FR2604904A1 - DEVICE FOR PROVIDING SUBSTANCES TO A SURROUNDING MEDIUM - Google Patents

Abstract

A DEVICE FOR SUPPLYING AN AGENT (SUBSTANCE) FORMULA TO A SURROUNDING ENVIRONMENT OF A HOT LIQUID. THIS DEVICE INCLUDES A SEMI-PERMEABLE EXTERNAL WALL 12 SURROUNDING AND APPLIED TO AN INFLATABLE HYDROPHILIC INTERNAL WALL 15. THESE WALLS DEFINE AN INTERNAL SPACE 14 TO CONTAIN AN AGENT 18 FORMULA SENSITIVE TO THE ACTION OF HEAT. A PASSAGE 13 THROUGH THE SEMI-PERMEABLE WALL CONNECTS THE EXTERIOR OF THE DEVICE TO THE INSIDE OF THE latter THROUGH AN OPENING IN THE INTERNAL WALL.

Description

The present invention relates to a device

  osmotic to bring over time to an envi-

  giving, at a regulated flow rate, a heat-sensitive composition which contains a substance (agent) to be supplied to this medium. Devices for supplying substances, called agents, to a surrounding environment of use, are known in this technique. For example, US Pat. No. 3,760,984 describes such a device consisting of a hot-shrinkable container with an osmotic solute on its external surface and a distant layer of a polymer material permeable to

  liquids, and a removable cap to fill the container.

  This device is activated by the liquid which impregnates it.

  gn by penetrating it and which dissolves the solute by forming a

  solution which exerts pressure against the container

  traceable, whose contraction delivers the agent. US Patent 3,865,108 describes a device consisting of a collapsible inner tube which contains a medicament placed in a base element formed of an inflatable material, device

  which delivers the drug from the base and the absorbing parts

  bant the liquid from the surrounding environment, which expands and - 2 -

  squeeze the tube out of the medication. The bre-

  vet US 3 971 376 describes another device consisting of a capsule with walls formed of a crosslinked gel which swells in liquids, with a textile fabric embedded in the material to give it resistance and reduce the difficulties due to bad characteristics mechanical

  related to matter, which appear during absorption

  tion of the liquid used to put the device into action.

  US Patent 3,987,790 describes an improvement made to an osmotic device formed by a conduit for filling a bag located in the device, which is actuated by

  an osmotic solution which impregnates it with liquid,

  which produces hydraulic pressure against the bag

  compressing it and bringing out the agent. The bre-

  vet US 3,995,631 describes a bag carrying on its outer surface

  a layer of osmotic solute with a wall

  distant formed of a material with permeability regulated at the

  keep liquids. In operation, a solution is formed.

  tion of the solute which compresses the bag by bringing out the agent. US Pat. No. 4,320,758 describes a device formed by a flexible bag, a sheath made from a dispersion of an osmotic solute in a soluble polymer and a

  liquid permeable outer wall, device which

  delivers a drug through the sheath soaking up water in the space between the wall and the bag, thus exerting on the latter a hydraulic pressure which causes the drug to exit. If the devices that have just been described are

  interesting to bring many agents to the environment

  teeming with employment, and if they represent advances in this technique, specialists can see that there are cases where further improvements would be of great commercial interest. For example, a device without a flexible bag and without fabric, thus bringing an improvement

  by reducing the number of operations and parts required

  res, would have an immediate welcome and represent a pro

  important sandstone. Likewise, a device enabling - 3 -

  remedy previous limits of single agent intake-

  ment in the form of solutions or suspensions by a dis-

  positive which currently provides soluble or insoluble agents in liquids, semi-solids or in other forms, would be immediately appreciated and would also represent a valuable contribution in the fields of

  science, medicine and commerce.

  The subject of the present invention is therefore a dis-

  new and improved positive for the intake of substances

  (also called agents) in all forms.

  Another object of this invention is to provide a self-contained, self-priming and self-actuated device in liquid environments, easy to manufacture and capable of being used for the delivery of agents to animals, including

  humans, as well as other environments, biological or not.

  Another object of the invention is a device which can house a thermo-sensitive hydrophobic composition.

  which includes insoluble to soluble drugs,

  sition which, under the action of the temperature of an

  biological change of shape and becomes liquid or

  semi-solid to facilitate the exit of the device.

  Another object is yet another device which

  includes an opening containing a thermo composition

  sensitive, an expandable element partially surrounding this

  composition, an external semi-permeable wall surrounding the element and the opening, and a filler passage, device

  which delivers the composition by fusion thereof which

  comes liquid or semi-solid and which maintains an immiscible separation limit at the interface of the element which

  expands, the latter swelling by displacing an equivalent amount

  slow composition outside the device.

  Another object of the invention is a delivery device which is empty until it is filled with a solid composition which liquefies when hot, and which once

  filled can administer the following liquefied composition

  for a complete pharmaceutical dosage regimen for a certain period of time, the use of which does not require

  an intervention only for the beginning and the end of the regime.

  Another object is a device capable of delivering drugs contained in a thermophilic lipophilic pharmaceutical vehicle which melts under the action of heat by giving a composition which can be delivered without harmlessness, this

  which prevents irritation of mammalian tissues and the inter-

  action with mammalian protein tissues.

  Another object is an osmotic delivery device.

  containing a eutectic composition formed from at least

  two components and one or more drugs,

  tion whose melting point is substantially the same as the temperature of a homeothermic animal, and which is brought

to the animal at that temperature.

  Yet another object is to provide a disposi-

  tif which can accommodate a hydrophilic thermosensitive composition

  which includes insoluble to soluble drugs,

  tion which, under the action of the heat of an environment

  organic, changes shape and can be added to the middle

surrounding place.

  Another object is finally a delivery device comprising a chemically unstable agent in a surrounding aqueous medium and which can be housed in a non-aqueous delivery vehicle, an agent which is protected in this vehicle

  during device exit.

