FR2489693A1 - MEDICAMENT FREE MEDIUM, PROCESS FOR PREPARING THE SAME, AND USE THEREOF - Google Patents

Abstract

MEDICINAL RELEASE MEANS, ITS PREPARATION METHOD AND ITS USE. THE SUBJECT OF THE INVENTION IS A SOLID OR SEMI-SOLID MEDIUM, FOR EXAMPLE IN THE FORM OF A MEMBRANE, A SHEET OR AN EGG CONTAINING ONE OR MORE MEDICINES. THE MEDIUM IS OBTAINED BY SOLVENT OR SUSPENSION, IN A SOLVENT CONTAINING WATER, AGAR AND OR AGAROSE AND OR ONE OF THEIR DERIVATIVE WITH ONE OR MORE OTHER POLYMERS AND MIXING WITH THIS SOLUTION OR SUSPENSION OF PARTICLES OF ONE OR MORE MEDICINAL PRODUCTS, THE SOLUTION OR SUSPENSION SO OBTAINED BEING MOLDED INTO A SOLID OR SEMI-SOLID OBJECT. THIS MEANS CAN BE APPLIED ON WOUNDS OR MUCOUS SITES SUCH AS THE EYE OR THE VAGINA AND ALLOWS THE MEDICINES CONTAINED IN IT TO BE RELEASED REGULARLY AND AT A PREDETERMINED SPEED.

Description

"Medium releasing drug, its method of preparation and

its use."

  The subject of the invention is a solid or semi-solid means containing one or more medicaments, a production process

such a way and its use.

  When treating the various stages of a disease, there are generally difficulties in obtaining a sufficient and uniform concentration of the drug. Often,

  by intermittent dosing, alternatively

  centers too large or too small compared to the

  ideal concentration for treatment.

  Thus if one wishes to maintain an appropriate minimum concentration, for a certain period of time, for example

  for the treatment of an infection, one is led to an over-

  dosing immediately after the intermittent dose. This often gives side effects that make it difficult to

varying degrees.

  As a result, the realization of a means of releasing the drugs, for a long period of time, to

  therapeutically satisfactory concentrations, constituting

kills an important need.

  According to U.S. Patent 3,867,519, attempts have already been made to

  To satisfy this need by using a means, for example in the form of a sheet, this means is made of a crosslinked polyelectrolyte with a divalent or polyvalent metal ion. This means contains one or more drugs, these drugs may, for example, be incorporated in microcapsules

  which in turn are incorporated in the medium. The micro-

  capsules are produced in the usual way, by coating

  drugs by a thin layer of polymer.

  This known means and its preparation include many

  disadvantages. For example, this means must be carefully cleaned

  after the crosslinking reaction. This results in significant losses of medication. In addition, the means is inflexible with respect to the drug release mechanism. After the crosslinking reaction, the polymer contains heavy metals that are poisons, such as cadmium

  or barium. These metals are then released during the bio-

  erosion of the polymer when using said means in the eye.

  The applicant has surprisingly discovered that it is possible to satisfy the above mentioned need.

  and make preparations of medicinal products which can

  during a long period of time, at therapeutically satisfactory concentrations, in order to

  overcome the disadvantages mentioned above.

  The subject of the invention is a solid or semi-solid means, for example in the form of a membrane, an ovum or a

  sheet containing one or more medicinal products, this means

  taking a polymer selected from agar, agarose and

riveted with these polymers.

  The means according to the invention is characterized by the fact that one or more chromatographic gel-based materials

  crosslinked, are incorporated in said means, said gel being

  material containing one or more drugs and that -

  said means is made of a polymer without any addition of a

crosslinking agent.

  According to an appropriate embodiment of the invention, - -

  the means is made of at least one of the agar, agarose or derivative polymers thereof. Particularly good results have been obtained using only as polymer

agarose.

  According to another embodiment, the means is made of a mixture of at least one of the agar polymers, agarose or one of their derivatives and at least one other polymer. This other

  The polymer advantageously contains hydroxyl groups.

  Examples of such polymers containing hydroxyl groups include starch, dextran, cellulose,

agaropectin and their derivatives.

  The means may contain functional groups such as anionic or cationic groups. The anionic groups may be, for example, carboxy groups, sulfonic acid groups or phosphoric acid groups, and the cationic groups may be, for example, diethylaminoethyl groups, ethyl-morpholino groups, and the like.

  or di- (hydroxyethyl) aminoethyl groups.

