non-toxic and physically and chemically stable, i.e. it is not degraded during the release time. The device 10 is manufactured so that it comprises a single unitary capsule 13, i.e. the capsule 13 cannot easily be separated into individual parts will. The term capsule here and in the late

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Ren use of this term hard- or soft-shell capsules. In Fig. 2, the capsule 13 surrounds an inner lumen or a cavity 14. The cavity 14 contains an active ingredient 15, indicated by dots, is a temperature-responsive one heat-sensitive mass 16, which is indicated by wavy lines and a driving part 17, the is in contact with the surface of the mass 16 via a surface. The driving member 17 is in a preferred embodiment an expandable member 17 which has a shape which corresponds to the internal shape of the capsule wall 13 and the Chamber 14 matches. The expandable part 17 lies in the form of a layer and consists of a hydrogel mass that is not crosslinked or optionally crosslinked and possesses osmotic properties such as the ability to draw in an external liquid through the semipermeable wall 12 and an osmotic pressure gradient across the semipermeable wall 12 to the exterior of the device 10 to surrender. In another embodiment, the driving member 17 may be a solid, osmotically effective, soluble one Be a substance that soaks up liquid through the semi-permeable wall. The device 10 has a passage 18 in the semipermeable wall 12 and through the capsule 13. The Passage 18 provides a connection between the chamber 14 and the exterior of the drug delivery device 10 15 from the device 10.

In the embodiment according to FIG. 2, this is at temperature appealing thermosensitive composition 16 a means of release and a carrier for active ingredient 15. The one disclosed in Kam-0 mer 14 contained active substance, which from the device 10 Can be released, includes active ingredients that are from insoluble to very soluble in both aqueous liquids as well as in a lipophilic medium. The temperature-responsive mass 16 containing the active ingredient 15

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homogeneously or heterogeneously dispersed or dissolved therein, consists, according to a preferred embodiment, of an anhydrous, heat-sensitive hydrophilic or hydrophobic material which ^{has solid-like properties at room temperature of 21 0} C and in the range a few degrees above or below and has a melting point that is in the Close to the body temperature of mammals, namely 37 ° C and in the range of a few degrees above and below. The terms "melting point", "softening point" or "liquefying" are used to indicate the temperature at which the temperature responsive composition melts, dissolves or is dissolved to form a releasable carrier so that it can be used to release the active ingredient 15 from the device 10.

FIG. 3 shows the device 10 of FIGS. 1 and 2 during the release of active ingredient 15 to a liquid environment of use. When the application environment has a temperature of 37 ^° C. or a few degrees above or below, the active substance 15 is released from the device 10 by a combination of thermodynamic and kinetic effects. That is, in use, the heat-sensitive mass 16 melts and forms a liquid semi-solid or similar phase for the release of the active ingredient 15 through the passage 18. When the mass 16 melts _; For example, liquid is drawn in through the semi-permeable wall 12 of the hydrophilic part 17 to establish an osmotic equilibrium, whereby this hydrophilic part continuously swells or expands and expands in the chamber 14 while the interface with the thermosensitive mass remains intact. While external liquid is sucked into the device 10 through the semipermeable wall 12, the capsule wall 13, which consists of a material soluble in liquid, slowly loosens and lubricates the inside of the device

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Device, what with too uniform expansion of the part and the resulting continuous release the mass 16 contributes. In ^ which the volume of the expandable Part 17 increases, this exerts pressure on the mass 16 and reduces its volume. The simultaneous occurrence the expansion of the part 17 of the contraction of the chamber 14 and the melting of the mass 16 causes the mass 16 containing the active ingredient 15 to pass through the passage 18 is released to the exterior of the device 10. The figures 2 and 3, viewed together, show the device 10, during the release of the active ingredient 15. FIG. 2 shows a release device 10 at the beginning of the release time and Fig. 3 shows the device near the end of the dispensing time. The melting of the mass 16, the immiscibility of the mass 16 5 with the part 17 and the swelling and expansion of the part with the associated increase in volume, as shown in FIG. 3 emerges, along with the simultaneous reduction in the volume of the chamber 14 represents the release of the active ingredient 15 continuously over at a regulated speed for a certain time.

In Fig. 4 a dispensing device 20 is shown comprising 2 parts, a main part 21 and a cap part 22, which are assembled into a unitary device. the Device 20 is conveniently made in 2 parts, one part 22 sliding over part 21 and this closed with a cap. The parts 21 and 22 surround an inner lumen and an inner cavity, which is shown in Fig. is not shown. The device 20 also includes a passage 30 which is indicated by dotted lines.

