JPH0137367B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention This invention relates to a new and useful dispenser. In particular, the present invention comprises a semi-permeable wall surrounding at least a portion of (a) an internal compartment or (b) a capsule disposed therein, wherein either (a) or (b) contains a heat-sensitive beneficial material. Dispenser containing a drug formulation and an inflatable drive member. The components that make up the dispenser work in perfect unison to release the beneficial agent at a controlled rate into the environment of use over an extended period of time.

BACKGROUND OF THE INVENTION Dispensers for delivering beneficial agents into a use environment are known in the pharmaceutical arts. For example, U.S. Pat. No. 3,760,984 issued to Theeuws describes a package consisting of a heat-shrinkable container carrying a permeable solute on its outer surface and a separate layer of a polymer permeable to the fluid. Disclosing Spencer. The dispenser has a stopper for filling the container. The dispenser is powered by a fluid drawn into it, which dissolves the solute and the resulting solution exerts pressure against the contractile container, causing the container to Upon contraction, the drug is released from the dispenser. Hartop, in US Pat. No. 3,865,108, discloses a dispenser consisting of an inner collapsible tube containing a medicament disposed in a base member made of a swellable material.
The dispenser releases the drug by having its bottom and other parts absorb fluid from the environment and expand thereby squeezing the collapsible tube and expelling the drug from the tube. Patentee Wichterle holds U.S. Patent No.
No. 3,971,376 discloses a dispenser consisting of a capsule having a unit wall formed from a crosslinked gel swellable in fluid. Textiles are incorporated into the material to provide strength and minimize problems caused by poor mechanical properties associated with the material as it absorbs fluids and powers the dispenser. Embedded. Patentee Eckenhoff, et al.
No. 3,987,790 discloses an improvement in an osmotic dispenser consisting of a conduit for filling the bag in the dispenser. The dispenser is powered by an osmotic solute drawing fluid into the dispenser, and the drawn fluid creates water pressure that is exerted against the bag, forcing the bag inward and releasing the drug. from the dispenser. In U.S. Pat. No. 3,995,631, Higuchi, et al. disclose a bag with an osmotic solute on its outer surface and a separate vessel formed of a material with partially reduced permeability to fluids. The walls are exposed. In operation, a solution of solute is created which squeezes the bag, thereby causing release of drug from the bag. US Patent No.
No. 4,320,758, Ekenhoff et al. disclose a dispenser consisting of a flexible bag, a sleeve made of a osmotic solute dispersed in a soluble polymer, and an outer wall that is permeable to fluids. In this dispenser, the sleeve draws water into the space between the outer wall and the bag, thereby applying water pressure to the bag, which squeezes the bag and releases the drug from the bag. US Pat. No. 4,350,271 discloses a liquid dispenser. The dispenser works by absorbing water into a composition, causing the composition to expand and exert pressure on a lipophilic fluid, which is then released through an outlet.

While the dispensers described above are useful for delivering a large number of drugs into an environment of use, and while dispensers represent a commercial advance in dispensing technology, those skilled in the art will appreciate that they can be made with inventive new improvements. It will be appreciated that dispensers may also enjoy wide commercial use and application in dispensing technology. For example, if a dispenser is provided with an initial internal capsule arrangement that makes manufacturing the dispenser easier and more effective at lower cost, and if the dispenser does not use a flexible bag and Such dispensers would be readily adopted if they could be made without the use of textile components, thereby reducing the number of steps and parts required to manufacture the dispenser, resulting in improvements in dispensers. Yes, it would also represent a major advance in the field. Similarly, if a dispenser is provided that overcomes the limitations of prior art dispensers in delivering drugs only in the form of solutions or suspensions, the dispenser may be soluble or insoluble in a fluid, such as a semi-solid or Such a dispenser would be immediately appreciated and would be a valuable contribution to science, medicine and commerce if it were possible to deliver drugs in the form of .

OBJECTS OF THE INVENTION It is therefore a direct object of the present invention to provide a dispenser for the delivery of active agents in all useful forms to an environment of use, a novel dispenser representing an improvement in dispenser technology. That's true.

Another object of the invention is a dispenser that is self-sufficient, self-starting, and self-powered in a fluidic environment, and that is easy to manufacture and that delivers effective drugs to animals, including humans, and other It is an object of the present invention to provide a dispenser that can be used to dispense medication into biological as well as non-biological use environments.

Another object of the present invention is to provide a dispenser capable of containing a heat-sensitive hydrophobic composition of insoluble to soluble drugs, which heat-sensitive composition can be used in a biological environment. Changes its form in response to temperature, becoming fluid, semi-solid, etc., making it convenient to dispense from a dispenser.

Yet another object of the present invention is to provide a dispenser with an initial internal capsule arrangement so as to facilitate manufacturing of the dispenser at low cost, thereby increasing the utility of the dispenser. It is.

Yet another object of the present invention is an inner capsule containing a heat-sensitive composition and an inflatable member disposed parallel to the heat-sensitive composition; , an outer semi-structured wall surrounding at least a portion of the capsule, and a delivery passageway. The dispenser is configured such that the composition melts into a fluid or semi-solid state, maintains a boundary where the composition does not mix with the inflatable member, and allows the inflatable member to melt the composition. The composition is then delivered by a combination of physico-chemical actions such as swelling into the space occupied and driving a significant amount of the composition out of the dispenser.

Yet another object of the invention is a dispenser which is empty until filled with a solid composition which liquefies at high temperatures, and which, once filled, complies with a complete drug dosing regime for a period of time. The use of a dispenser is to provide such a dispenser which requires intervention only at the beginning and end of the regimen.

Yet another object of the present invention is to provide a dispenser capable of delivering a beneficial agent contained in a thermosensitive and lipophilic pharmaceutically acceptable carrier, the carrier being biologically acceptable. It melts in the presence of thermal energy absorbed from the environment of use into a harmless administrable composition, thereby substantially avoiding mammalian tissue irritation and interaction with mammalian protein tissue.

Yet another object of the present invention is to provide an osmotic dispenser containing a eutectic mixture formed from at least two components and at least one drug, the eutectic mixture being Blood has a melting point approximately the same as the temperature of the animal and is administered to the animal from a dispenser at said temperature.