  In the attached drawings, not drawn to scale

  and which are given only to illustrate various mo-

  of the invention, the figures are as follows

  Figure 1 is a view of a device designed and manufactured for the oral administration of drugs to homeotherms; Figure 2 is an open view of the device of Figure 1 along line 2-2 of Figure 1 to show the internal compartment and the thermodynamic elements

  forming the system made into an integrated delivery device

  gral; FIG. 3 is an open view of the device

  Figure 1 showing the compartment filled with a composite

  thermosensitive tion which contains the agent to be supplied; Figure 4 is a view of the open device of Figure 3 showing the expansion of a control element for the supply of an agent of the device; Figure 5 is an open view of Figure 1 showing a closure element in the opening of the device; FIG. 6 represents an embodiment of the invention in which the elements forming the device are in a concentric arrangement; FIG. 7 represents an embodiment of the invention in which the elements forming the device are in partially circular arrangement; FIG. 8 represents an embodiment of the invention in which the elements forming the device are in parallel arrangement; FIG. 9 shows an embodiment of the invention in which the elements forming the device are in the form of a pocket; Figure 10 is a diagram of three methods of manufacturing the device of the invention;

  Figure 11 is a graph showing the speed

  se release at the time of a delivery device; and

  Figure 12 is a graph showing the amount

  total amount of thermosensitive composition delivered by

the device.

  In the drawings and the description the same

  The figures are identified by the same numbers.

  An example of a supply device is shown in Figure 1 where it is identified by the number 10. In this figure we see the device 10 comprising a body 11

  with a wall 12 and a passage 13 in this wall which re-

  binds the outside inside the device, as we

see in Figure 2.

  - 6 - Figure 2 is a cross-sectional view of Figure 1 showing the device 10 which comprises the body 11, the wall 12 surrounding an internal compartment 14 and a

  passage 13 in this wall which makes the comparator communicate

  timent 14 with the outside of the device. The wall 12 is formed of a semi-permeable polymeric material forming a composition permeable to the passage of an external liquid but practically impermeable to the passage of an agent and other ingredients contained in the compartment 14. This wall 12 is not toxic and she retains her physical integrity

  and chemical during the service of the device.

  The compartment 14 is also surrounded by a layer of an expandable actuating element which is in

  contact with the internal surface of the wall 12, this

  inner che 15 partially surrounding the compartment 14, except for a part 16 defined by the ends 17 of the layer 15, and the inner layer 15 has a shape which corresponds to that of the semipermeable wall 12 and of the compartment 14. The layer 15 is made of a hydrogel composition, non-crosslinked or possibly crosslinked, and it has osmotic properties, which can be impregnated with an external liquid through the semi-permeable wall 12 and exerting an osmotic pressure gradient through this

  wall against a liquid outside the device 10.

  Figure 3 shows the device 10 of the

  gure 1 in open cross section, figure in which the device includes the structural elements described with reference to FIGS. 1 and 2 and which shows the device containing in the compartment 14 an agent 18 represented

  by dots, and a thermosensitive composition 19 re-

  under the action of heat, represented by lines

  corrugated genes, composition which is a means of delivery and a vehicle for transporting agent 18. Agent 18 which is housed in compartment 14 and can be released by the device comprises insoluble agents with very soluble in - 7 -

  both in aqueous liquids and in lipo-

  philes. The heat-sensitive composition 19 containing the agent 18 dispersed in a homogeneous or heterogeneous manner or in solution,

  is formed, in a currently preferred embodiment

  re, a hydrophilic or hydrophobic anhydrous thermosensitive material, solid at ordinary temperature of approximately 20 C and whose melting point is close to the temperature of 37 C of a mammal, approximately. In the present invention, the terms “melting point”, “softening point” and “liquefaction” indicate the temperatures at which the heat-sensitive composition melts, dissolves partially or completely, forming a vehicle which makes it possible to provide

agent 18 of device 10.

  In operation, in the surrounding medium at a temperature of about 37 C, the device 10 releases the agent 18 by a thermodynamic action associated with a

  kinetic action, that is to say that the thermo-

  sensitive 19 melts by forming a fluid or semi-solid phase which brings the agent 18 through the passage 13. When the composition 19 melts, the liquid soaks the semi-permeable wall 12 with the hydrophilic layer 15 with a tendency towards balanced

  osmotic for continuous swelling, or expands and increases

  lies the volume of the layer 15 which expands at the same time in the compartment 14 while maintaining at the interface an immiscible separation limit. At the same time, as layer 15 increases in volume, it applies

  pressure against composition 19 by decreasing the volume

  me of it. The simultaneity of the dilation of the cou-

  che 15, the contraction of compartment 14 and the melting of composition 19 means that this composition containing agent 18 crosses passage 13 to go outside

  of the device 10. FIGS. 3 and 4 taken together show

  trent the device 10 in operation, delivering the agent 18. FIG. 3 represents the device 10 at the start of an agent supply period and FIG. 4 represents it - 8 -

  near the end of the intake period. The merger of the com-

  position 19 and its immiscibility are added to the expansion layer 15, to the swelling and expansion of this layer, which is accompanied by an increase in volume as shown in FIG. 4, with at the same time a corresponding reduction in the volume of compartment 14 as also shown in FIG. 4, which ensures the contribution of

  agent 18 at a regulated rate and continuous over time.

  FIG. 5 is an embodiment of the arrangement

  sitive 10 of Figures 1 to 4, further representing an element

  closure 20 in the open end of compartment 14.

  This closure 20 fits well in compartment 14 and

  it is in contact with the inner surface of the cou-

  che 15. The outside of the closure 20 forms a watertight seal

  che to liquids with the part of the internal surface of the layer 15 with which it is in contact. The closure 20, possibly called a plug, has a central axial opening 21 which extends completely through it, an opening which gives access to the interior of the device 10, mainly to the compartment 14, to garnish the latter with the composition 19 containing agent 18, and at the same time opening 21 gives access to passage 13 through the wall

  semi-permeable 12 for the contribution of the composition 19 containing

agent 18.