Figure 5 is a cut away view of a dispenser according to Fig. 4 without cap part. In Fig. 5, the device 20 comprises a main part 21, consisting essentially

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chen from a semipermeable wall 23, which is at least partially surrounds an inner capsule part 21 with the exception of the opening 25 of the capsule 21 and is in intimate contact therewith stands. The capsule used to manufacture the dispensing device comprises 2 parts, namely the one containing the components The main capsule part 21 and a cap part 22 as shown in FIG. 6. The capsule part 21 surrounds the cavity 26, containing an active ingredient 27, which is indicated by dots, a heat sensitive to temperature Mass 28, which is indicated by wavy lines and a swellable piston-like driving part 29, which is parallel to the interface with the mass 29 is arranged. The parts indicated in FIG. 5 are made of materials such as in Figures 1 to 3 and explained below,

Fig. 6 is a cut-away view of Figs. 4 and Fig. 6 shows the device 20 with the cap portion 22, This cap part 22 has been pushed over the capsule part 21 after the larger part 21 with the preselected Medicines ^ heat-sensitive masses and floating parts has been filled. After the cap 22 has been pushed over the main part 21, there is a semi-permeable wall has been applied over the outer surface of the main part 21 and the cap part. In another type of production the cap part 21 is filled with the respective components and has a semipermeable wall with the exception of the opening this capsule part is applied and then the cap 22 is put on. The cap 22 is then telescoped over the main part 21 pushed and also covered with a semipermeable wall 23. A passage 30 is used in each type of manufacture drilled through the semipermeable wall 2 3 and the capsule wall 22 to release the active ingredient 27 from the Device 20.

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7 shows the device 20 in use. There is only one semipermeable wall 23 towards the end of the dispensing period shown. The device 20 operates in the same way as indicated for the device 10.

Fig. 8 shows another embodiment to facilitate manufacture and increase the effectiveness of the device. In FIG. 8, a body such as the body or main part 31 in a preferred embodiment is a capsule shown, wherein in the opening 33 of the main part 31 an expandable Plug 32 is arranged. The main part can be made of a semipermeable material or a hydrophilic one Material. A passage 34 is through the wall 35 of the main part 31 on the opposite side to that expandable plug 32 is provided in order to insert a filling device with the aid of which the space 36 of the main part 31 can be filled.

In Fig. 9, the space 36 is temperature sensitive Mass 37, containing active ingredient 38, filled. After the room is filled, the body or the capsule is coated or surrounded by a semipermeable wall 3 9. The semipermeable Wall in each embodiment provides a means of liquid sucking into the expandable part 32 and closing the opening 33, thereby ensuring that the expansion of the plug 32 takes place only towards the space 36 and the passage 34. With this manufacturing method the passage 34 through the semipermeable wall becomes in correspondence with the passage in the capsule wall for release of the active ingredient 38 is drilled out of the capsule. In another form of manufacture, a semi-permeable wall 39 applied around an empty capsule part, in the opening of which there is a plug and a passage is made through the semipermeable wall and the capsule wall are drilled and the

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The space is then filled with a temperature-sensitive substance-containing mass.

The different specified in Figures 1 to 9 Dispensing devices are only exemplary. The inventive Device can take a wide variety of shapes and sizes for delivering active ingredients to different ones Accept application environments. For example, the device can be made for oral administration as a Buccal tablet, implant, artificial gland, for insertion into the cervix, uterus, ear, nose, the Skin, vagina, rectum, rumen of ruminants such as cattle and as a subcutaneous implant. The device may be of such a shape, size and structure that it is suitable for releasing an active ingredient into Liquid flows, aquariums, fields, factories, reservoirs, laboratories, greenhouses, transport facilities, Hospitals, at sea, in military facilities, veterinary clinics, clinics, agricultural Factories, zoos, hospital rooms, chemical reactors and other application environments.

It has been shown, surprisingly, that it is possible, the dispensing device 10 and the device 2 0 with a Capsule with two mutually different shapes to manufacture clie in connection with the invention as osmotic hard-shell capsule and osmotic soft-shell capsule are referred to. The osmotic hard-shell capsule consists consists of two parts, a cap and a main part, which

^ O be put together after the larger part with a predetermined corresponding active ingredient preparation filled has been. This is achieved by sliding the cap part telescopically over the main part so that the active substance Preparations are completely enclosed by the capsule. Hard-shell capsules are manufactured by thawing

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^ "35Ö3743

η

Chen of molds or cones in a bath containing a solution of the material forming the capsule layer, the Form is coated with the material. The mold is then withdrawn from the solution, cooled, and air dried. The capsule is stripped from the mold, cut to size and a part with an internal cavity is obtained. The cap that telescopes over the receiving agent preparation The main part is made in a similar way. The filled and sealed osmotic cape ο is covered with a semi-permeable wall or layer. This wall can be put together before or after the capsule parts are applied to the finished capsule on the parts. The parts of the hard-shell capsule can near their open end have nested rings serving for the closure, which provide a firm closure of the Capsule and the overlapping parts of the cap and main parts snap into place after filling with the active ingredient preparation enable. In this embodiment there is a pair of interlocking locking rings in the cap and main 0 part provided and these rings result in a closure that holds the capsule tightly together. The capsule can be manual or be mechanically filled with the active ingredient preparation. the The hard-shell capsule is finally surrounded by a semipermeable layer that allows liquid to pass through is permeable and is essentially impermeable to the passage of active ingredient, as explained in more detail below.

