CH650924A5 - SOLID OR SEMI-SOLID DEVICE CONTAINING ONE OR MORE DRUGS. - Google Patents

Description

The invention relates to a solid or semi-solid device containing one or more medicaments, to a use of this device, as well as to a method of manufacturing said device.

In the treatment of diseases, carried out at different stages, difficulties generally arise in maintaining a uniform and continuous concentration of the drug. Frequently, intermittent administration of the drug is too high or too low compared to the ideal concentration required for treatment.

It follows that, if it is desired to maintain an appropriate minimum concentration for a certain time, for example for the treatment of an infection, there is an over-concentration in relation to the intermittent dose and immediately after the administration of that. -this.

This frequently gives rise to side effects with disadvantages to varying degrees.

It is therefore essential to have a pharmaceutical preparation capable of releasing medicaments for a long period, at concentrations which are satisfactory from the therapeutic point of view.

According to American Patent No. 3867519, efforts have been made so far to meet this need by using a device which is for example in the form of a sheet. The device then consists of a polyelectrolyte crosslinked with a bivalent or polyvalent metal ion. The device contains one or more drugs. These drugs may for example be contained in microcapsules which, for their part, are incorporated into the device. These microcapsules are prepared in the usual way by coating the medicament with a thin layer of polymer.

The known device and its manufacture, however, have many drawbacks. For example, the device should be washed thoroughly after the crosslinking reaction. This results in significant drug losses.

In addition, the device offers little flexibility with respect to the drug release mechanism.

After the crosslinking reaction, the polymer contains toxic heavy metals such as cadmium or barium. These metals are then released by bioerosion of the polymer when the device is used in the eye.

In accordance with the invention, it appeared surprisingly that the aforementioned need could be met for obtaining pharmaceutical preparations capable of releasing medicaments for a long period of time, at concentrations which are satisfactory from the point of view

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therapeutic. This avoids the aforementioned drawbacks presented by preparations of known types.

Consequently, in accordance with the invention, a solid or semi-solid device is obtained, for example in the form of a membrane, an intravaginal membrane or a sheet, containing one or more drugs, said device consisting of a polymer comprising agar-agar, agarose and a derivative of one of these polymers.

The device is characterized in that particles of one or more crosslinked chromatographic materials, in gel form, are incorporated into said device, said chromatographic materials in gel form containing one or more medicaments, and in that this device is in an uncrosslinked polymer.

In a suitable embodiment of the invention, the device consists of at least one of the polymers comprising agar-agar, agarose or a derivative of any of these products. Particularly satisfactory results are obtained when the polymer is formed solely from agarose.

In another embodiment according to the invention, the device consists of a mixture of at least one of the agar-agar, agarose polymers or a derivative of any of these products,

with at least one other polymer. The other polymer will then preferably contain hydroxyl groups.

Examples of polymers containing hydroxyl groups include starch, dextran, cellulose, agaropectin or a derivative of any of these products. Other polymers containing hydroxyl groups can be used.

The device can contain functional groups, such as anionic or cationic groups. The anionic groups can then be formed by carboxy groups, sulfonic acid groups or phosphoric acid groups, while the cationic groups can be formed, for example, by diethylaminoethyl, P-morpholinoethyl or di (hydroxy-: thyI) groups. aminoethyl.

According to the invention, particles of one or more crosslinked chromatographic materials, in the form of a gel, are incorporated into the device, as already mentioned. Said gel-natographic material in the form of a gel can be formed by a labeled polymer which may contain hydroxyl groups, for example a crosslinked polyvinyl alcohol or a crosslinked carbohydrate, or a crosslinked derivative of one of these polymers. Crosslinked dextrin, starch, dextran, cellulose or a derivative of one of these products can be mentioned as examples of suitable arbone hydrates.

It is also possible to use other chromatographic materials in gel form, such as a crosslinked polyacrylamide or a polyvinyl lyrrolidone. In some cases, these polymers can happily contain hydroxyl groups.

The gel chromatographic material may contain anionic or cationic groups. The anionic groups can be formed, for example, by carboxy, ulfonic acid or phosphoric acid groups.