  Figures 6 and 7 show other embodiments of the device 10 of this invention, figures in which this device is made, in a method of

  currently preferred manufacture, by coextrusion of the elements

  structural elements that form it. In Figure 6, the dis-

  positive 10 is shown with its ends 22 and 23 open

  to represent its structure. This device is essential-

  formed of a semi-permeable wall 24 surrounding everything

  its exterior before the ends 22 and 23 are open

  green to show the structure of the device, a medial inflatable expandable push zone 25 and an internal zone 9-

  thermosensitive 26 as agent reservoir. The disposi-

  tif 10 further comprises two supply orifices 27 in the semipermeable wall 24 for supplying the agent formula

  closed ends 22 and 23 not shown in the figure

  Figure 6. Figure 7 shows the device 10 comprising

  a semi-permeable wall 28 surrounding and delimiting the interior

  laughing device, in cross section at its ends

  tees 29 and 30 to show the internal reservoir 31 of the agent

  and a contact layer of an inflating push member 32

  ble and expandable. The device 10 has three supply orifices 33 through the semi-permeable wall 28 which communicate

  with the reservoir of agent 31 for the supply thereof.

  An orifice is placed in the body of the device 10 and the

  two others are placed at its closed ends. The availability

  sitive 10 of Figures 6 and 7 operates in the following manner

  above described in its surrounding employment environment.

  FIG. 8 represents the supply device 10 in a rectangular form, but naturally it can have other shapes and dimensions suitable for its use in determined fluid media. In this figure the

  device is open along two of its safety limits

  paration, 9-9, to show its internal layout. It com-

  takes a supply orifice 35, a semi-permeable wall 36, a compartment 37 with a heat-sensitive composition 38

  containing agent 39, and a pushing composition 40

  flexible and expandable. This device operates to release the agent 39 as it was said above, that is to say that the thermosensitive composition 38 melts at a temperature of at 41 C and the composition 40 expands and passes through

  compression the composition 39 by the orifice 35.

  FIG. 9 illustrates a device 10 which can

  have various dimensions for use as a pump

  Harbor. In this embodiment, this device is miniaturized for use as an implant for administering an agent to an animal. It is shown in open view along the line

- 10 -

  8-8 and it comprises a wall 41 retaining its shape, formed at least in part of a semi-permeable material which surrounds an internal element of inflatable bag 42. This bag 42 is an open container with an internal space 43 and a opening 50 well closed by a closing piece 44,

  crossing of an entrance and exit port for the gar-

  nissage and intake. The bag 42 contains an agent 44 and a thermosensitive vehicle composition 47 for this agent. A passage 49 in the semi-permeable wall 41 is aligned with the orifice 45 to fill the device 10 and

to get agent 46 out.

  Figures 1 to 9 illustrate various devices

  in accordance with the present invention but which do not limit

  in any case, which may have shapes and dimensions

  very diverse ways to bring agents to the surrounding employment environment. The device can for example be

  designed for oral administration in various forms and di-

  common mensions, for example a circular shape from 4 to mm in diameter. The device can be adapted for a

  use as buccal device, implant, artificial gland -

  the, cervical, intrauterine, auricular, nasal, dermal,

  vaginal, anorectal, in rumen or rumen cap

  nants or subcutaneous. It can also be in a form and

  with dimensions and structures suitable for deli-

  check an agent in rivers, aquariums, fields, factories, reservoirs, laboratories, greenhouses, means of transport, hospitals, in the naval and military fields, veterinary clinics, nurseries, farms, zoos, sick rooms,

  chemical reactors and other environments.

  The present plaintiff has found that the provision

  filler 10 can be supplied with a wall comprising a semi-permeable material without prejudice to the recipient, permeable to the passage of an external aqueous liquid such as

  water or a biological liquid, while remaining practical-

  impermeable to the passage of agents such as drugs,

- li -

  osmagents (osmotic agents), and which maintains its integrity

  grity in the presence of a thermotropic composition. The materials

  selectively semi-permeable res forming the external wall are practically insoluble in liquids, they are not toxic and they are not erodible. Representative materials for forming the semi-permeable wall include homopolymers and copolymers

  semi-permeable etc, and in an embodiment of the materials

  res features include esters, mono-esters,

  di-esters and tri-esters of cellulose, cell ethers

  cellulosic esters and ethers. These cellulosic polymers have a degree of substitution, DS, on their anhydroglucose unit, greater than O and which can range up to 3 inclusive, by hearing by degree of substitution the average number of hydroxyl groups initially present on the anhydroglucose unit and which are replaced by a substituent and transformed into other groups. The reason

  anhydroglucose may be wholly or partially sub-

  set up by groups such as acyl groups, alca-

  nuclei, aroyles, alkyls, alkenyls, alkoxy, halogens, carboalkyl groups, alkylcarbamates, alkylcarbonates,

  alkylsulfonates, alkylsulfamates and the like

  wheat forming a semi-permeable polymer.

  The semi-permeable materials typically include the following: cellulose acylates, diacylates, and triacylates such as mono-acetate, di-acetate and tri-acetate, mono-, di- and tri-alkyl ethers, alkenyl and aryl cellulose etc., examples of polymers comprising acetate

  cellulose with a D.S. of 1.8 to 2.3 and an acety content

  the from 32 to 39.9%; cellulose diacetate having a D.S.

  from 1 to 2 and an acetyl content of 21 to 35%; tri-

  cellulose acetate having a D.S. of 2 to 3 and an acetyl content of 34 to 44.8% etc. More specific cellulosic polymers include cellulose propionate

- 12 -

  having a D.S. of 1.8 and a propionyl content of 38.5%; cellulose acetate propionate having an acetyl content of 1.5 to 7% and a propionyl content of 39 to 42%; cellulose acetate propionate having an acetyl content of 2.5 to 3%, an average propionyl content of 39.2 to 45% and a hydroxyl content of 2.8 to 5.4%; cellulose acetate butyrate having a D.S. of 1.8, an acetyl content of 13 to 15% and a butyryl content of 34 to 39%; cellulose acetate butyrate having an acetyl content of 2 to 29.5%, a butyryl content of 17 to 53% and a hydroxyl content of 0.5 to 4.7%; cellulose triacylates having a D.S. of 2.9 to 3, such as trivalerate, trilaurate, tripalmitate,

  tri-octanoate and cellulose tripropionate; di-

  cellulosic esters having a D.S. of 2.2 to 2.6 such that

  disuccinate, dipalmitate, di-octanoate, di-

  cellulose caprylate and others; mixed cellulose esters such as acetate valerate, acetate succinate,

  propionate-succinate, acetate-octanoate, valerate-

  palmitate and cellulose acetate octanoate etc. PO-

  Semi-permeable lymers are known from US Patent 4,077,407 and can be obtained by the methods described in Encyclopedia of Polymer Science and Technology, volume 3, pages 325 to 354, 1964, publication of Interscience

Publishers, Inc., New York.