The osmotic soft capsule as it is preferred according to the invention used in its final form consists of one piece. Generally the osmotic capsule is soft welded and the active ingredient preparation enclosed therein. The soft capsule is manufactured with the help of various processes such as plate stamping process, the process with rotating molds, the process with reciprocating

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Forms and the continuous process. In the plate punching process a set of shapes is applied. A warm sheet of a capsule-forming material is placed over the lower Form placed and the active ingredient preparation poured over it. A second sheet of the capsule forming material is made placed over the active ingredient preparation and then the upper molding. The mold is placed in a press and the two parts are pressed together with or without the application of heat with the formation of one-part soft capsules. The ο capsules are made with a solvent to remove excess Active ingredient preparation washed from the outside of the capsule and coating the air-dried capsule with a layer of a semi-permeable material.

In the method with a rotating shape or rotation method, two endless belts or films of the capsule-forming material between a pair will be matched against each of the rotating ^ forms and a filling wedge _f In this process, the capsules are simultaneously filled and sealed. The webs of the capsule-forming material are guided downwards over guide rollers and then between the filling wedge and the forming rollers. The active ingredient preparation to be encapsulated flows by gravity into a positive displacement pump. The pump measures the active substance preparation through the filling wedge into the foils between the forming rollers. The bottom of the wedge has small openings that are located above the pocket-shaped recesses of the forming rollers. The capsule is about half closed when the pressure of the pumped active ingredient preparation presses the film into the recesses of the mold, the soft-shell capsules being filled, shaped, hermetically sealed and punched out of the films of the capsule or layer-forming material at the same time. The tight sealing or welding of the soft-shell capsules

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is achieved by mechanical pressure on the forming rollers and heating of the foils by the wedge. After manufacture the capsules filled with active ingredient preparation are dried in a stream of air and a semipermeable layer applied around the capsule using the procedure described later.

In the reciprocating mold process, two sheets of capsule forming material are sandwiched between a set applied perpendicular shapes. By closing, opening and closing these forms form a continuous one vertical plate that forms pockets one after the other over the film. These bags are with the active ingredient preparation filled, and as they pass through the molds, they are tightly closed and formed from the punched moving foil. A semi-permeable layer is applied over the osmotic soft-shell Obtain dispensing device.

In the continuous process, rotating forming rollers are also used, with additional active ingredient in Can be filled into the soft-shelled capsules in the form of a dry powder and not just in liquid form. the Filled soft shell capsules obtained from the continuous process are also used to form an osmotic soft capsule coated with a semipermeable polymeric material.

The dispensing device according to the invention can be provided with a wall comprising a semi-permeable material that does not harm the host or animal for passage an external aqueous liquid such as water and biological fluids is permeable, while it is permeable to the The passage of active substances including drugs is essentially impermeable and in the presence of a thermo-

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tropics remains intact, i.e. it neither melts nor is degraded. The selectively semi-permeable Materials making up the outer wall are essentially insoluble in liquids, nontoxic and not degradable.

Representative materials for making the semipermeable wall include semipermeable homopolymers, semipermeable copolymers, and the like. In one embodiment, typical materials include cellulose esters, cellulose monoesters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose lose ester ethers, and mixtures thereof. The cellulose polymers have a degree of substitution, DS, of their anhydroglucose unit of more than 0 up to and including 3. The degree of substitution is to be understood as the average number of hydroxyl groups which were originally present in the anhydroglucose unit and which have been replaced by a substituting group or converted into another group are _? The anhydroglucose unit can be partially or completely substituted by groups such as acyl, alkanoyl, aryl, alkyl, alkenyl, alkoxy, halogen, carboalkyl, alkyl carbamate, alkyl carbonate, alkyl sulfonate, alkyl sulfamate and similar semipermeable polymer-forming groups.

The semipermeable materials are typically selected from the group consisting of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, Cellulose diacetate, cellulose triacetate, mono-, di- and tricellulose alkanylates, Mono-, di- and tri-alkenylates, mono-, di- and tri-aroylates, and others. Exemplary polymers are cellulose acetate with a degree of substitution of 1.8 to 2.3 and an acetyl content of 32 to 39.9%, cellulose diacetate with a degree of substitution of 1 to 2 and an acetyl content of 21 to 35%, cellulose triacetate with a substitute

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tution degree of 2 to 3 and an acetyl content of 34 to 44.8%, among others. In particular, cellulose polymers include cellulose propionate with a degree of substitution of 1.8 and a propionyl content of 38.5%, cellulose acetate propionate with an acetyl content of 1.5 to 7% and an acetyl content from 39 to 42%, cellulose acetate propionate with an acetyl content of 2.5 to 3%, an average propionyl content of 39.2 to 45% and a hydroxyl content of 2.8 to 5.4%, cellulose acetate butyrate with a degree of substitution of 1.8, an acetyl content of 13 to 15% and a butyryl content from 34 to 39%, cellulose acetate butyrate with an acetyl content of 2 to 29.5%, a butyryl content of 17 up to 53% and a hydroxyl content of 0.5 to 4.7%, cellulose triacylate with a degree of substitution of 2.9 to 3 such as cellulose trivalerate, cellulose trilaurate, cellulose tripalmitate, Cellulose trioctanoate and cellulose tripropionate, cellulose diesters with a degree of substitution of 2.2 up to 2.6 such as cellulose disuccinate, cellulose dipalmitate, cellulose dioctanoate, cellulose dicaprylate and others, mixed Cellulose esters such as cellulose acetate valerate, cellulose acetate succinate, Cellulose propionate succinate, cellulose acetate octanoate, cellulose valerate palmitate, cellulose acetate heptanoate Semipermeable polymers, among others, are known from U.S. Patent 4,077,407 and can be made by methods as described in Encyclopedia of Polymer Science and Technology, Vol. 3, pp. 325 to 354, 1964, Interscieace Publisher, Inc., New York.

