HU201683B - Process for producing pharmaceutical compositions for promoting healing of wounds - Google Patents

Description

The present invention relates to a process for the preparation of a pharmaceutical composition for the treatment of wounds and injuries which comprises a wound-covering carrier and an anti-inflammatory, exfoliating H 1. and / or H ₂ receptor blocking antihistamines, optionally other wound healing additives.

The pharmaceutical compositions of the invention can be used in both human and veterinary medicine.

Wound care, whether as a result of accidental injury, burns or surgical intervention, is an essential part of healing work.

The treatment of wounds for a long time was limited to the following operations:

- mechanical cleaning of the wound (which, in absolute terms, could never have been perfect),

- treatment with disinfectants,

- mechanical protection of the wound (bandage).

However, wound healing is a long process, even when combined and expertly applied.

Basically, healing work can be successful if the factors that influence wound healing can be satisfied simultaneously.

The most important of these external and internal factors are:

- normal metabolism of the surrounding tissues (adequate blood supply and oxygenation),

- Keeping the wound clean (removal of pus, decaying tissue residues),

- prevention or elimination of microbiological contamination.

The currently known methods of scintillation take these factors into account, but in most cases they are able to meet only one condition, while other factors are unaffected or sometimes negatively affected (e.g., antibiotic ointments prevent infection of the wound, but at the same time, they worsen the aeration of the wound).

Satisfactory wound breathing is a prime factor for wound healing. To this end, a number of solutions have been found which have in common the use of a porous layer for wound cover. It can be simply loose woven fabrics (cotton, fabric, gauze, swaddling) or a matrix of porous structure of synthetic and natural origin, or combinations thereof, with other wound healing agents, infectious agents, preservatives, etc. impregnated. For example, South African Patent No. 68/1631, an acrylic acid acrylic acid ester copolymer patch, U.S. Patent No. 3,932,602, a similar composition film, French Patent No. 4,656 M, a cellulose acetate-impregnated cotton cloth, U.S. Patent No. 4,336,243. and U.S. Patent Nos. 4,307,717 and 4,307,717, silicone polymers, either synthetic or synthetic. describes natural rubber based matrices.

The use of swellable cross-linked polysaccharide-type polymers as wound dressing powders has been a major breakthrough in the classical methods of scaffolding (British Patent No. 1,454,055). In the dry state, spherical particles of 100-300 μm diameter on the wound surface not only dry the wet wound by intense fluid uptake, but also remove the pus, tissue debris, and bacteria together with the liquid to clean the wound much more effectively (4,225). 580, U.S. Pat.

Research on the enhancement of wound healing properties of absorbent polymers has progressed with the addition of other additives, particularly disinfectant compounds, such as polyvinylpyrrolidone iodine complex to the crosslinked polymer particles or sheets as carrier. ) or silver sulfadiazine (Symp. Ser. 1984, 256.181-9).

Typically, the above-mentioned solutions provide external factors for wound healing.

A further step forward was the recognition that the level of calcium and potassium ions is important in the wound and in the wound tissue environment. German Patent No. 3,416,777 discloses a method which partially takes into account the intrinsic parameters of wound healing by raising the calcium and potassium ion concentrations to the desired level with the help of formulations containing calcium and potassium salt solutions.

SUMMARY OF THE INVENTION It is an object of the present invention to provide pharmaceutical compositions that simultaneously and optimally satisfy the external and internal conditions of wound healing.

The invention is based on the discovery that the topical use of anti-inflammatory H ₂ receptor blockers (e.g., cymclidine, ranitidine), by selecting an appropriate carrier for wound healing, enables the preparation of targeted pharmaceutical formulations that take into account both external and internal conditions of wound healing.

Explanation of the wound healing effect of H ₂ receptor blockers in the development and development of ulcer disease. in the pathophysiology of difficult to heal external wounds. There are three phases in the development of ulcer disease, which essentially starts with a chronic inflammatory process:

- amine phase (mediated by histamine and H substances),

- quinine phase (mediated by bradykinin),

- PG phase (mediators: various PG fractions responsible for inflammation).