  Other semi-permeable polymers include those of acetaldehyde and dimethyl acetate, cellulose acetate and ethyl carbamate, cellulose acetate and methyl carbamate, cellulose dimethylaminoacetate, polyamides, polyurethanes and semi-permeable polysulfones, semi sulfonated polystyrenes -crosslinked raincoats, selectively semi-waterproof polymers formed by coprecipitation of a poly-anion and a poly-cation as described in US Patents 3,173,876, 3,276,586, 3,541,005, 3,541,006

  and 3,546,142, selectively semi-silicone rubber

  permeable, semi-permeable polymers as described by

- 13 -

  Loeb and Sourirajan in US Pat. No. 3,133,132, semi-permeable polystyrene derivatives (sodium polystyrene-sulfonate), poly (vinylbenzyl-trimethyl) -ammonium chloride

  semi-permeable, semi-permeable polymers having a permeability

  liquid bility from 10-1 to 10-7 (cm3.0,025 mm / cm2.h.atm)

  (difference in hydrostatic or osmotic pressure through

  towards the semi-permeable wall). These polymers are known from US patents 3,845,770, 3,916,899 and 4,160,020 and are also found in the Handbook of Common Polymers, by ScoLt J.R. and Roff, W.J., 1971, CRC Press publication,

Cleveland, Ohio.

  The materials used to form the inner wall

  inflatable which expands and the pocket are poly-

  mothers, alone or mixed with osmotic agents which react with water or an absorbent biological liquid

  the liquid and swelling, expanding to a state of

  balance. The polymer has the power to retain a substantial fraction of the liquid which impregnates it, and the preferred polymers are polymer gels which can swell and expand.

  a very high degree, usually 2 to 50 times their volume.

  Hydrophilic swelling polymers, also called osmopolymers, may not be crosslinked or may

  be slightly cross-linked. The transverse links can-

  can be covalent or ionic bonds for a poly-

  mother can swell in the presence of a liquid, and if it is crosslinked it does not dissolve in the liquid. The polymer can be of vegetable, animal or synthetic origin. Of

  interesting polymeric materials here include a poly-

  (hydroxyalkyl methacrylate) with a molecular weight of

  5,000 to 5,000,000; a poly- (vinylpyrrolidone) of molecular mass

  ring 10,000 to 360,000; anionic or catio-

  picnics, polyelectrolyte complexes; polyvinyl alcohol with a low residual acetate content; an inflatable mixture of agar and carboxymethylcellulose; an inflatable composition comprising methylcellulose

- 14 -

  with slightly cross-linked agar; a water-swelling polymer formed by dispersing a finely divided copolymer

  maleic anhydride with styrene, ethylene, propy-

  lene or isobutylene; polymers which swell with water of N-vinyllactams etc. Other gelable polymers which retain the impregnating liquid, which are useful for forming the hydrophilic expandable pushing element, include pectin

  having a molecular weight of 30,000 to 300,000; of the gela-

  tine with a viscosity of 15 to 30 millipoises and a re-

  sistance up to 150 grams, gelatin having a "bloom" value from 160 to 250; polysaccharides

* such as agar, gum arabic, karaya or adragan-

  tea, algin and guar gum; a carboxy-polymer

  Carbopol acid and its salified derivatives; polyacrylami-

  , indene and maleic anhydrous polymers which swell with water; a Good-rite polyacrylic acid having a molecular weight of 80,000 to 200,000; polyoxyethylene polyox polymers having a molecular weight of 10,000 to 5,000,000; starch graft copolymers; Aqua-Keep polyacrylates which absorb approximately 400 times their initial weight of water; polyglucan diesters;

  a mixture of crosslinked polyvinyl alcohol and po (N-vinyl-2-pyrrolidone); zein which is found in the form of

  prolamine; a poly (ethylene glycol) having a molecular weight of 4000 to 100,000 etc. In a preferred embodiment, the expandable wall is formed with polymers and polymeric compositions which can be shaped

  hot. Representative polymers with characteristics

  hydrophilic are known from US Patents 3,865,108, 4,002,173, 4,207,893 and 4,327,725 and are also found

  in Scott and Roff's Handbook of Common Polymers, pu-

  Cleveland Rubber Company, Cleveland, Ohio.

  Osmotic-acting compounds that can be mixed

  to change homogeneously or heterogeneously with the polymer

- 15 -

  inflatable to form a push wall are the solutes

  with osmotic action which are soluble in the impregnated liquid

  inhibiting the swellable polymer, and which exert an osmotic pressure gradient across the semi-permeable wall against an external liquid. Osmotic-acting compounds are also called osmagents. Effective osmagents for the proposed purpose include magnesium sulfate and chloride, sodium chloride and lithium chloride, potassium sulfate and sodium sulfate, mannitol, urea, sorbitol, inositol, sucrose, glucose and others. The osmotic pressure in atmospheres (atm) of the appropriate osmagents here is greater than 0 atm,

  and generally between 0 atm and 500 atm or more.

  The term "agent" here designates any composition or formula or any compound which can be used to produce a specific advantageous result. These agents include algicides, antioxidants, air purifiers, biocides, catalysts, chemical reagents, cosmetics, drugs,

  disinfectants, fungicides, food, fertility inhibitors

  fertility activators, food supplements,

  fermentation agents, germicides, insecticides, mitigation

  contents of microorganisms, nutrients, products for plant growth and inhibitors of their growth,

  preservatives, surfactants, sterilants, sterilizers,

  sexual health, vitamins and other products beneficial for environments and surroundings, habitats and animals. These

  agents can be insoluble or very soluble in ma-

  temperature sensitive material that is housed in the

positive contribution.

