HU193372B - Process for the purification of a dextrane bead polymer of stereoscopic mesh structure suitable for pharmaceutical purposes - Google Patents

Description

Our method relates to the purification of a dextran bead polymer for pharmaceutical use.

According to the process of the present invention, the crosslinked bead polymer is swelled in pH 1.0 to 5.5, preferably pH 4.0, and treated with a water miscible organic solvent, preferably ethyl alcohol, after removal of the acidic water.

The pearl polymer thus dehydrated is, after removal of the alcoholic aqueous phase, re-swollen in deionized water, washed with anhydrous acid, graded for particle size, dried, and formulated in a pharmaceutical form, preferably by sterilization with gamma rays.

It is known that folk cure has already used absorbent solutions for the treatment of positive, infected, purulent wounds (using a cut tomato, a leaf of a leaf to cover the wounds).

The effectiveness of these treatments, although only based on experience, is due to the fact that open wounds were cleaned of tissue leaks, dead tissue remnants, thus reducing the chances of microorganisms to settle and proliferate on the wound surface, and protect the wound from metabolism. products, toxins, improved the air supply to the wound, and finally, the wound covering with the above-mentioned natural substances applied also provided a good absorbing effect. If the suction effect extended to the edema of the wound, the elimination of the edema could also provide a better blood supply around the wound, thus allowing tissue regeneration.

To provide the physico-chemical conditions for ideal wound healing, the company PHARMACIA manufactures a formulation according to English Patent No. 1,154,055 (Swedish Patent No. 73,01197, French Patent No. 2,215,230 and US Patent No. 4,225,580), commercially available as "Debrisan". known as. In the patent, the authors refer to the processes of their previous patents (845,715, 936,039, 974,054 and

British Patent No. 1,013,585).

British Patent 2,099,704 discloses cross-linked dextran polymers for use in the preparation of pharmaceutical compositions having similar additives, in particular disinfectant compounds (polyvinylpyrrolidone-iodine complex, silver-sulfadiazine) as a carrier for thin films. According to an improved version of the composition, silver nitrate is used as an additive (Symp. Ser. 1984, 256 181-9; C.A. 101 65595w).

In our experiments, we found that crosslinked dextran bead polymer (prepared according to Example 1 of British Patent No. 974,054) was used in suspension of epichlorohydrin in alkaline solution, using suspension as a stabilizer, although its water absorption and particle size , however, did not have it in animal experiments

British Patent I-454,055.

The pharmacological properties of the bead polymer prepared according to Examples 2, 3, 4 and 5 of the cited patent were also investigated, but the expected results were not achieved with these formulations. (Compared to Example 1, the other examples differ only with respect to the suspending agent, while in Example 1, toluene is used, in Example 2, ortho-dichlorobenzene, in Example 3, dichloromethane, in Example 4, ethane, 1,2-dichloroethane in Example 5).

In our animal experiments, 8-12 kg KAHIB pigs of both sexes were used. 170-180 ° C. Burning wounds of 35 mm / kg i.v. applied with Evipanos narcosis on both sides of the pigs. (Method: S. Jacobson, L. Jonsson, F. Ránk and U. Rothman, Scand.

J. Plast.Reconstr.Surg. 10, 97-101, 1976.) 6-6 animals were placed in the experimental and control groups and kept under observation for 14 days.

After wounding the animals, infected wounds were treated from day 3 on with bead beads prepared according to Example 1 of British Patent No. 974,054 and wound-powder powder marketed under the name "Debrisan". One side of the pigs was always treated with Debrisan and the wounds on the other side were treated with a bead polymer prepared according to the above patent. Treatment was given once a day.

In our experiments, it was found that the bead polymer prepared according to Example 1 of the cited patent, although bound to tissue tissues, removed bacteria and tissue debris to cleanse the wound, but also had an undesirable side effect which was very prominent in histological examination. : The wound and its surroundings became severely edematous. Thus, despite the wound healing, due to the formation of edema, the blood and oxygen supply was reduced, which prevented healing.

Debrisan produced the expected effect, the wounds healed, and no edema was observed.

Our studies above have concluded that only a very pure product meeting the highest quality requirements can be used for pharmaceutical purposes, and

-2193372 states that the bead polymer prepared in Example 1 of the cited patent may contain contaminants which during manufacture are entrapped in the granules and, when exuded from the wound surface, produce edema by irritation and delay healing.

Our hypothesis was confirmed by our microscopic examination: the cited patent

The bead polymer beads prepared according to Example 1 were opaque and opaque.

SUMMARY OF THE INVENTION The object of the present invention is to provide a purification process which ensures the proper quality and purity of epichlorohydrin crosslinked dextran bead polymer produced in any known manner and is suitable for the preparation of pharmaceutical compositions.

Surprisingly, it has been found that impurities can be removed from the bead polymer beads by swelling or washing in a dilute acidic medium, pH 1-5.5, preferably pH 4, followed by water-miscible organic solvent, e.g. with ethyl alcohol. The particles are swollen out of the inside of the particles that are swollen by the aqueous acid solution and then shrink after treatment with ethyl alcohol. Because of the favorable ion sizes, hydrochloric acid is most preferably used to provide the acidic medium. In order to de-acidify the granules, it is expedient to repeat the swelling with deionized water. If necessary, the treatments described above may be repeated.

