NL8602556A - Device for controlled release of biologically active material - comprises meltable compsn. in compartment having swellable inner wall, esp. polyethylene oxide, and semipermeable outer wall - Google Patents

Abstract

Device for controlled release of a heat-sensitive beneficial agent (I) comprises an internal wall defining a compartment which contains (I) and is provided with an orifice for filling with (and dispensing) (I). This wall is made of a compsn. which can absorb fluid, swelling and expanding into the compartment. An exterior wall surrounds this inner wall and is formed of a material permeable to fluid but not to (I), and a passageway in the outer wall communicates with the orifice. Partic. the inner wall comprises a polymeric hydrogel (opt. contg. an osmotically effective solute) and the external wall is partic. an ester; diester; ester-ether, mono-, di- or tri-acylate; mono-, di- or tri-acetate or acetobutyrate deriv. of cellulose. The internal wall is esp. polyethylene oxide (PEO), opt. mixed with polyethylene glycol (PEG) and a solute. Apart from cellulose derivs., the outer wall can be made of polysulphone, poly(meth)acrylate, poly(methyl methacrylate), or polyurethane. (I) particularly includes a solid which melts at above 33 deg.C, e.g. a glycerol ester of a satd. fatty acid.

Description

N.0. 34.088 '1' ISSUING DEVICE FOR THE DELIVERY OF A HEAT RESISTANT COMPOSITION.

This invention relates to both a new and useful delivery device. More particularly, the invention relates to an osmotic delivery device for delivering a heat-responsive composition containing a beneficial agent over time to a use environment at a controlled rate.

Delivery devices for delivering a beneficial agent to a use environment are known in the art. For example, U.S. Pat. No. 3,760,984 (Theeuwes) discloses a dispenser consisting of a heat-shrinkable container provided on the outside with an osmotic solvent and a layer of a liquid-permeable polymer separated therefrom. The dispensing device is provided with a stopper for filling the container.

The operation of the dispensing device is to draw a liquid into the device in which it dissolves the solvent, whereby a solution is formed which exerts pressure against the shrinkable container, causing it to shrink and release the agent from the device.

United States Patent 3,865,108 (Hartop) discloses a delivery device consisting of a compressible inner tube containing a drug in a base part formed by a swellable material. The device delivers the drug in that the base and the parts absorb liquid from the environment and press on the compressible tube thereby forcing the drug out of the tube.

In U.S. Patent 3,971,376, Wichterle discloses a dispenser consisting of a capsule having one-piece walls formed by a cross-linked gel that is swellable in liquids.

Included in the material is a textile fabric which imparts strength and reduces problems that arise due to poor mechanical properties of the material when incorporated into the liquid for operation of the dispenser. In U.S. Pat. No. 3,987,790, Eckenhoff et al. Discloses an improvement in an osmotic delivery device consisting of a conduit for filling a pouch in the device. The device operates by an osmotically effective solvent drawing liquid into the device and this fluid generates hydraulic pressure against the pouch thereby squeezing it and forcing the agent out of the dispenser. U.S. Pat. No. 40 3,995,631 (Higuchi et al.) Discloses a pouch attached to the outside. 3602556 9 2

P

lace is provided with a layer of an osmotic solvent and a separated wall which is formed by a material having controlled liquid permeability. When the device is in use, a solution of the solvent is formed which presses on the pouch 5, releasing the agent from the pouch. In U.S. Pat. No. 4,320,758, Eckenhoff et al. device consisting of a flexible bag, a jacket of a dispersion of an osmotically effective solvent in a soluble polymer and a liquid-permeable outer wall. The device delivers a drug by the jacket absorbing water into the space between the outer wall and the pouch, thereby applying hydraulic pressure to the pouch to squeeze the pouch and release the drug.

While the aforementioned delivery devices are useful for delivering a variety of agents to a use environment, and these devices represent a commercial advance in the dispensing technique, it is clear to those skilled in the art that there are instances where a novel and inventive improvement is made in the dosing technique can also be used and applied generally commercially. For example, if a dispenser was made without a flexible bag and without a woven part, which would be an improvement by reducing the number of steps and parts required to manufacture the dispenser, such a device would be accepted immediately and a significant improvement in represent the technique. Likewise, if a dispenser was provided that did not have the limitation of the prior art dispensers, n.1. that only agents are released in dissolved or suspended form, and now can deliver agents that are soluble or insoluble in liquid, or solid or the like forms, such a dispenser is immediately appreciated and also makes a valuable contribution to the areas of science, medicine and commerce.

It is therefore an immediate object of the invention to provide a new delivery device for delivering beneficial agents in all forms to use environments, which involves an improvement in the dispensing technique.

Another object of the invention is to provide a dispenser which is self-contained, self-propelled and self-propelled in liquid environments, is easy to manufacture and can use.

for delivering beneficial agents to animals, including K

people, and to other biological and non-biological use environments.

A further object of the invention is to provide a delivery device which can contain a heat-reacting, hydrophobic composition with insoluble or soluble drugs therein, which heat-reacting composition changes due to the temperature of a biological environment and becomes liquid, semi-solid or the like, thereby accelerating delivery from the device.

Yet another object of the invention is to provide a dispensing device comprising a compartment containing a temperature-sensitive composition, an expanding part partially surrounding the composition, a semipermeable outer wall surrounding the part and the compartment, and a delivery passage comprising The device releases the composition through the combined physical-chemical actions of melting and becoming liquid, semi-solid, or the like of the composition, the composition having an immiscible interface with the expandable member, and the expandable part swells and thereby expels a corresponding amount of the composition from the device.

Yet another object of the invention is to provide a dispenser that is empty until it is filled with a solid composition that liquefies at elevated temperatures and that when filled, the composition liquefies as a complete pharmaceutical course for a period of time. can administer requiring intervention only at the beginning and at the end of the course.

Another object of the invention is to provide a delivery device capable of delivering beneficial agents contained in a heat-responsive, lipophilic pharmaceutically acceptable carrier that melts in the presence of thermal energy into a administrable, harmless composition, with irritation of mammalian tissue and interaction with mammalian protein tissue is largely avoided.

