FI80052B - FOERBAETTRAT FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT ANVAENDBARA TVAERBUNDNA DEXTRANKORNPOLYMERER OCH DESSA INNEHAOLLANDE TERAPEUTISKA KOMPOSITIONER. - Google Patents

Description

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The invention relates to an improved process for the preparation of therapeutically useful dextran bulk polymers and therapeutic compositions containing them.

According to the process of the invention, the crosslinked granular polymer is swollen in water at a pH of 1.5 to 5.5, suitably at pH 4.0 and, after removal of acidic water, it is treated with a water-miscible organic solvent, suitably ethanol.

After removal of the aqueous ethanol phase, the dehydrated granular polymer thus redisturbed in deionized water is therefore washed until it is free of acid, dried and suitably formulated into a therapeutically useful form after sterilization by gamma irradiation.

It is known that water-absorbing methods 20 (using split tomato or yard leaves to cover wounds) have been used in folk medicine to heal succulent, infected and purulent wounds.

Although these treatments were based on experiment, their success could be attributed to the fact that open wounds were cleaned of tissue fluids and necrotic tissue residues, which reduced the ability of microorganisms to adhere to and proliferate on wound surfaces and, on the other hand, wounds. protected from the harmful effects of metabolites and toxins of micro-organisms; in addition, air permeation to the wounds was improved and a suitable water-absorbing effect was achieved by covering the wounds with the above-mentioned materials of natural origin. If this water-absorbing effect also extended to the swollen portions of 2,800,552 wounds, better blood flow to the wound environment could be achieved, which also made tissue healing possible.

The composition according to the Swedish trade name Pharmacia AB GB Patent Publication No. 1,454,055 (known in the trade as Debrisan) perfectly satisfies the physical and chemical conditions for optimal wound healing. In this patent, the inventors refer to the methods described in their previous patents for the preparation of a dextran gel as an active ingredient of a composition of matter (GB Patent Nos. 845,715, 936,039, 974,054 and 1,013,585).

In our studies, it has been found that dextran-15 nira polymers (prepared as shown in Example 1 of GB Patent Publication No. 974,054) cross-linked with epichlorohydrin in alkaline solution using polyvinyl acetate as a suspension stabilizer have no therapeutic effect in animal experiments. which is disclosed in GB Patent Publication No. 1,454,055, although its hygroscopic moisture (water absorbency) and particle size correspond to the information given in the latter patent publication. The pharmacological properties of the granular polymers prepared according to Examples 2, 3, 4 and 5 of GB Patent Publication No. 974,054 were also studied, but the expected result could not be obtained with these preparations either (compared to Example 1, these examples differ only in suspension medium: toluene is used in Example 1, o-dichlorobenzene in Example 2, dichloromethane in Example 3, dibromoethane in Example 4 and 1,2-dichloroethane in Example 5).

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During the animal experiments, KAHIB pigs (Hungarian breed) of both sexes with a body weight between 8 and 12 kg were used. A 20 mm diameter burn 5 was applied to both sides of the animals using the end of a copper rod heated to 170-180 ° C under anesthesia obtained using 35 mg / kg Evipan / sodium 5- (1-cyclohexen-1-yl). ) -1,5-dimethylbarbiturate7, which was administered intravenously according to the method of S. Jacobson et al. in: Scand. J. Plast.

Reconstr. Surg. 10, 97-101 (1976

Six animals were used in each test and control group. The observation period lasted 14 days.

After wounding the animals, from the third day onwards, the infected wounds were treated with a grain polymer prepared as described in Example 1 of GB Patent Publication No. 974,054 (shown again in Example 1 of this invention) or using a commercially available Debrisan. The wound on one side p of the pigs was treated with Debrisan, while the wound on the other side was treated with a granular polymer prepared as described in GB Patent Publication No. 974,054. The treatment was performed once a day.

During the experiments, it was found that although tissue fluids were absorbed and bacteria as well as tissue debris were removed and thus the wound was cleaned with a granular polymer prepared as described in Example 1 of GB Patent Publication 974,054, an undesirable side effect was observed. very clear when examining histological specimens: the wound and its surroundings swelled strongly. Thus, although the wound was cleansed, the supply of blood and oxygen was impaired, resulting in swelling, which prevented healing.

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The use of the Debrisan composition resulted in the expected effect: the wounds healed and no swelling was observed.

Based on the above studies, it was concluded that the polymer prepared as described in Example 1 of GB 974,054 may contain substances entrapped within the granules during manufacture, which resulted in swelling of the granules on the wound surface due to irritation and healing. slowed.

This assumption was supported by microscopic examination: the particles of the granular polymer prepared according to Example 1 of GB Patent Publication No. 974,054 were opalescent and opaque.

Surprisingly, it was found that the soiled material could be removed from the granules by washing at pH 1 to 5.5 and then treating with ethanol. After this treatment, the granules were swollen in water, stirred with water until free of acid, dehydrated using ethanol and dried to give clear, translucent granules (prepared as described in Example 5 of this invention) which gave the same advantageous results as described above. in animal experiments than 25 obtained with the comparative Debrisan.

The purified product can be formulated, e.g., as a wound powder in dosing boxes; a wound cover plug enclosed within the filter; or in the form of a will.

The process according to the invention is illustrated in detail by the following non-limiting examples.

