DE3509743C2 - Delivery device for releasing an active ingredient - Google Patents

Description

The invention relates to a new and inexpensive delivery direction (drug dispenser). The dispenser includes a semipermeable wall that an inner Capsule shell surrounds, inside the capsule shell a temperature attractive preparation of active ingredients and an expandable driving agent is included. The the dispenser forming parts work together to release the effect at a controlled speed over time Application environment.

Delivery devices or drug dispensers for release of an active ingredient to an application environment are known. For example, U.S. Patent 3,760,984 describes a delivery direction, consisting of a heat shrinking Container that has an osmotically soluble on the outside chen substance and a layer facing away from the container from one liquid permeable polymer. The levy device has a stopper for filling the container. The dispenser is powered by liquid is sucked into the device, whereby the soluble che fabric dissolves and forms a solution that a pressure on exercises the shrinkable container and causes the  water shrinks and releases active ingredient from the device. A delivery device is described in U.S. Patent No. 3,865,108 ben, consisting of an inner pipe or hose piece, that can collapse and contain a medicine and arranged in one part from a swellable material is. The device gives the active ingredient or the drug medium free by the base part and other parts liquid suck in from the environment, thereby expanding and press the tube piece together and thereby release the medicine. In U.S. Patent 3,971,376 discloses a dispenser consisting of a cap sel with uniform walls made of a cross-linked gel, the swells in liquids. In the material is a textile Embedded fabric to give it strength and the Largely reduce problems caused by bad mechanical properties of the materials occur and which are used to drive the Ab show feeding device. U.S. Patent 3,887,790 relates to one Improving an osmotic delivery device comprising a line for filling a bag in the device. The device is driven by an osmotic effect seed soluble substance, the liquid in the device which in turn sucks a hydraulic pressure exerts the bag and causes it to be pushed inward and thereby releases active ingredient from the device. U.S. Patent 3,995,631 describes a pouch that is based on the outside a layer of an osmotically soluble Fabric and a wall on the side facing away from the bag partly from a material controlling the liquid passage consists. When used, a solution of the solution is formed material that compresses the bag and thereby releases the active ingredient from the sachet. U.S. Patent 4,320,758 discloses a delivery device, be standing out of a flexible bag of a casing out of a  Dispersion of an osmotically active soluble substance in a soluble polymer and one for liquid casual outer wall. The dispenser places medication medium free, by sheathing water in the space between sucked in the outer wall and the bag and thereby this exerts a hydraulic pressure on the bag leads to the fact that the bag is compressed and active ingredient releases.

From US-PS 43 27 725 is an osmotic delivery device for the release of an active ingredient with regulated Known speed over time. The dispenser has a semipermeable wall that encloses a chamber with a Active ingredient surrounds a layer of a water-insoluble, however, water-swellable cross-linked hydrogel in the chamber, which acts as a blowing agent and is in contact with the active ingredient, and a passage through the semi-permeable wall for delivery of the active ingredient to the external environment. The cross-linked hydrogel is a hydrophilic, water-insoluble polymer, the osmotic Has properties: it can absorb external liquid and in this way an osmotic pressure gradient across to build the semipermeable wall.

From US-PS 43 50 271 a water-absorbing fluid is Dispenser known. This dispenser comprises a rigid one Housing surrounding a semipermeable material, a water insoluble but water swellable compound (hydrogel) in part of this space, a fluid, lipophilic mixture that contains an active ingredient and the rest of the room fills, as well as an opening through the housing.

DE-OS 22 01 357 discloses an osmotic delivery device for the release of active substances, which a at storage temperature tur - advantageous at room temperature - solid or semi-solid Active substance formulation comprises, in a preferred Ausfüh Form at the temperature of the intended application (at body temperature) is liquid. The active ingredient preferably contains substance formulation the active ingredient in combination with a carrier, the carrier being solid at room temperature, at body temperature on the other hand is liquid; Examples of such carriers are alcohols, such as polyethylene glycol. Controlled drug delivery takes place in the dispenser depending on the volume increase in a solution of an osmotically effective, ge dissolved compartment in the device Absorption of water from the surrounding liquid.

While the above dispensers are suitable for releasing numerous active ingredients to users environment and while being an economic fort step in the field of drug release it is clear to the person skilled in the art that this device can be further improved. If at game a dispenser would be available to next consists of an inner capsule through which the her position of the dispenser easier and better and cheaper ger is possible and if such a device none would include flexible bag and no fabric and thereby the Number of steps to make such a capsule and the number of parts required would be reduced such a delivery device immediately accepted and one significant progress. If possible would be to provide a device in which it is no longer necessary to use the active ingredient only in the form of Releasing solutions or suspensions would also be a sol dispenser on scientific, medical and economic area can be adopted immediately.  

It is therefore the subject of the invention, a dispensing device to release active ingredients in all possible environments to develop. This device is said to be all necessary Contain components in a liquid environment start the release and drive yourself, easily be manufactured and be suitable for the delivery of active ingredient target animals including humans, and others biologically and non-biological application environments.