A further object of the invention is to provide an osmotic delivery device containing a eutectic composition formed by at least two components and at least one drug, which composition has a melting point approximately at the temperature of a warm-blooded animal and at that temperature from the device is delivered to the animal.

8602556 4

Yet another object of the invention is to provide a delivery device which can contain a heat-reacting hydrophilic composition, which includes insoluble to soluble drugs, which shape-changes heat-reactive composition as a result of energy supply from a biological environment. and becomes administrable.

A further object of the invention is to provide a delivery device containing a beneficial agent which is chemically unstable in an aqueous environment and which can be incorporated into the delivery device in a non-aqueous carrier and upon delivery from the device into the non-aqueous medium. carrier is shielded.

Other objects, features and advantages of the invention will become apparent from the following description, drawings and claims.

15

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, which are not to scale, but are intended to illustrate the various embodiments of the invention, the figures have the following meanings.

FIG. 1 is a view of a delivery device designed and manufactured for oral administration of a beneficial agent to a warm-blooded animal.

Fig. 2 is a sectional view of the delivery device of FIG. 1 taken along 2-2, showing the interior compartment and the thermodynamic parts constituting the integral delivery device.

Fig. 3 is a sectional view of the device of FIG. 1 in which the compartment is filled with a temperature sensitive composition containing a beneficial agent.

FIG. 4 is a sectional view of the opened device of FIG. 3 illustrating the expansion of the propellant used to deliver a beneficial agent from the device.

Fig. 5 is a sectional view of FIG. 1 showing a closure member in the compartment.

Fig. 6 depicts an embodiment of the invention in which the components of the device are arranged concentrically.

Fig. 7 depicts an embodiment of the invention in which the parts of the device are arranged in a divided circular shape. Fig. 40 8 shows an embodiment of the invention in which the 8602556 * 5 parts of the Device are arranged in layers.

Fig. 9 shows an embodiment of the invention in which the parts of the device are arranged in bag form.

Fig. 10 is a flow chart of three methods of manufacturing the delivery device provided by the invention.

Fig. 11 is a graph illustrating the delivery rate from a delivery device.

Fig. 12 is a graph illustrating the total amount of composition released from the device.

In the figures and in the description, like parts in related figures are indicated with like numbers. The terms and embodiments thereof appearing earlier in the description of the embodiment and in the description of the drawings are explained elsewhere in the description.

15

DETAILED DESCRIPTION OF THE DRAWINGS

The drawings are examples of novel and beneficial release devices for the delivery of a beneficial agent and should not be construed as limiting.

Fig. 1 shows delivery device 10 with a body 11, a wall 12 and a passage 13 in wall 12 connecting the interior of the device to the environment.

Fig. 2 is a sectional view of the delivery device of FIG. 1, wherein device 10 consists of body 11, wall 12 around an internal compartment 14, and passage 13 in wall 12 connecting compartment 14 to the exterior of device 10. Wall 12 is formed by a semipermeable polymeric wall-forming composition which is permeable to an external fluid and substantially impermeable to a beneficial agent and other ingredients contained in compartment 14. Wall 30 12 is non-toxic and maintains its physical and chemical integrity throughout the life of dispenser 10.

Compartment 14 also includes a layer 15 of an expandable weir that abuts the interior of wall 12. Inner layer 15 partially encloses compartment 14, except at an opening area 16 35 defined by the separated ends 17 of layer 15. Inner layer 15 has a shape corresponding to the shape of semipermeable wall 12 and compartment 14. Layer 15 is made of a hydrogel composition , whether or not cross-linked, has osmotic properties such as the ability to draw an external fluid through semipermeable wall 12 and to exhibit an osmotic pressure gradient across the semipermeable wall 12 against a fluid outside of device 10602556 <6>.

Fig. 3 shows device 10 of FIG. 1 in a cross section. In FIG. 3, device 10 includes the same structural members as in FIGS. 1 and 2 and further contains in compartment 14 a beneficial agent 18 indicated by dots and a heat-responsive heat sensitive composition 19 indicated by wavy lines. Composition 19 is a delivery agent and a carrier for beneficial agent 18. Beneficial agent 18 in compartment 14 that can be delivered by the device includes agents which are insoluble to readily soluble in an aqueous liquid and in lipophilic medium. In a presently preferred embodiment, the heat-reacting composition 19 with agent 18 homogeneously or heterogeneously dispersed or dissolved therein is formed by an anhydrous, heat-sensitive, hydrophilic or hydrophobic material which, at a temperature of 21 ° C and approximately the property of has a solid and has a melting point near the mammalian body temperature of 37 ° C or thereabove. In the invention, the terms "melting point", "softening point" or "liquefaction" are used to indicate the temperature at which the heat-reacting composition melts, dissolves or liquefies into a dispensable carrier so that it can serve to from 18 out of 19.

When delivery device 10 is in the operating environment at a temperature of about 37 ° C, this agent 18 delivers by a combination of thermodynamic and kinetic actions. The heat sensing composition 19 then melts to form a liquid-like, semi-solid or the like deliverable phase for the delivery of agent 18 through passage 13. When composition 19 melts, liquid is aspirated through hydrophilic layer 15 through a hydrophilic layer 15 through a bias to osmotic equilibrium whereby layer 15 gradually swells and occupies more space in compartment 14, while maintaining a non-mixing boundary at the interface. At the same time, layer 15 presses against composition 19. By simultaneously expanding layer 15, contraction of compartment 14 and melting composition 19, composition 19 with agent 18 therein is released through passage 13 to the outside of device 35. Figures 3 and 4 together illustrate the operation of device 10 for delivering agent 18. In Figure 3, device 10 is shown at the beginning of delivery and in Figure 4 at the end of delivery. The melting of composition 19 and the immiscibility of composition 19 and expansion layer 15, the swelling of layer 15 40 as seen in Fig. 4 with the associated volume reduction 8602556 7 of compartment 14 as seen in Fig. 4, ensure for that agent, 18 at a controlled rate and being released gradually.