On the other hand, the cationic groups can be formed, by temple, by diethylaminoethyl, P-morpholinoethyl or di (hydroxyethyl) aminoethyl groups.

The aforementioned chromatographic materials, in gel form,) are not known per se, as described for example by Determann in publication "Gelchromatography" (1967), in British patents Nos. 854715 and 974054, American patents Nos. 3277025 and 275576 and Swedish patents Nos 209015 and 222291.

Advantageously, the chromatographic material in the form: gel has an average particle size of 10-1000 μm, per empire of 20-500 μm.

The particles of the chromatographic material in gel form; can advantageously be incorporated into the device by mixing them with the polymer used for the production of this device, as mentioned above, the device is, for example, in the form of a leaf, intravaginal membrane or membrane. It can be made by molding, for example.

The particles of the chromatographic material in gel form may contain one or more different drugs. These drugs can be incorporated into the gel chromatographic material in various ways, for example by absorption / adsorption, ionic bond, complex bond or chemical bond. The method chosen for incorporating the drug depends, first, on the physical and chemical properties of the drugs, but also, to some extent, on how quickly the drugs will be released during use.

Usually, the chromatographic material in gel form can be suitably adapted to the properties of the drugs.

According to the invention, separate chromatographic materials, in gel form, can be used, if desired, for each drug.

According to an embodiment of the invention, not only the chromatographic material in gel form, but also the device itself, contains one or more drugs. These drugs can be incorporated into the device material, in the same manner as previously described with respect to the incorporation of the drugs into the chromatographic material in the form of a gel.

In general, the device contains from 75 to 99% by weight of water in the state of swelling by water. When treating the skin, wounds or mucous membranes, the device should in particular be swollen in water or in a physiologically acceptable sodium chloride solution. The device must in particular be acceptable for tissues, in a state allowing it to be applied even in an eye cavity and the in situ release of drugs such as antibiotics or agents for lowering eye pressure, such as pilocarpine. Examples of other drugs that can be incorporated into the device are described in US Patent No. 3867519. In addition, the device may contain spermicides, enzymes or prostacyclin.

By incorporating particles of a chromatographic material in the form of a gel into the device according to the invention, the speed of release of the medicaments can be adjusted satisfactorily.

In this embodiment, the drugs must in particular first pass the chromatographic material in the form of a gel, then the device, and finally penetrate into a mucous membrane, for example.

It is possible to regulate the rate of release of the medicament by choosing chromatographic materials in the form of a gel having an appropriate impenetrability and corresponding diffusion properties. In addition, for the production of a device containing several distinct drugs, it is possible, as mentioned previously, to incorporate a specific chromatographic material, in the form of a gel, with each drug. The various chromatographic materials in gel form can then have the same impenetrability or a different impenetrability with associated diffusion properties. It is therefore possible to obtain combined preparations in which the different drugs are released at the same rate or at different rates. Of course, the proportion of drugs in the chromatographic material in gel form can vary within wide limits, depending on the type of drug and the type of chromatographic material in gel form.

In accordance with the invention, it was possible to obtain remarkable adjustment conditions, both from the point of view of release rate and from the point of view of proportion of drug.

If the drug contains anionic or cationic groups, it is possible to further improve the ability of the device to bind and then subsequently deliver a large amount of drug, provided that the chromatographic material in gel form contains complementary ions, that is, respectively, cationic or anionic ions.

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The release rate of such ion-bound drugs can be controlled to a greater extent, compared to the other embodiments previously described. The drugs will in fact be released only after an ion exchange process according to which mainly the sodium ions, in a wound or mucous membrane, in the liquid state, must first pass through the device,

then reach the particles of the chromatographic material in the form of a gel. The drug, in turn, will then have to diffuse through the chromatographic material in the form of a gel and the device, to finally penetrate a mucous membrane, for example.

The time required for the drug to diffuse from the particles of crosslinked chromatographic material, in the form of a gel, can also be increased by coating the particles with a thin sealing layer of a suitable product such as polyvinyl-

pyrrolidone.