Yet another object of the present invention is to provide a dispenser consisting of an internally disposed capsule containing a heat-sensitive hydrophobic composition containing an insoluble to soluble drug; The composition changes its form in response to the energy input present in the biological use environment and becomes administrable upon delivery action from the dispenser.

Yet another object of the invention is to provide a dispenser consisting of a thermoplastic composition and an inner capsule containing an expandable component, the composition being chemically unstable in an aqueous environment. As such, it contains a beneficial agent that can be contained within a dispenser in a non-aqueous dosage carrier, with the agent being protected by the non-aqueous carrier during delivery from the dispenser.

Still another object of the invention is to provide a heat-sensitive composition containing a heat-sensitive composition containing an active agent through a semi-permeable wall surrounding at least a portion of the compartment and a passageway communicating the compartment with the exterior of the dispenser. The object of the present invention is to provide a dispenser consisting of a medium for expelling objects.

Other objects, features and advantages of the present invention will become more apparent to those skilled in the pharmaceutical arts from the following detailed description, taken in conjunction with the drawings and the appended claims. Dew.

DETAILED DESCRIPTION OF THE DRAWINGS Turning now to the drawings in detail, these figures are examples of new and useful dispensers for administering beneficial agents, and these examples should not be construed as limiting. Shouldn't. An example of a dispenser is depicted in FIG. 1 with the numeral 10. In FIG. 1, the dispenser 10 is
It consists of a body 11 formed by a vessel wall 12 surrounding and delimiting an inner lumen or space (not visible in Figure 1) and a passageway 18 shown in broken lines.

FIG. 2 is a cross-sectional view of the dispenser 10 of FIG. The dispenser 10 in FIG. 2 has a main body 11.
and a vessel wall 12. Vessel wall 12 is formed from a semipermeable polymeric wall-forming composition and is substantially permeable to the passage of external fluids and of the beneficial agents and other ingredients contained within dispenser 10. It is substantially impermeable to passage. The vessel wall 12 is non-toxic and maintains its physical and chemical integrity, ie, does not erode during the period of administration. The dispenser 10 is finished into a final product containing a single unit capsule 13. That is, the capsule 13 cannot be easily separated into parts. Further use of the term capsule 13 and capsule refers to both hard and soft structures such as those embodied herein. Additionally, in FIG. 2, capsule 13 encloses an inner lumen or space 14. In FIG. Lumen 14 contains beneficial agent 1
5 (indicated by dots), heat-sensitive composition 1
6 (indicated by dashed lines), and a drive member 17 in layered contact with the surface of the composition 16. Drive member 17 in a preferred embodiment
is an inflatable member 17 having a shape corresponding to the shape of the capsule wall 13 and the inside of the compartment 14. The expandable member 17 is made from a layered, uncrosslinked or optionally crosslinked hydrogel composition, and is permeable. For example, it has the ability to draw in external fluid through the semi-permeable wall 12 and exhibit an osmotic pressure gradient across the semi-permeable wall 12 to the fluid external to the dispenser 10. In other embodiments, the drive member 17 may be a solid osmotic solute that draws fluid through the semi-permeable wall 12. The dispenser 10 has a passage 18 formed through the semi-permeable wall 12 and through the capsule 13.
Passageway 18 carries beneficial agent 1 from dispenser 10.
5 is communicated with the outside of the dispenser.

In FIG. 2, a thermally sensitive or thermosensitive composition 16 is the delivery vehicle and transport carrier for the beneficial agent 15. The beneficial agent 15 contained within the compartment 14 and delivered by the dispenser 10 includes agents that are insoluble to readily soluble in both aqueous fluids and lipophilic media.

The heat-sensitive composition 16 contains the drug 15 uniformly or non-uniformly dispersed or dissolved therein,
In a preferred embodiment of the invention, it is formed from an anhydrous, heat-sensitive, hydrophobic material. The substance exhibits solid-like properties at room temperature of 21°C and temperatures within 2-3°C thereof, and exhibits a melting point at temperatures close to and within 2-3°C of the mammalian body temperature of 37°C. . As used herein, the terms "melting point,""softeningpoint," or "liquefy" refer to the temperature at which the heat-sensitive composition melts, dissolves, or melts to deliver the drug 15 from the dispenser 10, respectively. The present invention is intended to form a pharmaceutical carrier that can be used for.

FIG. 3 depicts the dispenser of FIGS. 1 and 2 operating to deliver beneficial agent 15 to the fluid of the environment of use. 37℃ and part 2
When operated in an operating environment with a temperature within ˜3° C., dispenser 10 delivers drug 15 through a combination of thermodynamic and kinetic forces. That is, upon activation, heat-sensitive composition 16 melts to form a fluid, semi-solid, or similar deliverable phase to deliver drug 15 through passageway 18 . As the composition 16 melts, the hydrophilic member 17 draws in fluid through the semipermeable wall 12 with a tendency towards osmotic equilibrium, continuously swells, i.e. expands or fills, increasing the volume of the member 17, and At the same time, member 17 expands within compartment 14;
The immiscible boundary at the interface remains virtually unchanged. As external fluid is drawn into the dispenser 10 through the semi-permeable wall 12, the capsule wall 13 formed of a material soluble in the fluid gradually dissolves and lubricates the inside of the dispenser, thereby blocking the member 17. Helps to expand without
As a result, composition 16 is continuously released. Concomitantly, as the volume increasing member 17 increases its volume, it exerts pressure on the composition 16 in an attempt to decrease the volume of the composition. Upon simultaneous expansion of member 17, contraction of compartment 14, and melting of composition 16, composition 16 containing drug 15 is forced out of dispenser 10 through passageway 18. Looking at FIGS. 2 and 3 together, an example is shown in which the dispenser 10 operates to deliver the drug 15. FIG. 2 depicts the dispenser 10 at the beginning of the drug release period, and FIG. 3 depicts the dispenser 10 near the end of the drug release period. Melt of Composition 16, Composition 1
6 with the member 17 and the swelling, filling, and expansion of the medium 17 and the concomitant increase in volume as seen in FIG. A corresponding reduction in the volume of the drug 15 together ensures long-term delivery of the drug 15 at a controlled rate and continuously.

Figure 4 shows dispenser 2 consisting of two parts.
0 is shown as an example, and the main body member 21 and the cap member 22 are manufactured as a unit dispenser.
The dispenser 20 is conveniently made in two parts, with one part 22 sliding onto the other part 21 to cover the cap. Portions 21 and 22 completely enclose and encapsulate the inner lumen (not visible in Figure 4). dispenser 2
0 also includes a passageway 30 (shown in dashed line).