Fig. 5 is an embodiment of the delivery device 10 of FIGS. 1-4, which additionally shows a closure 20. Closure 20 5 fits snugly in compartment 14 and rests against the inner wall of layer 15. The exterior of closure 20 forms a liquid-tight barrier with the adjacent portion of the inner surface of layer 15. Closure 20, which may be termed a stopper, has a central hole 21 throughout its thickness. Hole 21 provides access to the interior of device 10 10, mainly compartment 14, whereby compartment 14 of composition 19 can be filled with beneficial agent 18 therein. At the same time, hole 21 provides access to passage 13 in semipermeable wall 12 for dispensing composition 19 containing means 18 from device 10.

Figures 6 and 7 show other embodiments of dispenser 10 according to the invention. Dispensing device 10 of Figs. 6 and 7 is manufactured by a presently preferred method by coextruding the structural parts of Device 10. In Fig. 6, Device 10 is shown with the ends 22 and 23 open so that the construction of device 10 becomes visible. Device 10 mainly consists of a semipermeable wall 24 which completely encloses the device, including the ends 22 and 23, a centrally located expandable propellant 25 and an inner space 26 for the heat-reacting agent. Device 10 further comprises a set of dispensing openings 27 in the closed ends 22 and 23 of semipermeable wall 24, which are not visible in the figure, for dispensing the composition with the beneficial agent. Fig. 7 illustrates device 10 which includes a semipermeable wall 28 that defines and defines the exterior of device 10 and is cut transversely in the drawing at the ends 29 and 30 so that the internal reservoir 31 for the heat-reacting agent and an abutting abutment layer of a swellable weir 32. Device 10 here has three dispensing openings 33 through semipermeable wall 28 through which the beneficial agent can be dispensed from reservoir 31. An opening is located in the body of device 10 and the other two are located at the closed ends of the device. Device 10 of Figs. 6 and 7 operates in the operating environment as described above.

Fig. 8 shows a rectangular configuration of device 10; however, delivery device 10 may also have other shapes adapted for use in certain liquid environments. In FIG. 8, direction 8602556 is cut away along two of the side edges to illustrate the interior structure. Device 10 comprises a dispensing opening 35, a semipermeable wall 36, a compartment 37 with a heat-reacting composition 38 containing beneficial agent 39 and a swellable 5 "propellant 40. Device 10 serves to dispense agent 39 as described above, ie that heat-reactive composition 38 melts in a temperature range of 35 to 41 ° C and layer 40 adjoining composition 40 then swells and pushes composition 39 through opening 35.

FIG. 9 illustrates a delivery device 10 that can be manufactured in various sizes for use as a metering pump. In the dispensed embodiment, device 10 has been miniaturized for use as an implant delivery device for administering a beneficial agent to an animal. Device 10 is shown in cross-section and comprises a form-retaining wall 41 which at least partly consists of a semipermeable material around an inner, swellable bag-shaped part 42. Bag 42 is an opened container with an inner space 43 and an opening 50 which is closed by closure 44. Closure 44 has a filling and dispensing hole 45. Bag 42 20 contains beneficial agent 44 and heat-reacting carrier composition 47. Passage 49 in semipermeable wall 41 is in line with hole 45 for filling device 10 and for delivering beneficial agent 46 from the device.

Figures 1-9 illustrate only some of the wide variety of shapes, sizes and designs of devices for delivering beneficial agents to the environment of use. For example, the delivery device can be made for oral administration in sizes from 5 to 25 mm, or for use as an implant, artificial gland, device for the neck, uterus, ear, nose, skin, vaginal, rectal, in bovine rumen or gizzard and as a sub-cutaneous delivery device. The dispenser may also be adapted to deliver an active agent in streams, aquariums, in fields, in factories, in reservoirs, in laboratory equipment, in greenhouses, in means of transport, in hospitals, in shipbuilding, for military purposes, in veterinary clinics , nursing homes, on farms, in zoos, in chemical reactors, etc.

DETAILED DESCRIPTION OF THE INVENTION

Surprisingly, it has now been found that dispenser 10 can be provided with a wall of a semipermeable material that does not adversely affect a host or animal, is permeable to an external aqueous fluid, such as water and biological fluids, and thereby substantially remains impermeable to agents such as drugs, osmotic agents and maintains its integrity in the presence of a thermotropic composition. The selectively semipermeable materials that form the outer wall are virtually insoluble in liquids, non-toxic and non-erodible.

Representative materials for forming the semipermeable wall include semipermeable homopolymers, semipermeable copolymers, and the like. In one embodiment, they are cellulose esters, cellulose monoesters, cellulose diesters, cellulose esters, cellulose ethers, and cellulose ester ethers. These cellulosic polymers have a degree of substitution (SG) on the anhydroglucose unit greater than 0 and up to and including 3. The degree of substitution is understood to mean the average number of hydroxyl groups originally present on the anhydroglucose unit which have been replaced by a substituent group or has been converted to another group. The anhydroglucose unit may be fully or partially substituted with groups such as acyl, alkanoyl, aroyl, alkyl, alkenyl, alkoxy, halogen, carboxyalkyl, alkyl carbamate, alkyl carbonate, alkyl sulfonate, alkyl sulfamate and the like semi-transparent polymer-forming groups.

Semipermeable materials include cellulose acylate, cellulose ediacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cell lazy triacetate, cellulose mono-, di- and tri-alkyl atoms, mono, di- and tri-alkenylates, and mono , di- and triaroylates and the like. Exemplary polymers include cellulose acetate having an SG of 1.8 to 2.3 and an acetyl content of 32 to 39.9%; cellulose diacetate with an SG of 1 to 2 and an acetyl content of 21 to 35%; cellulose triacetate with an SG of 2 to 3 and an acetyl content of 34 to 44.8% and the like. More specific cellulose polymers include cellulose propionate with an SG of 1.8 and a propionyl content of 38.5%; cellulose acetate propionate with an acetyl content of 1.5 to 7% and a propionyl content of 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 an SG of 1.8, an acetyl content of 13 to 15% and a butyryl content of 34 to 39%; cellulose acetate butyrate with an acetyl content of 2 to 29.5%, a butyryl content of 17 to 53%, and a hydroxyl content of 0.5 to 4.7%; cellulose triacylates with a SG of 2.9 to 3 such as cellulose triivalate, cellulose triaurate, cellulose tripalate, 8602556 mitate, cellulose trictanoate and cellulose tripropionate; cellulose diesters with an SG of 2.2 to 2.6 such as cellulose disuccinate, cellulose sedipalmitate, cellulose dioctanoate, cellulose propionate, morpholinobutyrate, cellulose acetate butyrate, cellulose acetate phthalate and the like; mixed cellulose esters such as cellulose acetate valerate, cellulose acetate succinate, cellulose propionate succinate, cellulose acetate octanoate, cellulose sevalerate palmitate, cellulose acetate heptanoate and the like. Semipermeable polymers are known from U.S. Patent 4,077,407 and can be made by methods described in Encyclopedia of Polymer Science and Technology, Vol. 3, pp. 325-354, 1964, published by Interscience Publishers, Inc . New York.