According to one embodiment of the invention, the device is advantageously manufactured by dissolving or suspending,

in a solvent containing water, agar-agar and / or agarose and / or a derivative of one of these polymers, optionally together with one or more other polymers, after what the particles of one or more crosslinked chromatographic materials,

in the form of a gel, containing one or more drugs are mixed, respectively, with the solution or the suspension. The mixture thus obtained is then transformed into a solid or semi-solid device, for example in the form of a sheet, an intravaginal membrane or a membrane, by applying it to a surface or in a mold, then letting it cool.

The solution or suspension of the above polymers is usually obtained by means of a heat source. 30

As already mentioned, the device obtained can be formed, for example, by a sheet, an intravaginal membrane or a membrane which can in turn be divided into the desired dimensions, for example by cutting. Of course, it is very rational to manufacture the sheet, the intravaginal membrane or the membrane by molding, since such a method makes it possible to carry out a continuous manufacturing process. The division of the sheet or membrane into smaller pieces can also be done rationally.

It is of course possible, in accordance with the invention, to make devices other than sheets, intravaginal membranes or membranes. However, these devices have a wide field of application.

As previously mentioned, the devices produced usually contain 75 to 99% by weight of water in the swelling state 45 in water. They often have this water content directly after manufacture. In general, a sheet according to the invention having such a water content is soft, flexible and of slippery properties.

It is often transparent. It can easily be observed under a microscope that the particles of chromatographic material in the form of a gel are embedded in the polymer constituting the sheet itself.

The invention will now be described in more detail with reference to the examples below. Example 1 illustrates the manufacture of a membrane in which particles of chromatographic gel are embedded. These particles contain pilocarpine as a medicine. Example 2 also relates to the manufacture of a membrane in which particles of chromatographic gel are incorporated. These particles then contain bound iodine in the form of a complex. Example 3 illustrates the manufacture of a cylindrical device 60 in which are incorporated particles of chromatographic gel containing prostaglandin. Example 4 relates to the manufacture of a combined preparation, in the form of a membrane, in which particles of two different chromatographic materials are incorporated, in the form of a gel. The first type of chromatographic gel particles contains a local anesthetic, while the other contains an anti-inflammatory drug. In addition, the material of the device itself contains a local anesthetic. Finally, Example 5 relates to the manufacture of a membrane in which are incorporated particles of chromatographic gel containing an antibiotic.

Example 1:

A gel chromatographic material, formed from a sodium salt of carboxymethylated dextrin produced from a dextrin, in accordance with American patents Nos. 3277025 and 3275576, has a gel layer volume of 6.5 ml / g and an ion exchange power of 0.4 mekv / g relative to the carboxymethyl groups.

40 g of this gel are transferred to a filtering funnel with a perforated plate, and treated with 400 ml of 0.16N hydrochloric acid in an aqueous solution containing 50% ethanol and 50% distilled water.

The gel is then washed until neutral reaction with 400 ml of a mixture containing 50% ethanol and 50% distilled water.

The gel is sucked dry, then treated on the perforating plate filter funnel with a solution of 10 g of pilocarpine hydrochloride (Merck) in 200 ml of a mixture of 50% ethanol and 50% distilled water .

The gel is washed until neutral reaction with a solution composed of 75% ethanol and 25% distilled water, then subjected to a volume reduction in 99.5% ethanol.

After drying in an oven at 75 ° C for 5 h, 38 g of an anhydrous powder with a nitrogen content of 0.34% are obtained.

A solution containing 4 g of agarose (Agarose A37, Indubiose 1 ', Pharmindustrie) in 100 g of water is obtained by heating on a boiling water bath. The solution is then cooled to 60 ° C., then 5 g of the powder of the abovementioned chromatographic material are added, in the form of a gel, containing ionically bound pilocarpine.

The suspension thus obtained is applied to a glass plate, in a layer 3 mm thick. The suspension is allowed to cool to room temperature. A device is thus obtained in the form of a transparent, soft, flexible membrane with slippery properties. It can be cut into pieces of desired shapes and dimensions. It can be established under the microscope that the chromatographic gel particles containing pilocarpine bound in ionic form are molded into the membrane.