FIG. 5 is a cross-sectional view of the dispenser of FIG. 4 with the cap removed. In FIG. 5, the dispenser 20 consists of a body member 21 which essentially surrounds at least a part of the capsule 21 inside the body, except for the mouth 25 of the capsule 21, and is in close contact with the capsule 21. It consists of semi-transparent walls. The capsule used to form the dispenser consists of two parts, namely the sixth
It consists of a capsule body member 21 and a cap member 22 which receive the ingredients as seen in the figure. Capsule 21 includes a beneficial agent 27 (indicated by dots), a heat-sensitive composition 28 (indicated by wavy lines), and an expanding, swellable piston disposed in parallel with the surface of composition 28. It surrounds a space 26 in which a drive member 29 is housed. The materials making up the portions of FIG. 5 are formed from the materials discussed for FIGS. 1-3, which are discussed further herein below.

FIG. 6 is a sectional view of FIGS. 4 and 5.
FIG. 6 depicts dispenser 20 with cap 22 on top. In Figure 6, cap 2
2 is snugly placed over the capsule body 21 after the larger body 21 has been filled with all the appropriate preselected drugs, heat-sensitive compositions and drivers. In FIG. 6, after the cap 22 is fitted into the main body 21, the semi-transparent wall is attached to the main body member 21.
and is applied onto the outer surface of the cap 22. In another manufacturing method, the capsule body 21 is filled with each component and then the semi-permeable wall is applied except for the mouth. Then cover with cap 22. At that time, the cap 22
It is fitted into the main body 21 covered with a semi-transparent wall 23. In either method of manufacture, a passageway 30 is drilled through the semipermeable wall 23 and the capsule wall 22 to deliver the drug 27 from the dispenser 20. FIG. 7 depicts device 20 in operation. 7th
In the figure, the dispenser is depicted as consisting only of semi-permeable walls 23 towards the end of the dispensing period. Dispenser 20 operates in the manner described for dispenser 10 above.

FIG. 8 depicts other embodiments provided for the manufacture and utility of the dispenser. 8th
In the figure, body portion 31 in a preferred embodiment.
A body, or capsule, is illustrated having an inflatable plug 32 inserted into an aperture 33 in a body portion 31. The body member can be made of semipermeable or hydrophilic materials. A passageway 3 is provided at a location spaced from the inflation plug 32 for inserting a filling device into the body portion 31 to fill the space 36.
4 is perforated through the vessel wall 35 of the main body portion 31. After the space is filled, the body or capsule is coated with a semi-permeable wall 39 and wrapped. The semi-permeable wall in either embodiment provides a medium for drawing fluid into the inflatable member 32 and also closes the aperture 33 so that expansion of the plug 32 is directed in the space 36 in one direction towards the passageway 34. It will be. In this method of manufacture, passageways 34 are drilled through the semipermeable membrane in alignment with passageways in the capsule wall to deliver the drug from the capsule. In another manufacturing method, a semi-permeable wall 39 is applied around an empty capsule member with a plug in its opening, a passageway is drilled through the semi-permeable wall and the capsule wall, and then the space in the capsule becomes available. filled with a heat-sensitive composition containing a drug.

Although Figures 1-9 illustrate various dispensers that can be made in accordance with the present invention, these dispensers should not be construed as limiting the invention. This is because dispensers can take on a wide variety of shapes, sizes, and formats for delivering beneficial agents to the environment of use. For example, dispensers can be made for oral administration, and dispensers can be made for buccal, implanted, artificial gland, cervical, intrauterine, otic, nasal, dermal, vaginal, anal, and oral administration. It can be adapted for use as a rectal, rumen (eg, bovine rumen), and subcutaneous dispenser. Dispensers can also take on a variety of shapes, sizes and configurations and can also be used in rivers, aquariums, fields, factories, storage tanks, research facilities, greenhouses, transportation facilities, hospitals, naval and military institutions, and veterinary clinics. ,
It can be adapted to deliver beneficial agents in nursing homes, farms, zoos, hospital rooms, chemical reactors, and other use environments.

DETAILED DESCRIPTION OF THE INVENTION In the practice of the present invention, it is surprising that the dispenser 10 and the dispenser 20 are capsules having two different forms, classified according to the purpose of the present invention: osmotic hard capsules and osmotic hard capsules. It has been discovered that soft capsules can be produced by this method. The osmotic hard capsule consists of two parts, a cap and a body, the larger body being filled with a suitable preselected drug formulation and the two parts being fitted together. This is accomplished by sliding or snapping the cap portion over the main portion, thus completely surrounding and encapsulating the useful drug formulation. Hard capsules are made by immersing the mold in a bath containing a solution of the material that will form the capsule layer, coating the mold with that material. The mold is then pulled out, cooled and then dried in a stream of air. The capsule is removed from the mold and trimmed to create a laminated member with an inner lumen. A mating cap that snaps over the body for receiving the drug formulation is manufactured in a similar manner. The closed and filled osmotic capsule is then encapsulated by a semipermeable wall or lamina. The semi-permeable wall can be applied to the capsule parts either before or after the capsule parts are combined into the final capsule. In other embodiments, hard capsules can be made by having each part fitted with a tight-fitting retaining ring near their open end, which loops between the cap and the body after being filled with the drug formulation. can be combined and fixed. In this embodiment, a pair of matched retaining rings are formed in the cap portion and the body portion, these rings providing a securing means for securely coupling the capsule. Capsules can be manually filled with the drug formulation or they can be filled with the drug formulation by machine. In the final step, the hard capsule is sealed with a semi-permeable thin layer that is permeable to the passage of fluids and substantially impermeable to the passage of the beneficial agent, as will be explained below. It will be enclosed.

The osmotic soft capsule as used according to the invention preferably constitutes a single piece in its final form. Generally, osmotic soft capsules have a sealed structure enclosing the useful drug formulation therein. Soft capsules are manufactured by various methods, including the flat plate method, rotary die method,
Includes reciprocating die method and continuous method. The plate method uses a set of molds. The prepared warm sheet of capsule lamina-forming material is placed on top of the bottom mold and the drug formulation is poured onto it. Second thin layer forming material
sheet is placed on top of the drug formulation and then the top mold is placed. The mold set is placed under a press and pressure is applied with or without heat to form unit soft capsules. The capsules are washed with a solvent to remove excess drug formulation from the outside of the capsules, and the air-dried capsules are then encapsulated with a semi-permeable wall material.