  According to the invention, particles of one or more crosslinked chromatographic gel (s) are incorporated in the means as indicated above. Said chromatographic gel must consist of a crosslinked polymer that may contain hydroxyl groups, such as crosslinked polyvinyl alcohol or a crosslinked carbohydrate or a crosslinked derivative of one of these polymers. As an example of suitable carbohydrate, mention may be made of crosslinked dextrin, crosslinked starch, crosslinked dextran or crosslinked cellulose, or one of their

crosslinked derivatives.

  Other chromatographic gels can also be used.

  such as crosslinked polyacrylamide or crosslinked polyvinylpyrrolidone. In some cases these polymers can also

contain hydroxyl groups.

  The chromatographic gel may contain anionic groups

  cationic or cationic. The anionic groups can be, for example, carboxy, sulphonic acid or phosphoric acid groups. The cationic groups can be, for example,

  diethylaminoethyl, -morpholinoethyl or di- (hydro)

  xyéthyl) amino-ethyl. The above-mentioned chromatographic gels are known

  as compounds, as indicated for example by the publications

  "Gelchromatography" cations by Determann (1967), British Patents 854,715 and 974,054, US Patents 3,277,025 and

  3,275,576 and Swedish Patents 209,015 and 222,291.

  Advantageously, the chromatographic gel is

  in the form of a material having a mean dimension of

  from 10 to 100 μm, for example 20-500Spm.

  Chromatographic gel particles may be

  appropriately in the means according to the invention.

  by mixing them in the polymer used for the preparation

  paration of the means. As indicated above, the means can be,

  for example in the form of a leaf, an egg or a mem-

  brane. The means according to the invention can be produced by

example, by molding.

  The chromatographic gel particles must contain

  one or more different drugs. These drugs can

  may be incorporated into the chromatographic gel, for

  such as absorption / adsorption, ionic

  that, complex bond or chemical bond. The method chosen to incorporate the drug depends first and foremost on

  physical and chemical properties of the drug, but also

  to a certain extent, the speed with which

  the drug must be released during use. Habi-

  the chromatographic gel can be adapted

  satisfactory, the qualities of the drug.

  According to the invention, it is possible to use, if desired,

  a different chromatographic gel for each drug.

  According to one embodiment of the invention, not only

  Chromatographic gel, but the medium itself contains one or more drugs. These medications can be

  incorporated in the material of the means in the same way as

  written above in connection with the incorporation of drugs

  in the chromatographic gel material.

  Generally the medium contains from 75 to 99% by weight of water, in the form of swelling water. During treatment

  skin, wounds or mucous membranes, it is particularly

  it is desirable that the means be inflated with water or a

  sodium chloride solution physiologically acceptable. The medium is so acceptable to the tissues, in this state that it can be applied even in the eye cavity and free there

  medicines such as antibiotics or dietary agents

  reducing intraocular pressure such as pilocarpine.

  Examples of other drugs that can be incorporated into the medium are found in U.S. Patent 3,867,519. In addition, the means may contain spermicides, enzymes, and the like.

or prostacyclin.

  By incorporating particles of a gel gel material

  in the means according to the invention, the speed of

  release of drugs can be adjusted

  tisfaisante. According to this embodiment, the drugs must

  especially going first through the chromium gel material

  tographic and then through the medium and finally enter,

for example, in a mucous membrane.

  By choosing chromatographic gel materials

  with appropriate impenetrability, as well as

  the diffusion rate of the drug can be adjusted. Moreover, when producing means containing several different drugs, it is possible, as indicated above, to incorporate a substance

  of specific chromatographic gel for each drug.

  The different chromatographic gel materials can in

  this case have the same or different properties

  impenetrability and u2ffusion rents. Thus it is possible to make combinations of preparations where the different drugs are released at the same speed or at different speeds. Of course the proportion of the drugs in the chromatographic gel material may vary within wide limits depending on the nature of the drug

  and the nature of the chromatographic gel material.

  According to the invention it is possible to realize conditions

  extraordinary adjustment arrangements with regard to

  release rate and the proportions of the drug.

  If the drug contains anionic or cationic groups, it is possible to increase the

  the means of linking and releasing a large quantity of

  drug product, provided that the chromium gel material

  the graph contains contrary ions, that is to say

  cationic and anionic ions.

