AU612387B2 - Pharmaceutical compositions promoting the wound healing and process for preparing same - Google Patents

Description

COMMONWEALTH OF AUSTRAL16 7I1 PATENTS ACT 1952-69 COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: Lodged: q .~omplete Specification .odged: Efiority: Acce..pt=U Published: J~elated Art:

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0* 6 6 66 6* 66 S 66 Nam- Applicant: ddress of Applicant: Actual Inventor Address for Service: BIOGAL GYOGYSZERCYAR 4042 Debrecen, Pallagi ut 13, Hungary JAN0S BALINT, SANDOR JANCSO, TAMAS FARAGO, JAN0S EPOEI, ISTVAN KOVACS, ZSUZSANNA EMR1 and KATALIN HORVATH EDWD, WATERS SONS, 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.

complete Specification for the lnventiQn entitled: PHARMACEUTICAL COMPOSITIONS PROMOTING THE WOUND HEALING AND PROCESS FOR PREPARING SAME The following statement Is a full description of this Invention, Including the best mrhod ol performing It known to us I1.

13a PHARMACEUTICAL COMPOSITIONS PROMOTING THE WOUNO HEALING AND PROCESS FOR PREPARING SAME The invention relates to pharmaceutical composi- 5 tions useful to cure wound-s and injuries which consist of a carrier for covering the wound as well as anti- S* inflammatory, epithelizing H-j or H-2 receptor-blocking antihistamines and optionally other additives promoting

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the wound healing.

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

According to an other aspect of the invention, there is provided a process for the preparation of 15 these compositions.

The wound care, as a result of either an accidental injury, burning or a surgical intervention, represents a fundamental part of the curing activity.

For a long time, tne curing of wounds has been limited to the following operations: the mechanical purification of the wound (which, when taken in the full sense, could not be complete in any case); treatment with disinfectants; and mechanical protection of the wound (dressing).

A 4338-741 MR-Sch However, the wound healing is a lengthy process even by using all these operations in a skilled manner.

Substantially, the medicating work can be successful in the case when the requirements influencing the wound healing are simultaneously satisfied.

The most important outer and inner factors of the wound healing are as follows: the normal metabolism of the surrounding

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tissues (adequate blood supply and oxygenation); keeping clean the wound (the removal of pus and decomposed tissue residues); and -prevention or elimination of the microbial Scontaminations.

The various wound-treating methods known at 15 present take these factors into consideration; however, they are usually capable to satisfy only one of these conditions without any influence on the other ones; in some cases, these factors are negatively affected, e.g.

the infection of the wound is prevented but the oxygenation is deteriorated by using ointments containing antibiotic, A condition of prime necessity concerning the wound healing is to satisfactorily assure the adequate respiration of the wound. A number of accomplishments have been found for this purpose, a common characteristic of which consists in the use of a porous layer which is useful for covering the wound. This porous layer may be a simple textile with a loose network cotton, I -o 3cloth, gauze, mull) or synthetic as well as native, porous matrices or their combinations impregnated with other materials such as disinfecting and preserving agents or the like propoting the wound healing. For th' purpose e.g. the following materials have been described: a plaster consisting of a copolymer of acrylic acid and acrylate ester according to the South- -African patent specification No. 68/1631; a film with a similar composition according to the United States patent specification No. 3,932,602; a cotton textile *660 impregnated with i:ullulo;e acetatd according to the French patent specification No. 4656 M; silicone ,polymers or synthetic as well as native rubber-based *matrices according to the United States patent specifications Nos. 4,336,243 and 4,307,717.

@6 In the area of the traditional wound-treating methods, the use of the swellable cross-linked poly- @0 saccharide-type polymers as wound-dusting powders represented an important break through (see the British patent specification No. 4,454,055). Owing to the strong absorption of liquids, the spherical particles of 100 to 300 /um in diameter spread in a dry state onto the surface of the wound not only dry the oozing wound but also take up the pus, tissue residues and bacteria together with the liquid and thus, they purify the wound in a much more effective manner than it can be achieved by using any mechanical method (see the United States patent specification No. 4,225,580).

t 4- As a continuation of the research work aimed to increase the wound-curing effect of hygroscopic polymers, other additives, first of all disinfecting agents such as the polyvinylpyrrolidone-iodine complex (see the British patent specification No. 2,099,704) or silver- -sulfadiazine /Symp. Ser. 256, 181 (1984)_7 were ;applied onto the cross-linked polymeric grains or lamellae used as carriers.