The rotating die method uses two continuous films of capsule-forming material that are assembled between a pair of rotating dies and an injector wedge. This method fills and seals the capsule by matching the two parts. In this method,
A sheet of capsule lamina-forming material is fed onto a guide roll and then lowered between a wedge injector and a die roll. The encapsulated drug formulation flows by gravity into the positive displacement pump. The pump meters the drug formulation through a wedge injector and into a sheet between die rolls. There is a small circular hole in the bottom of the wedge that is aligned with the die pocket of the die roll. When the pressure of the pumped drug formulation forces the sheet against the pocket, the capsule is approximately half-sealed, with the soft capsule being simultaneously filled, shaped, sealed, and separated from the sheet of lamination material. . Sealing of the soft capsule is accomplished by mechanical pressure on a die roll and heating with a wedge of sheet of lamination material. After the manufacturing process, the capsules filled with the drug formulation are dried in the presence of forced ventilation and then encapsulated with a semipermeable thin layer by the method described hereinafter.

The reciprocating die method produces soft capsules by introducing two films of capsule laminar-forming material between a set of vertical dies. As the die closes, opens and closes, it acts as a continuous vertical plate forming successive rows of pockets across the film. These pockets are filled with the drug formulation and as the pockets move through the die,
It is sealed, shaped and separated from the moving film as a capsule filled with the drug formulation. A semi-permeable wall is painted over it, creating an osmotic soft capsule dispenser. The continuous method also uses a rotating die, but adds another feature.
In addition to liquid encapsulation, this method also allows convenient filling of the beneficial agent in the form of a dry powder into soft capsules. The continuous filled soft capsules are encapsulated in a semipermeable polymeric material to become osmotic soft capsules.

Dispensers of the invention can include a vessel wall made of semipermeable material. Its semi-permeable wall has no adverse effects on the host or animal and is permeable to the passage of external aqueous fluids (e.g. water and biological fluids), but not to the passage of drugs, including pharmaceuticals. The semipermeable wall remains substantially impermeable and maintains its integrity in the presence of the thermotropic heat-sensitive composition, ie, the semipermeable wall does not melt or erode in the presence of the composition. The selectively semipermeable material forming the outer wall is substantially insoluble in fluids, non-toxic, and non-erodible.

Typical materials for forming semipermeable walls include semipermeable homopolymers, semipermeable copolymers, and the like. In some embodiments,
Typical materials include cellulose esters, cellulose monoesters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ester ethers, and mixtures thereof. These cellulosic polymers have a high degree of substitution (DS) on their anhydroglucose units.
It has from 0 to 3. The degree of substitution refers to the average number of hydroxyl groups originally present on anhydroglucose units that are replaced by substituents or converted to other groups. The anhydroglucose unit may be partially or completely composed of, for example, acyl, alkanoyl, aroyl, alkyl, alkenyl, alkoxy, halogen, carboalkyl, alkyl carbamate, alkyl carbonate, alkyl sulfonate, alkyl sulfamate, and similar semipermeable polymers. can be substituted by a group forming.

Typical examples of semipermeable materials include cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate,
A member selected from the group consisting of cellulose diacetate, cellulose triacetate, mono-, di- and tricellulose alkanilates, mono-, di- and tri-alkenylates, mono-, di- and triaroylates, etc. . Representative polymer examples include: cellulose acetate with a DS of 1.8-2.3 and an acetyl content of 32-39.9%; cellulose diacetate with a DS of 1-2 and an acetyl content of 21-35%;
such as cellulose triacetate with a DS of ~3 and an acetyl content of 34-44.8%. Even more specific polymers include a D of 1.8.
S. and cellulose propionate with a propionyl content of 38.5%; cellulose acetate propionate with an acetyl content of 1.5-7% and a propionyl content of 39-42%; acetyl content of 2.5-3%, 39.2-45% Cellulose acetate propionate with an average propionyl content of 2.8-5.4%; D. of 1.8.
S. Cellulose acetate butyrate with an acetyl content of 13-15% and a butyryl content of 34-39%; with an acetyl content of 2-29.5%, a butyryl content of 17-53%, and a hydroxyl content of 0.5-4.7% Cellulose acetate butyrate; 2.9
cellulose triacylate with a DS of ~3,
For example, cellulose trivalerate, cellulose trilaurate, cellulose tripalmitate, cellulose trioctanoate, and tripropionate; cellulose diesters with a DS of 2.2 to 2.6, such as cellulose disuccinate, cellulose dipalminate, cellulose diocta noate, cellulose dicarpyrate, etc.; mixed cellulose esters such as cellulose acetate valerate, cellulose acetate succinate, cellulose propionate succinate, cellulose acetate octanoate, cellulose valerate palmitate, cellulose acetate heptonate, etc. be. Semipermeable polymers are known in US Pat. No. 4,077,407, and they are described in the Encyclopedia of Polymer Science and Technology.
Polymer Science and Technology), Volume 3,
pp. 325-354, 1964 (Interscience Publishers, Inc., New York).
York).

Additional semipermeable polymers include acetaldehyde dimethylcellulose acetate; cellulose acetate ethyl carbamate; cellulose acetate methyl carbamate; cellulose dimethylamino acetate; semipermeable polyamide; semipermeable polyurethane; semipermeable polysulfan. ; semipermeable sulfonated polystyrene;
U.S. Patent Nos. 3173876, 3276586, 3541005
3,541,006, and 3,546,142; crosslinked selectively semipermeable silicone rubber formed by co-precipitation of polyanions and polycations; selectively semipermeable silicone rubber; U.S. Pat. No.
Loeb and Srirajyan in issue 3133132
semipermeable polymers as disclosed by Surirajan; semipermeable polystyrene derivatives; semipermeable poly(sodium sulfonate); semipermeable poly(vinylbenzyltrimethyl) ammonium chloride; hydrostatic pressure on both sides of the semipermeable wall. or 10 ^-1 to 10 ^-7 expressed as the difference in osmotic pressure per atmospheric pressure (cc.mil/cm ² hr.atm)
semipermeable polymers that exhibit a fluid permeability of .
Those polymers are U.S. Pat. No. 3,845,770;
3916899 and 4160020, and Handbook of Common Polymers.
Common Polymers) (Scott, J.R. and Roff, D.J.)
and Roff, W.J., 1971, published by CRC Press, Cleveland, Ohio), which is known to those skilled in the art.

