FR2561628A1 - DEVICE FOR DELIVERING SUBSTANCES WITH SEVERAL COMPONENTS OPERATING IN INTEGRATED UNIT SYSTEM - Google Patents

Abstract

DEVICE INTENDED FOR THE SUPPLY OF A USEFUL AGENT TO AN ENVIRONMENT OF USE. THE DEVICE 10 INCLUDES A SEMI-PERMEABLE WALL 12 SURROUNDING A COMPARTMENT 14 CONTAINING A THERMOSENSITIVE COMPOSITION 16, AND A EXPANDABLE COMPOSITION 17. A CHANNEL 18 IN THE WALL CONNECTS THE COMPARTMENT TO THE OUTSIDE OF THE DEVICE. APPLICATION IN PARTICULAR TO THE PHARMACEUTICAL FIELD.

Description

25616Z8

  The present invention relates to a device

  new and useful input. In particular, the invention

  relates to a delivery device comprising a wall /

  semi-permeable which at least partially surrounds (a) a

  internal part or (b) a capsule arranged inside-

  ment and housing in (a) or (b) a thermo-

  sensitive agent and an expandable actuating element

  is lying. The constituent elements of the device act in concert to deliver the beneficial agent in a certain time to

  a speed set in a use environment.

  Devices for providing a beneficial agent in a use medium are known in the preparative art. For example, the U.S. Patent. No. 3,760,984 granted to the patentee Theeuwes describes a device for

  consisting of a heat-shrinkable container whose

  outer face carries an osmotic solute and a remote layer of a polymer permeable to the fluid. These measures

  has a stopper for filling the container

  tainer. The device is actuated by the absorption of a fluid which, in the dispenser, dissolves the solute, so that a solution exerts a pressure on the retractable container, which makes it retract

  and release the agent from the device. In the U.S. Patent

  No. 3,865,108, the Hartop patentee describes a device for

  port consisting of an internal compressible tube which

  holds a medicine and is placed in a base element made of an inflatable material. The device delivers the drug because the base and some parts absorb fluid from the medium, so that it expands and compresses the compressible tube causing the drug to be expelled from the tube. In the U.S. Patent N 3 971 376,

  the patented Wichterle describes a device for

  both in a capsule having unit walls constituting

  of an inflatable cross-linked gel in the fluids. A textile fabric is embedded in the material to impart strength and minimize problems due to the poor mechanical properties associated with the material, which occur during the absorption of the fluid used to actuate the device. In the U.S. Patent No. 3,987,790, the patents Eckenhoff et al. describe an improvement to an osmotic device, consisting of a conduit

  intended to fill a pocket in the device. The provision

  The absorbent fluid is actuated by an osmotic-acting solute which absorbs fluid in the device, which absorbed fluid generates a hydraulic pressure which is applied against the bag by compressing it inwardly to drive the agent out of the device. In the U.S. Patent No. 3,995,631, the Higuchi et al. disclose a pouch having on its outer surface a layer of an osmotic solute, and a remote wall made of a material which partly has a fluid-controlled permeability. In operation, a solute solution is formed, which solution compresses the pouch causing release of the agent from the pouch. In the patent

  United States of America No. 4,320,758, the patents Eckenhoff et al.

  disclose a delivery device consisting of a flexible bag, a sheath formed of a dispersion of an osmotically active solute in a soluble polymer, and a fluid-permeable outer wall. The device delivers the drug in that the sheath absorbs water in the space between the outer wall and the pocket, so that there is a hydraulic pressure on the pocket, which pressure causes the compression of the pocket and

  makes him deliver the drug. The U.S. Patent

  No. 4,350,271 discloses a fluid delivery device which functions by absorption of water in a composition which expands against a lipophilic fluid which is delivered by

an orifice.

  Although the aforementioned delivery devices are useful for delivering many agents into a

  medium of use, and although these devices represent

  commercial development in preparatory art, specialists will realize that there are cases where a delivery device with a new inventive refinement would also meet large commercial domains

  uses and applications in the preparatory art.

  For example, if it were proposed a delivery device having an initial arrangement with internal capsule that facilitates the

  device and gives it a better return

  for a lower cost, and if the device was

  made without a flexible bag and without piece of cloth, which would improve the device by reducing the number of steps and elements necessary for its manufacture, such a delivery device would meet an immediate success

  and would also represent a significant advancement of the technique.

  Similarly, if a surge device was

  both the limitation of the delivery devices of the prior art

  that only agents under

  form of solution or suspension, the device

  therefore soluble or insoluble agents in the form of

  fluid, semi-solid, or the like, such a device

  would be an immediate success and would also represent an interesting contribution in the fields of

  science, medicine and commerce.

  Accordingly, an immediate object of the present invention is to provide a device for the delivery of useful agents, in all useful forms, to a medium

  of use, this new device representing a person

  preparation in the preparatory art.

  Another object of the invention is to provide a delivery device which is self-contained, spontaneously activating activation and autonomous actuation in fluid media, which is easy to manufacture, and can be used to provide agents useful for animals, including humans, and other biological and non-organic media

biological use.

  Another object of the invention is to provide a

  delivery device which can house a thermosetting composition.

  hydrophobic sensitizer comprising insoluble-to-soluble drugs, which thermosensitive composition, in response to the temperature of a surrounding biological medium, changes state and becomes fluid, semisolid, etc., to increase

  the release from the device.

  Yet another object of the invention is to provide a delivery device having an initial internal capsule arrangement, which makes the manufacture of the device easier and lower cost, which increases the

practicality of the device.

  Yet another object of the invention is to provide

  a delivery device which comprises a compartment containing

  a temperature sensitive composition, an expandable member arranged parallel to the temperature sensitive composition, an inner capsule containing the composition and the element in the capsule compartment, a wall

  semi-permeable outer shell surrounding at least part of the

  sule, and a release channel, which device delivers the composition by the joint physicochemical actions of the composition, which melts and becomes fluid to semi-solid or analogous state, the composition retaining a limit not

  miscible at the interface of the expandable element, and the

  expandable, which swells in the space occupied by the

  composition by moving an equivalent amount of

position off the device.

  Yet another object of the invention is to provide

  a delivery device that is empty until it

  wise with a solid composition which liquefies at high temperatures, and which, when filled, can administer the composition which liquefies by following a

  a complete pharmaceutical dosage regimen for a given

  a certain period of time, and the use of which does not require

  only at the beginning and end of the plan.