Further exemplary semipermeable polymers are acetaldehyde dimethyl cellulose acetate, Cellulose acetate ethyl carbamate, cellulose acetate methyl carbamate, cellulose dimethylamino acetate, semipermeable polyamides, semipermeable polyurethanes, semipermeable polysulfanes, semipermeable sulfonated Polystyrenes, cross-linked, selectively semipermeable poly-

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mers, which are formed by the common precipitation of a Polyanion and a polycation as disclosed in U.S. Patents 3,173,876, 3,276,586, 3,541,005, 3,541,006, and 3,546,142. Selectively semipermeable silicone rubbers, semipermeable polymers as indicated by Loeb and Sourirajan in U.S. Patent 3,133,132, semipermeable polystyrene derivatives, semipermeables Poly (sodium styrene sulfonate), semipermeable poly (vinylbenzyltrimethyl) ammonium chloride, semipermeable Polymers with a liquid permeability of

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25.4 χ 10 to 25.4 χ 10 (cm ^3. Μΐη / cm ² .h. Bar) [10 to _ -j

10 (cc.mil/cm ² hr.atm)] given per bar (atm) hydrostatic or osmotic pressure difference across the semipermeable wall. The polymers are known from US Pat. Nos. 3,845,770, 3,916,899 and 4,160,020 and from the Handbook of Common Polymers by Scott, JR and Roff, WJ, 1971, CRC Press, Cleveland, Ohio.

The materials suitable for producing the swellable, expandable inner part or the layer or the plug are polymeric materials alone and polymeric materials mixed with osmotic agents that are mixed with water or a biological fluid interact, absorb the fluid and thereby up to a state of equilibrium swell or expand. The polymers have the ability to absorb a significant proportion of the To hold liquid in the polymeric molecular structure. In a preferred embodiment, the polymers are management form gel-like polymers that swell or expand very strongly and usually a 2- to 50-fold increase in volume result. The swellable hydrophilic polymers are also known as osmopolymers and can not be networked or slightly networked. The cross-links can be covalent or ionic bonds, the polymers having the ability in the presence of

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- «- ■ · J509743 • 53.

To swell liquid and if they are cross-linked, not to dissolve in the liquid. The polymer can be vegetable, of animal or synthetic origin. Polymeric materials suitable for the purposes of the invention are, inter alia, poly (hydroxyalkyl methacrylate) with a molecular weight of 5,000 to 5,000,000, polyvinylpyrrolidone with a molecular weight of 10,000 to 360,000, anionic and cationic hydrogels, polyelectrolyte complexes, polyvinyl alcohol with a low residual acetate content, a swellable one Mixture of agar and carboxymethyl cellulose, a swellable mass comprising methyl cellulose in a mixture with a weakly crosslinked agar, a water swellable copolymer made by dispersing a finely divided copolymers of maleic anhydride and styrene, ethylene, propylene or isobutylene, swellable in water Polymers of N-vinyl lactams et al.

Other gelling liquid-absorbing and holding Polymers suitable for making the hydrophilic expandable pressing member include Pectin with a molecular weight in the range from 30,000 to 300,000, polysaccharides such as agar, acacia, karaya, tragacanth, Algine and guar, an acidic carboxy polymer and its salts (CarbopoiM, polyacrylamides, swellable in water hige indene maleic anhydride polymers, polyacrylic acid with a molecular weight of 80,000 to 200,000 (Good-rite ^ f, Polyethylene oxide polymers with a molecular weight of 100,000 to 5,000,000 and above (Polyox ^, grafted with starch Copolymers, polyanion and polycation exchange polymers, starch-polyacrylonitrile copolymers, acrylate polymers with a water absorbency of about 400 times of the original weight (aqua-keep ^ j, diester of polyglucan, a mixture of crosslinked polyvinyl alcohol and poly (N-vinyl-2-pyrrolidone), zein, which is used as a prolamine for

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Addition is polyethylene glycol having a molecular weight of 4,000 to 100,000 and others in a preferred embodiment the expandable part (the expandable wall) consists of polymers and polymeric masses that are thermally are deformable. Exemplary polymers with hydrophilic properties are known from US Pat. No. 3,865,108, 4,002,173, 4,207,893 and 4,327,725 and from the Handbook of Common Polymers by Scott and Roff, Cleveland Rubber Company, Cleveland, Ohio.