The membrane obtained is suitable for the treatment of ocular glaucoma. A piece of the membrane, of appropriate dimensions, is then placed under the upper eyelid, the pilocarpine then being gradually released into the mucous membrane of the eye.

Example 2:

A crosslinked chromatographic material, in the form of a gel, containing iodine, obtained from sucrose, in accordance with Swedish patent No. 405680, has an iodine content of 1.11%, an ion exchange power of 0, 92 mekv / g relative to the carboxymethyl groups in acid form, a gel layer volume of 7.3 ml / g and an average particle size of 70 [im.

3 g of this material in the form of a gel are added, with stirring, to a solution at a temperature of 45 ° C. and containing 6 g of agarose (Agarose A37 Kebo 1.7539) in 100 ml of distilled water. When the homogenization is carried out, the viscous suspension obtained is applied to a glass plate, in a uniform layer 2 mm thick. The suspension is allowed to cool to 22 ° C. It is then solidified so as to obtain a membrane suitable for disinfecting the skin and wounds, for example.

Example 3:

A crosslinked chromatographic material, in the form of a gel, based on hydroxyethylcellulose and containing prostaglandin,

according to British patent application No. 8001176, has a gel layer volume of 5.3 ml / g and contains 0.35% of prostaglandin (PGE,).

7 g of this gel are added, with stirring, to a solution at a temperature of 44 "C and comprising 1.06 g of agarose (Agarose A37, Indubiose -, Pharmindustrie) and 0.53 g of hydroxyethylcellulose

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(Hydroxyäthylcellulose, O Type 822068, Merck) in 50 ml of distilled water.

The suspension thus obtained is shaped so as to obtain intravaginal membranes, of cylindrical shape, with a diameter of 15 mm and a length of 30 mm, by cooling in a mold. This gives 10 intravaginal membranes. 5 of these membranes are dried by cold evaporation, in a manner known per se.

All membranes, whether or not dried by cold evaporation,

are intended for intravaginal applications, possibly io after sterilization by irradiation. They are used to speed up the completion of a pregnancy or for the termination of pregnancy, in the case of legal abortion.

Example 4: i5

0.2 g of lidocaine (Lidocaine, anhydrous chloride) is dissolved in 1 ml of distilled water, then the pH is adjusted to 6.5 by addition of sodium hydrate.

The solution thus obtained is mixed with 2 g of a chromatographic material, in the form of a gel, commercially available (Sephadex ", G-25, Pharmacia Fine Chemicals), with a particle size of 20 to 80 μm and having a gel layer volume of 4.8 ml / g in water. The solution is allowed to diffuse in the chromatographic gel,

with stirring, then the product obtained is dried.

5 g of an anti-inflammatory agent (Betnovat-, 0.1% solution, Glaxo Laboratories Ltd) are mixed with 2.5 g of a commercially available chromatographic material in gel form (Sephadex " LH-20, Pharmacia Fine Chemicals), with a particle size of 60 Jim and a gel layer volume of 4.1 ml / g in water.

The solution is allowed to diffuse in the chromatographic gel, with stirring, then the product obtained is dried.

A solution containing 0.6 g of agarose (Agarose A37, Indubiose ", Pharmindustrie) in 20 ml of water is prepared by heating on a boiling water bath, with stirring. The solution obtained is cooled to 45 ° C., then the two products obtained above are incorporated into the solution with stirring.

Then a solution of 0.2 g of lidocaine (Lidocaine, anhydrous chloride) in 1 ml of distilled water is added. The pH of this solution is adjusted to 6.5, by addition of sodium hydrate. The suspension thus obtained is applied to a glass plate, in a layer 2 mm thick, and allowed to cool to 20 ° C. The membrane obtained can be cut into various elements and is suitable, for example, for treating wounds or painful and infected wounds.

Example 5:

400 mg of an antibiotic (Chloromycetin ", Parke-Davis, USA) are dissolved in 8 ml of distilled water. The solution thus obtained is added, with stirring, to 2.0 g of a polyacrylamide chromatographic gel (Biogel P-6, Bio-Rad Laboratories, USA), with a particle size of 60 μm. The product thus obtained is dried by cold evaporation, in known manner.