  Yet another object of the invention is to provide a delivery device that can deliver useful drugs contained in a pharmaceutically acceptable lipophilic thermosensitive vehicle that melts in the presence of energy.

  heat absorbed from a biological medium of

  It is also a further object of the invention to provide an osmotic delivery device containing a composition, which composition is releasable and harmless, thereby substantially preventing irritation of mammalian tissues and interaction with them. eutectic composition consisting of at least two components and at least one drug, which eutectic composition has a melting point approximately at the temperature of a chick blood animal and is supplied to the animal by the

device at said temperature.

  Yet another object of the invention is to provide a delivery device comprising an inner capsule which houses a hydrophilic thermosensitive composition comprising insoluble soluble drugs, which thermosensitive composition, in response to the arrival of energy present in a medium. biological use, changes of state and

  becomes fit to be released to be provided by the

  positive. Yet another object of the invention is to provide a delivery device comprising an inner capsule which contains a thermoplastic composition and an expandable component, which composition comprises a beneficial agent which is chemically unstable in an aqueous medium and can be housed in the device in a non-aqueous delivery vehicle, which agent is protected in the non-aqueous medium during

  the release from the device.

  Yet another object of the invention is to provide a delivery device comprising a semipermeable wall surrounding at least in part a compartment which contains a thermosensitive composition containing an active agent, and a means for repressing the composition through a channel

  connecting the compartment to the outside of the device.

  Other objects, features and advantages of the invention will be apparent to those skilled in the art

  preparatory to the following detailed description,

  made with reference to the drawings and the appended claims.

  In the drawings, which are not to scale but are given to illustrate various embodiments of the invention, the figures are as follows: Figure 1 is a view of a delivery device

  structured in one piece and designed for the administration of

  Oral treatment of a drug useful to a warm-blooded animal Figure 2 is a sectional view of the device

  of Figure 1 taken along the vertical length of the

  positive, to show the internal compartment containing a

  thermodynamic thermosensitive element and an expansion element

  component table of the device which is manufactured as a one-piece system; Figure 3 is a sectional view of the device of Figure 1 and Figure 2, Figure 3 showing

  the device, which comprises a semi-permeable wall

  a compartment filled with the composition sensitive to

  the temperature and an actuating element, in operation

  and releasing a useful agent; Figure 4 is a view of a delivery device

  with two telescopic parts and made for

  to provide a useful agent in a certain time; Figure 5 is a sectional view of the device of Figure 4, showing the body of the device without the telescopic locking cap of the device; Figure 6 is a sectional view of the device of Figure 4, showing the body telescopically capped by a nested cap, the device compartment being loaded with a composition containing a temperature-sensitive agent and with an expandable actuating member; Figure 7 is a sectional view of the device of Figure 4 and Figure 6, showing the device, having a semi-permeable wall surrounding a compartment, in operation and releasing a beneficial agent in a given time; Figure 8 is a sectional view of the body of a capsule

  having an expandable inflatable plug located in the

  closure of the capsule; Figure 9 is a sectional view such as that of Figure 8 of the body of a capsule having an expandable inflatable plug arranged parallel to a composition containing a heat sensitive agent; and Figure 10 is a graph showing the release profile of a drug composition from a delivery device and over a prolonged period of time.

  On the drawings and in the description, elements

  Similar figures of corresponding figures are identified by the same references. The previously mentioned terms

  in the specification and in the description of the drawings,

  that the objects to which they apply, are described by

  elsewhere in more detail in the description.

  Referring now for further details to the figures which are examples of novel and useful delivery devices for delivering a beneficial agent, which examples are not limiting, one sees represented on the

  Figure 1 an example of a delivery device that is identical

  10. In Figure 1, the device 10 comprises a body 11 consisting of a wall 12

  surrounding and defining an internal compartment that is not

  shown in Figure 1, and a channel 18 indicated by

  Tilles. FIG. 2 is a sectional view of the device 10 of FIG. 1. The device 10 of FIG.

  body 11 and a wall 12. The wall 12 is formed of a

  position capable of forming a semi-permeable polymeric wall substantially permeable to the passage of an external fluid and substantially impervious to the passage of a beneficial agent and other ingredients contained in the device 10. The wall 12 is non-toxic and retains its physical integrity and chemical, that is to say that it does not undergo erosion

  during the release period. The device 10.is

  during its final manufacture, so as to comprise a single unit capsule 13. That is to say that the capsule 13 can not be easily separated into several

  parts. The capsule 13 may be of a hard structure or.

  soft, as understood here and in the subsequent meaning of the term "capsule". In addition, in Figure 2, the capsule

  13 surrounds an internal space or compartment 14. The

  14 contains a useful agent 15, identified by dots, a thermally sensitive heat-sensitive composition 16 identified by undulating lines, and an actuating element 17 which is in surface contact with the surface of the composition 16. The actuating element 17

  is, in a preferred embodiment, an expansion element

  table 17 whose shape corresponds to the inner shape of the wall of the capsule 13 and the compartment 14. The expandable element 17 in laminated form is made from a hydrogel composition, which is non-crosslinked or optionally crosslinked, and it is endowed with osmotic properties, for example an ability to absorb an external fluid through the semi-permeable wall 12, and gives

  -beyond an osmotic pressure gradient across the--

  semi-permeable wall 12 vis-à-vis a fluid external to the device 10. In another embodiment, the element

  actuator 17 may be a solid solute with osmogenic action

  which absorbs the fluid through the semi-per-

  12. The device 10 is made with a channel 18 which is formed in the semipermeable wall 12 and through the capsule 13. The channel-18 communicates with the compartment 14 and the outside of the device 10 in order to release the agent

  useful from device 10.

  In FIG. 2, the thermally sensitive heat sensitive composition 16 is a means of release and a drive vehicle for the beneficial agent 15. The beneficial agent 15, which is housed in the compartment 14 and can be delivered by the Device 10 is one of the agents that are insoluble to very soluble in both aqueous fluids and in a lipophilic medium. The thermosensitive composition 16, containing the dispersed or dissolved agent in a homogeneous or heterogeneous manner, consists, in a presently preferred embodiment, of a hydrophilic or hydrophobic thermosensitive anhydrous material having properties similar to those a solid at room temperature of 21 C, plus or minus a few degrees centigrade, and having a point

  of fusion approaching the temperatures of the body of mammals

  or in the present invention, the terms "melting point", "softening point" or "liquefies at" are

  indicate the temperature at which the thermo-

  sensitive substance, undergoes dissolution or dissolves into

  a releasable vehicle as it can be used

  to release the agent 15 from the device 10.