It has now been found that topical application of H ₂ receptor blockers prevents the first phase of continuously repetitive processes, i.e., wound propagation and deepening, and the absence of second and third stages of chronic inflammation greatly reduces the time course of wound healing. The practical significance of their application therefore stems from the prevention and / or reduction of symptoms due to secondary processes. they can often, by avoiding the very long treatment of these, ensure rapid and smooth healing of any wound or other condition.

In the formulation of a formulation for topical application of H ₂ receptor blockers, the primary consideration has been to select a vehicle that is highly capable of providing exogenous conditions for wound healing while at the same time avoiding unnecessary saturation of the healthy cells around the wound.

In our experiments on selecting the most effective carrier, liquid, ointment and solid carriers were tested. Our experiments have shown that carriers, especially solid carriers, are those which are highly absorbent.

Not only do they clean the wound, but they also prevent edema.

As a result, swellable, cross-linked polysaccharide-based hydrophilic polymers (e.g., epichlorohydrin-crosslinked dextran or cyclodextrin bead polymers) are particularly preferred, but may also include some carriers which have an absorbent, non-porous wound structure Thus, for example, good results have been achieved with a cimetidine-prepared wound topping foam or gauze with absorbent properties.

According to our studies, due to their favorable physiological activity, H ₃ receptor blockers can be used as active ingredients, e.g. dimethinden maleate, tripelenamine, phenindamine, etc. These substances reduce the permeability of the capillaries, inhibit the action of hyaluronidase, thereby reducing serous inflammation.

The present invention is directed to treating a wound, preferably porous, absorbent carrier with a solution of H or H ₂ receptor blocking antihistamine as active ingredient, and then drying and sterilizing.

Preferably, the active ingredient is cimetidine, preferably in the form of a 0.1 to 50% aqueous or ethyl alcohol solution. Other cytoprotective H ₂ receptor blockers such as ranitidine, famotidine, burinamide or methamide may be used instead of cimetidine.

In a preferred embodiment of the invention, the wound healing composition is prepared by impregnating hydrophilic polymer particles suitable for wound sprinkling powder, e.g. alcohol solution, then dried at below 50 ° C and sterilized.

According to our studies with dextran bead polymer powder containing 0.1-2.0% cimetidine, the carrier and the active ingredient reinforce each other in a synergistic manner, thus greatly reducing the wound healing time by several days.

Other hydrophilic polymers as carriers for wound powder are e.g. cellulose derivatives, alginates, cyclodextrin, etc. can also be used.

The solid support may also be formed by wet-gauze polymeric particles swollen in a solution of the active ingredient and dried to a defined moisture content, or by soaking a 5.0-50.0% solution of the active ingredient in a wound dressing polyurethane sheet. The plate contains 10200 mg of active ingredient per dynin, and the plate is dried and cut to size.

If desired, the composition may also be formulated as a gel. In this case, the carrier is acrylic acid polymers, which are swelled in a solution containing para-hydroxybenzoic acid methyl ester, and then mixed with a gel containing 5.0-30.0% sodium hydroxide solution to form a gel and added to the gel thus prepared. the solution containing the active ingredient, and after homogenization it is dispensed into tubes.

The composition may be supplemented with other additives which are beneficial for wound healing, such as water or water. it may also be supplemented with fat-soluble chlorophyll or hcxachlorophene.

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

Example 1

Dextran bead polymer cross-linked with 100 g of epichlorohydrin (particle size: 120-320 μτη) is swollen in a solution of 12 g of cimetidine in 600 ml of hydrochloric acid and adjusted to pH 2. The swollen polymer (3 to 4 times its original volume) is filtered off and resuspended in 300 ml of 0.01 M sodium hydroxide solution and then dehydrated again with 500 ml of ethyl alcohol. The ethyl alcohol treatment was repeated two more times. The dehydrated product is then dried below 50 ° C and placed in a spray can. Sterilized using a Co ⁶⁰ isotope at a radiation dose of 20 kGy or freon gas. The product obtained contains 0.15-0.21% cimetidine.