Other semipermeable polymers include cellulose acetaldehyde dimethyl acetate, cellulose acetate ethyl carbamate, cellulose acetate methyl carbamate, cellulose dimethylaminoacetate, semipermeable polyamides; semipermeable polyurethanes, semipermeable polysulfanes, semipermeable sulfonated polystyrenes, cross-linked, selectively semipermeable polymers formed by coprecipitation of a polyanion and a polycation as disclosed in U.S. Pat. Nos. 3,173,876; 3,276,586; 3,541,005; 3,541,006 and 3,546,142; Selective semipermeable silicone rubbers, semipermeable polymers as disclosed by Loeb and Sourirajan in U.S. Patent 3,133,132; semipermeable polystyrene derivatives, semipermeable polysodium styrene sulfonate, semipermeable polyvinyl benzyl trimethylammonium chloride, a semipermeable polymer with a liquid permeability of 10 µm to 10 micron (25.4 micron) per cm 2. per hour, per atm, expressed per atm hydrostatic or osmotic pressure difference over the semi-permeable wall. The polymers are known in the art from U.S. Pat. Nos. 3,845,770, 3,916,899, and 4,160,020 and in the Handbook of Common Polymers, by Scott, J.R. and 30 Roff. W.J., 1971, published by CRC Press, Cleveland, Ohio.

The materials used to form the swellable inner wall and the pouch are polymeric materials per se and polymeric materials that are mixed with osmotic agents that react to water or a biological fluid, soak up the fluid and swell to an equilibrium state. The polymer has the ability to retain a significant portion of the aspirated liquid in the molecular structure of the polymer. In a presently preferred embodiment, the polymers are gel polymers that can swell to a very great extent, usually undergoing a 2- to 50-fold volume increase. The swellable, hydrophilic polymers with osmotic properties 8602556 11 are also known as osmopolymers, which may or may not be cross-linked. The cross-links can be covalent or ionic bonds in which the polymer has the ability to swell in the presence of liquid and, when not cross-linked, the polymer does not dissolve in a water-like liquid. The polymers can be of vegetable, animal or synthetic origin. Polymeric materials useful for the present purpose are to form polyhydroxyalkyl methacrylic with a molecular weight of 5000 to 5,000,000, polyvinyl pyrrolidone with a molecular weight of 10,000 to 360,000, anionic and cationic expandable hydrogels, polyelectrolyte complexes, polyvinyl alcohol with a low acetate residue, a swellable mixture of agar and carboxymethyl cellulose, a swellable composition comprising methyl cellulose mixed with a very little cross-linked agar, a water-swellable eopolymer made by dispersion of a finely divided copolymer of maleic anhydride with styrene, ethylene , propylene or isobutene, a water-swellable polymer of N-vinyl lactams and the like.

Other gellable, liquid-absorbing and liquid-holding polymers useful for the formation of the hydrophilic, expandable propellant include pectin having a molecular weight ranging from 30,000 to 300,000, gelatin having a viscosity of 15 to 30 millipoise and a BI uncle strength up to 150 g, gelatin with a Bloom value of 160 to 250, polysaccharides such as agar, gum arabic, karaya, tragacanth, algines and guar, carbopolyacid carboxy polymer and salt derivatives thereof, polyacrylamides, water-swellable Deen maleic anhydride polymers, Good-rite polyacrylic acid with a molecular weight of 80,000 to 200,000, Polyoxyethylene oxide with a molecular weight of 100,000 to 5,000,000, starch (R1 graft copolymers, Aqua-keep acrylic polymers with a water absorption capacity of 400 times its own weight, diesters of polyglucan, a mixture of cross-linked polyvinyl alcohol and polyvinyl pyrrolidone, zeoline available as prolamine, polyethylene glycol with a molecular weight of 4000 to 100,000 and the like. In a preferred embodiment, the expandable wall is formed by polymers and polymeric compositions that are thermoformable. Representative polymers with hydrophilic properties are known from U.S. Patent Nos. 3,865,108, 4,002,173, 4,207,893, and 4,327,725 and in Handbook of Common Polymers, by Scott and Roff, published by Cleveland Rubber Company, Cleveland, Ohio.

The osmotically effective compound that can be homogeneously or heterogeneously mixed with the swellable polymer into a propelling wall is an osmotically effective solvent which is soluble in the liquid drawn up into the swellable polymer. The osmotically effective compounds have an osmotic pressure gradient over a semi-permeable wall opposite an external fluid. Osmotically effective compounds are also known as osmagents in the dosing technique. Osmotically active osmagents useful for this purpose include magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium chloride, potassium sulfate, sodium sulfate, mannitol, urea, sorbitol, inositol, sucrose, glucose and the like. The atmospheric osmotic pressure (atm) of the osmagents suitable for the invention is greater than zero atm, generally from 8 to 500 atm or higher.

The swellable, expandable polymer not only provides the driving force for the delivery of a beneficial agent from the delivery device, but also serves as a support matrix for an osmotically effective solvent. The osmotic solvent can be mixed homogeneously or heterogeneously with the polymer to form the desired swellable wall or swellable bag. In a presently preferred embodiment, the composition comprises at least one polymer and at least one osmotic solvent. Generally, a composition comprises about 20 to 90 wt% polymer and 80 to 10 wt% osmotic solvent with a preferred composition of 35 to 75 wt% polymer and 65 to 25 wt% osmotic solvent.