  Figure 3 shows in operation the dis-

  Positive 10 of Figures 1 and 2, delivering a

  useful agent to a fluid use medium. In function

  when the environment of use is at a

  37 C, more or less a few degrees, the

  sitive 10 releases the agent 15 by a conjunction of actions

  thermodynamic and kinetic. That is, as a function of

  In one embodiment, the thermosensitive composition 16 melts and passes into a fluid, semi-solid, releasable phase, or the like, to release the agent 15 through the channel 18. At the same time as the composition 16 melts, the fluid is absorbed by the element. hydrophilic 17 through the semipermeable wall 12 in a tendency towards an osmotic equilibrium, so that it makes continuously swell, expand or fill the element 17 whose volume increases and, simultaneously,

  the element 17 expands in the compartment 14 while maintaining

  holding an immiscible limit intact at the interface. In

  same time that the external fluid is absorbed into the

  positive 10 through the semi-permeable wall 12, the capsule wall 13, consisting of a material capable of dissolving in the fluids, dissolves slowly and lubricates the interior.

  the device, which favors expansion without

  element 17 and the resultant continuous release

  16. At the same time, as the expandable member 17 increases in volume, it applies pressure against the composition 16 and pushes it to reduce its volume. The simultaneous appearance of the dilation of the element 17, the contraction of the compartment 14 and the melting of the composition 16 causes the composition 16

  agent 15 is released to the outside of the device.

  10 and 3, taken together, illustrate the device 10 in operation and releasing agent 15. FIG. 2 shows the device at the beginning of an agent release period, and FIG. Figure 3 shows the device 10 towards the end of a

  release period of the agent. The merger of the composi-

  16, the immiscibility of composition 16 in

  17, and the swelling, filling and dilation of the means 17, with its concomitant increase in volume,

  seen in Figure 3, together with the decrease in

  Simultaneously, the corresponding volume of the compartment 14 shown in FIG. 3 ensures the continuous release of the agent at a set speed over a period of time. Figure 4 illustrates a delivery device 20 comprising two parts, a body 21 and a cap 22, and embodied as a unitary device. The device

  is conveniently made in two parts, one 22

  on the other part 21 and styling it. Parts 21 and 22 completely surround and encapsulate an internal compartment, not shown in FIG. 4. The device 20

  also includes a channel 30, indicated in dashed lines.

  Figure 5 is a sectional view of the device of Figure 4, without its cap. In Figure 5,

  the device 20 comprises a body 21 consisting essentially of

  in a semipermeable wall 23 which at least partially surrounds the inner capsule of the body 21 and is

  intimate contact with it, except at the mouth

  25 of the capsule 21. The capsule used to

  storing the device comprises two parts, the capsule body 21 receiving the ingredients and the cap 22, as seen in Figure 6. The capsule 21 surrounds a compartment 26 containing a useful agent 27, identified by points, a thermally sensitive composition 24 sensitive to heat, identified by wavy lines, and

  an expandable and inflatable actuating element 29, working

  The materials constituting the parts and elements of FIG. 5 are the same as those mentioned with reference to the FIGS.

  1 to 3, and they will be described in more detail in

have memory.

  Figure 6 is a sectional view of the device of Figures 4 and 5. Figure 6 shows a device 20 capped with a cap 22. In Figure 6, the cap 22 is fitted on the cap 21 after the body 21, larger, was filled with all the drugs, compositions

  temperature sensors and appropriate actuating elements

  determined. Figure 6 shows that after adjusting the cap 22 on the body 21, a semi-permeable wall 23 is applied to the outer surface of the body 21 and the cap 22. In a variant of manufacture, the capsule

  21 is filled with the respective ingredients and a semi-circular wall

  Permeable is applied except at the mouth, then

  is cap 22. The cap 22, fitted with telescopes

  copically on the body 21, is then coated with a wall

  semi-permeable 23. In one or the other variant of

  cation, a channel 30 is made through the semi-circular wall

  permeable 23 and the wall of the cap 22 to release the agent 27 of the device 20. Figure 7 shows the device in operation. In Figure 7, the device is

  represented as it is towards the end of the release period.

  The device 20 operates in the manner described above at

About the device 10.

  Figure 8 represents another embodiment of

  tion to improve the manufacture and utility of the delivery device. In Figure 8 is shown a body

  which, like the body 31, is a capsule in a mode of

  preferred embodiment, and which is provided with an expandable plug 32 inserted into the mouth 33 of the body 31. The body may be made of a semi-permeable material or a hydrophilic material. A channel 34 is made through the wall 35

  of the body 31, at a distance from the expandable plug 32, for introducing

  providing a filling instrument in the body 31 to fill a compartment 36. Figure 9 shows the compartment 36 filled with a heat-sensitive composition 37 containing a beneficial agent 38. Once the compartment has been filled, the body or capsule is coated and surrounded by a semi-permeable wall 39. The semipermeable wall is, in each embodiment, a means for absorbing the fluid into the expandable element 32 and closes the mouth 33 to ensure that the expansion of the plug 32 will be effected in one direction in the compartment 36 to the channel 34. In this mode of

  manufacture, a channel 34 is pierced through the semi-circular wall

  permeable collinearly with respect to the canal of the

  capsule wall, in order to release the agent 38 from the capsule.

  In another method of manufacture, a semi-permeable wall

  39 is applied around an empty capsule provided with a

  chon in its mouth, a channel is pierced through the semipermeable wall and the wall of the capsule, then the compartment of the capsule is filled with a composition

  thermosensitive containing the beneficial agent.

  Although Figures 1 to 9 show various delivery devices that can be made in accordance with the invention, it is obvious that these devices should not be considered as limiting the invention, because the delivery device can take a great diversity of structures, dimensions and shapes for the supply of agents useful to the environment of use. For example, the device can be made for oral use and

  it can be made to be nilizse co-same device dapper

  buccal port, implant, cervical gland

  intrauterine, auricular, nasal, deriic, vaginal, ano-

  rectally, subcutaneously or in ruminants, for example in cattle caps. The device may also be structured, dimensioned and conforin to release an active agent in currents, currants, plants, reservoirs, laboratory facilities, greenhouses, toy vehicles, hospitals, naval and military facilities, veterinary clinics of farm clinics, zoos, sickrooms, chemical reactors and others

environments of use.

  According to the practice of this invention

  It has now surprisingly been found that the device 10 and the device 20 could be made with a capsule having two distinct forms, classified for purposes of the present invention as hard osmotic capsules and soft osmotic capsules. hard osmotic capsule consists of two parts, a cap and a body, which fit together after the body, plus

  large, was filled with an appropriate agent composition

  requested. We realize this adaptation by making

  slide or telescopically engage the section of

  chon on the body section, thus completely encapsulating and encapsulating the useful agent compositions. The hard capsules are made by dipping molds in a bath containing a solution of a material capable of forming capsule walls, so as to coat the mold with the material. The molds are then removed, cooled and dried in a stream of air. The capsule is removed from the mold and deburred to give a wall having an internal compartment. The cap which telescopically caps the body receiving the agent composition is made in an analogous manner. Then the osmotic capsule closed and

  filling is embedded in a wall or semi-

  permeable. The semipermeable wall may be applied to the capsule portions either before or after the parts have been joined together to form the final capsule.