The acid-washed and dehydrated bead polymer is graded and dried according to particle size. The resulting clear transparent bead polymer was as good as the control Debrisan formulation in animal experiments using the method described above. results. The purified product was formulated as a wound powder in spray cans, a tampon in filter paper, or as a paste.

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

Example 1

Reproduction of Example 1 of British Patent No. 974,054: 40,000 average Ms dextran was wetted with 20% water and a 6 molar sodium hydroxide solution was added to a final concentration of 40%. 600 g of the resulting dextran solution were poured into a cylindrical reaction vessel. As suspension slurry, 430,000 average molecular weight polyvinyl acetate dissolved in 500 ml of toluene was added and the stirring rate was adjusted to disperse the aqueous phase in the form of small droplets in the toluene phase. Then 50 g of epichlorohydrin was added with further stirring and the temperature was maintained at 50 ° C. Gel formation occurred within 1 hour.

Upon completion of the reaction, the particles were filtered from the reaction mixture with toluene and ethyl alcohol; then washed with water to remove acid and dried at 110 ° C.

Particle size distribution: 30-100 microns

Moisture absorption: 3.0 g / g (dry product)

Example 2

100 g of dry dextran resin polymer obtained in Example 1 were swelled in 1000 ml of water adjusted to pH 4 with hydrochloric acid for 4 hours with constant gentle stirring, checking the pH. The acidic liquid was then discarded and then further swelled with 500 mL of water adjusted to pH 4 with hydrochloric acid with constant gentle stirring for 1 hour. The acidic water was discarded, and the swollen granules were stirred with 500 mL of ethyl alcohol for 1 hour and the supernatant discarded with alcoholic treatment as above. The dehydrated pellets were swollen with deionized water, washed to pH 5.5 and then dried with 500 ml of ethyl alcohol, and the bead polymer was dried at 80 ° C. The water uptake and particle size are the same as in Example 1.

Example 3

The dry dextran bead polymer obtained in Example 1 (100 g) was swollen in 1000 ml of water and then adjusted to pH 1 with hydrochloric acid with constant gentle stirring, followed by the procedure of Example 2 below.

The water uptake and particle size are the same as in Example 1.

Example 4

The dextran bead polymer obtained in Example 1 (100 g) was swelled in 2000 ml of water adjusted to pH 4 with hydrochloric acid for 4 hours under constant stirring to check the pH.

Thereafter, the procedure of Example 1 was followed.

Example 5

32 g of polyvinyl acetate (Ms: 430,000) were dissolved in 380 ml of toluene with stirring at 50-55 ° C and then cooled to 20 ° C. Dextran powder (MS: 40000) (100 g) was dissolved in water (100 ml) and a solution of sodium hydroxide (24 g) in water (27 ml) was added. After stirring, 42 ml of epichlorohydrin and polyvinyl acetate solution in toluene were added and the reaction mixture was stirred at 50-55 ° C for an additional 16 hours.

The resulting bead polymer was washed with toluene to remove polyvinyl acetate, then washed with ethyl alcohol followed by water, and the beads were then stirred in 500 mL of water adjusted to pH 4 with hydrochloric acid for 1 hour.

The acidic wash was repeated, followed by a

Ex. we acted. The product obtained has a water absorption of 2.8 g / g and a particle size of 40-100 microns.

-3193372

Example 6

The final product obtained in Example 1 was graded by particle size. The particles, 100-350 μm in diameter, were packed in 60 g batches and sterilized in unit packets with Co ⁶⁰ radiation source at 25kGy dose and 20 kg / 0.1 m ³ .

Example 7

The final product obtained in Example 1 was graded by particle size, 40-100 μm diameter particles were added in 1 g portions between two layers of physiologically indifferent filter paper, and the layers were welded. Sterilization was carried out according to the procedure of Example 6.

Example 8

The final product obtained in (1) was graded according to particle size. 6800 g of particles having a diameter of 40-100 μ, suspended in a mixture of 2900 g of polyoxyethylene in 200 and 300 g of sorboxetene monooleate, were placed in 10 g portions of polyethylene-lined aluminum foil sachets for 30 minutes and sealed. Sterilization was carried out according to the procedure of Example 6.

Claims (2)

⁵ PATENT CLAIMS A process for the preparation of a pharmaceutically acceptable cross-linked dextran bead polymer by purifying the dextran bead polymer by swelling with water followed by a further aqueous wash after swelling with a water-miscible organic solvent, preferably ethyl alcohol, characterized in that the bead polymer is 0 to 5.5, preferably 4.0, in acidic, preferably hydrochloric acid, deionized water and, if desired, the swelling is repeated and the dehydrated The 2q granules are washed with deionized water to anhydrous. 2. A process according to claim 1, wherein the acidic wash is carried out with 5-30 volumes of acidic water, based on the weight of the bead polymer.