Example 2

Dextran bead polymer crosslinked with 1000 g of epichlorohydrin (particle size: 120-320 gm) was moistened with 100 ml of 96% ethyl alcohol and then uniformly impregnated with a solution of 10 g of dimethylindene maleate in 250 ml of 96% ethyl alcohol. The wet set of granules is dried at a temperature below 50 ° C so that the drying loss does not exceed 8% by weight. The teas are put up in a spray box and sterilized using a Co 'isotope at a radiation dose of 20 kGy.

The product has a dimethylindene maleate content of 0.921%.

Example 3

Dextran bead polymer crosslinked with 1000 g of epichlorohydrin (particle size: 40-120 gm) was moistened with 100 ml of 96% ethyl alcohol and then uniformly impregnated with a solution of 20 g of thenalidine in 300 ml of 96% ethyl alcohol. The wet set of granules is dried at a temperature below 50 ° C so that the loss on drying does not exceed 8%. The dried particle assembly was placed in a paper filter bag, then soldered between aluminum foil and sterilized as described in Example 1.

The product thenalidin content is 1.851%.

Example 4

Dextran bead polymer crosslinked with 1000 g of epichlorohydrin (particle size: 120-320 gm) was moistened with 100 ml of 96% ethyl alcohol and then uniformly impregnated with a solution of 5 g of ranitidine in 200 ml of 96% ethyl alcohol. The wet set of granules is dried at a temperature below 25 ° C so that the loss on drying does not exceed 8%. The product is disassembled in a spray can and sterilized as described in Example 2, or the entire operation is performed under aseptic conditions.

The product contains 0.4% ranitidine.

Example 5

The dextran bead polymer cross-linked with epichlorohydrin having a particle size of 40-120 gm was prepared as in Example 4. The dried product is placed in a paper filter bag and soldered between aluminum foil. The product is sterilized by radioactive radiation or is prepared under aseptic conditions.

Example 6

Polyurethane foam sheet used for wound dressing ci3

HU 201,683 Β methidine was impregnated with a 5% solution of 96% ethyl alcohol. The Alcmcz's are dried at temperatures below 40 ° C and cut to size. Sterilization is performed by radioactive radiation or ethylene oxide, or is prepared under aseptic conditions.

The product contains 25 mg of cimetidine per dynin.

Example 7

As described in Example 6, a 10% solution of cimetidine was soaked in a molino sheet which was cut to the desired size to form a quick-setting adhesive plaster.

The product has a cimetidine content of 50 mg per dm ² .

EXAMPLE 8 G acrylic acid polymer was swollen under 500 g sterile distilled water containing 1.5 g of para-hydroxybenzoic acid methyl ester under germ-poor conditions, and then mixed with 5 g of 30% sodium hydroxide solution to form a smooth gel. To the gel thus prepared, a solution of 1 g of hydrochloric acid cimetidine in 300 g of sterile distilled water is added with continuous stirring and the gel is made up to 1000 g with sterile distilled water. The composition is formulated in tubes in a manner known per se.

The product contains 0.1% cimetidine.

Example 9 Water-soluble chlorophyll (g) was homogenized with 998 g of dextran bead polymer cross-linked with epichlorohydrin (120-320 µm particle size). A solution of 5 g of cimetidine in 200 ml of 96% ethyl alcohol was added to the homogenate and stirred for 2 hours at room temperature. The product is dried under stirring at a temperature below 60 ° C. The dry product was removed in a spray can and stained with 20 kGy gamma radiation.

The product contains 0.5% cimetidine.