It is characteristic of the solutions described 0 10 hereinbefore that the outside conditions of the wound healing are chiefly assured by them.

A further progress appeared in the recognition 0S that the assuring of an appropriate level of calcium and potassium ions plays an important role both in the 15 wound and in the tissue environment of the wound. In the Federal Republic of Germany patent specification No. 3,416,777 a process is described, in the case of which the inner parameters of the wound healing are also partially considered in that the concentration of the calcium and potassium ions is increased to the desired level by using compositions containing solutions of calcium and potassium salts. The aim of the present invention is to prepare pharmaceutical compositions which satisfy simultaneously and optionally the outer and inner conditions of the wound healing.

The invention is based on the recognition that the preparation of pharmaceutical compositions simultaneously assuring the aimed, both outer and inner

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conditions of the wound healing can be ensured by using antiinflammatory H-2 receptor-blocking agents (e.g.

cimetidine or ranitidine) together with a suitable carrier which is useful for covering the wound.

The wound healing promoting action of the H-2 receptor-blocking agents can be explained by the pathological process of development of the ulcer disease or outer wounds which heal with difficulties.

Three phases are distinguished in the development of 10 an ulcer disease, which essentially starts with a *'chronic inflammation process: the amine phase (mediated by histamine and S@ H -s ubstances); Stne quinine phase (mediated by bradykinin); and 15 the PG phase (mediated by various prostaglandin fractions which are responsible for the inflammation).

According to our recognition the first phase of the continuously recurrent processes, i.e. the enlargement and deepening of the wounds, can be prevented by the topical use of H-2 receptor-blocking agents whereby the proceeding in the time of the wound healing will be shortened to a great extent due to the absence of the second and third phase of the chronic inflammation. Thus, the practical importance of their use lies in that they are capable to assure the rapid and untroubled healing of a wound caused by any injury or other circumstances by the prevention of the 6 6 symptoms developing as a consequence of secondary processes or by avoiding the frequently lengthy treatment.

In the course of working out a composition useful for the topical use of H-2 receptor-blocking agents, it was considered a most important viewpoint to select a carrier which is capable to extensively assure outer conditions of the wound healing and to simultaneously provide that the healthy cells surrounding the wound 10 are not superfluously saturated by the active ingredient.

In the course of our investigations aimed to select the most preferable carrier for the desired effect, liquid, ointment-like and solid carrying 15 materials were tried. According to our results such carriers, first above all liquid carriers are most suitable, which are capable to purify the wound and simultaneously to prevent the development of an edema due to their hygroscopic properties.

As a conclusion swellable, cross-linked polysaccharide-type hydrophilic polymers (such as dextran or cyclodextrin grain polymers cross-linked with epichlorohydrin) are particularly preferred; however, some other carriers may be considered which possess hygroscopic properties and simultaneously a satisfying porous structure not to close the wound in an airtight manner.

Thus, good results were achieved by using a hygroscopic, sponge foam-based wound-covering sheet or gauze I I I I 7 containing cimetidine.

According to our investigations H-1 receptor- -blocking agents, e.g. dimethindene maleate, tripelenamine, phenindamine and the like may also be used as active ingredients due to their favourable biological effects. These drugs diminish the permeability of the capillaries, inhibit the action of hyaluronidase and thus moderate the serous inflammation.

0* According to the process of the invention a

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10 suitably porous, hygroscopic carrier, which is useful for em covering the wound, is treated with a solution containing a H-1 or H-2 receptor-blocking antihistamine as active ingredient, then it is dried and sterilized.

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It is preferable to use cimetidine, suitably in 15 the form of an 0.1 to 30% by weight aqueous or ethanolic solution. Instead of cimetidine, other H-2 Leceptor- -blocking agents such as ranitidine, famotidine, burinamide or metiamide may be used, which exert a cytoprotective effect.

According to a preferred embodiment of the invention, the wound-curing composition is prepared in such a way that hydrophilic polymer grain which is useful as wound-dusting powder, such as a dextran grain polymer cross-linked with epichlorohydrin is soaked by the solution containing cimetidine by swelling the grains in an aqueous or ethanolic solution containing 0.1 to by weight of cimetidine, then drying it at a temperature below 5 OC and sterilizing.