By the term beneficial agent used herein is meant a composition, preparation or compound that can be delivered in view of achieving a predetermined beneficial and useful result. These include algicides, antioxidants, air purifying agents, biocides, catalysts, chemical reactants, cosmetics, pharmaceuticals, disinfectants, fungicides, foodstuffs, fertility inhibitors and fertility promoters, food additives, fermenters, germicides, insecticides, attenuators of microorganisms, nutrients, plant growth promoting and plant growth inhibiting agents, preservatives, surfactants, sterilizing agents, sex sterilizing agents, vitamins and other compositions useful for the environment or the environment of animals. The agent can be insoluble to readily soluble in the temperature sensitive material incorporated into the device.

In the description and in the claims, the term medicament means any physiologically or pharmacologically active substance that has a local or systemic effect in animals, including warm-blooded animals, humans and primates, birds, fish, home, sport - and breeding animals, laboratory animals and zoo animals. The term physiological here refers to the administration of a drug that leads to normal concentrations and functions. The term pharmacologically refers to variations in the response to amounts of drug administered to the host (see Stedman's Medical Dictionary, 1966, edited by Williams and Wilkins, Baltimore). The active drug that can be released includes inorganic and organic drugs without restrictions, drugs that act on the nervous system, tranquilizers, hypnotics, stimulants, convulsants, muscle relaxants, anti-Parkinson's drugs, pain killers, anti-inflammatory drugs, anti-malarials, hormonal, contraceptive, sympathomimetic, diuretic, antiparasitic, hypoglycemic, eye, electrolyte, diagnostic and cardiovascular. The amount present in the dispenser can range from 0.05 ng to 20 g or more.

For medical applications, the device may contain various amounts, for example, 25 ng, 1 mg, 125 mg, 1.5 g, etc. The device may be used one or more times a day, one or more times a week and the like.

The term "heat-reactive" as used in the invention encompasses thermoplastic compositions which can soften in response to heat and cure again upon cooling. The term also includes thermo-tropic compositions that may change in response to the gradual supply of energy. These materials are also temperature sensitive in their response to the supply and extraction of energy. The term "heat-reactive" as used for this invention in a preferred embodiment refers to the physicochemical property of a composition of agent and carrier to exhibit solid or solid properties at temperatures up to 34 ° C, usually between 20 ° and 33 ° C. and, on application of heat, usually become liquid, semi-solid or viscous from 33 ° C in the range of 33 ° C to 40 ° C. The heat-reacting carrier is heat-sensitive and has the property of melting, dissolving, at higher temperature. solution, to soften or to become liquid, allowing the dispenser to deliver the heat-reacting carrier with the beneficial agent mixed homogeneously or heterogeneously therein. The heat-reacting carrier may be lipophilic, hydrophilic or hydrophobic. The shelf of the carrier is the ability to maintain the stability of the agent contained therein during storage and during delivery of the agent. Representative heat-reactive compositions and their melting points are as follows: cocoa butter 32-34 ° C, cocoa butter plus 2% beeswax 35-37pC, propylene glycol monostearate and distearate 32-35 ° C, 5 hydrogenated oils such as hydrogenated vegetable oil> 36- 37.5 ° C, 80¾ hydrogenated vegetable oil and 20¾ sorbitan mono-palmitate 39-39.5 ° C, 80¾ hydrogenated vegetable oil and 20¾ poly-sorbate 60 36-37 ° C, 77.5¾ hydrogenated vegetable oil, 20¾ sorbi -tantrioleate and 2.5¾ beeswax 35-36 ° C, 72.5¾ hydrogenated vegetable oil, 20% sorbitan trioleate, 2.5¾ beeswax and 5.0% distilled water 37-38 ° C, mono-, di- and triglycerides of acids with 8-22 carbon atoms including saturated and unsaturated acids such as palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid and arachidonic acid, triglycerides of saturated fatty acids with mono- and diglycerides 34-35.5 ° C, 15 mono and distearates of propylene glycol 33-34 ° C, partially hydrogenated cottonseed oil 35 -39 ° C, hydrogenated alcohols and fats 33-36 ° C, hexadienol and anhydrous lanolin triethanolamine glyceryl monostearate 38 ° C, eutectic mixtures of mono-, di- and triglycerides 35-39 ° C, Witepsol15, triglyceride of saturated vegetable fatty acids with monoglycerides, 33.5-35.5 ° C, Witepsol ^ H32 free from (R) hydroxyl groups 31-33 ° C, Witepsor 1 W25 with a saponification value of 225-240 and a melting point of 33.5-35.5 ° C, Witepsol E 75 with a saponification value of 220-230 and a melting point of 37-39 ° C, a polyalkylene glycol such as polyethylene glycol 1000, an unbranched polymer of ethylene oxide 38-41 ° C, polyethylene glycol 1500, melting point 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 , mixture of mono-, di- and triglycerides of saturated fatty acids with 11-17 carbon atoms 33-35 ° C, and the like jke. The heat-reactive composition is an agent for storing a beneficial agent in a solid composition at a temperature of 20-33 ° C, for maintaining an immiscible boundary on the interface with the swelling composition, and for dispensing of the agent in a more or less liquid composition at a temperature above 33 ° C and usually from 33-40 ° C. When the heat-reacting compositions are released into a biological environment, they are easily excreted, metabolized, assimilated or the like so that the beneficial agent can be used effectively.

The semipermeable wall can be applied to the expandable wall or bag or on the 8602556 heat-reactive layer by molding, pouring, spraying or dipping with a semipermeable wall forming composition.

Other and presently preferred methods that can be followed for wall mounting are the air suspension method and the pan coating method. The air suspension method consists of suspending and tumbling the laminate or pouch in an air stream and a semipermeable wall forming composition until the part is surrounded and lined with the wall. The process can be repeated with another semipermeable wall-forming composition to create a semipermeable layered wall. The air suspension procedure is described in U.S. Patent 2,799,241, J. Am. Pharm. Assoc., Vol. 48, pp. 451-459, and Ibid., Vol. 49, pp. 82-84, 1960. Other standard manufacturing procedures are described in Modern Plastics Encyclopedia, Vol. 46, pp. 62-70, 1969 and in Pharmaceutical Sciences, van Remington, 14th ed., Pp. 1626-1678, 1970, published by Mack Publishing Co., Easton, PA.