  In another embodiment, the hard capsules may

  be made in such a way that each part includes

  matching locking rings near their end.

  open and allow to unite and block

  together the body and the lap cap after

  pleating with the agent composition. In this mode of

  In use, two matching locking rings are formed in the cap and the body, and these rings constitute a locking means for holding the capsule firmly together. The capsule may be filled manually with the agent composition, or it may be filled with the agent composition using a machine. In its final stage of manufacture, the hard capsule is coated with a semi-permeable layer, permeable to the passage of fluid and substantially impermeable to the passage of the agent.

useful, as described below.

  The soft osmotic capsule, as used by the present invention, is preferably made in one piece in its final form. In general, the soft osmotic capsule is of sealed construction and encapsulates the beneficial agent composition. The soft capsule is made by various processes including the plate process, the rotary die process, the die process

  reciprocating, and the process continuously. The pro-

  assigned to plates uses a set of molds. A hot sheet of a prepared capsule wall formation material is placed on the lower mold and the agent composition is

  poured on it. A second sheet of the training material

  The wall composition is placed on the agent composition and is then covered by the upper mold. The set of molds is placed under a press and pressure is applied, with or without heating, to form a soft unit capsule. The capsule is washed with a solvent to remove excess agent composition from the outside of the capsule, and the air-dried capsule is coated - in a diaper

semi-permeable material.

  The rotary die process uses two -pel-

  Continuous solids of cap wall formation material

  sule that converge between two rotating dies and a wedge injector. The process performs the filling and

  the sealing of the capsules in two coincident operations.

  In this process, the sheets of capsule wall forming material are advanced on guide rollers, and then down between the wedge injector and the die rolls. The agent composition to be encapsulated flows by gravity into a positive displacement pump. The pump doses the agent composition passing through the wedge injector and extending to the sheets between the rolls of

  matrix. The lower part of the wedge injector pre-

  small orifices aligned with the cells of the matrix rollers. The capsule is approximately half closed when the pressure exerted by the pumped agent composition is discharging the leaves into the cells of the cells.

  matrices, in which the soft capsules are simul-

  at once filled, shaped, hermetically sealed and cut from the sheets of wall forming material. The sealing of the soft capsule is achieved by the mechanical pressure of the matrix rollers and by the

  heating, with the help of the corner, sheets of

  wall matrix. After manufacture, the capsules filled with the agent composition are dried in the presence of air force, and a semi-permeable layer is applied thereto.

the methods described below.

  The reciprocating die process produces soft capsules by advancing two pellets of capsule wall forming material between

  vertical matrices. The matrices, as they go

  open and close, act as a continuous vertical plate forming, row by row, cells on the film. The cells are filled with the agent composition and, as the cells pass between the dies, they are sealed, shaped and cut from the moving film into capsules filled with the agent composition. A semipermeable layer is applied thereto to form the soft capsule osmotic delivery device. The continuous process is a manufacturing system which also uses rotating dies, with the additional feature that this process successfully fills a soft capsule with an active agent in dry powder form, in addition to the possibility of encapsulating liquids. The filled soft capsule issue

  continuous process is embedded in a poly-

  semipermeable to form the soft osmotic capsule. The delivery device of the present invention

  may be provided with a wall made of semi-finished

  permeable which does not adversely affect a host or animal, which is permeable to the passage of an external fluid of the aqueous type, for example water and biological fluids, while remaining essentially impervious to the passage of agents, including medications, and which preserves its integrity in the presence of a heat-sensitive thermotropic composition,

  that is to say, does not melt or erode in his presence.

  The selectively semi-permeable materials constituting the outer wall are substantially insoluble in the

  fluids, they are non-toxic and are not erodible.

  Representative materials intended to constitute

* kill the semipermeable wall include semipermeable homopolymers, semi-permeable copolymers, etc. In a first embodiment, examples of typical materials include cellulosic esters, mono-

  cellulose esters, cellulosic diesters, tri-

  cellulose esters, cellulose ethers, ester-esters

  ceilulosic ethers, and mixtures thereof. These cellulosic polymers have a degree of substitution, DOS.

  on their motive for anhydroglucose from more than

  than 3 inclusive. "Degree of substitution" means the average number of hydroxyl groups initially present on the anhydroglucose unit which are replaced by a

  substitute group, or transformed into another group.

  The anhydroglucose unit may be partially or completely

  is substituted by groups such as acyl, alkanoyl, aroyl, alkyl, alkenyl, alkoxy, halogen, carboalkyl, alkylcarbamate, alkylcarbonate, alkylsulfonate, alkylsulfamate, and the like.

semi-permeable polymer.

  Semi-permeable materials are typically elements selected from the class consisting of

  cellulose, cellulose diacylate, triacylate of

  lulose, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di- and trialkylates, mono-, di- and trialkenates, cellulose mono-, di- and triaroylates, etc. Examples of polymers include cellulose acetate having a D.S. of 1.8 to 2.3 and an acetyl content of 32 to 39.9%; cellulose diacetate having a D.S. of 1 to 2 and an acetyl content of 21 to 35%; cellulose triacetate having a D.S. of 2 to 3 and an acetyl group content of 34 to 44.8%,

  etc. More specific cellulosic polymers include

  cellulose propionate having a D.S. of 1.8 and

  propionyl group content of 38.5%; acetate-propionic

  cellulose acetate having an acetyl group content of 5 to 7% and a propionyl content of 39 to 42%;

  cellulose acetate propionate having a group content

  2.5 to 3% acetyl, average group

  propionyl from 39.2 to 45% and a content of hydro-

  xyl from 2.8 to 5.4%; cellulose acetate butyrate having a D.S. of 1.8, an acetyl group content of 13 to 15%,

  and a butyryl group content of 34 to 39%; acetate-the

  cellulose butyrate having an acetyl group 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 having a D.S. of 2, 9 to 3, by

  cellulose trivalerate, the trilaurate of

  lulose, cellulose tripalmitate, cellulose trioctanoate and cellulose tripropionate; cellulosic diesters having a D.sub.2 of 2.2 to 2.6, for example cellulose disuccinate, cellulose dipalmitate, cellulose dioctanoate, cellulose dicaprylate, etc .; mixed cellulosic esters such as acetate-valerate

  of cellulose, cellulose acetate-succinate, propylene

  cellulose acetate-succinate, cellulose acetate-octanoate

  cellulose valerate-palmitate, acetate-hepto-

  cellulose nate, etc. Semi-permeable polymers are known from U.S. N 4,077,407 and it is possible

  produce them by the procedures described in Encyclopaedia

  pedia of Polymer Science and Technology, Vol. 3, pp. 325-354, 1964, edited by Interscience Publishers, Inc.,

New York.