The tasks mentioned are carried out by the Dispensing described in the claims directions solved. The delivery direction contains a temperature-sensitive hydrophobic mass comprising insoluble to soluble drugs, the temperature sensitive mass in response to temperature the biological environment changes its shape and is fluid, becomes semi-solid or the like, which makes them easily out of the Device is released. The device initially has an inner capsule assembly that facilitates their manufacture and cheaper and thereby the applicability of the device elevated. The dispenser according to the invention comprises a Lumens or a cavity containing a temperature sensitive Liche mass, an expandable part or means that with the temperature 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 that the Capsule surrounds, and a passage, the front direction of the mass through a combination of physical surfaces emits processes by melting and flowing the mass sig or semi-solid or the like and one (not mixed bare) interface between the mass and the expand the part remains and the expanding part swells and expands into the space occupied by the crowd and a corresponding amount of mass from the device delivers. The device is initially empty until it is used solid mass is filled, which is at elevated tempera doors liquefied. You can then measure the mass over time  space in a complete pharmaceutical dosage Submit the program, only at the start and at the end intervention in the program. The delivery direction can contain active ingredients that are sensitive to temperature Chen contain lipophilic pharmaceutically acceptable carriers are in the presence of biological application environment of absorbed energy to a releasable mass melts, which is harmless, causing irritation of the acid animal tissue and an interaction with mammalian protein essentially be avoided. The osmotic delivery device can be a eutectic of at least two Contain components and at least one drug, the sen melting point essentially the body temperature of a Warmblood corresponds - and at this temperature from the Device to be delivered to the animal's organism can. The device can also be in the inner capsule contain temperature-sensitive hydrophilic mass, comprising Insoluble to soluble drugs, the temperature sensitive mass also in response to the ingested my energy changes its shape and exits the device can be given. The thermoplastic mass can also contain an active ingredient that is chemically active in an aqueous environment is unstable and in the device in a non-aqueous Carrier is dispersed and by this during the Release from the device is protected. The levy device includes a semipermeable wall that the chamber surrounds one in temperature appealing active substance-containing mass is included and means with the help of the crowd through a passage that the Kam mer connects with the exterior of the device, pressed out can be.

In the accompanying drawings, which are not to scale are, but only different embodiments  illustrate the invention, the individual figures show fol gendes:

Fig. 1 is a view of a dispenser in one piece, which has been prepared for oral Verab submission of a drug to a warm-blooded animal,

Fig. 2 is a cutaway view of the delivery device of FIG. 1 in the vertical direction and shows the inner chamber containing a thermodynamically effective temperature-sensitive part and an expandable part, which together form the delivery device,

Fig. 3 is a cutaway view of the Abgabevorrich processing according to FIG. 1 and FIG. 2, showing this Vorrich tung comprising, in the temperature sensitive means and a driving member are a semipermeable wall that surrounds a Kam mer, while the application and release of the active ingredient,

Fig. 4 shows a dispensing device consists of two telescoped parts produced wor is at the release of a drug over time,

Fig. 5 is a cutaway view of the device according to Fig. 4, the processing of the main part showing Abgabevorrich without the telescopically engaging cap member,

Fig. 6 is a cutaway view of the device according to Fig. 4, which showed the main part of a cap member is pushed onto the teles kopartig, and wherein an active substance-containing temperature-sensitive mass and a expan dierbares driving member located in the cavity of the device,

Fig. 7 is a cutaway view of the Abgabevorrich processing of Fig. 4 and 6, the device, delivery comprising illustrates a semipermeable wall that surrounds a compartment, the substance during the delivery of an active over time,

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

Fig. 9 is a cutaway view of the capsule main part as in Fig. 8, containing an expandable ren 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 long time.

In the drawings, exemplary embodiments of the inventive device for dispensing an active ingredient are described. An example of such a device is designated as 10 in FIG. 1. The device 10 of FIG. 1 comprises a body 11 from a wall 12 which surrounds and defines an inner cavity or a lumen (not shown in FIG. 1) and a passage 18 which is dotted.

Fig. 2 is a cutaway view of the device 10 of FIG. 1. The device 10 of FIG. 2 comprises a body by 11 and a wall 12th The wall 12 consists of a semi-permeable polymeric wall-forming mass which is essentially permeable to the passage of external liquid and essentially impermeable to the passage of active ingredient and other constituents contained in the device. The wall 12 is non-toxic and physically and chemically stable, ie it is not degraded during the release period. The device 10 is manufactured so that it comprises a single unitary capsule 13 , ie the capsule 13 cannot easily be separated into individual parts. The term capsule here and in the later use of this term includes hard or soft-shell capsules. In FIG. 2, capsule 13 surrounds an inner lumen or cavity 14 . The cavity 14 contains an active substance 15 , which is indicated by points, a temperature-sensitive heat-sensitive mass 16 , which is indicated by Wel lenlinien, and a driving part 17 which is in contact with the surface of the mass 16 over a surface. The driving part 17 is in a preferred imple mentation form an expandable part 17 , which sits a form that matches the inner shape of the capsule wall 13 and the chamber 14 . The expandable part 17 is in the form of a layer and consists of a hydrogel mass which is not cross-linked or possibly cross-linked and has osmotic properties such as the ability to suck in an external liquid through the semi-permeable wall 12 and an osmotic pressure gradient across the semi-permeable wall 12 compared to the exterior of the device 10 . In another embodiment, the floating part 17 can be a solid, osmotically active, soluble substance that draws in liquid through the semi-permeable wall 12 . The device 10 has a passage 18 in the semipermeable wall 12 and through the capsule 13 . The passage 18 represents a connection between the chamber 14 and the exterior of the device 10 for releasing the active substance 15 from the device 10 .

In the embodiment according to FIG. 2, the temperature-sensitive heat-sensitive mass 16 is a means for releasing and a carrier for the active substance 15 . The active ingredient contained in the chamber 14 , which can be released from the device 10 , comprises active ingredients which are insoluble to highly soluble both in aqueous liquids and in a lipophilic medium. The temperature-responsive mass 16 , containing the active ingredient 15 homogeneously or heterogeneously dispersed or dissolved therein, is, according to a preferred embodiment, made of an anhydrous, heat-sensitive hydrophilic or hydrophobic material which is at room temperature of 21 ° C. and in the range of a few degrees Above or below it has solid-like properties and has a melting point that is 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 "liquefy" who uses the to indicate the temperature at which the temperature-sensitive mass melts, dissolves or is dissolved to form a releasable carrier so that they are used can in order to release the active substance 15 from the device 10 .