The materials used to form the swellable, expandable internal member or layer and the plug are pure polymeric materials and polymeric materials mixed with osmotic agents, and those materials may be mixed with water or biological fluids. interact, absorb fluid, and swell or expand to an equilibrium state. The polymer exhibits the ability to retain a significant portion of absorbed fluid within the polymer's molecular structure. The polymer in a preferred embodiment is a gel polymer that can swell or swell to a very high degree, typically exhibiting a volume increase of 2 to 50 times. Swellable, hydrophilic polymers, also known as osmotic polymers, can be uncrosslinked or lightly crosslinked. Crosslinks in polymers that have the ability to swell in the presence of fluids can be covalent or ionic, so that once crosslinked the polymer will no longer dissolve in the fluid. The polymer may be of vegetable, animal or synthetic origin. Polymeric materials useful for the purposes of this invention include poly(hydroxyalkyl methacrylates) with a molecular weight of 5,000 to 5,000,000;
~360000 poly(vinylpyrrolidone); anionic and cationic hydrogels; polyelectrolyte complexes; polyvinyl alcohol with low acetate residues; swellable mixtures of agar and carboxymethylcellulose; from methylcellulose mixed with slightly crosslinked agar a water-swellable copolymer produced by finely dispersing a copolymer of maleic anhydride and styrene, ethylene, propylene, or isobutylene; water-swellable composition of N-vinyl lactam; Polymers, etc.

Other gelling, fluid-absorbing and retaining polymers useful for forming hydrophilic, expandable extruded members include pectin having a molecular weight in the range of 30,000 to 300,000; Polysaccharides such as agar, gum arabic, gum karaya, gum tragacanth, algin and guar; Carbopol acidic carboxy polymers and their salt derivatives; polyacrylamides;
Water-swellable inday-maleic anhydride polymer; Good-rite polyacrylic acid
with a molecular weight of 80,000 to 200,000; Polyox polyethylene oxide polymers with a molecular weight of 100,000 to 5,000,000 and higher; starch graft copolymers; exchange polymers of polyanions and polycations; starch-polyacrylonitrile copolymers Polymer: Aqua-Keep has a water absorption capacity of approximately 400 times its original weight.
) acrylate polymer; diester of polyglucan; crosslinked polyvinyl alcohol and poly(N
-vinyl-2-pyrrolidone); zein that can be used as prolamin; molecular weight 4000-100000
polyethylene glycol; etc. In preferred embodiments, the expandable vessel wall is formed from a thermoformable polymer and polymer composition.
Typical hydrophilic polymers are listed in the U.S. Patent No.
No. 3865108, No. 4002173, No. 4207893, No.
4327725, and Handbook of Common Polymers.
Polymers (Scoot and
Roff, Cleveland Rubber Company, Cleveland, Ohio.
Published by Rubber Company, Cleveland, Ohio).

The osmotic compound for forming the extruded member may be pure or may be mixed homogeneously or heterogeneously with the swellable polymer; A solute that is soluble and has an osmotic effect,
Demonstrates an osmotic pressure gradient across a semipermeable wall relative to the outside fluid. Compounds with osmotic effects are also known as osmagents. Osmotic penetrants useful for the purpose of the present invention are selected from the group consisting of magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, mannitol, urea, sorbitol, inositol, sucrose, glucose, etc. Contains solid compounds. The osmotic pressure in atmospheric pressure (ATM) of the osmotic agent suitable for the present invention is zero.
Larger than an ATM, typically 0 to 500 ATMs
It will probably go up to or even higher.

In addition to providing the driving force for delivering the beneficial agent from the dispenser, the swellable, expandable polymer also serves as a matrix to retain the osmotic solute. The osmotic solute is homogeneously or heterogeneously mixed with the polymer to create the desired dilatable genital wall or dilatable pocket. In a preferred embodiment of the invention, the composition comprises (a) at least one
(b) at least one solid permeable solute. Generally, the compositions will consist of about 20% to 90% (by weight) polymer and 80% to 10% (by weight) osmotic solute, and in compositions preferred for this invention, 35% to 75%
(by weight) polymer and 65% to 25% (by weight) permeable solute.

The term "thermosensitive" as used for purposes of the present invention includes thermoplastic compositions that soften, ie, become dosable, in response to heat and solidify again upon cooling. The term also includes thermotropic compositions that can undergo gradual changes upon the application of energy. These objects are thermosensitive in that they respond to the addition or removal of energy. The term "thermosensitive" as used for the purposes of the present invention, in a preferred embodiment, exhibits solid or solid-like properties at temperatures below 33°C, and at temperatures above 32°C, typically from 32°C to
Describes the physicochemical properties of a composition drug carrier that becomes fluid, semi-solid, or viscous when perturbed by heat in the range of 40°C. Thermosensitive carriers are thermosensitive and have the property of melting, dissolving, dissolving, softening, or liquefying at elevated temperatures, thereby forming a dispenser. It allows the thermosensitive carrier to be delivered with the beneficial agent homogeneously or heterogeneously mixed therein. The thermosensitive carrier is hydrophobic. Another important property of a carrier is its ability to maintain the stability of the drug contained therein during storage and delivery. The heat-sensitive carrier used in the present invention includes waxes, fats, hydrogenated oils, partially hydrogenated oils, glycerides, esters of saturated fatty acids, polyethylene glycol, block polymers of butylene oxide and ethylene oxide, block polymers of propylene oxide and ethylene oxide, and block polymers of polyoxyalkylene and propylene glycol. These representative heat-sensitive compositions and related compositions and their melting points are as follows: Cocoa butter 32-34°C; Cocoa butter with 2% beeswax 35-37°C; Propylene glycol mono Stearates and distearates 32-35°C; hydrogenated oils, such as hydrogenated vegetable oils 36-37.5°C; 80%
Hydrogenated vegetable oil and 20% sorbitan monopalmitate 39-39.5℃; 80% hydrogenated vegetable oil and 20% polysorbate 60, 36-37℃; 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; with 8-22 carbons Mono-, di- and triglycerides of saturated and unsaturated acids such as palmitic, stearic, oleic, linoleic, linolenic and arachidonic acids; triglycerides and mono- and diglycerides of saturated fats at 34-35.5°C; propylene Glycol mono- and distearates 33-34°C; partially hydrogenated cottonseed oil 35-39°C; block polymers of polyoxy-alkylene and propylene glycol; 1.2
- Block polymer made by adding ethylene oxide to butylene oxide; Block polymer of propylene oxide and ethylene oxide; Hydrogenated fatty alcohol and fat at 33-36°C; Hexadienol and hydrated lanolin triethanolamine glyceryl monostearate at 38°C; Mono- Witepsol #15, triglycerides and monoglycerides of saturated vegetable fatty acids 33.5-35.5°C; Witepsol H32 without hydroxyl groups 31-33
Witepsol W25 with saponification number 225-240 and melting point 33.5-35.5°C; saponification number 220-
Witepsol E75 with 230 and melting point 37-39°C; polyalkylene glycol,
For example polyethylene glycol 1000, a linear 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℃; 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 having 11-17 carbon atoms, 33-35°C, etc. Thermosensitive compositions store the beneficial agent within a solid composition at a temperature of 20-33°C, maintain an immiscible boundary at the interface with the swellable composition, and store the beneficial agent at a temperature above 33°C, preferably 33°C. A vehicle for administering drugs in a fluid composition in the -40°C range. When administered to a biological environment, thermosensitive compositions are readily excreted, metabolized, assimilated, etc., facilitating the effective use of beneficial agents.