  Other semi-permeable polymers include

  acetaldehyde-dimethylcellulose acetate; acetate-the

  cellulose ethyl carbamate; cellulose acetate methyl carbamate; cellulose dimethylamino acetate; the

  semi-permeable polyamides; polyurethanes semi-per-

  méables; semi-permeable polysulfanes; polystyrene

  Semipermeable sulfonated resins, selectively semipermeable crosslinked polymers formed by coprecipitation of a polyanion and a polycation, as described in U.S. N 3 173 876; 3,276,586; 3,541,005

  3,541,006 and 3,546,142; the silicone rubbers selected

  highly semi-permeable; semipermeable polymers as described by Loeb and Sourirajan in U.S. Pat. No. 3,133,132; semi-polystyrene derivatives

  permeable; semi-polar poly (styrenesulfonate)

  permeable; poly (vinylbenzyltrimethyl) chloride -

  semi-permeable ammonium; the semipermeable polymer having a fluid permeability of 10-1 to 10-7 cm3. 25im / CM2H bar

  expressed by bar of difference of hydro-

  static or osmotic across a semi-permeable wall.

  These polymers are known in practice from the patents

  United States of America No. 3,845,770; 3,916,899 and 4,160,020 and Hand-

  book of Common Polymers, by J. R. Scott and W. J. Roff, 1971,

  edited by CRC Press, Cleveland, Ohio.

  The materials used to form the element or inner layer and the plug, inflatable and dilatablessont

  pure polymeric substances, and poly-

  mixed with osmotic agents

  act with water or a biological fluid, absorb the

  fluid and swell or dilate to a state of equilibrium

  free. The polymer has the ability to retain a substantial fraction of the fluid absorbed in the polymeric molecular structure. The polymers are, in a preferred embodiment, polymeric gels which can swell or expand to a very high degree, generally

  from 2 to 50 times in volume. The hydrophilic polymers

  flats, also known as osmopolymers, can

  be uncrosslinked or slightly crosslinked. The cross-links

  These can be covalent or ionic bonds, the polymer having the ability to swell in the presence of fluid and, when crosslinked, does not dissolve in the fluid. The polymer may be of plant or animal origin

  or synthetic. Polymeric materials useful for

  thin layers include poly (hydroxy methacrylate)

  alkyl) having a molecular weight of between 5,000 and 10,000,000; poly (vinylpyrrolidone) having a molecular weight of between 10,000 and 360,000; hydrogels

  anionic and cationic; polyelectrolyte complexes

  lytes; polyvinyl alcohol having a low residual acetate content; an inflatable mixture of agar and

  carboxymethylcellulose; an inflatable composition comprises

  methylcellulose in a mixture with an agar plate

  reticulated; a water-swellable copolymer produced by dispersing a finely divided anhydride copolymer

  maleic and styrene, ethylene, propylene or iso-

  butylene; a water-swellable polymer of N-vinyl

lactams; etc. -

  Other gellable polymers absorbing and retaining

  the fluids. useful for forming the hydrophilic expandable push member, include pectin having a weight

  molecular weight of between 30,000 and 300,000; polysac-

  chars such as agar, gum arabic, karaya gum, gum tragacanth, algin and guar gum; carbopolic acid carboxylic polymer and its salts; polyacrylamides; polymers of indene and anhydride

  male inflatable with water; Good-polyacrylic acid

  Rit2 having a molecular weight of 80,000 to 200,000; polyethylene poly (ethylene oxide) polymers having a molecular weight of from 100,000 to 5,000,000 and over; graft copolymers of starch; exchange polymers of

  polyanions and polycations; copolymers of polyvinylamine

  acrylonitrile; Aqua-Keey acrylic polymers having a water absorbability of about 400 times its initial weight; polyglucan diesters; a mixture of cross-linked polyvinyl alcohol and poly (N-vinyl-2-pyrrolidone);

  zein available as prolamine; the poly-

  (ethylene glycol) having a molecular weight of 4000 to 000; etc. In a preferred embodiment, the expandable wall is formed from polymers and polymeric compositions that are thermoformable. Representative examples of polymers with properties

  hydrophilic are known from U.S. patents.

  No. 3,865,108; 4,002,173; 4,207,893; 4,327,725, and Handbook of Common Polymers, by Scott and Roff, edited by

  Cleveland Rubber Company, Cleveland, Ohio.

  The osmotic compound that can be used

  pure or in a homogeneous or heterogeneous mixture with poly-

  inflatable mother to constitute a pushing element is an osmotically active solute that is soluble in the fluid

  absorbed in the inflatable polymer and gives rise to a

  osmotic pressure through the semi-permeable wall.

  able to an external fluid. The compounds with action

  osmotic are also known as osmotic. The-

  Osmotic osmagents useful herein include solid compounds selected from the class consisting of magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, mannitol, and the like. , urea, sorbitol, inositol, sucrose, glucose,

  etc. Osmotic pressure in bars, osmosis

  suitable for the invention is greater than zero bazed,

  and it generally goes from zero bar to 500 bar or more.

  The inflatable expandable polymer, in addition to being an actuating means for the release of a beneficial agent from the delivery device, further serves

  of support matrix for an osmotic action solute.

  The osmotic solute may be homogeneously or heterogeneously mixed with the polymer to provide the expandable wall or expandable pocket desired. The composition comprises, in a presently preferred embodiment, (a) at least one polymer and at least one osmotic solute, or (b)

  at least one solid osmotic solute. In general, a

  position will comprise approximately 20% to 90% by weight of poly-

  mother and 80% to 10% by weight of osmotic solute, a

  currently preferred position comprising 35% to 75%

  polymer weight and 65% to 25% by weight of osmotic solute

tick.

