SE448203B - FORM BODY MANUFACTURED FROM AGAR AND / OR AGAROS AND / OR A DERIVATIVE THEREOF CONTAINING PHARMACOLOGICALLY ACTIVE SUBSTANCE - Google Patents

Description

448,203 Attempts have previously been made to satisfy this need according to, inter alia, U.S. Pat. No. 3,867,519 by using a shaped body in the form of, for example, a foil. The shaped body is then made of a polyelectrolyte crosslinked with a divalent or polyvalent metal ion. The shaped body contains one or more pharmacologically active substances. These substances can e.g. be enclosed in microcapsules which in turn are incorporated into the mold body. The microcapsules are prepared in the usual way by coating the pharmacologically active substance with a thin polymeric film.

The known shaped body and its production have several disadvantages. The shaped body must, for example, be washed carefully after the crosslinking reaction, whereby large losses of the pharmacologically active substance usually occur.

The shaped body also provides little flexibility with regard to the release mechanism for the pharmacologically active substance.

After the crosslinking reaction, the polymer will contain toxic heavy metals such as cadmium or barium, which are then released during the biodegradation of the polymer using the shaped body in the eye.

It has now surprisingly been found that according to the present invention one can satisfy the above-mentioned need to be able to produce pharmaceutical preparations which release pharmacologically active substances for a long time in therapeutically satisfactory concentrations, thereby avoiding the said disadvantages of previously known preparations.

Thus, according to the invention, there has been provided a solid or semi-solid shaped body, for example in the form of a membrane, a vagitorium or a foil, containing one or more pharmacologically active substances, which shaped body is made of agar and / or agarose and / or a derivative. of any of these polymers.

A particularly good result is obtained if the polymer in the shaped body consists only of agarose or a derivative thereof. 4A 448 203 3 The shaped body may contain functional groups such as anionic or cationic groups. In this case, the anionic groups may, for example, consist of carboxyl groups, sulfonic acid groups or phosphoric acid groups, while the cationic groups may consist of e.g. diethylaminoethyl groups, β-morpholinoethyl groups or di- (hydroxyethyl) aminoethyl groups.

The shaped body is characterized in that one or more particulate, crosslinked gel chromatographic materials having an average particle size of 10-1000 μ and consisting of crosslinked dextrin, starch, dextran, cellulose or a derivative of any of these or a crosslinked polyvinyl alcohol, polyacrylamide or polyvinyl pyrrolide are incorporated into the mold body, which material contains one or more pharmacologically active substances, and that the mold body is prepared without the addition of crosslinking agent to the polymer.

The gel chromatographic material may contain anionic or cationic groups. The anionic groups may be, for example, carboxyl groups, sulfonic acid groups or phosphoric acid groups. The cationic groups may in turn be, for example, diethylaminoethyl groups, β-morpholinoethyl groups or di- (hydroxyethyl) -aminoethyl groups.

The gel chromatographic materials described above are per se known per se, as shown i.a. in the publication Gelchromatographie av Determann- (1967), the British patents 854,715 and 974,054, the American patents 3,277,025 and 3,275,576 and the Swedish patents 209,015 and 222,291.

The gel chromatographic material preferably has an average particle size of 20-500 .mu.m.

The particulate gel chromatographic material can be conveniently incorporated into the shaped body by blending into the polymer used to make the shaped body. According to the above, the shaped body has, for example, the shape of a foil, a vagitorium or a membrane. The shaped body can i.a. produced by casting. 448 203 The particulate gel chromatographic material must contain one or more different pharmacologically active substances. These substances can be incorporated into the gel chromatographic material in various ways, e.g. by absorption / adsorption, ion formation, complex bonding or chemical bonding. The method chosen for incorporation of the pharmacologically active substances is determined primarily by the physical and chemical properties of the substances, but also to some extent by how quickly one wants the substances to be released during use. The gel chromatographic material can generally be satisfactorily adapted to the properties of the pharmacological substances.

According to the invention, it is possible, if desired, to use different gel chromatographic materials for each pharmacologically active substance. in an embodiment according to the invention not only the gel chromatographic material but also the shaped body itself contains one or more pharmacologically active substances. These substances can be incorporated into the body material in the same manner as described above in connection with the incorporation of pharmacologically active substances into the gel chromatographic material.

The worm body according to the invention generally contains 75-99% by weight of water in a water-swollen state. When treating skin, wounds or mucous membranes, it is particularly suitable that the shaped body is swollen in water or physiological saline solution.

