HU200092B - Process for production of dextrane perle-polimers for poudre for wounds suitable for improvement of its medical utilization - Google Patents

Abstract

The medical usefulness of swellable hydrophylic polymers used for the prepn. of culinary powders is improved by saturating cation accepting loci of the polymer chains with identical or dissimilar metal ions and/or positively charged antibiotic molecules.

Description

FIELD OF THE INVENTION The present invention relates to a process for improving the therapeutic utility of epichlorohydrin crosslinked dextran bead polymer for the preparation of wound powders by treating cationic binding sites within the polymer molecules with pharmaceutically acceptable amino acid glycosides having the same or different metal ions and / or positive charges.

Crosslinked swellable polysaccharide-type polymers were first used and marketed by Swedish company Pharmacia. The wound powder produced according to Swedish Patent No. 73.01197 is particularly suitable for cleaning the wettable boron surface, wounds, mucous membrane and preventing the formation of edema during wound healing, mainly due to the swelling properties of the polymer particles in water.

The preparation of a polymer with appropriate swelling properties is described in British Patent Nos. 845,715, 936,033, 974,054 and 1,013,585. The polymer produced may be a spherical bead polymer or an irregularly shaped particulate material, which is produced after polymerization by grinding to a suitable size (10-1000 microns).

The polymer is typically dextran, dextran derivative, cellulose derivative or other polysaccharide crosslinked with epichlorohydrin.

In view of the favorable results obtained with cross-linked dextran bead polymer (Debrisan, Crupodex), attempts have been made to improve the formulation.

For example, English Patent No. 2,099,704 and a presentation by its inventor on its development (Symp. Ser. 19, 256, 181-9; CA

101 65595 w) discloses the preparation of wound treatment pharmaceutical compositions supplemented with various additives (polyvinylpyrrolidone-iodine complex, silver sulfadiazine, silver nitrate).

Compositions prepared according to the above-mentioned methods utilize, amongst the advantageous properties of the cross-linked hydrophilic polymer, its swellability and treat the polymer backbone as a chemically neutral molecule.

SUMMARY OF THE INVENTION It is an object of the present invention to improve the therapeutic utility of crosslinked hydrophilic polymers for wound powders by preserving their wound cleaning and wound healing properties by saturating cationic binding sites within the polymer molecules with pharmaceutically acceptable positively charged ions or molecules.

It is known that cross-linked dextran and dextran derivatives as molecular sieves are also widely used in practice and that they have a certain ion exchange capacity, in particular cation-binding ability. The ion exchange capacity of derivatives containing carboxylic or sulfonic acid groups is particularly significant.

Consideration of this circumstance is important because polymer particles, by virtue of their cation-binding capacity, can significantly alter the ionic concentration of tissues around the wound and at the same time shift the pH to an acidic range. Its significance lies in the observation that the levels of calcium and potassium in the wound and in the tissue surrounding the wound play an important role in wound healing. This observation is utilized in U.S. Patent No. 3,416,777, which discloses a solution for adjusting calcium and potassium ion concentrations in tissues around the wound to optimal levels for wound healing. Water-binding materials, such as gauze or bandages, or any wound dressing material saturated or impregnated with a solution containing calcium and potassium salts, are used for the desired purpose.

The use of a swellable gel, such as methyl hydroxyethyl cellulose, as a water-binding agent is also described.

However, when a swellable hydrophilic polymer is used to bind the solution containing the calcium and potassium salts, the aqueous solution-saturated polymer is no longer capable of swelling and loses its wound cleansing and wound healing properties.

It is an object of the present invention to realize that by saturating the cationic binding sites of a hydrophilic swellable polymer with pharmaceutically acceptable positively charged ions or molecules while preserving the swellability of the polymer, it is possible to produce more pharmaceutically effective wound powders.

According to the present invention, the dextran bead polymer crosslinked with epichlorohydrin is swelled in an aqueous solution containing a pharmaceutically acceptable salt or salts. For example, the bead polymer is placed in a 1M sodium chloride solution. During the cation binding, the pH of the solution is neutralized with 0.1 M sodium hydroxide solution to replace the sodium ions until the neutral pH is stabilized. Saturation is then considered complete, the polymer is washed with several portions of water, dehydrated with ethyl alcohol, dried and sterilized as a pharmaceutical formulation.

The polymer so treated is no longer capable of uptake of cation, therefore it does not reduce the calcium and potassium3 concentrations that are essential for wound healing on the wound surface and its immediate vicinity and, in addition, maintains or influences slightly acidic pH. At the same time, the swelling capacity of the composition remains intact and can thus exert its wound cleansing and wound healing properties.

The swelling hydrophilic polymer suitable for use as a wound powder can be saturated by the process of the invention.