2 5 6 1628

  The term "thermosensitive" as used for the purposes

  of the present invention, includes the thermosetting compositions

  plastics that may soften or become liberated

  in response to heat input, and harden again when cooling. This term also encompasses thermotropic compositions susceptible to change in response to gradient energy application. They are sensitive to temperature by their response to the application or removal of energy. The term "heat-sensitive" as used for the purposes of the present invention, in a preferred embodiment, refers to the physico-chemical property of an agent carrier in which it has the properties of a solid or the like of a solid at temperatures up to 330C and becomes fluid, semi-solid or viscous when disturbed by heat at temperatures exceeding 32WC, ordinarily

  in the range of 32 to 40 ° C.

  is susceptible to heat and has the property of melting, dissolving, dissolving, softening, or liquefying at elevated temperatures, thereby forming

  a composition that can be released, which can be

  positive intake of delivering the thermosensitive vehicle

  containing the beneficial agent in a homogeneous or heterogeneous mixture.

  The thermosensitive vehicle may be lipophilic, hydrophilic or hydrophobic. Another important property of the vehicle is its ability to maintain the stability of the agent it contains during storage and during release of the agent. Representative heat-sensitive compositions, with their melting points, are as follows: Cocoa butter, 32-34 C; cocoa butter and 2% wax

  bee, 35-37 C; monostearate and propylene distearate

  ethylene glycol, 32-35 C; hydrogenated oils such as

  hydrogenated vegetable oil, 36-37.5 C; 80% vegetable oil

  hydrogenated salt and 20% sorbitan monopalmitate, 39-39.5 ° C; 80% of hydrogenated vegetable oil and 20% of Polysorbate 60, 36-37 C; 77.5% of hydrogenated vegetable oil% of sorbitan trioleate and 2.5% of beeswax,

  -36 C; 72.5% hydrogenated vegetable oil, 20% trihydrate

  sorbitan oleate, 2. 5% beeswax and 5.0% distilled water, 37-38 C; mono-, di- and triglycerides of acids having 8 to 22 carbon atoms, including saturated and unsaturated acids such as palmitic, stearic, oleic, linoleic, linolenic and arachidonic acids;

  triglycerides of saturated fatty acids with mono- and di-

  glycerides, 34-35.5 ° C; mono- and distearates of propylene-

  glycol, 33-34WC; partially cottonseed seed oil

  hydrogenated, 35-39 ° C, a polyoxyalkyl block polymer

  lene and propylene glycol; composite block polymers

  taking 1,2-butylene oxide to which ethylene oxide is added; block copolymers of propylene oxide and ethylene oxide; hardened fatty alcohols and fats, 33-36 C; hexadienol and glyceryl triethanolamine-lanolin monostearate hydrate, 38WC; eutectic mixtures of mono-, di- and triglycerides, 35-39 C; Witepsol NO 15, vegetable fatty acid triglyceride with monoglycerides, 33.5-35.5 C; Witepsol H32 free of hydroxyl groups, 31-33WC; Witepso0W25 having a subscript

  saponification of 225-240 and a melting point of 33.5-

  , 5 C; Witepso $ E75 having a saponification number

  220-230 and a melting point of 37-39 C; a polyalkyl

  ethylene glycol such as polyethylene glycol 1000, a linear polymer of ethylene oxide, 38-41 C; polyethylene glycol 1500 melting at 38-410C; polyethylene glycol monostearate,

  39-42.5 ° C; 33% polyethylene glycol 1500, 47% poly-

  ethylene glycol 6000 and 20% distilled water, 39-41WC;

  30% polyethylene glycol 1500, 40% polyethylene

  glycol 4000 and 30% polyethylene-glyco-1 - 400, 33-38 C; a mixture of saturated fatty acid mono-, di- and triglycerides having 11 to 17 carbon atoms, 33-35WC-; etc. The thermosensitive composition provides a means for storing a beneficial agent in a solid composition at a temperature of 20-33 C, to maintain an immiscible limit at the interface of the swelling composition, and to release the agent as a composition that

  to flow at a temperature above 33 C, and to

  in the range of 33 to 400C. The thermosensitive composition, when released in a biological medium, is easily excreted, metabolized, assimilated,

  etc., for efficient use of the beneficial agent.

  The materials used to form the capsule are the commercially available materials comprising gelatin, the gelatin having a viscosity of 1.5 to 3 mPa.s and a Bloom resistance of up to 150 grams; gelatin having a Bloom degree of 160 to 250; a composition comprising gelatin, glycerin,

  water and titanium dioxide; a composition comprising

  gelatin, erythrosine, iron oxide and titanium dioxide; a composition comprising

  gelatin, glycerin, sorbitol, potassium sorbate

  sium and titanium dioxide; a composition comprising gelatin, gum arabic, glycerine and water; etc. The term "beneficial agent" as used herein refers to any composition, formulation, mixture or compound that can be provided to produce an effect.

  beneficial and useful predetermined. Useful agents

  take algicides, antioxidants, air purifiers, biocides, catalysts, chemical reagents, cosmetics,

  drugs, disinfectants, fungicides, foods,

  fertility promoters, fertility activators, adjuvants

  foodstuffs, fermentation agents, germicides, insecti-

  cides, attenuators of microorganisms, nutrients,

  plant growth promoters, growth inhibitors

  plant life, preservatives, surfactants, sterilizing agents, sexual sterilants, vitamins, and other compositions that are useful to the environment, the environment, habitats and animals. The agent may be insoluble to very soluble in the temperature sensitive material

housed in the delivery device.

  In the description and the appended claims,

  the term "medicinal product" includes any substance with a physiological

  Siologic or pharmacological that produces a local or systemic effect in animals, including warm-blooded mammals, humans and primates, birds, fish, domestic animals, sport and farm animals,

  laboratory animals, and animals from zoological parks

  cal. The term "physiological" as used here is

  relates to the administration of a medicinal product aimed at

  to obtain normal rates and functions. The term "pharmacolo-

  "marks variations in response to the amount of drug administered to the host." Stedman's Medical Dictionary,

  1966, edited by Williams and Wilkins, Baltimore, Maryland.

  Active drugs that can be delivered include, without limitation, inorganic and organic drugs, solid form medications, oil medications, nervous system medications, depressants, hypnotics, sedatives, psychic stimulants , tranquilizers, anti-convulsive, relaxing

  muscle, anti-parkinsonian, analgesic, anti-inflammatory

  matures, anti-malarial, hormonal agents, contraceptives,

  sympathomimetic, diuretic, anti-parasitic, neo-

  plastics, hypoglycemic agents, ophthalmic agents, electro-

  lytes, diagnostic agents and cardiovascular drugs

  lar. The amount of agent present in the device may be from 0.05 ng to 20 g or more. For medical applications, the device may contain various amounts, for example 25 ng, 1 mg, 5 mg, 125 mg, 250 mg, 500 mg, 750 mg, 1.5 g, etc. The device can be used one, two or three times a day; it can be used twice a week, etc.