Fig. 3 shows the device 10 of FIGS. 1 and 2 in the release of active ingredient 15 to a liquid application environment. If 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. In use, this means that the heat-sensitive mass 16 melts and forms a liquid, semi-solid or similar phase for releasing the active substance 15 through the passage 18 . When the mass 16 melts, liquid is sucked through the semi-permeable wall 12 from 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 heat-sensitive mass remains intact. As external fluid is drawn into the device 10 through the semi-permeable wall 12 , the capsule wall 13 , which is made of a liquid-soluble material, slowly dissolves and lubricates the inside of the device, resulting in the uniform expansion of the part 17 and the resultant result continuous release of mass 16 contributes. By increasing the volume of the expandable part 17 , this exerts pressure on the mass 16 and reduces its volume. The simultaneous occurrence of the expansion of the part 17, the contraction of the chamber 14 and the melting of the mass 16 results in that the mass containing the drug 15 is delivered through the passageway 18 to the exterior of the device 10 16th Figs. 2 and 3 considered together, the device 10, currency rend the delivery of the drug 15th FIG. 2 shows a delivery device 10 at the beginning of the release time and FIG. 3 shows the device near the end of the delivery time. The melting of the mass 16 , the immiscibility of the mass 16 with the part 17 and the swelling and expansion of the part 17 with the associated increase in volume, as can be seen in FIG. 3, together with the simultaneous reduction in the volume of the chamber 14 constitutes the release of the active substance 15 continuously at a controlled speed for a certain period of time.

In FIG. 4, a dispenser 20 is shown comprising two parts, a main part 21 and a cap portion 22 which are joined together to form a unitary device. The device 20 is advantageously manufactured in two parts, one part 22 sliding over the part 21 and closing it with a cap. The parts 21 and 22 surround an inner lumen and an inner cavity, which is not shown in FIG. 4. The device 20 also includes a passage 30 , which is indicated by a dotted line.

Fig. 5 is a cutaway view of a Abgabevor direction of FIG. 4 without the cap part. In Fig. 5, the device 20 comprises a main part 21 consisting essentially of a semipermeable wall 23 which 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. The capsule used to manufacture the dispenser comprises 2 parts, namely 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 points, a temperature-responsive heat-sensitive 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 consist of materials as explained in FIGS. 1 to 3 and further below.

FIG. 6 is a cut-away view of FIGS . 4 and 5. FIG. 6 shows the device 20 with the cap part 22 . This cap member 22 has been pushed over the capsule section 21 after the larger portion 21 has been filled len heat sensitive masses and driving Tei with the selected drugs. After the cap 22 has been pushed over the main part 21 , a semi-permeable wall 23 has been applied over the outer surface of the main part 21 and the cap part 22 . In another type of manufacture, the cap part 21 is filled with the respective components and a semipermeable wall is applied to this capsule part with the exception of the opening and then the cap 22 is placed on. The cap 22 is then telescoped over the main part 21 and also covered with a semi-permeable wall 23 . A passageway 30 is drilled through the semi-permeable wall 23 and the capsule wall 22 for each type of manufacture to release the active ingredient 27 from the device 20 .

Fig. 7 shows the device 20 in use. Only one semipermeable wall 23 is shown towards the end of the delivery period. The device 20 operates in the same manner as indicated for the device 10 .

Fig. 8 shows another embodiment to facilitate the manufacture and increase the effectiveness of the device. In FIG. 8, a body such as the body or main part is shown in a preferred embodiment of a capsule 31, with an ex pandierbarer plug 32 is disposed in the opening 33 of the main portion 31. The main part can consist of a semipermeable material or a hydrophilic material. A passage 34 is provided through the wall 35 of the main part 31 on the opposite side to the expandable plug 32 in order to use a filling device by means of which the space 36 of the main part 31 can be filled.

In Fig. 9, the space 36 is filled with a temperature-sensitive composition 37, comprising active ingredient 38th After the space is filled, the body or capsule is covered or surrounded with a semi-permeable wall 39 . The semi-permeable wall in each embodiment provides a means to draw liquid into the expandable member 32 and close the opening 33 , thereby ensuring that the plug 32 expands only toward the space 36 and the passage 34 . In this method of manufacture, the passage 34 is drilled through the semipermeable wall in accordance with the passage in the capsule wall to release the active substance 38 from the capsule. In another form of manufacture, a semipermeable wall 39 is applied around an empty capsule part, in the opening of which there is a plug and a passage is drilled through the semipermeable wall and the capsule wall and the space is then filled with a temperature-sensitive substance containing active substance.

The different dispensing devices indicated in FIGS . 1 to 9 are only examples. The device according to the Invention can take a wide variety of shapes and sizes for releasing active substances to different application environments. For example, the device can be manufactured for oral administration, as a buccal tablet, implant, artificial gland, for insertion into the cervix, uterus, ear, nose, skin, vagina, rectum, rumen of ruminants such as cattle and as a subcutaneous implant. The device can have such a shape and size and be constructed in such a way that it is suitable for releasing an active substance in liquid streams, aquariums, in fields, in factories, reservoirs, laboratories, greenhouses, transport devices, hospitals, in seafaring, in military Facilities, veterinary clinics, clinics, farms, zoos, hospital rooms, chemical reactors, and other application environments.