Solvents suitable for fabrication of the walls are, for example, inert inorganic and organic solvents that do not damage the materials, the heat-reactive composition, the expandable wall, the pouch, and the final delivery device. These generally include water-based solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, alicyclic hydrocarbons, aromatic hydrocarbons, heterocyclic solvents and mixtures thereof. Common solvents include acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butanol, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, methyl isobutyl ketone, methyl propyl ketone, hexane, heptane, ethylene glycol monoethyl ether, 1,2-dichloroethyl, 1,2-dichloroethyl acetate 2-dichloropropane, carbon tetrachloride, nitroethane, nitropropane, tetrachloroethane, diethyl ether, diisopropyl ether, cyclohexane, cyclooctane, benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, diglyme, water and mixtures thereof such as acetone / water, acetone / methanol, acetone / ethanol, dichloromethane / -35 methanol and dichloroethane / methanol. In general, in this invention, the semipermeable wall is applied at temperatures several degrees below the melting point of the heat-reacting composition. Alternatively, the thermoplastic composition can be applied to the dispenser after the semipermeable wall has been applied.

8602556 16

The expandable wall, bag-shaped member or expandable layer can be manufactured by conventional thermoforming polymer methods, such as spraying a spindle, dipping a mold into a wall-forming composition, blow molding, vacuum molding, injection molding, extrusion and laminating . In a presently preferred embodiment, a bag-shaped part or an expandably formed propellant part is manufactured according to the compression molding method illustrated in Fig. 10. A molding cavity and plunger are used in compression molding. The mold cavity (mold) forms a surface of the molded part and the polymeric wall-forming composition is introduced into the mold. The plunger forms the other surface of the cast part. The plunger compresses the polymeric composition when the mold is closed to form the final bag-shaped part. The mold and plunger are held in this position until the polymeric composition has hardened. In Fig. 10, the bag-shaped part or the molded weir part is indicated by the letter a and is shown after the compression mold has been removed. Then, in one embodiment, the bag is brought to a filling point, b, where it is placed under a filling funnel and filled with a molten composition containing the agent. After cooling, the filled compartment at c is lined with a semipermeable wall and an aperture is drilled through the semipermeable wall with a laser to provide a delivery device. In a similar process, the formed compartment a at d is closed with a closure having a filling and unloading hole 25 and the closed compartment is filled with a molten composition at the filling point e at room temperature. Finally, the filled compartment is coated at f with a semipermeable wall and an opening is drilled through that wall in the extension of the hole with a laser and the dispenser is obtained. In a similar process, the closed compartment is coated at g with a semipermeable membrane and an aperture is laser drilled through the semipermeable wall in the extension of the hole to create the empty dispenser. This is then filled with the molten preparation at room temperature at h, after which the final dispenser is created.

The terms aperture and passage used herein include provisions in the semipermeable wall through which a beneficial agent formulation may be delivered from the dispenser. The opening can be formed by mechanical drilling or laser drilling or by eroding an erodible element into the wall such as a gel atin plug. A detailed description of openings and the preferred maximum and minimum dimensions for an opening are disclosed in U.S. Pat. Nos. 3,845,770 and 3,916,899.

5 DESCRIPTION OF THE EXAMPLES

The following examples illustrate the invention and are not to be construed as limiting the scope of the invention.

Example I

A delivery device is manufactured as follows: An expandable capsule-shaped container is formed by injection molding a polymeric composition. The holder has a diameter of 12 mm and a depth of 40 mm. The container wall is formed by a composition comprising 30 wt% sodium chloride and 70 wt% polyethylene oxide with a molecular weight of 3,000,000. The wall-forming constituents are mixed into a homogeneous composition in a commercially available mixer for 20 minutes. The composition is pressed into tablets and placed in an injection molding machine and the container is injection molded at 145-150 ° C at 6.5-7.0 x 10 ^ kPa.

The container is then filled with a heat sensitive composition comprising 0.5 wt% theophylline, 77 wt% hydrogenated vegetable oil, 20 wt% sorbitan trioleate and 2.5 wt% beeswax. Filling takes place at 36-37 ° C. After cooling to 21 ° C, the semipermeable outer wall is applied to the filled container by coating in a 25 Wurster Air suspension coater. The semipermeable wall is formed from a solution of 5% by weight of celulose acetate butyrate in dichloromethane. The semipermeable wall is applied to a thickness of 0.4 mm and the filled and coated container is dried in an oven at 50 ° C for 5 to 10 days. Finally, an aperture of 0.75 mm is drilled through the semipermeable wall with a laser for the release of the drug preparation from the compartment of the delivery device.

Example II

According to Example I, a container is made and filled with a drug preparation containing 0.20 g of paracetamol, 0.02 g of codeine-35 phosphate, 0.15 g of acetyl salicyl acid and 2.0 g of Witepsol ^ H35, a mixture of glycerol esters of saturated fatty acids in which lauric acid predominates. The composition is prepared by finely grinding all ingredients and mixing thoroughly and then adding the Witep gun carrier at 38-40 ° C. The containers are filled with the melted composition which, when cooled, acquires a creamy consistency. The 8602556 18 holders are covered with a semi-permeable wall and an opening is drilled as above.

Example III

A dispenser with a compartment containing a heat-reacting temperature-sensitive composition layered against an expandable composition is manufactured as follows: A mold is successively filled with a molten composition containing 2.5% phenobarbital, 20.5% glycergelatine and 77.0% theobromo oil, a glyceride of stearic, palmitic and lauric acids, which forms the heat-reacting layer upon cooling to room temperature, then with a mixture of 30 parts of ethylene glycol monomethacrylate, 0.12 parts of ethylene glycol dimethacrylate and 10 parts of a 0.13% solution of sodium disulfate in water / ethanol. This mixture polymerizes at 30 ° C and after 20 minutes after equilibration at room temperature, the solid laminate is removed from the mold.