The materials for forming the capsules are commercially available materials including gelatin, e.g.
Gelatin with ~30 millipoise and a bloom strength of 150 g or less; gelatin with a bloom number of 160-250; a composition consisting of gelatin, glycerin, water and titanium dioxide; a composition consisting of gelatin, erythrosine, iron oxide and titanium dioxide; gelatin, Glycerin, sorbitol, potassium sorbate and titanium dioxide; compositions of gelatin, gum acacia, glycerin and water, and the like.

As used herein, the term "beneficial agent" refers to any composition, formulation, or compound that can be administered to produce a desired beneficial and useful result.
Refers to a mixture or compound. Beneficial agents include algaecides, antioxidants, air fresheners, biocides, catalysts, chemical reactants, cosmetics, pharmaceuticals, disinfectants, fungicides, foods, fertility suppressants, and antiseptics. Fat promoters, food supplements, fermentation chemicals, fungicides, insecticides, microbial attenuators, nutrients, plant growth promoters, plant growth inhibitors, preservatives, surfactants, sterilizers, sterilizers, vitamins and other compositions that benefit the environment, surroundings, habitat and animals. The drug can be insoluble to very soluble in the heat-sensitive material contained within the dispenser.

As used herein and in the appended claims, the term "medicine" includes any physiologically or pharmacologically active substance that produces a local or systemic effect in animals, and includes warm-blooded animals. , human and primate animals, birds, fish, domestic, sport and farm animals, laboratory animals, and zoo animals. The term "physiological" as used herein refers to the administration of a drug to produce normal levels and function. The term "pharmacological" refers to changes in the amount of drug administered to the host. Stedman's Medical Dictionary
Dictionary, 1966, Williams and Wilkins,
Published by Baltimore, MD). Active drugs that can be administered include, without limitation, inorganic and organic drugs, solid drugs, oil drugs, drugs that act on the nervous system, depressants, hypnotics,
Sedatives, stimulants, tranquilizers, anticonvulsants, muscle relaxants, antiparkinsonism drugs, analgesics, anti-inflammatory drugs, antimalarial drugs, hormonal drugs, contraceptives, sympathomimetics, diuretics, anthelmintic drugs , oncology drugs, hypoglycemic drugs, ophthalmic drugs, electrolytes, diagnostic drugs, and cardiovascular drugs. The amount of drug present in the dispenser is
It may be from 0.05ng to 20g or more. For medical use, the dispenser can contain various amounts, e.g. 25 ng, 1 mg, 5 mg, 125 ng.
mg, 250mg, 500mg, 750mg, 1.5g, etc. The dispenser can be used once, twice or three times daily. The dispenser can also be used twice a week.

The semi-permeable wall-forming composition can be lathed by primary molding, secondary molding, air blowing, dipping or brushing to create a thin layer on the outer surface of the capsule. can. Other techniques that can be used to coat semi-permeable walls and are preferred for this invention are air flotation and pan coating. The air flotation method consists of suspending and rotating the capsule in a flow of air and semipermeable wall-forming composition until the wall envelops and covers the capsule member. This process can be repeated using additional semipermeable wall-forming compositions to form semipermeable laminate walls. The air flotation method is US Patent No. 2799241; Journal of American Pharmaceutical Association (J.Am.Pharm
Assoc.), Vol. 48, pp. 451-459, 1979;
Volume 49, pages 82-84, 1960, etc. Other standard manufacturing methods are listed in the Modern Plastics Encyclopedia (Modern Plastics Encyclopedia).
Plastics Encyclopedia), Volume 46, pp. 62-70,
1969 and Pharmaceutical Sciences, by Remington, 14th edition, pp. 1626-1678, 1970
Mack Publishing Co., Easton P.A.
Published by Easton PA).

Typical solvents suitable for producing semipermeable walls include inert, inorganic solvents that do not adversely affect the materials, the capsule wall, the beneficial agent, the heat-sensitive composition, the intumescent member, and the final dispenser. and organic solvents. Such solvents broadly include aqueous solvents, alcohols, ketones, esters,
The solvent is selected from the group consisting of ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic, aromatic, heterocyclic solvents and mixtures thereof. Typical solvents include acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane, n
-Heptane, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene dichloride, ethylene dichloride,
Propylene dichloride, carbon tetrachloride, nitroethane, nitropropane, tetrachloroethane, ethyl ether, isopropyl ether, cyclohexine, cyclooctane, benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, diglyme, water, and mixtures thereof. , such as acetone and water, acetone and methanol, acetone and ethyl alcohol, methylene dichloride and methanol, and ethylene dichloride and methanol. Generally, for purposes of this invention, the semi-permeable wall is coated at a temperature a few degrees below the melting point of the heat-sensitive composition. Alternatively, the thermoplastic composition can be applied to the dispenser after applying the semi-permeable wall.