It has surprisingly been found that it is possible to manufacture the dispensing device 10 and the device 20 with a capsule with two different shapes which are referred to in the context of the invention as osmotic hard-shell capsule and osmotic soft-shell capsule. The osmotic hard-shell capsule consists of two parts, a cap and a main part, which are put together after the larger part has been filled with a predetermined corresponding active substance preparation. This is achieved by pushing the cap part telescopically over the main part, so that the active substance preparations are completely enclosed by the capsule. Hard-shell capsules are produced by immersing molds or cones in a bath which contains a solution of the material forming the capsule layer, the mold being coated with the material. The mold is then pulled out of the solution, cooled and dried in a stream of air. The capsule is stripped off the shape, trimmed to form a part with an internal cavity. The cap, which is telescoped over the main part taking the active substance preparation, is produced in a similar manner. The filled and closed osmotic capsule is covered with a semipermeable wall or layer. This wall can be brought up to the finished capsule on the parts before or after plugging together the capsule parts. The parts of the hard-shell capsule can have mutually fitting closure rings near their open ends, which enable the capsule to be firmly closed and the overlapping parts of the cap and main part to snap into place after filling with the active ingredient. In this embodiment, a pair of interlocking closure rings is provided in the cap and main part and these rings result in a closure that holds the capsule firmly together. The capsule can be filled with the active ingredient preparation manually or by machine. The hard-shell capsule is finally surrounded with a semipermeable layer which is permeable to the passage of liquid and is essentially impermeable to the passage of active substance, as explained in more detail later.

The osmotic soft capsule, as proposed according to the invention preferably used in its final form, consists of egg a piece. Generally, the osmotic soft capsule welded and the active ingredient preparation included therein sen. The soft capsule is made using various procedures produced like plate stamping process, the process with rotating forms, the process with back and forth  Forming and the continuous process. With the record a set of shapes is used. A warm Foil from a capsule-forming material is over the un tter form and the active ingredient preparation over it poured. A second film of the capsule-forming material is made placed over the active ingredient preparation and then the upper molding. The form is placed in a press and the two parts are put together with or without heat pressed to form one-piece soft capsules. The Capsules are removed with a solvent for removal liquid active ingredient preparation from the outside of the capsule wash and the air-dried capsule with a Layer of a semipermeable material coated.

In the case of the rotating form or Rotationsver Two endless belts or foils will travel out of the cap self-forming material between a couple against each other of rotating shapes and a filler wedge.

In this process, the capsules are simultaneously ge fills and closes. The pathways of the capsule-forming Ma terials are placed over leadership roles and then between the Filling wedge and the form rollers down. The ver Encapsulating active ingredient preparation flows into by gravity a positive displacement pump. The pump measures the effectiveness fabric preparation through the filler wedge into the foils between the form rolls. The bottom of the wedge has small openings gene that over the pocket-shaped depressions of the Form rolls are located. About half of the capsule is ver closed when the pressure of the pumped drug the film presses into the recesses of the mold, whereby the soft-shelled capsules are simultaneously filled, shaped, hermetically sealed and made from the films of the capsule or layer-forming material are punched out. The dense Sealing or welding the soft-shell capsules  is achieved by mechanical pressure on the forming rollers and heating the foils through the wedge. After making the capsules filled with active ingredient preparation in an air stream dried and a semipermeable layer using the procedure described later around the capsule upset around.

The reciprocating process uses two Films of the capsule-forming material between a sentence vertical shapes applied. Form these shapes by they close, open and close a continuous vertical plate, one after the other pockets over the Foil forms. These bags come with the active ingredient accessories and filled by riding through the forms go, they are tightly sealed, shaped and from the stamped out moving foil. A semipermeable layer is applied over the osmotic soft shell Get dispenser.

The continuous process also rotates Forming rollers applied, with additional active ingredient in Form of a dry powder and not just in liquid form can be filled into the soft-shell capsules. The filled soft-shell capsules that are used in the continuous process obtained are also used for Bil Formation of an osmotic soft capsule with a semiperme ablen polymeric material coated.

The dispensing device according to the invention can with a wall are provided, comprising a semipermeable material which does not harm the host or animal, for the passage an external aqueous liquid such as water and biological liquids is permeable, while it is for the Passage of active substances including drugs in the is essentially impermeable and in the presence of a thermo  tropics temperature-sensitive mass remains intact, d. H. neither melts nor degrades. The selectively semi permeable materials that form the outer wall essentially insoluble in liquids, non-toxic and not degradable.

Representative materials for the production of the semiperme ablen wall include semipermeable homopolymers, semiperme able copolymers u. a. In one embodiment, include typical materials cellulose esters, cellulose monoesters, Cellulose diesters, cellulose triesters, cellulose ethers, Cellu loose ester ethers and their mixtures. The cellulose polymers have a degree of substitution, DS, of their anhydroglucose unit from more than 0 up to and including 3. Under Substi Degree of tution is the average number of hydroxyl groups understand that originally in the anhydroglucose unit were present and that by a substituting group replaced or changed to another group. The anhydroglucose unit can be partial or complete be substituted by groups such as acyl, alkanoyl, aroyl, Alkyl, alkenyl, alkoxy, halogen, carboalkyl, alkyl carbamate, Alkyl carbonate, alkyl sulfonate, alkyl sulfamate and the like semipermeable polymer-forming groups.