  The term "drug" here includes any substance

  this having a physiological or pharmacological action which

  produces a local or systemic (general) effect in animals

  evil, including homeothermic mammals, human and primary

  mates, avians, fish and domestic animals, sport or farm, laboratories and zoos. The term

- 16 -

  physiological refers to the administration of a drug to produce normal levels and functions and the term pharmacological changes in response to the amounts of drug that are administered to the host. Stedman's Medical'Dictionary, 1966, published by Williams and Wilkins, Baltimore, MD. The

  drugs that can be administered include drugs

  limitless mineral or organic caments, drugs

  elements that act on the nervous system, depressants,

  hypnotic, sedative, psychic stimulants, tranquili-

  health, anti-convulsants, muscle relaxants, antiparkinsonian agents, analgesics, anti-inflammatories,

  anti-malarials, oral agents, contraceptives, sympathico-

  mimetics, diuretics, anti-parasitic, neoplastics, hypoglycemic, ophthalmic, electrolytes, products

  cardiovascular drugs and diagnostics. The quan-

  The amount of agent in the delivery device can be from 0.05 ng to 20 g or more. For medical applications the device can contain various amounts, for example 25 ng, 1 mg, 5 mg, 125 mg, 250 mg, 500 mg, 750 mg, 1.5 g etc, and the device can be used one, two or

  three times a day, twice a week or otherwise.

  Called compositions that respond to the action

  heat, or heat-sensitive compositions, of the

  thermo-plastic positions which can soften or which

  can be brought to the middle under the action of cha-

  their and which harden when cooled, and this also includes thermotropic compositions which can undergo modifications in response to the application of an energy gradient. These compositions are sensitive to

  raising or lowering the temperature. The express-

  thermosensitive ion designates the physicochemical property of an agent and vehicle composition of being solid or semi-solid at temperatures up to 34 C, generally between 20 and 33 C, and to become liquid, semi-solid or viscous under heat from 33 C,

- 17 -

  generally between 33 and 40 C. The thermosensitive vehicle melts, dissolves totally or partially, softens or liquefies at high temperatures, which makes it possible to bring it to the medium in question with the agent which it contains. a homogeneous or heterogeneous mixture. The heat-sensitive vehicle can be lipophilic, hydrophilic or hydrophobic, and another important characteristic of the vehicle is that it can maintain the stability of the agent it contains.

  agent storage and supply. Compounds

  Representative thermosensitive conditions, given with their melting point, are as follows: cocoa butter, 32-34 C; cocoa butter with 2% beeswax, -370C; propylene glycol monostearate and distearate,

  32-35 C; hydrogenated oils such as vegetable oils

  them, 36-370C; 80% of a hydrogenated vegetable oil with 20% of sorbitan monopalmitate, 39-39.5 C; 80% of a hydrogenated vegetable oil with 20% of polysorbate 60, 36-37 C; 77.5% of a hydrogenated vegetable oil with 20% of sorbitan trioleate and 2.5% of beeswax, 35-36 C; 72.5%

  a hydrogenated vegetable oil, 20% sorbid trioleate

  tanne, 2.5% beeswax and 5% distilled water, 37-380C; mono-, diet triglycerides of C8 to C22 acids comprising saturated and unsaturated acids such as

  palmitic, stearic, oleic, linoleic, linoleic acids

  picnic and arachidonic; fatty acid triglycerides

  saturated with mono- and diglycerides, 34-35.5 C; mono-

  and propylene glycol distearates, 33-34 C; an oil of

  partially hydrogenated cotton, 35-39 C; hard fatty alcohols

  cis and fats, 33-36 C; hexadienol and monostearate

  anhydrous lanolin glyceryl triethanolamine, 38 C; me-

  eutectic diapers of mono-, di- and triglycerides, 35-39 C; Witepsol 15, triglyceride of saturated fatty acids of vegetable origin with monoglycerides, 33.5-35.5 C; Witespol

  H32 without hydroxyls, 31-33 C; Witespol W25 having an indi-

  this saponification of 225-240 and a melting point of

- 18 -

  33.5-35.5 C; Witespol E75 having a saponifica- index

  tion of 220-230 and a melting point of 37-39 C; a polyalkylene glycol such as polyethylene glycol 1000, a linear polymer of ethylene oxide, 38-41 C; polyethylene glycol 1500, 38-41 C; monoethylene-

  polyethylene glycol, 39-42.5 C; 33% polyethylene-

  glycol 1500, 47% polyethylene glycol 6000 and 20% distilled water, 3941 C; 30% polyethylene glycol 1500, 40% polyethylene glycol 4000 and 30% polyethylene glycol 400, 33-38 C; a mixture of mono-, di- and triglycerides of saturated fatty acids having from 11 to 17 carbon atoms, 33-37 C; etc. The heat-sensitive composition is a means of preserving an agent in a solid composition at

  temperatures from 20 to 33 C, maintain a separation limit

  immiscible ration at the interface of the swelling composition, and to provide the agent in a fluid composition to

  a temperature generally higher than 33 C, ordinary-

  ment from 33 to 40OC. The thermosensitive composition which is

  brought to a surrounding biological environment can be facilitated

  slightly excreted, metabolized, assimilated etc, for use

effective agent.

  The semipermeable wall can be applied to the thermosensitive expandable layer laminated by molding, shaping, spraying or immersion in a material forming this wall. Other currently preferable techniques which allow the semi-permeable wall to be applied are the air suspension method and the powder coating methods. The first method consists in suspending the laminate or the pocket in a stream of air and in rolling it, with a composition forming the semi-permeable wall, until the wall surrounds it and coats it, and we start this operation again

  with a composition forming a diffuse semi-permeable wall

  ferent to obtain a semi-permeable laminate wall.

  The air suspension process is described in the brief.

  vet US 2,799,241 and in J. Am. Pharm. Assoc. volume 48,

- 19 -

  pages 451 to 459, 1979, and idib. volume 49, pages 82 to 84, 1960. Other manufacturing processes are described in Modern Plastics Encyclopedia, volume 46, pages 62 to 70, 1969 and in Pharmaceutical Sciences, by Remington, 14th edition, pages 1626 to 1678, 1970, Mack publication

Publishing Co., Easton PA.