  The semi-permeable wall-forming composition

  able can be applied in a laminar arrangement to the over-

  face of the capsule by molding, forming, air atomization, immersion or brush coating with a semipermeable wall forming composition. Other techniques that can be implemented to apply the semi-permeable wall are the fluidized air bed coating method and the turbine coating methods. The fluidized air bed process consists of suspending and shaking the capsules in a stream of air and semi-permeable wall-forming compositions until the wall surrounds and coats the capsules. This process may be repeated with another semipermeable wall forming composition to form a laminated semipermeable wall. The fluidized air bed process is described in U.S. N, 2,799,241; J. Am. Pharm. Assoc., Vol. 48, pp. 451-459, 1979; and ibid, Vol. 49, pages 82-84, 1960. Other conventional manufacturing techniques are described in Modern Plastics Encyclopedia, Vol. 46, pp. 62-70, 1969; and in Pharmaceutical Sciences, of Remington, 14th Edition, pages 1626 to 1678, 1970, edited

  by Mack Publishing Co., Easton, Pennsylvania.

  Examples of suitable solvents for the manufacture

  Semi-permeable wall cation include inert inorganic and organic solvents which do not adversely affect the materials, the capsule wall, the beneficial agent, the thermosensitive composition, the expandable element, or the final device. The solvents broadly comprise the elements selected from the class consisting of aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic solvents,

  aromatic, heterocyclic, and mixtures thereof. Examples

  Examples of 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, dichloride of ethylene, propylene dichloride, carbon tetrachloride, nitroethane, nitropropane, tetrachloroethane, ethyl ether, isopropyl ether, cyclohexane, cyclooctane,

  benzene, toluene, naphtha, 1,4-dioxane, tetra-

  hydrofuran, diglyme, water, and their mixtures such as acetone and water, acetone and methanol, acetone and alcohol

  ethyl chloride, methylene dichloride and methanol, and dichlo

  ethylene and methanol. In general, for the present

  For this purpose, the semi-permeable wall is applied at a temperature a few degrees lower than the melting point of the composition.

  thermosensitive. Or, the thermoplastic composition can be loaded into the device after

  application of the semi-permeable wall.

  The term "orifice" or "channel" as used herein includes means and systems provided in the wall and suitable for releasing a useful agent composition from the device. The orifice may be formed by mechanical or laser drilling, or by erosion of an erodible element of the wall, for example a gelatin plug. The orifice may be a polymer inserted in the semi-permeable wall, which polymer is a porous polymer and has at least one pore, or it is a microporous polymer which

  has at least one micropore. A detailed description

  openings and maximum and minimum dimensions

  for an orifice is found in U.S. patents.

Nos. 3,845,770 and 3,916,899.

  The following examples are merely intended to illustrate the present invention and should in no way be construed as limiting the scope of the invention, as these and other examples which are equivalent to them will become clearer for the purposes of the invention.

  specialists in view of the present description, drawings

and the appended claims.

EXAMPLE 1

  A delivery device is prepared in the following manner: Firstly, the body is provided with a two-part capsule so that its mouth is turned upwards and the hemispherical end of the mouth is loaded.

  capsule with an expandable-inflatable composition. The com

  position comprises 30% by weight of sodium chloride and 70% by weight of polyethylene oxide having a weight

  molecular weight of 3,000,000.

  training tables in a commercial mixer during

  minutes while heating to obtain a homogeneous

  gene. The heated composition is introduced into the hemispherical end of the capsule to form a layer which occupies about a quarter of the capsule. Then, cap the body of the capsule with the cap of the capsule and pierce a filling hole through the cap for

  establish a communication with the compartment of the

  sule assembly. Then, we introduce a thermo

  sensitive drug in the capsule compartment

  filling hole so as to fill the compartment

  BUILDING. Finally, a semi-permeable wall is applied around

  of the assembled capsule and pierces an exit channel through

  towards the semi-permeable wall so that it communicates with

  the filling orifice so that the composition of

  cament can be released from the device.

EXAMPLE 2

  A delivery device is prepared in the following manner: Firstly, the body is provided with a two-part capsule so that its mouth is turned upwards and the rounded hemispherical end of the capsule is loaded with a layer of 500 mg of CyanamerA, a

  hydrogel having a molecular weight of about 200,000.

  Then, cover the body of the capsule with the cap of the capsule. Then, a semi-permeable wall is formed

  around the assembled capsule. The semi-circular wall is

  permeable by mixing 85 g of cellulose acetate having an acetyl content of 39.8% with 200 ml of methylene chloride and 200 ml of methanol, and spraying the assembled capsule in an air bed apparatus fluidized until a semi-permeable wall

  0.25 mm thick surrounds the capsule. We dry

  sule and laser drill a 1.0 mm channel communicating with

  the compartment of the capsule through the semi-per-

  méable and the wall of the capsule. Next, a thermosensitive eutectic mixture consisting of 77% of neutral fat melting at 35-37 ° C and 19.5% of paraffin with a melting point of 52 ° C is heated and liquefied, and 3 5% acetylsalicylic acid The heated mixture is then cooled to about 40 ° C,

  it is injected through the canal into the compartment of the cap.

  and the device is cooled to room temperature.

ambient temperature.

EXAMPLE 3

  A device for

  bring a beneficial agent to a warm-blooded animal:

  folds a mold whose shape and structure correspond

  at the mouth and the internal diameter of the body of a cap-

  sule with an expandable forming composition comprising

  30 parts of ethylene glycol monomethacrylate, 0.12 parts

  of ethylene glycol dimethacrylate and 10 parts of a 0.13% aqueous solution of sodium disulfate in aqueous ethanol. The composition polymerizes at 30 ° C and, 20 minutes after equilibrium at room temperature, the solid phase is removed from the mold. The solid expandable layer is then placed in the mouth of the capsule so as to provide an internal compartment for the medicament in the space between the rounded hemispherical end.

  of the capsule and the inner surface of the poly-

  expandable mother. We then pierce the hemisphere end

  There is a fill-out port connecting the outside of the capsule and the inner compartment. We can fill

  at this point the compartment with a composition of

  thermosensitive camera, or one can possibly

fill in later.

  For example, we can fill the compartment

  with a melted composition comprising 2.5% phenobarbital

  bital, 20.5% of glycerogelatine and 77% of cocoa butter, a glyceride of stearic, palmitic and lauric acids, to form, by cooling to room temperature, the thermosensitive composition superimposed on the expandable layer. The body of the capsule is then closed by sliding the cap over the mouth of

the capsule.