The semi-permeable materials are typically made chooses from the group consisting of cellulose acylate, Cellulose diacylate, cellulose triacylate, cellulose acetate, Cellulose diacetate, cellulose triacetate, mono-, di- and tri cellulose alkanylates, mono-, di- and tri-alkenylates, mono-, Di- and tri-aroylates and the like Exemplary polymers are Cellu loose acetate with a degree of substitution from 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 substi  Degree of tution of 2 to 3 and an acetyl content of 34 to 44.8% and the like In particular, cellulose polymers include Cellu loose propionate with a degree of substitution of 1.8 and egg 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 of 34 to 39%, cellulose acetate butyrate with a Acetyl content of 2 to 29.5%, a butyryl content of 17 to 53% and a hydroxyl content of 0.5 to 4.7%, Cellu loose triacylates with a degree of substitution of 2.9 to 3 such as cellulose trivalerate, cellulose trilaurate, cellulose tripalmitate, cellulose trioctanoate and cellulose tripropio nat, cellulose diester with a degree of substitution of 2.2 up to 2.6 such as cellulose disuccinate, cellulose dipalmitate, Cellulose dioctanoate, cellulose dicaprylate and the like, mixed Cellulose esters such as cellulose acetate valerate, cellulose acetate-succinate, cellulose-propionate-succinate, cellulose acetate octanoate, cellulose valerate palmitate, cellulose acetate heptanoate and the like Semipermeable polymers are known from U.S. Patent 4,077,407 and they can be made following procedures as described in Encyclopedia of Polymer Science and Technology, Vol. 3, pp. 325 to 354, 1964, Interscience Publisher, Inc., New York.

Further exemplary semipermeable polymers are acetal dehyd-dimethyl cellulose acetate, cellulose acetate ethyl carbamate, cellulose acetate methyl carbamate, cellulose dimethyl amino acetate, semipermeable polyamides, semipermeable poly urethanes, semipermeable polysulfanes, semipermeable sulfonated polystyrenes, crosslinked, selectively semystyrene Poly mers formed by co-precipitating a polyanion and a polycation as specified in U.S. Patent Nos. 3,173,876, 3,276,586, 3,541,005, 3,541,006 and 3,546,142. Selectively semipermeable silicone rubbers, semipermeable polymers as specified by Loeb and Sourirajan in US Pat. No. 3,133,132, semipermeable polystyrene derivatives, se mipermeable poly (sodium styrene sulfonate), semipermeable poly (vinylbenzyltrimethyl) ammonium chloride, a liquid permeable polymer with a semipermeable permeability 25.4 × 10 ^-1 to 25.4 × 10 ^-7 (cm³ · µm / cm² · h · bar) [10 ^-1 to 10 ^-7 (cc · mil / cm² hr · atm)] given per bar (atm ) hydrostatic or osmotic pressure difference across the semi-permeable wall. The polymers are known from U.S. Patents 3,845,770, 3,916,899 and 4,160,020 and from Handbook of Common Polymers by Scott, JR and Roff, WJ, 1971, CRC Press, Cleveland, Ohio.

The manufacture of the swellable expandable inner Part or layer or graft suitable materia lien are polymeric materials alone and polymeric materials lien mixed with osmotic agents that with water or interact with a biological fluid, absorb the liquid and thereby up to an equal swell or expand weight. The polymers possess the ability to take a significant portion of the sucked liquid in the polymeric molecular structure to hold on. The polymers are in a preferred embodiment gel form polymers that swell very strongly or can expand and usually a 2- to 50 times the volume increase. The swellable hydro Philene polymers are also known as osmopolymers and can not networked or slightly networked. The network genes can be covalent or ionic bonds where where the polymers have the ability in the presence of  Liquid to swell, and when they are cross-linked, in not to dissolve the liquid. The polymer can vegetable be of animal, synthetic or synthetic origin. Polymers Materials suitable for the purposes of the invention are, among others, poly (hydroxyalkyl methacrylate) a molecular weight of 5,000 to 5,000,000, polyvinyl pyrrolidone 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 source capable mixture of agar and carboxymethyl cellulose, a swellable mass, comprising methyl cellulose mixed with a weakly cross-linked agar, a co-swellable in water polymer made by dispersing egg fine particle copolymer of maleic anhydride and Styrene, ethylene, propylene or isobutylene, in water source capable polymers of N-vinyl lactams and the like

Other gelling liquid-absorbing and retaining Polymers used to make the hydrophilic expandable Ren pressing part are suitable, among others Pectin with a molecular weight in the range of 30,000 up to 300,000, polysaccharides such as agar, acacia, karaya, traga canth, algine and guar, an acidic carboxy polymer and the salts (Carbopol®, polyacrylamides, swellable in water hige Inden-maleic anhydride polymers, polyacrylic acid with a molecular weight of 80,000 to 200,000 (Good-rite®, Polyethylene oxide polymers with a molecular weight of 100,000 to 5,000,000 and above (Polyox®, with starch ge grafted copolymers, polyanions and polycation exchangers polymers, starch-polyacrylonitrile copolymers, acrylate polymers with a water absorption capacity of about 400 times the original weight (Aqua-keep®, diester from Poly glucan, a mixture of cross-linked polyvinyl alcohol and Poly (N-vinyl-2-pyrrolidone), zein, which is used as a prolamine for ver  stands, polyethylene glycol with a molecular weight from 4,000 to 100,000 and the like In a preferred embodiment form is the expandable part (the expandable part Wall) made of polymers and polymeric masses that are thermally are deformable. Exemplary polymers with hydrophilic Properties are known from US-PS 3 865 108, 4 002 173, 4,207,893 and 4,327,725 and from Handbook of Common Polymers by Scott and Roff, Cleveland Rubber Company, Cleveland, Ohio.