  Examples of solvents for the manufacture of

  the semi-permeable wall are mineral or organic solvents

  picnics without drawbacks for the materials used, pa-

  expandable king, pocket, heat-sensitive composition and final delivery device. These solvents generally comprise aqueous solvents, alcohols, ketones,

  esters, ethers, aliphatic hydrocarbons, halo solvents

  genes, cycloaliphatic, aromatic or heterocyte solvents

  cliques and their mixtures, characteristic solvents

  being acetone, diacetone alcohol, methanol, etha-

  nol, isopropyl alcohol, butyl alcohol, acetates

  methyl, ethyl, isopropyl, n-butyl, methyl isobutyl ketone, methylpropyl ketone, n-hexane, n-heptane, monoethyl ethylene glycol ether, monoethyl acetate ethylene glycol, methylene, ethylene or propylene dichloride, tetrachloride

  carbon, nitro-ethane, nitro-propane, tetra-

  chloroethane, ethyl ether, isopropyl ether, cyclohexane, cycloheptane, benzene, toluene, solvent naphtha, 1,4-dioxane, tetrahydrofuran, diglyme, water and mixtures thereof such as a mixture of acetone and water, acetone and methanol, acetone and ethyl alcohol, methylene dichloride and methanol or ethylene dichloride

  and methanol. Usually the semi-permeable wall is ap-

  plicated at a temperature a few degrees below the melting point of the heat-sensitive composition, or else

  the thermo-plastic composition can be placed in the dis-

  positive contribution after applying the semi-permeable wall.

  The expandable wall, pocket or dilated layer

  ble can be made by polymerization processes

- 20 -

  known thermoforming, for example spraying on

  a mandrel, immersion of a mold in a form composition

  mant the wall, blow molding, vacuum forming,

  compression or injection molding, extrusion and stratification

  fication. However, in a currently preferred embodiment, a pocket or a push compartment is manufactured.

  molded by the compression process illustrated in the figure

  re 10. In this compression process, one operates with a mold cavity and a piston. The mold cavity forms a

  surface of the molded part and the composition is placed in the mold

  position forming the polymer wall, the mold piston

  mant the other surface of the pocket. The piston compresses the composition and when the mold is closed the composition is compressed to the shape of the final pocket, the mold cavity and the piston being held in this position until the composition is hardened. In Figure 10 the pocket

  or molded thrust compartment is designated by the letter

  be a, and it is seen when you remove the compression mold

  if we. The bag is then placed in a filling position placed under a filling hopper and it is filled

  a melted agent formula. After cooling the com-

  filled part is covered in c with a semi-wall

  permeable in which a filler hole is drilled by laser. In a similar process the molded compartment a is closed (in d) with a closure having a filling and discharging orifice and it is filled at the filling station e, at ordinary temperature, with a formula

  of melted agent. Finally, the filled compartment is re-

  covered, in f, with a semi-permeable wall crossed by a

  laser-drilled orifice in axial arrangement with the opening

  ture, which gives the delivery device. In a process

  similar, the closed compartment is covered with a mem-

  brane or semi-permeable wall traversed by a laser-drilled orifice in an axial position relative to the opening, which gives the empty device designated by the letter g, which

- 21 -

  is then filled at room temperature with the melted agent formula, which gives the final device h.

  The opening or passage through the semi-wall

  permeable releases the agent formula from the disposable

  tif contribution. The orifice can be formed mechanically or at

  laser, or by erosion of an erodible element of the pa-

  king, for example of a gelatin plug or cap. A

  detailed description of orifices and their dimensions

  maximum and minimum preferable is given in briefs

vets US 3,845,770 and 3,916,899.

  The following examples are given only at half

  be purely illustrative and in no way limit the

  scope of the invention, and they will be better understood

  of the description and the attached drawings.

Example 1

  We form a delivery device in the way

  following: by injection molding a polymer composition-

  re we first form an expandable container in the shape of a cap-

  sule, 12 mm in diameter and 40 mm deep, the wall of which is formed of a composition comprising 30% by weight of sodium chloride and 70% of a polyoxyethylene having a

  molecular mass of 3,000,000, which is mixed for 20 minutes

  nutes to have a homogeneous composition. This composition is compressed into tablets which are placed in an injection molding machine and the container is formed by injection molding at 145-150 C under a pressure of 6.5-7.0 x kPa. This container is then filled with a thermosensitive composition comprising 0.5% by weight of theophylline, 77% of a hydrogenated vegetable oil, 20% of sorbitan trioleate and 2.5% of beeswax, using temperature of

  36-37 C, and after cooling to 20 C, cover the re-

  container lined with an external semi-permeable wall by the

  air suspension method in a Wurster device.

  The semi-permeable wall is formed of a solution in

- 22 -

  methylene chloride 5% by weight acetate butyrate

  cellulose and it is applied to a thickness of 0.4 mm.

  The packed devices thus obtained are dried in an oven at

   C for 5 to 10 days then through the semi-wall

  permeable, a 0.75 mm orifice is pierced with the laser allowing the drug formula to be brought from the compartment to the

outdoor environment.

Example 2

  The container or pouch with a large opening is prepared as in Example 1, which is filled with a drug formula comprising 0.20 g of paracetamol, 0.02 g of codeine phosphate, 0.15 g of acetylsalicylic acid and 2.0 g of Witepsol H35, a mixture of glycerol esters and

  saturated fatty acids of plant origin in which predo-

  mine lauric acid. This composition is prepared in tri-

  and mixing well all the medicinal substances

  liars and then adding the Witepsol vehicle at 38-40 C, filling the pockets with the melted composition, which after

  cooling has a creamy consistency and then we re-

  covers the pocket with a semi-permeable wall in which a laser orifice is made in the manner previously indicated.

Example 3

  We form in the following way, with a composition

  expandable sition, a delivery device which comprises a compartment containing a thermosensitive composition in

  layered arrangement: successively put in a

  first, a molten composition of 2.5% phenobarbital, 5% glycerogelatin and 77.0% theobromic essence, glyceride of stearic, palmitic and lauric acids,

  to form after cooling to ordinary temperature

  re the heat-sensitive layer, then put in the mold a

  mixture of 30 parts of ethylene monomethacrylate-

  glycol 0.12 parts ethylene glycol dimethacrylate

  and 10 parts of a 0.13% aqueous solution of bi-

  sodium sulfate in aqueous ethanol. We polymerize this

- 23 -

  mixing at 30 ° C. and 20 minutes after equilibrium at room temperature

  ordinary rature the solid layer is removed from the mold.