Then, a 15% by weight solution of cellulose acetate with an acetyl content of 39.8% in acetone is prepared and the laminate is coated by dipping in this solution 15 times, first once for 10 seconds. then 1 min. each time per immersion, between which 5 min. each is dried. After dipping, the dispensers are dried at 22 ° C for 10 days. By this method, a semipermeable passage speed controlling wall of 0.7 mm is formed around the laminate. A passage is drilled through the semipermeable wall with a laser, which connects the exterior of the device to the heat-responsive layer 25.

Example IV

A dispenser is manufactured as follows: First, a heat-sensitive eutectic mixture of 77% neutral fat with a melting point of 35-37 ° C and 19.5% paraffin wax with a melting point of 52 ° C is heated to liquid. 3.5% acetylsalicylic acid is added to the melt and the mixture is poured into a mold. After cooling and solidifying, 500 mg of Cyanamer® polyacrylamide, a hydrogel with a molecular weight of about 200,000, is introduced into the mold and the layers are compressed into a heat-reactive layer which is in contact with a hydrogel layer and the counter overlapping layers taken from the mold.

A semipermeable wall is then applied by mixing 85 g of cellulose acetate with an acetyl content of 39.8% with 200 ml of dichloromethane and 200 ml of methanol and coating the two-layer 40-compartment part by spraying in an air suspension device 8602556 19. a semipermeable wall of 0.25 mm thickness has formed around the compartment. The devices are dried for two weeks and a 0.4 mm passage is drilled with a laser through the semi-permeable wall, which forms the connection with the heat-sensitive composition.

Example V

The procedure of example IV is repeated with the described sa

compositions, with the exception of the heat-reacting composition I

In this example, it comprises a partially esterified with (Cx4 ** Cig) fatty acids and 2 to 5 units epoxidized polyhydroxy compound. The composition contains a medicament and the heat-reacting composition melts quickly and completely at body temperature into a liquid composition that is easy to dispense from the delivery device.

Example VI

The procedures of Examples IV and V are repeated to prepare a heat-reacting composition containing 85 mg of 4 units of epoxidized sorbitan monostearate with a melting point of 38 ° C, 5 mg of 20 units of epoxidized sorbitan monostearate, 5 mg of 20 sorbitan monoricinoleate and 15 mg sodium indomethacin.

Example VII

A heat sensitive composition for use in the dispenser of Example I is prepared by heat mixing 30% polyethylene glycol 1500, 30% polyethylene glycol 4000, 30% polyethylene glycol 400, 9% cocoa butter and 1% oxyprenolol hydrochloride. The composition has a melting time of 15 to 20 min at 37 ° C.

Example VIII

In an osmotic capsule in the form of a thin-walled cylinder with a hemispherical bottom, a composition was injection-molded consisting essentially of 65% sodium chloride, 20% polyoxyl), a polyoxyethylene with a molecular weight of approximately 200,000 and 15 polyethylene glycol 200,000 exists. The injection molding conditions were as follows: 8602 5bó 20

nozzle temperature 180 ± 20 ° C

zone 1 out

zone 2 230 ± 25 ° C

5 zone 3 220 ± 25 ° C

hot point temperature 180 ± 25 ° C

cavity temperature 18 ± 3 ° C

temperature at 8 ± 3 ° C

temperature stopper plate 8 ± 3 ° C

10 lamp time 13.5 ± 2 sec.

spray time 1.9 ± 0.5 sec.

spray speed 5 ± 1 spray pressure 84 + 7 kg / cm ^ back pressure 42 ± 7 kg / cm ^ 15 cycle duration 20 sec.

The internal and external diameters were resp. 11.7 and 13.3 mm and the internal and external length, respectively. 37.0 and 38.5 mm.

The osmotic capsule was charged with 2.88 g of H-15 Witepsol, glyce-20 rol ester of a saturated fatty acid with 0.1¾ red dye oil. The filled osmotic capsules were coated in a panater (Accela-Cota) with cellulose acetate butyrate in a solvent consisting of 95% dichloromethane and 5% ethanol, until a semipermeable membrane with a uniform thickness of 0.5 mm was formed. The devices were dried at 55 ° C for 7 days and a 1 mm outlet was drilled. The release rate of these devices was investigated. Figure 11 shows the release rate of the heat sensitive composition in mg / h per day from the system. In Fig. 12, the cumulative amount of heat sensitive composition released is shown as a percentage of the total amount delivered by the system.

The circles refer to delivery from the device in a vertical position and the squares relate to delivery from the device in a horizontal position.

An embodiment of the invention relates to a method of administering a beneficial drug at a controlled rate in the vaginal or rectal passage of a warm-blooded animal, the method comprising the following steps: (A) in the body passage a dispenser comprising the following 40 parts: (1) an inner wall formed by an 8602556 21 swellable polymeric composition that forms and surrounds an internal compartment, (2) a mouthpiece in the inner wall, (3) a preparation of a beneficial medicament in the compartment comprising a unit amount of medicament to complete a therapeutic program and a heat-sensitive carrier that melts or dissolves at body temperature and is a means of transporting a medicament from the device; (4) an outer wall around the inner wall and the mouthpiece which is formed by a semipermeable polymeric composition which allows liquid to pass through and drug does not pass through and (5) an opening through the built-in wall which connects to the inner compartment via the mouthpiece; (B) through the semipermeable wall, liquid is aspirated through the inner wall at a rate determined by the permeability of the semipermeable wall and the osmotic pressure gradient across the semipermeable wall, causing the inner wall to swell; (C) the drug formulation melts in the compartment and becomes a liquid formulation and (D) the beneficial drug formulation is released from the compartment due to the inner wall swelling and exerting pressure on the molten formulation, thereby placing the formulation in a therapeutic effective amount delivered through the passage 20 at a controlled rate and having the desired medical effect for a long time, for example from 1 hour to several months, preferably from 1 to 24 hours.

To the extent that the foregoing description includes preferred embodiments of the invention, it is noted that variations and modifications can be made in accordance with the disclosed inventive principles without departing from the scope of the invention.