The osmotically active compounds, alone or in homogeneous or heterogeneous mixture with the swellable Polymer can be used to form a bustle the osmotically effective parts are soluble or dissolved Substances that are sucked into the swellable polymer Liquid are soluble and have an osmotic pressure gradient across the semipermeable wall opposite the outer rivers surrender. Osmotically active compounds are also known as an osmotic agent. Osmostically effective connection that are suitable for the purposes according to the invention, are among other things fixed connections, selected from the Group magnesium sulfate, magnesium chloride, sodium chloride, Lithium chloride, potassium sulfate, sodium sulfate, mannitol, urine substance, sorbitol, inositol, sucrose, glucose and the like The os Motive pressure in bar (atm) of the osmotic agent for the purposes of the invention are suitable is greater than 0 bar and is generally from 0 to 500 bar or about that.

The swellable expandable polymer serves in addition to its Effect as a driving force for the delivery of an active ingredient the device, also as a carrier matrix for an osmotic effective soluble substance. The osmotic substance can be homogeneous or mixed heterogeneously with the polymer to form  the desired expandable wall or expandable Bag. The mass (for the production of the driving part) preferably comprises a) at least one polymer and at least an osmotically active soluble substance or b) at least a solid osmotically active soluble substance. In all such a mass generally comprises about 20 to 90% by weight Polymer and 80 to 10 wt .-% osmotically active soluble Substance, masses with 35 to 75 wt .-% polymer and 65 to 25% by weight of osmotically active substance are preferred.

The temperature-responsive substance as he fiction According to is used comprises thermoplastic compositions which in are able to soften in response to heat or can be released from the device and when Ab cool solid again. The term also includes thermo tropical masses capable of responding to the an use of energy to change gradually. This Substances are sensitive to temperature in their reaction to the Application and withdrawal of energy. The on temperature attractive materials, such as those for the invention Purposes that are preferably used are physical chemical properties of an active ingredient carrier and are in Temperatures up to 33 ° C solid or solid and who the liquid, semi-solid or viscous when on tempera doors of 32 ° C or above, preferably in the range of 32 to 40 ° C. The temperature responsive Carrier is sensitive to heat and possesses the property melt at elevated temperatures, dissolve, dissolve dissolve, soften or liquefy and thereby a To form mass that are released from the device can, which makes it possible for the temperature to speaking carrier together with the homogeneous or heterogeneous thus mixed active ingredient released from the device becomes. The temperature-sensitive carrier can be lipophilic,  be hydrophilic or hydrophobic. Another important property The wearer 's shaft is his ability to maintain the stability of the active ingredient contained therein during storage and To maintain the levy. Typical on temperature speaking masses 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 oil, 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 acid, triglycerides of saturated Fatty acids with mono- and diglycerides 34-35.5 ° C, propylene glycol mono- and distearate 33-44 ° C, partially hydrogenated Cottonseed oil 35-39 ° C, a block copolymer made of polyoxyal kylene and propylene glycol, block copolymers comprising 1,2- Butylene oxide to which ethylene oxide has been added, block copolymers of propylene oxide and ethylene oxide, hardened fat alcohols and fats 33-36 ° C, hexadienol and aqueous lanolin triethanolamine glyceryl monostearate 38 ° C, eutectic Ge mix of mono-, di- and triglycerides 35-39 ° C, Witepsol® 15 (modified triglyceride of saturated vegetable fatty acids with monoglycerides, melting point 33.5-35.5 ° C), Witepsol® H32 (modified triglyceride from saturated plants fatty acids free of Hydroxyl groups, melting point 31-33 ° C), Witepsol® W25 (modified triglyceride from saturated plants fatty acids with saponification number of 225-240 and a melting point of 33.5-35.5 ° C), Witepsol® E75 (modified triglyceride from saturated plants fatty acids with a saponification count of 220-230 and a melting point of 37-39 ° C), a polyalkylene glycol such as poly ethylene glycol 1000, a linear polymer of ethylene oxide 38-41 ° C, polyethylene glycol 1500 mp. 38-41 ° C, polyethylene  glycol monostearate 39-42.5 ° C, 33% polyethylene glycol 1500, 47% polyethylene glycol 6000 and 20% distilled water 39-41 ° 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 11 to 17 carbon atoms 33-35 ° C and the like The on temperature attractive mass is a means of storing a Active ingredient in a solid mass at a temperature of 20-33 ° C, which is an immiscible interface with the source maintains capable mass, and to release the active ingredient in a flowable medium at temperatures <33 ° C preferably in the range of 33-40 ° C. That depends on temperature speaking means when it is in a biological reverse exercise is released, easily excreted, metabolized, assimilated or the like and can be used effectively by anyone the.

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 a bloom resistance of up to 150 g, gelatin with a bloom value of 160-250 , a composition containing gelatin, glycerin, water and titanium dioxide, a composition comprising gelatin, erythrosine, iron oxide and titanium dioxide, a composition comprising gelatin glycerol, sorbitol, potassium sorbate and titanium dioxide, a composition comprising gelatin, acacia, glycerin and water and the like.

The term active substance as used here means meaning any mass, preparation, mixture or mixture Compound that can be delivered from the device to have a certain beneficial effect. The active ingredient fe include algicides, antioxidants, air purifiers, Biocides, catalysts, chemical reactants, Kos Metics, drugs, disinfectants, fungicides, Nah  agents, fertility inhibiting and promoting agents, Food additives, fermentation agents, germicides, insecticides, Mi Croorganism-weakening agents, nutrients, vegetable wax accelerators and inhibitors, preservatives, surfactants, sterilizers, sexual Sterilizers, vitamins and other agents with a gün effect on the environment, lounges and animals. The active ingredient can be in the temperature sensitive material be insoluble to very soluble.