  The rate of release of such ion-bound drugs can be further adjusted in comparison to the other embodiments described above. In this case, in particular, the drugs will only be released after the exchange process.

  of ions, mainly sodium ions from the

  that a wound or mucous membrane must first pass

  in and through the medium then into the particles of the

  chromatographic gel. The medicine in turn must

  then diffuse through the chromatographic gel material

  that and through the means to finally enter for example,

in the membrane of a mucous membrane.

  The time required for the drug to diffuse from the particles of crosslinked chromatographic gel material can be prolonged by coating the particles with

  a thin layer of filling by means of a suitable material

  such as polyvinylpyrrolidone. According to one embodiment of the invention, the means is suitably prepared by dissolving or suspending in a solvent containing water, agar and / or agarose and / or a derivative of one of these polymers, optionally together with one or more other polymers,

  particles of one or more chromatographic gel materials

  cross-linked phial containing one or more drugs being

  mixed with the solution or suspension, respectively.

  The mixture thus obtained is then converted into a solid or semisolid means, for example, in the form of a sheet, an ovum or a membrane, by applying it to the surface of a mold or in a mold and by cooling it quickly or

by letting it cool down.

  The solution or suspension of the aforementioned polymers is--

  usually performed with heat supply.

  As indicated above, the means obtained can be

  ter in the form of a sheet, an egg or a membrane which in turn can be divided to the desired size, for example by cutting. Of course it is practical to make the sheet, the egg or the membrane, by molding, this way

  to proceed allowing to use a continuous manufacture.

  The division of the sheet or membrane into pieces more

  small can also be done in a rational way.

  Of course it is possible, according to the invention, to pre-

  the medium in forms other than leaf, ovum or membrane. However the means having the aforementioned forms is

an extended scope.

  As indicated above, the means produced usually contain from 75 to 99% by weight of water when swollen with water. Often the means possess this content in

  water directly after their preparation. Generally a sheet

  the, according to the invention, containing such a water content is

  flexible, flexible and slippery and often it is transparent ..

  It is easy to see in a microscope that particles

  of chromatographic gel are embedded in the material of

lymere constituting the sheet.

  The invention will be explained in more detail by means of the nonlimiting examples below. Example 1 relates to the production of a membrane in which the chromatographic gel particles are embedded. The particles contain

  as medicine pilocarpine. Example 2 is about

  duction of a membrane in which particles are embedded

  chromatographic gel. These particles contain

iodine in the form of a complex.

  Example 3 relates to the production of a cylindrical means

  in which chromium gel particles have been incorporated

  Tgraphic containing prostaglandin. Example 4

  identify the production of a combination of

  form of a membrane in which are incorporated par-

  two different chromatographic gel materials.

  The first chromatographic gel particles contain

  local anesthesia and the others contain a medi-

  anti-inflammatory cament. In addition, the material of the medium itself contains a local anesthetic. Finally, example 5 relates to the production of a membrane in which particles of

  chromatographic gel containing an antibiotic were in-

corporées.

EXAMPLE 1

  Chromatographic gel material consisting of salt

  of sodium carboxymethyldextrin, produced from dex-

  trine, according to U.S. Patents 3,277,025 and 3,275,576, and

  a swelling ability of 6.5 ml / g and an ability to

  ion exchange rate of 0.4 meq / g (milliequivalent / gram) with

  relates to carboxymethyl groups.

  A swelling ability of 6.5 ml / g means that

  gram of material can, by swelling, absorb 6.5 ml of water.

  g of this material in gel form are transferred to a Nutsch funnel and treated with 400 ml of 0.16 N hydrochloric acid in aqueous solution containing 50%

  ethanol and 50% distilled water.

  the gel is then washed to neutrality with 400 ml

  * mixture containing 50% ethanol and 50% distilled water.

  The gel is then drained to dryness on a Nutsch funnel and then treated with a solution of 10 g of pilocarpine hydrochloride (Merck) in 200 ml of a mixture of 50% ethanol and 50% of water. 'distilled water. We wash the gel

  until neutrality, with a solution containing 75% ethanol

  25% distilled water and then shrink

99.5% ethanol.

  After drying in an oven at 750 ° C. for 5 hours, 38 g of a dry powder having a nitrogen content are obtained.

0.34%.

  A solution containing 4 g of agarose ("AGAROSE A 37, INDUBIOSE", Pharmindustrie) in 100 g of water is prepared by heating on a boiling waterbath. The solution is cooled to 600 ° C. and 5 g of the above-mentioned chromatographic gel material powder containing pilocarpine is added thereto.

bound by ionic bond.