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Example 1 (Comparative Example) Re-representation of Example 1 of GB Patent Publication No. 974,054

Dextran having an average molecular weight of 40,000 was moistened with 20% water, and to this mixture was added 6N aqueous sodium hydroxide solution to adjust the final concentration of the solution to 40%. The dextran solution thus obtained, weighing 600 g, was poured into a cylindrical reaction flask equipped with a thermometer and a stirrer. A solution of polyvinyl acetate having an average molecular weight of 430,000 in 500 ml of toluene was added portionwise as a suspension stabilizer, stirring was started and continued at such a rate that the aqueous phase was dispersed in the toluene phase in small droplets. 50 g of epichlorohydrin were then added portionwise while maintaining the temperature at 50 ° C. The gel formed within an hour. After the reaction was complete, the gel granules were separated by filtration, the suspension stabilizer was washed off with toluene, after which the toluene was removed by washing with ethanol. Finally, the product was washed with water until neutral and dried at 110 ° C. The granules thus obtained had a particle size of 30 to 100 yU and a water absorption capacity of 3.0 g / g of dry matter.

Example 2 100 g of the dry dextran crude polymer obtained as described in Example 1, cross-linked with epi-chlorohydrin, were swollen for 4 hours in 100 ml of water adjusted to pH 4. During the swelling, the mixture was stirred continuously and gently and the pH was adjusted. was controlled. The acidic liquid was then discarded and the swelling was repeated using 500 ml of water adjusted to pH 4 with 35 hydrochloric acid while stirring the mixture gently and continuously for 6 hours. After the acidic water was discarded, the swollen granules were stirred with 500 ml of ethanol for one hour, the liquid above the granules was discarded, and the treatment with ethanol was repeated as described above. The dehydrated granules were swollen using deionized water, therefore washed until the pH reached 5.5, and after the granules were dehydrated using 500 ml of ethanol, the granular polymer was dried at 80 ° C. The granules thus obtained had the same grain size and water absorption capacity as shown in Example 1.

Example 3 100 g of a dry dextran-rane polymer crosslinked with epichlorohydrin obtained as described in Example 1 was swollen for 4 hours in 100 ml of water, then the pH was adjusted to 1 by adding hydrochloric acid with constant and gentle stirring, followed by the procedure of Example 1. instructions. The water absorbency and size of the granules thus obtained were the same as shown in Example 1.

Example 4 100 g of a dry dextran crude polymer cross-linked with epichlorohydrin obtained as described in Example 1 were swollen for 4 hours in 2000 ml of water adjusted to pH 4 by the addition of hydrochloric acid. During this swelling, the mixture was stirred continuously and the pH was controlled. The instructions of Example 1 were then followed. The water absorbency and size of the granules thus obtained were the same as those shown in Example 1.

Example 5 32 g of polyvinyl acetate having an average molecular weight of 430,000 were dissolved in 380 ml of toluene with stirring between 50 and 55 ° C, followed by cooling to 20 ° C. 100 g of dextran powder having an average molecular weight of 40,000 was dissolved in 100 ml of water, and a solution of 24 g of sodium hydroxide in 27 ml of water was added thereto. The mixture thus obtained was stirred, then 42 ml of epichloro-5-rhydrin and the toluene solution of polyvinyl acetate prepared above were added, and the reaction mixture was stirred at 50-55 ° C for another 16 hours. The granular polymer thus formed was washed with toluene until it was free of polyvinyl acetate, after which it was washed with ethanol 10 and water. The granules were then stirred for 1 hour in 500 ml of water, the pH of which had been adjusted to 4 by adding hydrochloric acid. The acid wash was repeated and the procedure of Example 1 was followed. The granules thus obtained had a particle size between 40 and 100 yU and a water-15 absorption capacity of 2.8 g / g of dry matter.

Example 6

The final product obtained as described in Example 1 was sorted by particle size. Doses of 60 g of granules with a diameter of between 100 and 350 μU were filled into boxes and sterilized in unit packs using a value of 20 kg / 0.1 m 2 and using Co 2 irradiation at a dose of 25 kGy.

Example 7

The final product 25 obtained as described in Example 1 was sorted by particle size. Granules with a diameter of between 40 and 100 yU were divided into 1 g aliquots, each placed between two physiologically neutral layers of filter paper, and the paper layers were welded together. Sterilization was performed as described in Example 6.

Example 8

The final product obtained as described in Example 1 was sorted by particle size. 6800 g of granules with a diameter of 40 to 100 yU were suspended in a mixture of 2900 g of polyoxyethylene-200 and 300 g of sorboxyethylene monooleate over a period of 30 minutes to 35 minutes. portions of the pace thus obtained into folding papers made of aluminum foil laminated with polyethylene, after which the folding papers were sealed by welding. Sterilization was performed as described in Example 6.

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Claims (5)

9 80052 An improved process for preparing a therapeutically useful crosslinked dextran granular polymer and a composition containing it, characterized in that the crosslinked granular polymer is swollen in water at a pH between 1.0 and 5.5, suitably at a pH of 4.0, while stirring, the acidic water is removed and the dehydration is performed using a water-miscible organic solvent, preferably ethanol, the liquid above the granules is removed while stirring, the dehydrated granular polymer is swollen in deionized water, washed free of acid, dehydrated and / or dried. , sorted according to particle size and formulated into a form, e.g. a powder, a stopper or a barrier, optionally after sterilization by gamma irradiation. Process according to Claim 1, characterized in that the acid washing is carried out using acidic water in a volume of 5 to 20 times the weight of the granular polymer. Process according to Claim 1, characterized in that the granules obtained in the sorting of the dried granular polymer with a diameter of between 25,100 and 350 μm are formulated as a dustable powder. Process according to Claim 1, characterized in that the granules obtained by sorting the dried granular polymer with a diameter of between 40 and 100 μl are formulated as a stopper sandwiched between two physiologically neutral filter papers. Process according to Claim 1, characterized in that the granules obtained by sorting the dried granular polymer with a diameter of between 35 and 100 μU are formulated as a suspension suspended in a mixture of polyoxyethylene and sorboxyethylene monooleate. 10 80052