The osmotically active compounds alone or in the homogeneous or heterogeneous mixture with the swellable polymer can be used to form a driving Some of the osmotically active soluble or dissolved substances are sucked into the swellable polymer Liquid are soluble and have an osmotic pressure gradient across the semipermeable wall towards the outer liquid result. Osmotic compounds are also known as osmotic agents. Osmostically effective connections, which are suitable for the purposes of the invention include solid compounds selected from Group magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, mannitol, urea, Sorbitol, inositol, sucrose, glucose, etc. The osmotic pressure in bar (atm) of the osmotic agent used for the purposes of the invention are suitable, is greater than 0 bar and is generally from 0 to 500 bar or about that.

In addition to its effect, the swellable expandable polymer serves as a driving force for the release of an active ingredient of the device also as a carrier matrix for an osmotically active soluble substance. The osmotic substance can be homogeneous or heterogeneously mixed with the polymer to form

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the desired expandable wall or pocket. The mass (for making the driving part) preferably comprises a) at least one polymer and at least one osmotically active soluble substance or b) at least a solid osmotically active soluble substance. In general, such a composition comprises about 20 to 90% by weight Polymer and 80 to 10 wt .-% osmotically active soluble Substance, compositions with 35 to 75% by weight of polymer and 65 to 25% by weight of osmotically active substance being preferred.

The temperature responsive material as used in the present invention includes thermoplastic compositions which are capable of softening in response to heat or which can be released from the device and solidify again on cooling. The term also includes thermotropic masses which are able to change gradually in response to the application of energy. These substances are sensitive to temperature in their reaction to the use and withdrawal of energy. On temperature 0 appealing substances _(such as they are preferably used for the purposes of this invention have physicochemical properties of a drug carrier and at temperatures up to 33 ° C solid or solid-like and liquid, semisolid, or viscous when at tempera doors of 32 ⁰ C or above, preferably in the range from 32 to 40 ^° C. The temperature-sensitive support is heat-sensitive and has the property of melting, dissolving, dissolving, softening or liquefying and thus forming a mass at elevated temperatures, which can be dispensed from the device, thereby enabling the temperature-responsive carrier to be dispensed from the device together with the active ingredient homogeneously or heterogeneously mixed therewith. The temperature-responsive carrier may be lipophilic,

/ 23

be hydrophilic or hydrophobic. Another important property of the carrier is its ability to maintain the stability of the active ingredient contained therein during storage and delivery. Typical masses that respond to temperature and their melting points are: cocoa butter 32-34 ° C, cocoa butter + 2% beeswax 35-37 ° C, propylene glycol monostearate and distearate 32-35 ° C, hydrogenated oils such as hydrogenated vegetable oil 36- 37.5 ° C, 80% hydrogenated vegetable oil and 20% sorbitan monopalmitate 39-39.5 ° C, 80% hydrogenated vegetable oil and 20% polysorbate 60 36-37 ° C, 77.5% hydrogenated vegetable oil 20% Sorbitan trioleate and 2.5% beeswax 35-36 ° C, 72.5% hydrogenated vegetable 20% sorbitan trioleate ₍ 2.5% beeswax and 5.0% distilled water 37-38 ° C, mono- di- and Triglycerides of acids with 8 to 2 carbon atoms including saturated and unsaturated acids such as palmitic, stearic; oleic, linoleic, linolenic and arachidonic acids, triglycerides of saturated fatty acids with mono- and diglycerides 34-35.5 ° C, propylene glycol monound-distearate 33-44 ° C, partially hydrogenated cottonseed oil 35-39 ° C, a block copolymer of polyoxyalkylene and propylene glycol, block copolymers include according to 1,2-butylene oxide has been added to the ethylene oxide, block copolymers of propylene oxide and ethylene oxide, hardened fatty alcohols and fats 33-36 ° C, hexadienol and aqueous lanolin triethanolamine glyceryl monostearate 38 ° C, eutectic genes

mix of mono-, di- and triglycerides 35-39 ⁰ C, Witepsor * - 'ί $ "Ί5, triglyceride of saturated vegetable fatty acids with monoglycerides 33.5-35.5 ° C, Witepsor ^ H32, free of hydroxyl groups 31-33 ° C, WitepsolV'W25 with a saponification number of 225-240 and a melting point of 33.5-35.5 ° C, Witepsol · - ^ E75 with a saponification number of 220-230 and a melting point 37-39 ° C, a polyalkylene glycol such as polyethylene glycol 1000 a linear polymer of ethylene oxide 38-41 ⁰ C, polyethylene glycol 1500 melting point 38-41 ⁰ C, polyethylene

/ 24

35Ö9743

glycol monostearate 39 to 42.5 ° C, 33% polyethylene glycol 1500, 47% polyethylene glycol 6000 and 20% distilled water 39-41 ⁰ C, 30% polyethylene glycol 1500.40% polyethylene glycol 4000 and 30% polyethylene glycol 400 33-38 ° C , Mixtures of mono-, di- and triglycerides of saturated fatty acids with 11 to 17 carbon atoms 33-35 ° C, etc. The temperature-sensitive mass is a means of storing an active ingredient in a solid mass at a temperature of 20-33 ° C, that has an immiscible interface with the swellable

T ο retains capable mass and releases the active ingredient in a flowable agent at temperatures "^ 33 ⁰ C, preferably in the range of 33-40 ⁰ C. The temperature-responsive agent is easily excreted when it is released into a biological environment, metabolized, assimilated, or the like, and can be used effectively.