  The suspension thus obtained is applied to a glass plate in a layer having a thickness of 3 mm and allowed to cool to room temperature. The medium is obtained in the form of a transparent, soft, flexible and slippery membrane. This membrane can be cut into pieces having the desired shape and size. It is found under the microscope that the chromatographic gel particles containing the ionically bonded pilocarpine were molded into

the membrane.

  The resulting membrane is suitable for the treatment of eye disease called glaucoma. We place a piece

  membrane of the desired size under the eyelid

  where the pilocarpine will be released and will pass into

mucosa of the eye.

EXAMPLE 2

  A crosslinked chromatographic gel material containing

  iodine, obtained from sugar, according to the application for

  Swedish patent No 405 680, has an iodine content of 1,11%, a

  ion exchange capacity of 0.92 meq / g with regard to the

  carboxymethyl groups in acid form, an ability to

  7.3 ml / g and a mean particle size of Pm. 3 g of this gel material are added, with stirring, to a solution having a temperature of 45 ° C. and containing 6 g of agarose ("Agarose A 37, Kebo 1. 7539") in 100 ml of distilled water. After homogenization, the viscous suspension obtained is applied to a glass plate in the form of a layer having a thickness of 2 mm which is allowed to cool to 22 ° C. When it is solidified in the form of a membrane, it is suitable for example, for the disinfection of the skin

or wounds.

EXE'TPLE 3

  A crosslinked chromatographic gel material, containing

  Prostaglandin prepared from hydroxyethylcellulose

  according to British Patent Application 8001176, has a swelling ability of 5.3 ml / g and contains 0.35% of

prostaglandin (PGE2).

  7 g of this gel material are added, with stirring, to a solution having a temperature of 44 C and containing 1.06 g of agarose ("Agarose A 37, Indubiose" Pharmindustrie) and 0.53 g of hydroxyethylcellulose ( Art 822068, Merck) in

50 ml of distilled water.

  The suspension thus obtained is converted into cylindrical ovules with a diameter of 15 mm and a length of 30 mm, by cooling in a mold. In this way 10 eggs are obtained, 5 of which are freeze-dried,

in known manner.

  All eggs, whether freeze dried or not, are intended for intravaginal application after possible sterilization by radiation. These eggs are used to accelerate the completion of the pregnancy or to

  legal interruption of pregnancy.

EXAMPLE 4

  0.2 g of lidocaine (anhydrous lidocaine hydrochloride) is dissolved in 1 ml of distilled water, the pH being adjusted

  at 6.5 by addition of sodium hydroxide.

  The solution thus obtained is mixed with 2 g of commercially available chromatographic gel material.

  ("Sephadex, G-25", Pharmacia Fine Chemicals) having a di-

  particle size of 20-80 μm and an ability to swell

  4.8 ml / g. The solution is allowed to diffuse into the

  chromatographic gel material, while stirring, and the pro--

The result is dried.

  g anti-inflammatory drug ("Betnovat" 0.1% solution, Glaxo Laboratories Ltd) are mixed with 2.5 g of commercially available chromatographic gel material ("Sephadex LH-20", Pharmacia Fine Chemicals) having a mean particle size of 60 μm and a swellability of 4.1 ml / g. Let's spread the

  solution, while stirring, to form a gel-like gel material

  material, and the product thus obtained is dried.

  A solution containing 0.6 g of agarose ("Agarose A 37, Indubiosis", Pharmindustrie) in 20 ml of water is prepared by heating on a boiling bath with stirring. We

  cooled the solution obtained to 45 C, the two products

  obtained, being introduced into the solution by stirring.

  tion. A solution of 0.2 g of lidocaine (anhydrous lidocaine chloride) in 1 ml of distilled water is then added. The pH of the solution is adjusted to 6.5 by the addition of sodium hydroxide. The suspension thus obtained is applied in a

  2 ml thick on a glass plate and allowed to cool

  dir at 20 C. The membrane obtained can be cut into pieces and is suitable, for example, for the treatment of wounds

infected and painful.

EXAMPLE 5

  400 mg of an antibiotic ("Chloromycetin",

  Parke-Davis, USA) in 8 ml of distilled water. We add the

  the resultant solution, while stirring with 2.0 g of poly-

  Chromatographic acrylate ("Biogel P-6", Bio-Rad Laboratories, USA) having a mean particle size of 60 m. We

  the product thus obtained is dried by freezing in a known manner.