In the description and claims, the term includes Drug any physiological or pharmacological effective substance that has a local or systemic effect in animals including warm-blooded animals, humans and Primates, birds, fish, pets, sports and farmers animals, laboratory animals and zoo animals. The expression physiologically as used here refers to the administration of a drug to produce norma contents of the substance in question or normal functions The term pharmacologically refers to changes in response to the amount of drug administered (Stedman’s Medical Dictionary, 1966, Williams and Wilkins, Baltimore, MD). The drug that was invented with the help of device according to the invention can be delivered includes organic and organic solid and oily drugs without limitation like drugs that affect the nervous system act, depressants, hypnotics or sleeping pills, Seda tiva, psychic stimulants, tranquilizers, anticonvulsants medium, muscle relaxants, anti-Parkinson drugs, analgesics, anti-inflammatory, antimalarial, hormonal Medium, contraceptives, sympathomimetic, diuretic, anti parasitic agents, neoplastics (anti-tumor agents), hypoglycaemics, Ophthalmic, electrolytes, diagnostics and on the cardiovascular system effective means. The amount of active ingredient in the pre-delivery direction can be 0.05 ng to 20 g or more. For me  the device can be used for medical applications amounts, for example 25 ng, 1 mg, 5 mg, 125 mg, 250 mg, 500 mg, 750 mg, 1.5 g and the like Amounts included. The Vorrich Tung can be used or taken 1, 2 or 3 times a day or just 2 times a week or similar Intervals.

The mass forming the semipermeable wall can be on the outside side of the capsule in a laminar arrangement by molding, molding, spraying, dipping or Spread the mass forming the semipermeable wall. Other and preferred methods of applying the semi permeable wall are the air swirling method and that Cover in the boiler. The air swirling process is that the capsule assembly in one stream Air and a mass forming the semipermeable wall whirls and falls until the wall surrounds the capsule and covers. The process can be done with a different who repeats a semipermeable wall forming mass to form a laminated semi-permeable wall. The air swirling 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 to 84, 1960. Other Stan Manufacturing processes are given in Modern Plastics Encyclopedia, Vol. 46, pp. 62 to 70, 1969 and in Pharmaceu tical Sciences von Remington, 14th ed., pp. 1626 to 1678, 1970, Mack Publishing Co., Easton, PA.

Exemplary solvents used to manufacture the semi permeable wall are suitable, among others, anorga niche, and organic solvents, which are the materials the capsule wall, the active ingredient, the temperature sensitive Mass, the expandable part and the dispenser not adversely affect. The solvents include generally those from the group of aqueous solvents,  Alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic compounds genes, aromatics, heterocyclic solvents and their Mixtures. 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, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene dichloride, ethylene di chloride, propylene dichloride, carbon tetrachloride, nitro ethane, nitropropane, tetrachloroethane, ethyl ether, isopropyl ether, cyclohexane, cyclooctane, benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, diethylene glycol dimethyl ether, water and their mixtures 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 made according to the invention at a temperature a few degrees below the enamel point of the temperature sensitive mass applied or the temperature sensitive mass can be in the device be introduced after the semipermeable wall is opened has been brought.

The expression opening or passage as used here includes means and procedures by means of which it is possible is a drug preparation from the device release. The opening can be done by mechanical or Laser drilling can be made or by dismantling one buildable element like a gelatin plug in the wall. The opening can also consist of a polymer in the semi-permeable wall is inserted, which is porous and has at least one pore or that is microporous and closed has at least one micropore. A detailed description exercise of openings and their preferred maximum and mi nominal dimensions are given in U.S. Patent No. 3,845,770 and 3 916 899.  

The invention is illustrated by the following examples purifies.

example 1

An active substance dispenser was produced as follows: Zu next, the main part of a two-part capsule the opening up and into the hemisphere End of the capsule a layer of an expandable source capable mass introduced. The mass comprised 30% by weight Sodium chloride and 70 wt .-% polyethylene oxide with a Mo molecular weight of 3,000,000. The expandable mass constituents were in a commercial Mixer using heat mixed for 20 min Formation of a homogeneous mass. The heated wet was in inserted the capsule and formed a layer that approximately Took 1/4 of the capsule. Then the cap part the capsule and a filling opening through the Cap drilled with the cavity of the composite Capsule communicated. Then there was a warmth sensitive drug preparation through the filler introduced into the cavity of the capsule. Finally a semipermeable wall was applied around the capsule and a passage drilled through the semipermeable wall, the communicated with the fill opening to the drug dispense preparation.

Example 2

A dispenser was made as follows: First of all, the main part of a two-part capsule the open end up and into the semis Gelgel lower end of the capsule a 500 mg layer of polyacrylamide (Cyanamer® a hydrogel with a Mo molecular weight of about 200,000. Subsequently the cap was put on the main part. Then one became semipermeable wall around the capsule formed by mixing  85 g of cellulose acetate with an acetyl content of 39.8% and 20 ml methylene chloride and 20 ml methanol and application this mixture onto the capsule by swirling air a 0.25 mm thick semipermeable wall surrounded the capsule. The capsule was dried and a 1.0 mm pass with Help a laser through the semipermeable wall and the Capsule wall drilled to the cavity of the capsule. Subsequently a heat-sensitive intestinal soluble (gastric juice consistent) mixture of 77% neutral fat with a melt point of 35-37 ° C and 19.5% paraffin with a melting point heated and liquefied at 52 ° C and 3.5% acetylsalicyl acid added. The heated mixture was then brought to about Cooled 40 ° C and through the passage into the cavity of the Capsule injected and the dispenser to room temperature cooled down.