  A solution is then prepared in acetone of cellulose acetate at 15% by weight having an acetyl content of 39.8%, the laminate of which is covered by immersing it 15 times in the solution, first once for seconds then the other times for 1 minute with

  intermediate drying for 5 minutes, and after these immers-

  let's dry the devices at room temperature

  of 22 C for 10 days. We thus apply a semi-wall

  0.7 mm permeable which regulates the flow, wall through the

  which is practiced with the laser a passage to connect the exterior

  laughing device to the heat-sensitive layer.

Example 4

  We form a delivery device in the way

  next: a eutectic mixture is heated to liquefy it

  that 77% thermo-sensitive neutral fat melting at -37 C and 19.5% paraffin wax melting at 52 C, we

  add 3.5% acetylsalicylic acid to the liquid and

  mix it in a mold. After cooling and soli-

  dification add 500 mg of the polyacrylamide Cyanamer, a hydrogel having a molecular weight of about 200,000, the layers are pressed to form a heat-sensitive layer in contact with a layer of hydrogel and removed from the mold

the layers in contact.

  A semi-permeable metal wall is then formed

  dipping 85 g of cellulose acetate at 39.8% acetyl with ml of methylene chloride and 200 ml of methanol and the two-layer compartment is spray coated in an air suspension machine until a 0.25 mm semi-permeable wall surrounds the compartment. We

  dry the devices for two weeks and then

  that with the laser in the semi-permeable wall a passage of

  0.4 mm communicating with the thermosensitive composition.

Example 5

  The process of Example 4 is repeated with the

  24 - positions indicated, except that the thermosensitive composition comprises a polyoxyethylene ether of a partial fatty acid ester and an internal polyhydroxylic cyclic ether containing the drug, the polyoxyethylene ether having from 2 to 5 oxide groups ethylene and the partial ester

  fatty acid having from 14 to 18 carbon atoms. The composition

  sition contains a drug and the composition thermo-

  sensitive melts quickly and completely at body temperature while liquefying for easy supply of the device

in the outside environment.

Example 6

  The processes of Examples 4 and 5 are repeated to form a heat-sensitive composition comprising 85 mg of a hydroxypolyoxyethylene ether of sorbitan monostearate with 4 groups of ethylene oxide per mole and melting at 38 ° C., 5 mg of a sorbitan monostearate hydroxypolyxoyethyl ether with 20 ethylene oxide groups per mole, 5 mg sorbitan monoricinoleate

  and 15 mg of indomethacetin sodium.

Example 7

  A thermosensitive composition is prepared for the device of Example 1 by hot mixing 30% of polyethylene glycol 1500 with 30% of polyethylene glycol 4000, 30% of polyethylene glycol 400, 9% of cocoa butter and 1% oxyprenolol hydrochloride, melting composition

  in 15 to 20 minutes at a temperature of 37 C.

Example 8

  We mold by injection an osmostic capsule

  in the form of a cylinder with thin walls and hemi-

  spherical with a composition comprising 65% sodium chloride, 20% of the Polyox product, an ethylene oxide polymer having a molecular weight of approximately 200,000, and 15% of a polyethylene glycol 2,000,000, the conditions for injection in which the capsule is molded being the following:

- 25 -

  Nozzle temperature 18020 C Zone 1 off Zone 2 230 250c Zone 3 220 25 C Temperature of hot tip 180 25 C Temperature of mold cavity 18 3 C Temperature of central spindle 8 * 3 C Temperature of plate shutter 8 3 C

Lighting time 13.5 2 sec.

Injection time 1.9 0.5 sec.

  Injection speed 5 * 1 Injection pressure 84 7 bars Discharge pressure 42i7 bars Cycle time 20 seconds

  The inside and outside diameters and the lengths

  indoor and outdoor races are respectively

  1.17 cm and 1.33 cm, and 3.70 cm and 3.85 cm.

  This osmotic capsule is filled with 2.88 g of Witespol H15, glycerol ester of a saturated fatty acid of vegetable origin at 0.1% with a red and oily dye and

  it is covered with cellulose acetate butyrate in a soil

  vant 95: 5 of methylene chloride and ethanol until the regular formation of a semi-permeable membrane 0.5 mm thick. The capsules are dried at 55 ° C. for 7 days and then an outlet opening of 1 mm in diameter is pierced therein.

  we examine their release rate. In the drawings an-

  attached Figure 11 shows the release rate of the

  thermosensitive composition in mg / hour for one day-

  born, and figure 12 gives the cumulative amount of compound

  thermosensitive release as a percentage of the total released from the system. Circles indicate system release

  upright and squares the system release

me in a horizontal position.

  An embodiment of this invention relates to a method for delivering a drug at a controlled rate

- 26 -.

  by the vaginal or anorectal route to a homeothermic animal, method according to which: (A) a delivery device is introduced into the passageway comprising: (1) an internal wall formed of a polymer composition which expands in swelling, surrounding and delimiting an internal compartment;

  (2) an opening in this internal wall; (3) a form

  the drug in the compartment comprising a quan-

  tity of dose units of the drug for a therapeutic program, with a heat-sensitive vehicle which melts or dissolves at body temperature and is used to bring out

  the drug from the delivery device; (4) an outer wall

* not surrounding the pocket and the opening, a wall formed of a semi-permeable polymer composition, permeable to liquids, but impermeable to the drug; and (5) an orifice in this external wall which communicates through the opening with the internal compartment; (B) the body fluid permeates the internal wall through the semi-permeable wall at a rate determined by the permeability of this wall and the osmotic pressure gradient through this semi-permeable wall, which makes the swell and expand internal wall; (C) the formula of the drug melts in the compartment forming a fluid composition; and (D) release of the formula

  compartment drug through the inner wall which

  fle and expands against the melted formula, which does not-

  ser the formula in a desired therapeutic amount through the orifice, at a regulated rate, at the passageway, to produce the desired medical effect in an extended period of one to several months, preferably from one hour to

24 hours.