Squeeze holes or passageways as used herein constitute means and methods in the wall suitable for releasing the beneficial drug formulation from the dispenser.
The circular holes can be formed by mechanical or laser drilling or by eroding an erodible component in the wall, such as a plug of gelatin.
The pores can also be polymers inserted into the semipermeable wall, where the polymer is a porous polymer with at least one pore or a microporous polymer with at least one micropore. It is. A detailed description of the holes and preferred maximum and minimum dimensions of the holes are disclosed in US Pat. Nos. 3,845,770 and 3,916,899.

DESCRIPTION OF EMBODIMENTS OF THE INVENTION The following examples are merely illustrative of the invention and are not to be construed as limiting the invention. These embodiments and other equivalents will become more apparent to those skilled in the art in light of this disclosure, the drawings, and the claims below.

Example 1 A dispenser is prepared as follows.
That is, the body of the two-piece capsule is first placed vertically over its mouth, and the hemispherical end of the capsule is filled with a layer of expandable, swellable composition. Its composition is 30% (by weight) sodium chloride and 70%
(by weight) consisting of poly(ethylene oxide) with a molecular weight of 3 million. The ingredients forming the expandable composition are mixed with heat in a commercial mixer for 20 minutes to produce a homogeneous composition. This heated composition is injected into the hemispherical end of the capsule to form a layer that occupies approximately 1/4 of the capsule. The cap portion of the capsule is then placed over the body portion of the capsule and a fill port is drilled through the cap for communication with the lumen of the assembled capsule.
A heat-sensitive pharmaceutical formulation is then injected into the lumen of the capsule through the fill port to fill the lumen. Finally, apply a semi-transparent wall around the assembled capsule,
An exit passageway is drilled through the semi-permeable wall to communicate with the fill port to enable delivery of the pharmaceutical formulation from the dispenser.

Example 2 A dispenser is prepared as follows.
The body of the two-piece capsule is first placed vertically with its opening facing upwards, and the curved hemispherical end of the capsule is filled with a 500 mg layer of Cyanamer polyacrylamide (a hydrogel with a molecular weight of approximately 200,000). Next, place the cap part of the capsule over the main part of the capsule. A semi-permeable wall is then formed around the assembled capsule. For the semi-permeable wall, 85 g of cellulose acetate with an acetyl content of 39.8% is mixed with 200 ml of methylene chloride.
and 200ml of methanol, then sprayed onto the assembled capsules in an air flotation machine to form a 0.25mm
A thick semi-permeable wall is formed by enclosing the capsule. After drying the capsule, 1.0
A mm passage is laser drilled through the semipermeable wall and the capsule wall to communicate with the capsule lumen. Next, a heat-sensitive enteric mixture of 77% neutral fat with a melting point of 35-37°C and 19.5% paraffin with a melting point of 52°C is liquefied by heating, and 3.5% acetylsalicylic acid is added thereto. The heated mixture is then cooled to about 40°C and injected into the capsule lumen through the passageway before
Allow dispenser to cool to room temperature.

Example 3 A dispenser for administering beneficial agents to warm-blooded animals is prepared as follows. That is, 30 parts of ethylene glycol monomethacrylate containing 0.12 parts of ethylene glycol dimethacrylate and 0.13 parts of sodium sulfate were placed in a mold having a shape and relative arrangement corresponding to the opening and inner diameter of the capsule body.
% aqueous solution in aqueous ethanol. The composition polymerizes at 30° C. and the solid layer is removed from the mold after 20 minutes of equilibration with room temperature. The solid expandable layer is then fitted into the mouth of the capsule, thereby forming an internal drug compartment within the space between the curved hemispherical end of the capsule and the inner surface of the layer of expandable polymer. A fill-outlet hole is then drilled through the hemispherical end to communicate the exterior and interior compartments of the capsule.
The compartment can be filled with the heat-sensitive drug composition at this time, or can optionally be filled later.

For example, if the above compartment is filled with a molten composition consisting of 2.5% phenobarbital, 20.5% glycerol gelatin, and 77% theobroma oil, glycerides of stearic, palmitic, and lauric acids and allowed to cool to room temperature, A heat-sensitive composition can be formed at a location where it is laminated with the expansion layer. The body of the capsule is then closed with a capsule cap by sliding the cap over the mouth of the capsule.

Then, a 15% by weight solution of cellulose acetate with an acetyl content of 39.8% was prepared and the fully assembled capsules were immersed in the solution for 10 seconds initially, then for 1 minute each time, and so on. The capsules are coated with a semipermeable wall by dipping 15 times, with 5 minutes of drying time in between. After soaking, heat the dispenser to 72°F.
Dry for 10 days at room temperature (approximately 22 °C). In this step, a semi-transparent wall of about 2 mm is painted. Passages are laser drilled through the semi-permeable wall to communicate the exterior of the dispenser with the fill port-outlet and the heat sensitive layer.

Example 4 A dispenser for administering a beneficial drug formulation is manufactured as follows. That is, the hemispherical end of the gelatin capsule was first injected into a molten composition consisting essentially of 30% sodium chloride and 70% coagulant grade polyethylene oxide.
Fill with g. Next, tighten the cap of the capsule by 2mm.
After soaking in water until the end of the capsule, slide it over the opening of the capsule and cover the open body of the capsule. The water firmly bonds the cap and body members of the capsule. Next, thread a 50 mil (1.3 mm) through the cap edge of the assembled gelatin capsule.
The exit of the hole is drilled. Then, 9.9 g of a heat-sensitive drug formulation consisting of a 15% suspension of theophylline and 8% Cabosil anhydrous in polyethylene glycol 400 was injected into the drug chamber of the capsule through the drug port at 50°C. It is layered in close contact with the inflatable plug at the end of the hemisphere. The heat-sensitive drug formulation then contacts the inner walls of the gelatin capsule. The assembled dosage form capsule is then covered with a surrounding wall of cellulose acetate butyrate containing 10% polyethylene glycol 400. The semi-transparent walls are coated in a Pan Hi-coater.
The solvent used to form the wall consisted essentially of methylene chloride and methanol, 95 parts by weight to 5 parts by weight, respectively.
Consists of parts by weight. A 12 mil (0.03 mm) thick cellulose acetate butyrate wall is applied to the outer wall of the capsule. Figure 10 shows the release rate in mcg/hour at 37°C.