  A 15% by weight solution of cellulose acetate having an acetyl group content of 39.8% is then prepared and the fully assembled capsule is coated with a semi-permeable wall by dipping it into the solution 15 times. , the first time for 10 seconds, then for 1 minute at each immersion, with an intermediate drying period of 5 minutes. After immersion treatment, the devices were dried at an ambient temperature of about 22 ° C for 10 days. This procedure makes it possible to apply a semi-permeable wall

  about 2 mm. Laser is pierced through the semi-circular wall

  permeable a channel that connects the outside of the device to

  the fill-out port and the thermosensitive layer.

EXAMPLE 4

A delivery device for dispensing a useful agent composition is manufactured as follows: First, the hemispherical end of a gelatin capsule is filled with 3.25 g of a melt composition consisting essentially of 30% of sodium chloride and 70% of polyethylene oxide, quality for coagulant. Then, the cap of the capsule is immersed in the water for two millimeters, then the cap is slid over the mouth to cover the body of the capsule.- Under the action of the water, the cap and the body of the capsule bind firmly. Then, a 1.3 mm exit orifice is pierced through the end of the cap of the assembled gelatin capsule. 9.9 g of a thermosensitive drug composition consisting of a 15% suspension of theophylline with 8% anhydrous Cabosil in polyethylene glycol 400 distearate is then introduced through the drug port into the compartment. drug the capsule at 50 C, to form a layer in intimate contact with the expandable cap located at the hemispherical end of the capsule. The thermosensitive drug composition comes into contact with the inner wall of the gelatin capsule. Then we put on

  the assembled capsule dosed with an acetate-buty-

  cellulose spleen containing 10% polyethylene glycol 400.

  The semi-permeable wall is applied by means of a turbine

  high speed coating. The solvent used for forming

  The wall composition is essentially a mixture of parts by weight of methylene chloride and 5 parts by weight of methanol. It is applied to the outer surface of the capsule a wall of cellulose acetate-butyrate having a thickness of 0.03 mm. Figure 10 shows

  the release rate in micrograms per hour at 37 C.

  An application of the invention relates to a

  method of administering a drug useful at a speed adjusted to the vaginal or anorectal route of a blood animal

  the method comprises the steps of: (A) introducing

  ducting in the path of a delivery device comprising:

  (1) an outer wall made of a poly-

  semipermeable, permeable to fluid passage and substantially impervious to the passage of a drug; this surrounding wall (2) a capsule containing a layer of a useful agent composition located in the compartment

  consisting of a unit dose of medicinal

  to carry out a therapeutic program, in a

  thermosensitive vehicle that melts at the temperature and

  a means of transporting the drug out of

  positive; (3) a layer of an expandable hydrogel located in

  the capsule, said layer being in contact with the composition

  thermosensitive drug release; and (4) an orifice that passes through the outer wall and the wall of the capsule

  which communicates with the thermosensitive composition of

  CAMENT; (B) absorption of the fluid through the semi-

  permeable at a rate determined by the permeability of the semipermeable wall and the osmotic pressure gradient across the semipermeable wall, resulting in the expansion and swelling of the hydrogel layer;

  (C) melting the drug composition to forma-

  a flowable composition; and (D) liber

  ration of the useful drug composition of the

  by the continuous dilation of the layer against the

  melted composition, whereby the composition is deli-

  in the way through the orifice at a controlled rate and in a therapeutically effective amount so as to produce the desired medical effect over a prolonged period of 1 hour to several months, preferably 1 hour to 24 hours. An example of a drug that can be

  delivered by use of the delivery device is an oes-

  trogenous conjugate delivered in a composition comprising

  0.875 mg of conjugated estrogens in a thermoset

sible.

  Although the foregoing description relates to

  preferred embodiments of the invention, it is obvious

  that variations and modifications may be made in accordance with the described inventive principles,

  without departing from the scope of the invention.

Claims (10)

  1. Device for supplying a controlled speed of a thermosensitive composition of beneficial agent to a use medium, characterized in that it comprises: (a) a capsule (13) having an internal compartment (14, 26, 36);   (b) a thermosensitive useful agent composition (16, 28, 37) (15, 27, 38) which is in the solid state up to 32 C and melts at a temperature above 32 C in the compartment of the capsule;   (c) a hydrophilic composition (17, 29, 32) which   a means for absorbing fluid and swelling in the compartment, said hydrophilic composition being in contact with the thermosensitive composition; (d) a wall (12, 23, 39) surrounding the capsule, the wall being constituted at least in part by a semipermeable composition which is permeable to the passage of fluid and substantially impermeable to the passage of the beneficial agent; and   (e) a channel (18, 30, 34) passing through the wall and   imparting with the thermosensitive composition useful agent   to release the agent from the device in a while.   2. Device for supplying a controlled speed of a thermosensitive useful agent composition according to claim 1, characterized in that the capsule comprises   a body (21) and a cap (22) adapted fitted telescopic   to define the compartment (26).   A device for supplying at a controlled speed a thermosensitive useful agent composition according to claim 1, characterized in that the capsule is a capsule (31) in one piece having a compartment internal (36).   4. Device for supplying a thermal composition   agent of claim 1, characterized in that   in that the hydrophilic composition comprises a hydrophilic   gel and an osmotic action solute.   5. Device for supplying a thermosetting composition   agent according to claim 1, characterized in that the hydrophilic composition comprises   polyethylene, polyacrylic acid and its salts, poly-   ethylene glycol and optionally an osmotic solute. 6. Device for supplying a thermosensitive agent composition according to claim 1, characterized in that the semipermeable wall composition is composed of a member selected from the class consisting of esters   cellulose diesters, cellulose ethers,   lulose, cellulose ester-ethers, acylates of   lulose, cellulose diacylates, triacylates of   lulose, cellulose acetate, cellulose diacetate,   cellulose triacetate and cellulose acetate butyrate   lose. 7. Device for supplying at a controlled speed a thermosensitive useful agent composition according to the   Claim 1, characterized in that the thermal composition   a message selected from the class consisting of   in both saturated fatty acid glycerol esters, polyethylene glycol, butylene oxide and propylene oxide block copolymers, block polymers of propylene oxide and ethylene oxide, and polymers   polyoxyalkylene and propylene glycol sequences.   8. Device for supplying a controlled speed of a thermosensitive agent useful composition according to claim 1, characterized in that the compartment houses   a layer of thermosensitive useful agent composition.   9. Apparatus for supplying at a controlled speed a thermosensitive useful agent composition according to claim 1, characterized in that the compartment houses   a layer of the hydrophilic composition.   10. Device for feeding at a set speed   of a beneficial agent to a biological medium according to the   cation 1, characterized in that the capsule is a capsule gelatin.