Namely, in that state the shaped body is so tissue-friendly that it can even be applied inside an eyelid and emit pharmacologically active substances such as antibiotics or intraocular pressure-reducing agents of the pilocarpine type. Examples of other possible pharmacologically active substances that may be included in the shaped body are given in U.S. Pat. No. 3,867,519. Furthermore, the shaped body may contain spermicides, enzymes or prostacyclin.

By incorporating a particulate gel chromatographic material into the shaped body according to the invention, the release rate of the pharmacologically active substances can be controlled in a satisfactory manner. Namely, in this embodiment, these substances must first pass through the gel chromatographic material and then through the shaped body to finally penetrate into, for example, a mucous membrane.

By selecting gel chromatographic materials with a suitable density and associated diffusion properties, the release rate of the pharmacologically active substance can be controlled.

In addition, in the preparation of a shaped body containing several different pharmacologically active substances as above, a special gel chromatographic material can be incorporated for each pharmacologically active substance. In this case, the different gel chromatographic materials can have the same or different density and associated diffusion properties. Thus, it is possible to produce combination preparations where the different pharmacologically active substances are released at the same or different rate. The amount of pharmacologically active substances in the gel chromatographic material can of course be varied within wide limits depending on the type of pharmacologically active substance and gel chromatographic material.

According to the invention, it has been possible to achieve extremely good control conditions with regard to both the release rate and the amount of pharmacologically active substance.

If the pharmacologically active substance contains anionic or cationic groups, the ability of the shaped body to bind and later release a larger amount of the pharmacologically active substance can be further enhanced, provided that the gel chromatographic material contains counterions, i.e. cationic and anionic groups, respectively. The release rate of such ion-bound, pharmacologically active substances can be further regulated in relation to other embodiments described above by first delivering the substances after a G ion exchange process where mainly sodium ions in wound or mucosal fluids must first pass into and through the mold body and then into the particulate, the gel chromatographic material. 448 203 The pharmacologically active substance must in turn diffuse through the gel chromatographic material and the shaped body to finally penetrate into, for example, a mucous membrane.

The time of diffusion of the pharmacologically active substance out of the particulate crosslinked gel chromatographic material can also be extended by coating the particles of gel chromatographic material with a thin sealing layer of a suitable material, such as polyvinylpyrrolidone.

The shaped body according to an embodiment of the invention is conveniently prepared by transferring agar and / or agarose and / or a derivative of any of these polymers in dissolved or suspended form in an aqueous solvent, whereupon one or more particulate, crosslinked, gel chromatographic materials having an average particle size of 10-1000 u and consisting of crosslinked dextrin, starch, dextran, cellulose or a derivative of any of these or of crosslinked polyvinyl alcohol, polyacrylamide or polyvinylpyrrolidone containing one or more pharmacologically active substances is mixed, that the mixture is transferred to a solid or semi-solid shaped body , for example in the form of a foil, a vagitoria or a membrane, by being applied to a surface or in a mold and then cooled or allowed to cool.

The solution or suspension of the above polymers is often accomplished during heat application.

The resulting shaped body can, as mentioned, consist of a foil, a vagitoria or a membrane which in turn can be divided into the desired size, for example by cutting. It is of course very rational to produce the foil; the vagitorium or the membrane by casting, such a method enables continuous production. The division of the foil or membrane into smaller pieces can also take place rationally.

It is of course possible according to the invention to produce other c ._._._.._ V, ._ _. 448 203 shaped bodies other than foils, vagitorias or membranes. The latter, however, have a very large area of use.

According to the above, the shaped bodies produced usually contain 75-99% by weight of water in the water-swollen state. Immediately after production, they usually have that water content. A foil according to the invention with such a water content is usually soft, flexible and slippery. It is often transparent. In a microscope it can then be clearly seen that the particles of gel chromatographic material are embedded in the polymeric material which forms the foil itself.

The invention is explained in more detail in connection with the following exemplary embodiments, of which Example 1 shows the preparation of a membrane in which gel chromatographic particles are embedded.

The particles then contain the pharmacologically active substance pilocarpine. Example 2 also shows the preparation of a membrane in which gel chromatographic particles are embedded. The particles then contain iodine in complexed form. Example 3 relates to the preparation of a cylindrical shaped body in which gel chromatographic particles containing prostaglandin are incorporated.

Example 4 relates to the preparation of a combination preparation in the form of a membrane in which gel chromatographic particles of two different kinds are incorporated. One type of particle contains a local anesthetic, while the other contains an anti-inflammatory agent. In addition, the shaped body material itself contains a local anesthetic. Finally, Example 5 relates to the preparation of a membrane in which gel chromatographic particles containing an antibiotic are incorporated.