The materials used to manufacture the capsule are the commercially available substances gelatin, gelatin with a viscosity of 1.5 to 3 mPa.s (15-30 mP) and one Bloom strength up to 150 g, gelatin with a bloom value of 160-250, a mass containing gelatin, glycerine, water and titanium dioxide, a mass comprising gelatin, erythrosine, iron oxide and titanium dioxide, a mass comprising gelatin Glycerin, sorbitol, potassium sorbate and titanium dioxide, a mass comprising gelatin, acacia, glycerin and water, among others.

The term active ingredient as used herein means any mass, preparation, mixture or one Compound that can be dispensed from the device to exert a certain beneficial effect. The active ingredients include algicides, antioxidants, air purifiers, biocides, catalysts, chemical reactants, cosmetics, Medicines, disinfectants, fungicides, local

/ 25

drugs, fertility inhibiting and destructive agents, Food additives, fermentation agents, germicides, insecticides, microorganisms debilitants, nutrients, plant growth accelerators and inhibitors, preservatives, surfactants, sterilants, sex sterilants, Vitamins and other means with a beneficial effect on the environment, lounges and animals. The active ingredient can be insoluble to very soluble in the temperature-sensitive material.

In the description and claims, the term medicament includes any physiological or pharmacological active substance that has a local or systemic effect in animals including warm-blooded animals, humans and Primates, birds, fish, domestic animals, sport and farm animals, laboratory animals and zoo animals. The expression physiological as used herein refers to the administration of a drug to produce normal Contents of the substance concerned or normal functions.

The term pharmacological refers to changes in response to the amount of drug administered (Stedman's Medical Dictionary, 1966, Williams and Wilkins, Baltimore, MD). The medicament which can be delivered with the aid of the device according to the invention comprises inorganic ones and organic, solid and oily medicines without limitation such as medicines that affect the nervous system act, depressants, hypnotics or sleeping pills, sedatives, psychological stimulants, tranquilizers, anti-seizure drugs, Muscle relaxants, anti-Parkinson drugs, analgesics, anti-inflammatory agents, antimalarials, hormonal agents, contraceptives, sympathomimetics, diuretics, antiparasitic agents, Neoplastics (anti-tumor agents), hypoglycemics, Ophthalmics, electrolytes, diagnostics, and cardiovascular agents. The amount of active ingredient in the delivery device can be 0.05 ng to 20 g or more. For me-

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3S09743

The device can have different medical applications Amounts, for example 25 ng, 1 mg, 5 mg, 125 mg, 250 mg, 500 mg, 750 mg, 1.5 g and other amounts contain. The device can be used or taken 1, 2 or 3 times a day or only 2 times a week or similar Intervals.

The mass forming the semipermeable wall can be applied to the outside of the capsule in a laminar arrangement by molding, compression molding, spraying, dipping or brushing on the mass forming the semipermeable wall. Other and preferred methods of applying the semi-permeable wall are the air turbulence method and the Coating in the kettle. The air turbulence process exists in that the capsule arrangement swirls in a stream of air and a mass forming the semipermeable wall and is overturned until the wall surrounds and coats the capsule. The procedure can be different with one a semipermeable wall-forming mass is repeated to form a laminated semipermeable wall.

The air turbulence process is described in U.S. Patent 2,799,241, in J. Am. Pharm. Assoc, Vol. 48, pp. 451 to 459, 1979 and ibid, Vol. 49, pp. 82-84, 1960. Other standard manufacturing methods are given in Modem Plastics Encyclopedia, Vol. 46, pp. 62-70, 1969 and in Pharmaceutical Sciences von Remington, 14th ed., Pp. 1626 to 1678, 1970, Mack Publishing Co., Easton, PA.

Exemplary solvents that are used to produce the semipermeable Wall are suitable include inorganic and organic solvents, which the materials, the capsule wall, the active ingredient, the temperature sensitive mass, the expandable part and the delivery device not adversely affect. The solvents generally include those from the group of aqueous solvents,

/ 27

Alcohols, ketones, esters / etherealiphatic hydrocarbons, halogenated solvents, cycloaliphatic compounds, aromatics, heterocyclic solvents and their Mix. Typical solvents include acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, Butyl alcohol, methyl acetate, ethyl acetate, isopropy ^ -acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, η-hexane, n-heptane, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, Methylene dichloride, ethylene eii chloride, Propylene dichloride, carbon tetrachloride, nitroethane, nitropropane, tetrachloroethane, ethyl ether, isoprepyl ether, Cyclohexane, cyclooctane, benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, diethylene glycol dimethyl ether, Water and mixtures thereof such as acetone and water, acetone and methanol, acetone and ethyl alcohol, methylene dichloride and methanol and ethylene dichloride and methanol. In general, the semipermeable wall is in accordance with the invention at a temperature a few degrees below the melting point the temperature-sensitive mass applied or 0 the temperature-sensitive mass can be in the device be introduced after the semi-permeable wall has been applied.