-27 -

Claims (30)

  1. A device for supplying to a surrounding environment of employment, at a regulated flow rate, a formula of a substance (also called agent), sensitive to the action of heat, device which comprises:   a) an inner wall surrounding and forming a compartment   internally to contain the agent formula, with an ori-   fice in this wall to fill it with the formula and in   bring it out, this wall being formed of a composition   sition to absorb liquids by swelling and spreading   latent in the compartment; b) an outer wall surrounding the inner wall, an outer wall which is formed of a composition permeable to the passage of liquids but practically impermeable to the passage of the agent; and c) a passage in the outer wall which communicates with the opening to bring the agent formula to the surrounding medium. 2. The delivery device according to claim 1, the compartment of which contains an agent formula which remains solid up to 33 C and melts above this temperature. 3. The delivery device according to claim 1, the inner wall of which is formed of a composition comprising a polymer hydrogel and a solute with osmotic action. 4. The delivery device according to claim 1, the inner wall of which is formed of a composition comprising a polymer hydrogel which swells and expands in presence of a liquid.   5. The supply device according to claim 1 which comprises a closure element in the orifice of the   wall, with a perforation in the closure element.   6. The supply device according to claim 1, the outer wall of which is formed from a material chosen from the following: esters, diesters, ethers, cellulose ether esters, acylates, diacylates, triacylates of   cellulose, acetate, diacetate, triacetate and acetate-bu- cellulose tyrate.   7. The delivery device according to claim 1, the outer wall of which is formed of a hydrophilic composition which swells and expands in the presence of liquids. aqueous impregnation.   8. The supply device according to claim 1, the inner wall of which is formed from a polyethylene oxide. 9. The supply device according to claim 1, the inner wall of which is formed of a polyoxide.   ethylene, a polyethylene glycol and an acute solute osmotic tion.   10. The delivery device according to claim   1, the compartment of which contains a thermosen-   sible comprising an ester of glycerol and saturated fatty acids. 11. A device for supplying a substance (agent) at a regulated flow rate and to a surrounding medium of a biological liquid at a temperature above 33 C, device which comprises:   a) a wall formed of a semi-polymer composition   permeable which surrounds and defines: b) a compartment;   c) a first means in the compartment for transforming   mer a solid composition into a composition deliverable under the action of the temperature of the biological medium, this first means comprising an agent and being in contact with a second means in the compartment to impregnate with   liquid through the semi-permeable wall and to expand   ter in the compartment; and d) a passage in the wall which connects the outside of the device in the first way.   -29 - 12. The delivery device according to claim   11, the first means of which is a strip.   13. The delivery device according to claim   11, the second means of which is also a strip.   14. The delivery device according to claim   11 in which the solid composition is a gel.   15. The supply device according to claim 11 in which the solid composition melts at temperature of the surrounding biological environment.   16. The delivery device according to claim   11 in which the solid composition liquefies at the time   temperature of the surrounding biological environment.   17. A device for supplying a substance (agent) at a regulated flow rate to a surrounding liquid medium whose temperature is that of a homeotherm, device which comprises:   a) a wall formed from a semi-polymer composition   permeable which defines a closed tube with an internal space; b) a first means placed in the center of this space for   transform an undeliverable composition into a composition   tion deliverable at the temperature of the surrounding medium, means which contains an agent and which is surrounded by a second means in the space which is impregnated with liquid through the semi-permeable wall while expanding against the first means; and c) a passage in the wall communicating with   the exterior of the device and the first means.   18. The supply device according to claim 17 wherein the second means is placed between the first and the inner surface of the wall.   19. The device according to claim 17 in   which the passage in the wall is at the iron end from the tube.   20. The delivery device according to claim 17 in which the composition which cannot be delivered is -30 - a semi-solid composition.   21. The delivery device according to claim 17 in which the composition which cannot be delivered is a solid composition.   22. The delivery device according to claim 17 in which the composition which cannot be delivered does not   does not flow at a temperature below 33 C.   23. A device for supplying a substance (agent) which comprises: a) a tubular body closed at its ends,   which is formed of a polymer composition permeable to step-   sage of an external liquid but practically impermeable to the passage of the agent; b) a space in this body;   c) a first layer in the space formed of a composition   a sition comprising an agent and a vehicle for this agent; d) a second layer in the space in contact with the first, formed of a hydrogel which expands in the presence of the liquid entering the space; and   e) a passage in the body connecting the exterior of the device positive at the first layer.   24. The supply device according to claim 23 in which the vehicle is a non-hydrogenated oil.   toxic for pharmaceutical uses.   25. The delivery device according to claim   23 in which the vehicle is chosen from monoglycerides   wrinkles, diglycerides and non-toxic triglycerides.   26. The supply device according to claim 23 in which the vehicle is a non-hydrophilic material.   toxic with a molecular weight greater than 1000.   27. The delivery device according to claim 23 in which the vehicle is a non-toxic eutectic composition comprising a glyceride and a hydrogenated oil. 28. The delivery device according to claim -31 - 23 wherein the vehicle is a non-toxic glyceride   of a fatty acid having from 8 to 22 carbon atoms.   29. The delivery device according to claim 23, in which the vehicle is a non-toxic composition comprising a mixture of two or more polyethylene glycols,   one of which has a molecular weight greater than 1000.   30. A device for supplying, at a regulated flow rate, a formula of agent (substance) sensitive to heat to a surrounding environment of use, device which comprises:   a) an inner wall surrounding and forming a comparison   inner shell for containing the agent formula, with a hole in the wall for filling and removing the compartment for the agent formula, a wall which is formed of a liquid absorbing composition by swelling and dilating around the compartment;   b) an outer wall surrounding the inner wall, pa-   outer king which is formed of a composition permeable to the passage of a liquid but practically impermeable to the passage of the agent, composition which comprises a material   chosen from polysulfones, polyacrylates, polymetha-   crylates, polymethylmethacrylates and polyurethanes; and c) a passage in the external wall which communicates with the supply orifice of the agent formula of the device.