Example 1 A gel chromatographic material consisting of the sodium salt of carboxymethyldextrin made from dextrin according to Swedish patent 204,906 had a bed volume of 6.5 ml / g and an ion exchange capacity of 0.4 meq / g for carboxymethyl groups. 40 g of this gel material were transferred to a nut funnel and treated with 400 ml of 0.16 N hydrochloric acid in an aqueous solution containing 50% f '/'. The membrane prepared is suitable for treatment of / 448 203 ethanol and 50% distilled water.

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

The gel was sucked dry and then treated on the nut 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 was washed to neutral reaction with a solution consisting of 75% ethanol and 25% distilled water and then shrunk in 99.5% ethanol. after drying 1 drying cabinet at 75 ° c 1 powder with a nitrogen content of 0.34%. 5 hours 38 g were obtained dry A solution containing 4 g of agarose (AGAROSE A 37, INDUBIOSER, Pharmindustrie) in 100 g of water was prepared by heating on a boiling water bath. The solution was then cooled to 60 ° C and charged with 5 g of the powdered gel chromatographic material as above containing ion-bound pilocarpine.

The suspension thus obtained was discharged into a 3-gauge disk. The suspension was allowed to cool to room temperature.

Thereby, a shaped body was kept in the form of a flexible and slippery membrane which could be of the same size and size. mm thick layer of a transparent, soft, cut into pieces to the desired In the nucroscope it could be found that the gel chromatographic particles containing ion-bound pilocarpine were embedded in the Membrane. In the eye disease glaucoma. A piece of the membrane of suitable size is then placed under the upper eyelid where it will be delivered to the mucous membrane of the eye. pilocarpine gradually successively n "-l ä .." fl- m .. m 448 203 Example 2 An iodine-containing, cross-linked gel chromatographic material made from sugar according to Swedish Offenlegungsschrift 405,680 had an iodine content of 1.11%, an ion exchange capacity of 0.92 meq / 9 for carboxymethyl groups in acid form, a bed volume of 7.3 ml / g and an average particle size of 70 u. 3 g of this gel material were taken with stirring into a solution with 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 was achieved, the resulting viscous suspension was passed over a glass plate in a 2 mm evenly thick layer, the suspension was allowed to cool to 22 ° C, solidifying to a membrane, which is e.g. suitable for disinfection of skin and wound surfaces.

Example 3 A prostaglandin-containing, cross-linked gel chromatographic material made from hydroxyethylcellulose according to Swedish patent application 7900737-3 (publication number 431,821) had a bed volume of 5.3 ml / g and contained 0.35% prostaglandin (PGE2). 7 g of this gel material were taken with stirring into a solution with a temperature of 4 ° C and consisting of 1.06 g of agarose (Agarose A 37, IndubioseR, Pharmindustrie), 0.53 g of hydroxyethylcellulose (Hydroxyethylcellulose, Art 822068, Merck) in 50 ml of distilled water. The suspension thus obtained was formed by cooling in mold to vagitoria which had a cylindrical shape with a diameter of 15 mm and a length of 30 mm. Thereby, 10 vagitoria were obtained, of which 5 were freeze-dried in a known manner.

All vagitorias, whether freeze-dried or not, after possible radiation sterilization are intended for intravaginal application to facilitate the initiation of labor or tubes to terminate pregnancy in connection with legal abortion. Example 4 0.2 g of lidocaine (lidocaine, chloride anhydride) was dissolved in 1 ml of distilled water, after which the pH was adjusted to 6.5% by adding sodium hydroxide solution.

The solution thus obtained was mixed with 2 g of a commercially available gel chromatographic material (SephadexR, G-25, Pharmacia Fine Chemicals) having a particle size of 20-80 μ and having a bed volume of 4.8 ml / g in water. The solution was allowed to diffuse into the gel chromatographic material with stirring, after which the product thus obtained was dried. 5 g of anti-inflammatory agent (BetnovatR, 0.1% solution, Glaxo Laboratories Ltd.) was mixed with 2.5 g of a commercially available gel chromatographic material (SephadexR LH-20, Pharmacia Fine Chemicals) with an average particle size of 60 n and a bed volume of 4.1 ml / g water.

The solution was allowed to diffuse into the gel chromatographic material with stirring, after which the product thus obtained was dried.