The term opening or passage as used herein includes means and methods by which it is possible is to release an active ingredient preparation from the device. The opening can be mechanical or Laser drilling can be made or by breaking down a degradable element such as a gelatin plug in the wall. The opening can also consist in that a polymer in the semipermeable wall is used, which is porous and has at least one pore or which is microporous and at least has a micropore. A detailed description of openings and their preferred maximum and minimum Dimensions are given in U.S. Patents 3,845,770 and 3,916,899.

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The invention is illustrated in more detail by the following examples.

example 1

A drug dispenser was made as follows: First the main part of a two-part capsule was placed with the opening facing up and into the hemispherical one At the end of the capsule, a layer made of an expandable swellable material is introduced. The mass comprised 30% by weight Sodium chloride and 70% by weight molecular weight polyethylene oxide of 3,000,000. The components forming the expandable mass were in a commercially available Mixer mixed with application of heat for 20 minutes to form a homogeneous mass. The heated mass was in The capsule was inserted, forming a layer that took up about 1/4 of the capsule. Then the cap part the capsule is placed on top and a filling opening is drilled through the cap which is connected to the cavity of the assembled Capsule was in communication. A heat-sensitive drug preparation was then passed through the filling opening introduced into the cavity of the capsule. Finally, a semi-permeable wall was applied around the capsule and a passage drilled through the semipermeable wall, which was in communication with the filling opening, around the drug preparation submit.

Example 2

A delivery device was made as follows:

First, the main part of a two-part capsule was set up with the open end up and inserted into the hemispherical one lower end of the capsule a 500 mg layer of polyacrylamide (Cyanamei> -i a hydrogel with a molecular weight of about 200,000 introduced. Then the cap was placed on the main part. Then became a semipermeable wall around the capsule formed by mixing

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• 3a-

of 85 g of cellulose acetate with an acetyl content of 39.8% and 20 ml of methylene chloride and 20 ml of methanol and applying this mixture to the capsule by swirling air until a 0.25 mm thick semipermeable wall surrounded the capsule. The capsule was dried and a 1.0 mm passage was drilled with the aid of a laser through the semipermeable wall and the capsule wall up to the cavity of the capsule. Subsequently, a heat-sensitive enteric (enteric) mixture of 77% neutral fat having a melting point of 35-37 ° C and 19.5% of paraffin was heated liquefied with a melting point of 52 ⁰ C and 3.5% of acetylsalicylic acid was added. The heated mixture was then cooled to about 40 ⁰ C and sprayed through the passage in the cavity of the capsule and cooled to room temperature, the dispenser door.

Example 3

A delivery device for delivering a drug to a warm-blooded animal was made as follows:

A mold corresponding to the opening and the inner diameter of the main part of the capsule was filled with an expandable part-forming _{composition f} comprising 30 parts of ethylene glycol monomethacrylate, 0.12 part of ethylene glycol dimethacrylate and 10 parts of 0.13 % strength aqueous solution of sodium disulfate in aqueous ethanol. The mass polymerized at 30 ^° C. and 20 minutes after the room temperature had been set, the solid layer was removed from the mold. The solid expandable layer was then placed in the opening of the capsule and formed an internal drug containing chamber in the space between the hemispherical end of the capsule and the inner surface of the expandable polymer. A fill exit port was then drilled through the hemispherical end connecting the exterior of the capsule to the interior chamber. The chamber can then be filled with a thermosensitive drug formulation

/ 30

be filled or it can optionally also become one can be filled with it later.

For example, ₄ the chamber can be filled with a molten mass comprising 2.5% phenobarbital, 20.5% glycerol gelatin and 77% theobroma oil, a glyceride of stearic, palmitic and lauric acids, which at room temperature the temperature-sensitive mass in a laminar arrangement forms to the expandable layer. The main part of the capsule is then closed by sliding the cap over the open end of the main part.

A solution of 15% by weight cellulose acetate with an acetyl content of 39.8% was then prepared and the plugged-together capsule was covered with a semipermeable wall by immersing it 15 times in the solution, initially TOs and then 1 min each with intervening drying times of 5 min. After the immersion, the device was at room temperature, ie, about 22 ⁰ C, 0 ¹ O days dried. This procedure resulted in a semi-permeable wall approximately 2 mm thick. With the aid of a laser, a passage was drilled through the semipermeable wall connecting the exterior of the device to the fill opening and the temperature-sensitive layer.

Example 4

A delivery device for releasing an active ingredient preparation was produced as follows: First, the hemispherical end of a gelatin capsule containing 3.2-5 g a molten mass consisting essentially of 30% sodium chloride and 70% polyethylene oxide (for coagulation) filled. Then the cap of the capsule was immersed a few mm deep in water and then the cap over the open Pushed the end of the main body of the capsule. The water caused the cap and the main body of the capsule to stick together

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"- ■ ^::; 35Ό9743 31» ·

connected to each other. A 1.3 mm passage was then drilled through the cap portion of the assembled gel capsule. Subsequently, 9.9 g of a temper atujrempfindlichen pharmaceutical preparation consisting of a 15% suspension of theophylline with 8% anhydrous polyethylene glycol 400 distearate (Cabosir * M through the opening in the drug chamber of the capsule is introduced at 50 ⁰ C, with a layer The temperature-sensitive drug preparation was also in contact with the inside of the gelatin capsule. The finished capsule was then covered with a wall of cellulose acetate butyrate containing 10% polyethylene 400. The semipermeable wall was applied in a Hi-Kessel coater. The solvent used to form the wall consisted essentially of 95 parts by weight of methylene chloride and 5 parts by weight of methanol. A layer 0.03 mm thick Cellulose acetate butyrate was applied to the outside of the capsule.