A solution of 0.5 g of agarose (Agarose A37, Indubiose *, Pharmindustrie) in 20 ml of distilled water is prepared by heating on a boiling water bath, with stirring.

The solution thus obtained is cooled to 46 ° C, then the above-mentioned product is mixed with this solution.

The suspension obtained is applied to a glass plate, in a layer 2.5 mm thick, and cooled to 20 ° C. The solidified membrane can be cut to the desired dimensions, for the treatment of wound infections or eye injuries and infections, for example.

The invention is not limited to the embodiments described, these being able to be modified in different ways without departing from the scope of the invention.

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Claims (21)

650,924 CLAIMS 1. Solid or semi-solid device, containing at least one drug, this device being formed by a polymer comprising agar-agar, agarose and a derivative of one of these polymers, characterized in that particles of one or more cross-linked chromatographic materials, in gel form, are incorporated into said device, said chromatographic materials in gel form containing one or more medicaments, and in that the device is made of a non-crosslinked polymer. 2. Device according to claim 1, characterized in that the chromatographic material in gel form as well as the device itself contain one or more drugs. 3. Device according to one of claims 1 or 2, characterized in that it is formed of a mixture of agar-agar and / or agarose and / or a derivative of one of these polymers and at least one other polymer. 4. Device according to claim 3, characterized in that it is formed of agar-agar and / or agarose and / or a derivative of one of these polymers and of at least one other polymer containing a hydroxyl group. 5. Device according to claim 4, characterized in that the polymer containing a hydroxyl group comprises starch, dextran, cellulose, agaropectin or a derivative of one of these polymers. 6. Device according to one of claims 1 or 2, characterized in that it is formed of agarose or an agarose derivative. 7. Device according to one of claims 1 to 6, characterized in that it contains functional groups, such as anionic or cationic groups. 8. Device according to claim 7, characterized in that the anionic groups include carboxy groups, sulfonic acid groups or phosphoric acid groups. 9. Device according to claim 7, characterized in that the cationic groups comprise diethylaminoethyl groups, P-morpholinoethyl groups or di (hydroxyethyl) aminoethyl groups. 10. Device according to one of claims 1 to 9, characterized in that the chromatographic material in the form of gel is formed by a crosslinked polymer. 11. Device according to claim 10, characterized in that the chromatographic material in gel form is formed by a crosslinked polymer containing a hydroxyl group, such as a carbohydrate or a derivative thereof. 12. Device according to claim 11, characterized in that the chromatographic material in gel form is formed by a crosslinked dextrin, starch, dextran, cellulose or a derivative of one of these polymers. 13. Device according to claim 10, characterized in that the chromatographic material in gel form is formed of a crosslinked polyvinyl alcohol, a polyacrylamide or a polyvinyl pyrroli-done. 14. Device according to one of claims 1 to 13, characterized in that the chromatgoraphic material in gel form contains anionic or cationic groups. 15. Device according to claim 14, characterized in that the anionic groups comprise carboxy groups, sulfonic acid groups or phosphoric acid groups. 16. Device according to claim 14, characterized in that the cationic groups comprise diethylaminoethyl groups, P-morpholinoethyl groups or di (hydroxyethyl) aminoethyl groups. 17. Device according to one of claims 1 to 16, characterized in that the chromatographic material in gel form has an average particle size of 100-1000 | im, for example 20-500 jtm. 18. Device according to one of claims 1 to 17, characterized in that the particles of the chromatographic material in gel form are molded in this device. 19. Device according to one of claims 1 to 18, characterized in that it contains from 75 to 99% by weight of water in the state of swelling in water. 20. A method of manufacturing a device according to one of claims 1 to 19, characterized in that one dissolves or suspends, in a solvent containing water, agar-agar and / or agarose and / or a derivative of one of these polymers, together with one or more other polymers, then particles of one or more crosslinked chromatographic materials are mixed, in the form of a gel, containing one or more drugs, respectively with the solution or the suspension, then the mixture thus obtained is transformed into a solid or semi-solid device, by applying it to a surface or in a mold, and the device is then cooled or allowed to cool. 21. The method of claim 20, characterized in that the solution or the suspension is obtained by means of a heat source.