Example 3

A drug delivery delivery device to a warm-blooded animal was made as follows: A shape that matches the opening and inner diameter of the Main part of the capsule was filled with one the expandable part forming mass, comprising 30 parts Ethylene glycol monomethacrylate containing 0.12 part of ethylene glycol dimethacrylate and 10 parts 0.13% aqueous solution of sodium disulfate in aqueous ethanol. The mass poly merized at 30 ° C and 20 min after setting the room the solid layer was removed from the mold at the temperature. The solid expandable layer was then in the opening given the capsule and formed an internal drug containing chamber in the space between the hemispherical end the capsule and the inner surface of the expandable Polymers. Then there was a filler outlet drilled through the hemispherical end that defines the exterior of the Capsule connected to the inner chamber. The chamber can then with a heat-sensitive pharmaceutical preparation  can be filled or, if necessary, also to a filled with it later.

For example, the chamber can be filled with a ge melted mass comprising 2.5% phenobarbital, 20.5% Gly ceringelatine and 77% theobroma oil, a glyceride of stearin, Palmitic and lauric acids, the tem temperature sensitive mass in laminar arrangement to the ex pandable layer forms. Then the main part of the capsule by sliding the cap over the open one End of the main part closed.

Then a solution of 15 wt .-% cellulose manufactured with an acetyl content of 39.8% and the assembled capsule with a semi-permeable wall coated by immersing it in the solution 15 times first 10 s, then 1 min in between drying times of 5 min. After immersion the device was operated at room temperature, i.e. H. about 22 ° C, Dried for 10 days. This procedure gave approximately a 2 mm thick semipermeable wall. With the help of a laser a passage drilled through the semipermeable wall, the the exterior of the device with the fill opening and the bonded to temperature-sensitive layer.

Example 4

A drug delivery delivery device was prepared as follows: First, the hemispherical end of a gelatin capsule was filled with 3.25 g of a molten mass consisting essentially of 30% sodium chloride and 70% polyethylene oxide (for coagulation). The cap of the capsule was then immersed in water a few mm and the cap was then pushed over the open end of the main part of the capsule. The water caused the cap and the main part of the capsule to bind tightly together. A 1.3 mm passage was then drilled through the cap portion of the assembled gelatin capsule. Then 9.9 g of a temperature-sensitive pharmaceutical preparation consisting of a 15% suspension of theophylline with 8% water-free polyethylene glycol 400 distearate (Cabosil®) were introduced through the opening into the pharmaceutical chamber of the capsule at 50 ° C., one Layer in intimate contact with the expandable plug at the hemispherical end of the capsule was formed. The temperature sensitive drug preparation was also in contact with the inside of the gelatin capsule. The finished capsule was then coated with a wall of cellulose acetate butyrate, containing 10% 400 polyethylene. The semi-permeable wall was applied in a hi-pan 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 0.03 mm thick layer of cellulose acetate butyrate was applied to the outside of the capsule. Fig. 10 shows the release rate in µg / h at 37 ° C.

The capsule according to the invention is suitable for an active ingredient at a controlled speed to the vagina or that To deliver the rectum of a warm-blooded animal. A) is in the Body cavity introduced a device comprising 1) a outer wall made of a semipermeable polymeric mass, the permeable for the passage of liquid and for the Passage of drugs essentially impermeable and which surrounds 2) a capsule containing a layer from a pharmaceutical preparation in the chamber comprising a unit dose of medication to perform the thera program, in a heat-sensitive medium, that melts at body temperature and a means of trans  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 medicine preparation and 4) an opening through the outer Wall and the capsule wall that with the heat sensitive Drug preparation is in contact, B) Liquid through the semipermeable wall with a ge sucked in speed, which is determined by the permeability the semipermeable wall and the osmotic pressure gradient over the semipermeable wall, creating 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 melted preparation and causes the Preparation in a therapeutically effective amount with ge controlled speed passes through the opening and the desired medical effect over a period of time from 1 h to months, preferably from 1 to 24 h practices. An example of a drug that is particularly good Stig can be delivered using the device is conjugated estrogen in a preparation to containing 0.875 mg conjugated estrogens in a heat sensitive basic substance.

Claims (4)

1. A delivery device for releasing a heat sensitive drug formulation at a controlled rate over time to an application environment, the delivery device comprising:

• a) a one-part or two-part capsule comprising gelatin, which has an internal cavity,
• b) a layer comprising a hydrophobic, heat-sensitive active ingredient formulation with a melting point between 31 ° C and 42.5 ° C, said heat-sensitive formulation comprising an ingredient selected from the group consisting of beeswax, cocoa butter, a hydrogenated vegetable oil , partially hydrogenated cottonseed oil, a glyceride, an ester of a saturated fatty acid, a 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;
• c) a hydrophilic mass in the cavity, which absorbs and swells liquid, the hydrophilic mass being in contact in a layered arrangement with the heat-sensitive active ingredient formulation;
• d) a wall surrounding the capsule, the wall comprising a semi-permeable cellulose composition which is permeable to the passage of liquid and impermeable to the passage of the active substance, and
• e) a passage through the wall, which is a connection with the heat-sensitive active ingredient formulation.

2. Device according to claim 1, characterized characterized in that the hydrophilic mass Hydrogel and an osmotically active soluble substance sums up. 3. Device according to claim 1 and 2, characterized characterized in that the hydrophilic mass Polyethylene oxide, polyacrylic acid and its salts, polyethylene glycol and optionally an osmotically active solvent Chen contains fabric. 4. Device according to one of claims 1 to 3, characterized characterized that the semipermeable wall has been made from cellulose ester, cellulose diesters, 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.