10 shows the rate of release in ^ g / h 37 ° C.

The capsule according to the invention is suitable for delivering an active ingredient to the vagina or rectum of a warm-blooded animal at a controlled rate. A) a device is introduced into (the body cavity! Comprising. 1) an outer wall made of a semipermeable polymeric mass which is permeable to the passage of liquid and essentially impermeable to the passage of medicament and which surrounds 2) a capsule containing a layer of a drug preparation in the chamber, comprising a dosage unit of drug for carrying out the therapeutic program _# in a heat-sensitive carrier that melts at body temperature and a means for transmitting

/ 32

represents port of the drug from the device, 3) a layer of an expandable hydrogel in the capsule, which is in contact with the heat-sensitive pharmaceutical preparation and 4) an opening through the outer wall and the capsule wall connected to the thermosensitive Drug preparation is in contact, B) liquid through the semipermeable wall at 'one speed sucked in, which is determined by the permeability of the semipermeable wall and the osmotic pressure gradient 0 over the semipermeable wall whereby the hydrogel layer expands and swells, C) the drug preparation melted to form a flowable preparation and D) the drug preparation is released from the chamber by the swellable layer continuously against the molten preparation expands and results in the preparation in a therapeutically effective amount with controlled Speed through the opening and the desired medicinal effect over a period of time from 1 hour to months, preferably from 1 to 24 hours. An example of a drug that can be dispensed particularly inexpensively with the aid of the device is conjugated estrogen in a preparation comprising 0.875 mg of conjugated estrogens in a heat sensitive Basic substance.

6238

lee

Claims (10)

PATENTANWÄLTE i> k.-ing »ranz wuesthoff, y WUESTHOFF - v. PECHMANN - BEHRENS -GOFTZ ™ tHlu rREDA ™ ESTHO "('9 * 7-1" ") f DIPL.-ING. GERHARD PULS (19J2-I971) EUROPEAN PATENTATTORNEYS D" L, cHt ". Dr. H. Freiherr von ρεοημλνν % DR.-ING. DIETER BEHRENS f \ r- f \ Cl Ί f O DiPL.-iNG .; dipl.-virtsch.-ing.Rupert goetz 1A-58 960 D-8000 MUNICH Note: Alza Corp. SCHWEIGERSTRASSE2 phone : (089) 66 ίο ji TELEGRAM: PROTECTPATENT TELEX: J 24 070 TELEFAX: VIA (089) 2 7I'6o 6} (m) Patent Claims 1. Dispensing device for releasing an active ingredient with regulated speed over time, comprehensively a) an active ingredient preparation, b) a hydrophilic mass in contact with this, which absorbs liquid from the environment and swells, c) a wall surrounding the active substance preparation and the hydrophilic mass λ , which wall consists at least partially of a semi-permeable mass which is permeable to the passage of liquid and essentially impermeable to the passage of the active substance, and d) a passage through the wall which provides a connection between the active ingredient preparation and the exterior of the device forms, characterized in that the active ingredient preparation is a heat-sensitive mass which is ^{solid up to 32 0} C and melts at a temperature above 32 ⁰ C and that e) the active ingredient preparation and the hydrophilic mass in a capsule, which is surrounded by the outer wall 0. 2. Apparatus according to claim 1, characterized in that the capsule consists of a main part and / 2 consists of a cap part pushed over it like a telescope. 3. Device according to claim 1, characterized in that g e k e η η, that the capsule is made of one piece, 4. Device according to one of claims 1 to 3, characterized in that the hydrophilic mass is a Hydrogel and an osmotically active solute. 5. Device according to one of claims 1 to 3, characterized characterized in that the hydrophilic mass is polyethylene oxide, polyacrylic acid and its salts, polyethylene glycol and optionally an osmotically active soluble contains a substance. 6. Device according to one of claims 1 to 5, characterized characterized in that the semipermeable wall is made of cellulose ester, cellulose diester, Cellulose ether, cellulose ester ether, cellulose acylate, Cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate butyrate or a mixture of these compounds. 7. Device according to one of claims 1 to 6, characterized characterized in that the heat-sensitive composition is selected from glycerol esters of saturated Fatty acids, polyethylene glycol, a block copolymer of butylene oxide and ethylene oxide, a block copolymer of propylene oxide and ethylene oxide and a block copolymer of polyoxyalkylene and propylene glycol. / 3 8. Device according to one of claims 1 to 7, characterized in that the heat-sensitive
Active ingredient preparation is present as a layer in the cavity of the capsule. 9. Device according to one of claims 1 to 8, characterized in that the hydrophilic mass as Layer is present in the cavity of the capsule. 10. Device according to one of claims 1 to 9, characterized characterized in that the capsule is a gelatin capsule. 6238