  A solution of 0.5 g of agarose (Agarose A 37, Indubiosis, Pharmindustrie) in 20 ml of distilled water is prepared by heating, with stirring, on a boiling water bath. The solution thus obtained is cooled to 460 ° C. and the mixture is mixed.

  product thus obtained with the solution.

  The suspension obtained is applied in a layer of 2.5

  ml on a glass plate and allow to cool to 200C.

  The solidified membrane can be cut into pieces of

  desired and used for the treatment of, for example, infected wounds or eye infections. -

Claims (23)

REVENDI CATIONS   1.- solid or semi-solid medium, for example in the form of a membrane, an egg or a leaf, containing one or more drugs, this means comprising a polymer selected from agar, agarose and the derivatives of these polymers   res, characterized by the fact that the particles of one or more   cross-linked chromatographic gel materials are incor-   pores in the medium, said chromatographic gel material containing one or more drugs and the middle-east   made from a polymer without any addition of re-agent   ticulant. 2. Medium according to claim 1, characterized in that the chromatographic gel material and the   medium itself contains one or more drugs.   3. Medium according to claims 1 or 2, characterized   in that it consists of a mixture of agar and / or agarose and / or a derivative of one of these polymers and minus another polymer.   4. Medium according to claim 3, characterized in that it is made of agar and / or agarose and / or a derivative   of one of these polymers and at least one other polymer   holding one or more hydroxyl groups.   5. Medium according to claim 4, characterized in that the hydroxyl-containing polymer consists of starch, dextran, cellulose, agaropectin or a   similar polymer or a derivative of one of these polymers.   6. Medium according to claims 1 or 2, characterized   by the fact that it is made of agarose or a derivative of agarose pink.   7. Medium according to any one of claims 1   to 6, characterized in that it contains functional groups   such as anionic or cationic groups.   8. Medium according to claim 7, characterized in that the anionic groups consist of, for example, carboxy groups, sulfonic acid groups,   phosphoric acid or similar groups.   9. A means according to claim 7, characterized in that the cationic groups consist of diethylaminoethyl groups, -morpholinoethyl groups, groups   di- (hydroxyethyl) aminoethyl or similar groups.   10. Medium according to any one of claims 1   to 9, characterized in that the chromatographic gel material   graphic comprises a crosslinked polymer. 11. Medium according to claim 10, characterized by the   that the chromatographic gel material comprises a poly-   crosslinked mother containing hydroxyl, such as a hydrate of   carbon or a carbohydrate derivative.   Medium according to Claim 11, characterized in that the chromatographic gel material comprises   crosslinked dextrin, crosslinked starch, crosslinked dextran   cross-linked cellulose, a similar cross-linked polymer   or a derivative of any of these polymers.   Medium according to claim 10, characterized by   that the chromatographic gel material comprises of   cool polyvinyl crosslinked, crosslinked polyacrylamide,   cross-linked polyvinylpyrrolidone or a similar cross-linked polymer lar.   14. Medium according to any one of claims 1   13, characterized in that the chromatographic gel material   graphic contains cationic or anionic groups.   15. Medium according to claim 14, characterized in that the anionic groups consist of groups   carboxy, sulfonic acid groups, phosphoric acid groups, phoric or similar groups.   16. The means according to claim 14, characterized by   the fact that the cationic groups consist of groups   diethylaminoethyl, of morpholinoethyl groups,   di- (hydroxyethyl) aminoethyl groups or similar groups.   17.-Medium according to any one of claims 1   16, characterized in that the chromium gel material   has a mean particle size of 10- 1000> m.   18. A means according to claim 17, characterized by   the average particle size of 20 to 500 μm.   19. Medium according to any one of the claims   11 to 18, characterized in that it is obtained by molding   of particles of chromatographic gel material.   20. Medium according to any one of claims 1   at 19, characterized by the fact that it contains in the inflated state from 75 to 99% by weight of water.   21.- Use of a means according to any of   Claims 1 to 20, by application to wounds, on skin or mucous membranes.   22.- A method of producing a means according to any one   of claims 1 to 20, characterized in that   dissolved or suspended in a solvent   holding water, agar and / or agarose and / or a derivative of one of these polymers, optionally together with one or more other polymers, mixed with the solution or suspension of particles of one or more crosslinked chromatographic gel material containing one or more drugs, which is transformed into a solid or semi-solid medium, for example in the form of a sheet, an egg or a membrane, that is put in place   on the surface or inside of a mold, and that it is cooled say or let it cool.   23.- Process according to claim 21, characterized by   the fact that the solution or suspension is obtained by heat.