Example 10

2.5 g of fat soluble chlorophyll were homogenized in a melt of 268.5 g of macrogol in 400.20 g of macrogol 1540 and 29 g of polysorbate. The melt was cooled to 30 ° C and 660 g of a 40-120 µm epichlorohydrin crosslinked dextran bead polymer was dispersed therein with stirring. The bead polymer was previously saturated with 20 g of cimetidine as described in Example 1.

The resulting paste is conveniently packed in aliquots of polyethylene in 10 g portions and sterilized by gamma irradiation at a dose of 20 kGy.

The product has a cimetidine content of 1.98% by weight.

The chemical names of the brand names in the examples are as follows: macrogol: polyctylene glycol (a series of different molecular weight members) polysorbate 80: sorboctene olate.

The following are comparative test results for the composition of the present invention:

To investigate the effect of the composition on the wound healing effect, a full thickness skin excision method as described by Limszki et al. (1974) and Roves et al. (1975) was applied, which is suitable for testing the influence of human burns and traumatic injuries.

The experimental animal model was tgnger guinea pig.

1. A dextran bead polymer impregnated with cimetidine impregnated according to Example 1 herein.

2. Cimetidine solution for injection (200 mg cimetidine in 2.00 ml solution)

Referent:

3. Dextran Bead Polymer (Wound Spray Powder)

control:

4. Physiological saline

Comparative studies show that the cimetidine-impregnated bead polymer (1) treated animals were completely wound on day 2, with the formation of cartilage at the wound base significantly,

By day 4, 80% fills the wound base and by day 5, the wounds have healed.

In dextran bead polymeric (3) treated animals, scbszélck adhesion occurred only on day 3, the formation of cartilage tissue is significantly slower, and roasting begins only on day 5, before the cartilage tissue fills the scbalap.

The wounds of animals treated with cimctidine-containing injection solution (2) and physiological saline (4) behaved almost identically. Adhesion of scbszélck started on day 4, and the appearance of cartilage tissue was seen on days 7 and 8, respectively. The roasting did not start on day 8 either.

Experimental evidence shows that cimetidine alone does not significantly affect wound healing but at the same time significantly accelerates the healing process compared to dextran bead polymer impregnated with cimetidine, a dextran bead polymer.

The chemical equivalent of the fantasy names used in this description:

cimetidine: 1-cyano-2-methyl-3- [2- (5-methylimidazol-4-yl) methylthioethyl] guanidine ranitidine: 1- (diphenylmethyl) -4- (3-phenyl-2- propynyl) piperazine thenalidine: N- (4-methyl-6-phenyl-3-pyridazinyl) -4-morpholinectanamine dimethylindeneate: N, N-dimethyl-3-L- (2-pyridimyl) ethyl] -1H inden-2-ethanamine.

Claims (6)

1. A method for promoting wound healing pharmaceutical preparation wounds to cover a suitable carrier from compounds represented by H and / or H ₂ receptor blocking antihisztaminokból optionally chlorophyll, characterized in that the preferably porous solid supports the IP and / or _H2 receptor blocking antihistamine Treated with a 0.3 to 30% solution, preferably aqueous or ethanol - or a formulation containing from 0.05 to 2.5% by weight of active ingredient, or 10-200 mg of active ingredient per 1 dm ^{2 of} the carrier. 2. A process according to claim 1 wherein the active ingredient is cymcudine, ranitidine, thcnalidine, or dimelinden malcate. A process according to claim 1 or 2, wherein The swellable hydrophilic polymer, preferably dextran bead polymer or cyclodextrin crosslinked with epichlorohydrin, is used as a solid support. 4. The process of claim 3, wherein the hydrophilic polymer is swelled in a 0.3 to 10% solution of the active ingredient. The process according to claim 1 or 2, characterized in that the solid support is a polyurethane foam sheet or a molino sheet. 6. The method of claim 5, wherein the carrier is soaked in a 5 to 10% solution of the active ingredient.