A solution containing 0.6 g of agarose (Agarose A 37, IndubioseR, Pharmindustie) in 20 ml of water was prepared by heating on a boiling water bath with stirring. The solution thus obtained was cooled to 45 ° C, after which the two products prepared according to the above were stirred into the solution.

Then a solution of 0.2 g of lidocaine (Lidocaine chloride anhydr.) In 1 ml of distilled water was added, in which solution the pH was adjusted to 6.5 by adding sodium hydroxide solution. The suspension thus obtained was passed over a glass plate in a 2 mm thick layer and allowed to cool to 20 ° C.

The resulting membrane could be cut into parts and was suitable e.g. for the treatment of painful and inflamed wounds. Example 448 203 1] Example 5 400 mg of an antibiotic, (Chloromycetin R, Parke-Davis, USA) was dissolved in 8 ml of distilled water. The solution thus obtained was immersed in 2.0 g of gel chromatographic polyacrylamide gel (Biogel P-6 Bio-Rad Laboratories, USA) having an average particle size of 60 μ with stirring. The product thus obtained was freeze-dried in a known manner.

A solution was prepared from 0.5 g of agarose, (Agarose A 37 IndubioseR, Pharmindustrie) in 20 ml of distilled water by heating on a boiling water bath with stirring. The solution thus obtained was cooled to 46 ° C, after which the product as above was mixed with the solution.

The resulting suspension was passed over a glass plate in a 2.5 mm thick layer and allowed to cool to 20 ° C. The solidified membrane could be cut into desired dimensions for treatment of e.g. wound and eye infections.

The invention is not limited to the embodiments shown, as these can be modified in various ways within the scope of the invention.

Claims (12)

448 203 12 PATENT REQUIREMENTS 1. A solid or semi-solid shaped body, for example in the form of a membrane, a vagitorium or a foil, containing one or more pharmacologically active substances, which shaped body is made of a polymer consisting of aqar and / or agar and / or a derivatives of any of these polymers, characterized in that one or more particulate, crosslinked gel chromatographic materials having an average particle size of 10-1000 μm and consisting of crosslinked dextrin, starch, dextran, cellulose or a derivative of any of these or a crosslinked polyvinyl alcohol, polyacrylamide or polyvinylpyrrolidone, are incorporated into the mold body, which material contains one or more pharmacologically active substances, and that the mold body is prepared without the addition of crosslinking agents to the polymer. A molding according to claim 1, characterized in that both the gel chromatographic material and the molding itself contain one or more pharmacologically active substances. A shaped body according to claim 1 or 2, characterized in that it is made of agarose or a derivative thereof. A shaped body according to any one of claims 1-3, characterized in that it contains anionic groups in the form of carboxyl groups, sulfonic acid groups or phosphoric acid groups. A shaped body according to any one of claims 1 to 3, characterized in that it contains cationic groups in the form of diethylaminoethyl groups, Ä -morpholinoethyl groups or di- (hydroxyethyl) -aminoethyl groups. A shaped body according to any one of claims 1-5, characterized in that the gel chromatographic material contains anionic groups in the form of carboxyl groups, sulfonic acid groups or phosphoric acid groups. Molding according to one of Claims 1 to 5, characterized in that the gel chromatographic material contains cationic groups in the form of diethylaminoethyl groups, -E-morpholino-ethyl groups or di- (hydroxyethyl) -aminoethyl groups. l-Jx 13 448 203 8. A shaped body according to any one of claims 1-7, characterized in that the gel chromatographic material has an average particle size of 20-500 μm. Form body according to one of Claims 1 to 8, characterized in that the particulate gel chromatographic material is embedded in the body. A molded body according to any one of claims 1 to 9, characterized in that it contains 75-99% by weight of water in a water-swollen state. 11. ll. Process for the preparation of a shaped body according to any one of claims 1-10, characterized in that agar and / or agarose and / or a derivative of any of these polymers are transferred in dissolved or suspended form in an aqueous solvent, whereupon one or more particulate, crosslinked, gel chromatographic materials having an average particle size of 10-1000 μm and consisting of crosslinked dextrin, starch, dextran, cellulose or a derivative thereof or of crosslinked polyvinyl alcohol, polyacrylamide or polyvinylpyrrolidone containing one or more pharmacologically active substances , that the mixture is transferred to a solid or semi-solid shaped body, for example in the form of a foil, a vagitorium or a membrane, by being applied to a surface or in a mold and then cooled or allowed to cool. 12. A process according to claim 11, characterized in that the solution or suspension is obtained during heat supply.