8602556

Claims (30)

1. Delivery device for delivering a heat-sensitive preparation of a beneficial agent to a use environment at a controlled rate, characterized in that: a) an inner wall surrounding and forming an internal compartment containing the beneficial agent preparation, having a opening in the wall through which the composition can be introduced into and dispensed therefrom, which wall is constituted by a composition, which is an agent that absorbs liquid and swells in the compartment; b) an outer wall around the inner wall, which outer wall is formed by a composition which is permeable to a liquid and substantially impermeable to a beneficial agent and c) a passage in the outer wall which connects to the opening, whereby a preparation of a beneficial agent can be delivered from the device. 2. Dispensing device according to claim 1, characterized in that the compartment contains a preparation of a beneficial agent which is solid up to 33 ° C and melts above 33 ° C. Dispensing device according to claim 1 or 2, characterized in that the inner wall is formed by a composition comprising a hydrogel polymer and an osmotically effective solvent. Dispensing device according to claim 1 or 2, characterized in. That the inner wall is formed by a composition comprising a hydrogel polymer that swells in the presence of liquid. 5. Dispensing device as claimed in any of the claims 1-4, characterized in that in the opening in the inner wall there is a closure provided with a hole. Dispensing device according to any one of claims 1 to 5, characterized in that the outer wall is formed by a cellulose ester, diester, triester, ether or ester ether such as cellulose acetate, diacetate, triacetate or acetate butyrate. 7. Dispensing device according to any one of claims 1-5, characterized in that the outer wall is formed by a hydrophilic composition which swells in the presence of aqueous liquids soaked up in the device. Dispensing device according to claim 1 or 2, characterized in that the inner wall is formed by polyethylene oxide. Dispensing device according to claim 1 or 2, characterized in that the inner wall is formed by polyethylene oxide and an osmotically effective solvent. Dispensing device according to any one of claims 1-9, characterized in. that the compartment contains a heat-sensitive composition comprising a glycerol ester of a saturated fatty acid. 11. Dispenser for delivering a beneficial agent at a controlled rate to a liquid biological use environment with a temperature higher than 33 ° C, characterized in that: a) a wall formed by a semipermeable polymer composition around and to limit : b) a compartment; c) a first device in the compartment that changes from a solid composition to a dispersible composition in response to the temperature of the biological environment and contains a beneficial agent 15 and is arranged against a second device in the compartment that absorbs liquid through the semipermeable wall and swells in the compartment; and d) a passage in the wall connecting the exterior of the device to the first facility. 12. Dispensing device according to claim 11, characterized in that the first provision is a layer. Dispensing device according to claim 11 or 12, characterized in that the second provision is a layer. 14 ·. Dispensing device according to any one of claims 11-13, characterized in that the solid composition is a gel. Dispensing device according to any one of claims 11-14, characterized in that the solid composition melts in response to the temperature of the biological environment. 16. Dispensing device according to any one of claims 11-14, characterized in. that the solid composition liquefies in response to the temperature of the biological environment. 17. Delivery device for delivering a beneficial agent at a controlled rate to a liquid environment at a temperature corresponding to the temperature of a warm-blooded animal, characterized in that: a) a wall formed by a semipermeable polymeric composition comprising a closed tube bounded with an internal compartment; b) a first device located in the center of the compartment that changes from 8602556 t in response to the temperature of the environment and contains a non-dispersible composition to a dispersible composition and a beneficial agent and is surrounded by a second provision in the compartment that absorbs liquid through the semipermeable wall and swells against the first provision; and d) a passage in the wall connecting the outside of the device to the first facility. Dispensing device according to claim 17, characterized in that the second provision is located between the first provision and the inside of the wall. Dispensing device according to claim 17 or 18, characterized in that the passage is located in the wall at the closed end of the tube. Dispensing device according to any one of claims 17-19, characterized in that the non-dispersible composition is a semi-solid. Dispensing device according to any one of claims 17-19, characterized in that the non-dispersible composition is a solid. Dispensing device according to any one of claims 17-19, characterized in that the non-dispersible composition does not flow at a temperature below 33 ° C. 23. A beneficial agent delivery device; a) an end-closed tubular body formed by a polymeric composition which is permeable to an external liquid and substantially impervious to a beneficial agent; b) a compartment in the body; C) a first layer in the compartment formed by a composition comprising a beneficial agent and a beneficial agent carrier; d) a second layer in the compartment which abuts the first layer and is formed by a hydrogel that swells in the presence of the liquid entering the compartment; and e) a passageway in the body connecting the exterior of the device to the first layer. 24. Delivery device according to claim 23, characterized in that the carrier is a non-toxic, pharmaceutically acceptable hydrogenated oil. Delivery device according to claim 23, characterized in that the carrier is a non-toxic monoglyceride, diglyceride or triglyceride. 26. Delivery device according to claim 23, characterized in that the carrier is a non-toxic hydrophilic polymer with a molecular weight 8602556 of more than 1000. - " Delivery device according to claim 23, characterized in that the carrier is a non-toxic eutectic composition comprising a glyceride and a hydrogenated oil. Dispenser according to claim 23, characterized in that the carrier is a non-toxic glyceride of a fatty acid with 8 to 12 carbon atoms. 29. A delivery device according to claim 23, characterized in that the carrier is a non-toxic composition comprising a mixture of at least two polyethylene glycols, one of which has a molecular weight of more than 1000. 30. Delivery device for delivering a heat-sensitive preparation with a beneficial agent to a use environment at a controlled rate, characterized in: a) an inner wall surrounding and forming an internal compartment containing the beneficial agent preparation with a opening in the wall through which the composition can be introduced into and dispensed from, the wall being formed by a composition which is an agent that absorbs liquid and swells in the compartment; b) an outer wall surrounding the inner wall which is formed by a liquid permeable composition and substantially impermeable to a beneficial agent and is a composition comprising a polysulfone, polyacrylate, polymethacrylate, polymethyl methacrylate or polyurethane; and c) a passageway in the outer wall connecting to the opening through which a beneficial agent formulation may be released from the device. 8602556