One aspect of the present invention relates to a method for administering a beneficial agent at a controlled rate to the vaginal canal or anorectal canal of a warm-blooded animal. The method consists of the following steps.

(A) introducing into said tube a dispenser comprising: (1) a semipermeable material that is permeable to the passage of fluids and substantially impermeable to the passage of pharmaceutical products; an outer wall formed of a polymeric composition; (2) a capsule surrounded by said outer wall and containing within its compartment a beneficial pharmaceutical formulation, said pharmaceutical formulation implementing a therapeutic program in a heat-sensitive carrier; the thermosensitive carrier melts at body temperature,
(3) a layer of expandable hydrogel within the capsule, the layer being placed in contact with the heat-sensitive composition of the pharmaceutical formulation; and (4) (B) a circular hole that penetrates the outer wall and the capsule wall and communicates with the heat-sensitive composition of the pharmaceutical formulation; drawing fluid through the wall to swell and swell the hydrogel layer; (C) melting the pharmaceutical formulation to form a flowable formulation; and (D) continuously expanding the molten formulation. from one hour to several months, by delivering a beneficial drug formulation from the compartment by a layer of water and administering said formulation in a medically effective amount to said tube at a controlled rate through the borehole. Preferably 1
It produces the desired therapeutic effect over a long period of time, from hours to 24 hours.

A typical example of a pharmaceutical product that can be administered using a dispenser is conjugated follicular hormone, which is administered as a formulation containing 0.875 mg of conjugated follicular hormone in a heat-sensitive base.

Since the foregoing specification constitutes preferred embodiments of the invention, it will be appreciated that changes and modifications may be made in accordance with the inventive principles disclosed herein without departing from the scope of the invention.

[Brief explanation of drawings]

FIG. 1 is an overview of a dispenser designed in a one-piece arrangement and manufactured for oral administration of beneficial agents to warm-blooded animals. FIG. 2 is a cross-sectional view through the vertical length of the dispenser of FIG. 1, containing a thermodynamic heat-sensitive member and an inflatable member;
Figure 3 illustrates an internal compartment forming a dispenser and manufactured as one piece. FIG. 3 is a cross-sectional view of the dispenser of FIGS. 1 and 2, wherein the dispenser comprises a semi-permeable wall surrounding a compartment filled with heat-sensitive composition and a drive member; FIG. depicts a dispenser working and dispensing a beneficial drug. FIG. 4 is an overview of a dispenser consisting of two telescoping parts and constructed for delivering beneficial agents over an extended period of time. FIG. 5 is a cross-sectional view of FIG. 4, consisting of the main body of the dispenser excluding the snap-in cap portion of the dispenser. Figure 6 is the 4th
2 is a cross-sectional view of the figure depicting the body portion telescopingly capped by a mating cap portion and the lumen of the dispenser filled with a composition containing a heat-sensitive drug and an inflatable drive member; FIG. ing. FIG. 7 is a cross-sectional view of the dispenser of FIGS. 4 and 6, which in FIG. I'm drawing. Figure 8 shows
Figure 3 is a cross-sectional view of the body portion of the capsule including an inflatable, swellable plug at the mouth of the capsule. FIG. 9, like FIG. 8, is a cross-sectional view of the body portion of the capsule including the expandable, swellable stopper disposed parallel to the heat-sensitive composition containing the drug. FIG. 10 is a graph depicting the release pattern of the drug formulation from the dispenser over time. 10...Dispenser, 11...Main body, 12
... vessel wall, 13 ... capsule, 14 ... lumen, 1
5... Drug, 16... Heat-sensitive composition, 17... Drive member, 18... Channel, 20... Dispenser, 21... Main body or capsule, 22... Cap, 23... Semi-transparent wall, 25 ...Aperture, 26...
Space, 27...Drug, 28...Thermosensitive composition, 2
9... Drive member, 30... Passage, 31... Main body or capsule, 32... Expandable plug, 33... Opening, 34... Passage, 35... Vessel wall, 36... Space, 37... Heat-sensitive composition, 38...Drug, 39
...Semi-transparent wall.

Claims (1)

Claims: 1. A dispenser for releasing a heat-sensitive beneficial drug formulation into a use environment at a controlled rate, comprising: (a) a one-piece or two-piece gelatin capsule having a lumen; (b) Heat-sensitive beneficial drug hydrophobic formulations that melt in the lumen of the capsule at a temperature of 31°C to 42.5°C, comprising waxes, fats, hydrogenated oils, partially hydrogenated oils, glycerides, esters of saturated fatty acids, A pharmaceutical formulation comprising one selected from the group consisting of polyethylene glycol, block polymers of butylene oxide and ethylene oxide, block polymers of propyleoxide and ethylene oxide, and block polymers of polyoxyalkylene and propylene glycol, c) a hydrophilic composition that is a medium for absorbing and swelling fluid in the lumen and is in contact with the heat-sensitive drug formulation; (d) a vessel wall surrounding the capsule, which comprises at least a vessel wall formed in part of a semipermeable composition that is permeable to the passage of fluids and substantially impermeable to the passage of beneficial agents; and (e) A dispenser comprising: a passageway through the vessel wall communicating with a heat-sensitive beneficial agent for the purpose of releasing the agent from the dispenser over an extended period of time. 2. A dispenser as claimed in claim 1, wherein the capsule comprises a matching cap telescopingly connected to the body and delimiting the lumen. 3. Dispenser according to claim 1, wherein the capsule is a one-piece capsule with an internal compartment. 4. The dispenser according to claim 1, wherein the hydrophilic composition consists of a hydrogel and a solute with an osmotic effect. 5. Dispenser according to claim 1, wherein the hydrophilic composition consists of polyethylene oxide, polyacrylic acid and its salts, polyethylene glycol and, optionally, a solute with osmotic effect. 6 The semipermeable organ wall composition is a cellulose ester,
From one selected from the group consisting of cellulose diester, cellulose ether, cellulose ester ether, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, and cellulose acetate butyrate. 2. A dispenser according to claim 1, wherein the dispenser is formed as claimed in claim 1. 7. The dispenser of claim 1, wherein the lumen contains a layer of heat-sensitive beneficial agent formulation. 8. The dispenser of claim 1, wherein the lumen contains a layer of hydrophilic composition.