In addition to the pharmaceutically acceptable metal ions (alkali metals, alkaline earth metals, silver, etc.), saturation can also be accomplished with positively charged molecules, preferably antibiotics.

In addition to the above, in the case of saturation with antibiotics, the wound powder treated in this manner provides a uniform, homogeneous distribution and, by slow cation exchange, a uniform release of the active ingredient.

In a preferred embodiment, the dextran bead polymer crosslinked with epichlorohydrin is swelled in a 1% aqueous solution of an aminoglycoside antibiotic such as neomycin sulfate.

It is known that silver or silver. silver ions have a very significant antiseptic effect. In this way, dextran, which is saturated with silver ions, has antiseptic properties in addition to its favorable properties. In this case, the dextran bead polymer may be swelled in a 2% silver nitrate solution and the supernatant replaced with fresh solution until the pH is stabilized. In this way, the bead polymer can be saturated to a maximum silver content of 8.5 to 10.1 mg / g.

For therapeutic reasons, the concentration of silver in the polymer may be reduced as desired using a solution containing a calculated amount of silver ion. However, to keep the bead polymer saturated, the remaining cation-binding sites may be saturated with other ions or molecules.

Based on similar considerations, the concentration of antibiotics in the polymer molecules may be chosen to be lower than the saturation value, or the vacant sites may be saturated with metal ions.

In this way, combination preparations may be prepared which may meet special needs.

Experimental experience suggests that prior to saturation, particularly with dextran bead polymer crosslinked with epichlorohydrin, an acid treatment is employed to purify any cation binding sites that may be present in the polymer backbone during the preparation or purification of the bead polymer.

In clinical trial conditions, a dextran bead polymer saturated with sodium ions and a wound dressing powder commercially available as Crupodex as a control were used to treat equal sized wounds in dogs. According to the results of the experiments, signs of peeling on the wound surface occurred 5 days earlier when treated with saturated bead polymer, and the treatments were less painful.

The invention is illustrated by the following examples, without limiting our claims.

Example 1

500 g of epichlorohydrin-crosslinked dextran bead polymer (particle size: 120-320 µm) was swollen in 3 L of 1M sodium chloride solution and the pH was reset to 0.1 with sodium hydroxide solution (0.1 N). Saturation is considered complete when the pH no longer decreases after reconstitution.

After pH stabilization, the brine was decanted and the product was washed twice with 3 L of deionized water and then dehydrated three times with 3 L of ethyl alcohol. The product is then dried at 20-25 ° C and sterilized in a pharmaceutical composition using a Co ⁶⁰ radiation source at a dose of 20 kGy. The product has a sodium content of 8.6 mg / g.

Example 2

500 g of dextran bead polymer cross-linked with epichlorohydrin (particle size: 40-120 µm) was swelled in 3 liters of deionized water, the solution was adjusted to pH 2.0 with hydrochloric acid and allowed to stir occasionally for 3 hours. The pH of the solution is regularly monitored and adjusted to pH 2.0 with additional hydrochloric acid if necessary. After pH stabilization, the supernatant is decanted and the polymer is dehydrated with 3 times 2 L of ethyl alcohol.

After dehydration, the polymer is swelled again in deionized water and rinsed several times with deionized water until pH 5 to remove acid residues. The product was isolated by filtration and suspended in a 2% solution of silver nitrate. Regularly check the pH of the solution and replace the silver nitrate solution with a fresh solution until the pH is stabilized. Subsequently, the silver-saturated product is isolated by filtration, washed with deionized water, dehydrated as described in Example 1, dried and sterilized after formulation.

The silver content of the product is 9.2 mg / g.

Example 3 Dextrene bead polymer crosslinked with epichlorohydrin (particle size: 120-320 μιη) was subjected to acidic 6 treatment as described in Example 2, then dehydrated with ethyl alcohol and swelled in 100 ml of pH 8 phosphate-buffered neomycin solution.

hours. (The solution contains 1.0% neomycin sulfate.) The product is filtered and rinsed several times with 200 ml portions of deionized water, dried and sterilized after reconstitution. Neomycin content of product: 10.700 mg / g (based on biological measurement).

Claims (4)

PATENT CLAIMS CLAIMS 1. A process for improving the therapeutic use of epichlorohydrin-crosslinked dextran bead polymer 20 for preparing wound dressing powders, wherein the cationic binding sites within the polymer molecules are saturated with pharmaceutically acceptable same or different metal ions and / or amino glycoside antibiotics. 2. A process according to claim 1 wherein the metal ion is sodium, potassium, calcium or silver. The process according to claim 1 or 2, wherein the aminoglycoside antibiotic is neomycin. 4. A process according to any one of claims 1 to 5, characterized in that the bead polymer is subjected to acid treatment before saturation.