I I 8 According to our investigations carried out with a wound-dusting powder prepared from a dextran grain polymer containing 0.1 to 2.0% by weight of cimetidine, the carrier and the active ingredient mutually nnd synergistically enhance the effect of another and thus, the period of the wound healing becomes shorter to a great extent, i.e. by several days.

Other hydrophilic polymers such as cellulose derivatives, alginates, cyclodextrin or the like may 10 also be used as carriers for the wound-dusting powders 00 0 of the invention.

The solid carrier may also be built up in such a 00 way that the polymeric particles swollen in the solution of the active ingredient are applied in a wet state onto 15 a gauze and dried until reaching a defined moisture content; or a polyurethane sheet, which is useful for covering the wound, is soaked by a solution containing

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to 50.0% of active ingredient in such a manner that the sheet contains 10 to 200 mg/dm 2 of active ingredient, then the sheet is dried and cut into pieces of appropriate size.

If desired, the composition may also oe formulated as a gel. In this case an acrylic acid polymer is used which is swollen in a solution containing methyl 4- -hydroxy-benzoate, then transformed to a gel by using to 30.0% by weight of sodium hydroxide solution under stirring, then the solution containing the active ingredient is added to the gel thus prepared and, after T- 9 homogenizing, it is packaged in tubes.

The composition may be supplemented by adding other additives such as water-soluble or fat-soluble chlorophyll or hexachlorophen which possess advantageous properties for the wound healing.

The invention is illustrated in detail by the following non-limiting Examples.

Example 1 10 100 g. of a dextran grain polymer cross-linked 4 *with epichlorohydrin (with a grain size of 120 to 320 /um) are swollen in 600 ml. of an aqueous solution containing 12 g. of cimetidine and adjusted to a pH value of 2 with hydrochloric acid. The polymer swollen 15 to the 3 to 4-fold of its original volume is filtered off, re-suspended in 300 mi. of an 0.01 M sodium hydroxide solution, filtered off again and then dehydrated by using 500 ml of ethanol. The treatment with ethanol is twice repeated. Then, the dehydrated product is dried below 50 °C and packaged in spraying boxes. It is sterilized by using Co isotope with a radiation dose of 20 kGy or by using freon gas.

The product obtained contains 0.15 to 0.2% by weight of cimetidine.

Example 2 1000 g. of a dextran grain polymer cross-linked with epichlorohydrin (with a grain size of 120 to C -iI 10 320 /um) are moistened with 100 ml. of 96% ethanol, then uniformly soaked by a solution of 10 g. of dimtthindene maleate in 250 ml. of 96% ethanol. The wet aggregation of grains is dried at a temperature below 50 OC in such a way that the drying loss does not exceed 8% by weight. The product is packaged in spraying boxes and sterilized by using 60 Co isotope with a radiation dose of 20 kGy.

Th3 product obtained contains 0.92% by weight of 10 dimethindene maleate.

.0 .1000 g. of a dextran grain polymer cross-linked with epichlorohydrin (with a grain size of 40 to 120 /um) are moistened with 100 ml. of 96% ethanol, then uniformly soaked by a solution of 20 g, of thenalidine in 300 ml.

of 96% ethanol. The wet aggregation of grains is dried 0 at a temperature below 50 °C in such a way that the drying loss does not exceed 8% by weight. The dried grain aggregation is put into a paper filter-bag, then sealed between aluminum foils and sterilized as described in Examp.3 1.

The product obtained contains 1,85% by weight of thenalidine.

Example 4 1000 g. of a dextran grain polymer cross-linked with epichlorohydrin (with a grain size of 120 to 320 ,um)

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11 are moistened with 100 ml. of 96% ethanol, then uniformly soaked by a solution containing 5 g. of ranitidine in 200 ml. of 96% ethanol. The wet aggregation of grains is dried at a temperature below 25 OC in such a way that the drying loss does not exceed 8% by weight. The product is packaged in spraying boxes and sterilized as described in Example 2, or the whole

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operation is carried out under aseptic conditions.

The product obtained contains 0.4% by weight of 10 ranitidine.

00 Example

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The process described in Example 4 is followed by S* to using a dextran grain polymer cross-linked with epi- 15 chlorohydrin (with a grain size of 40 to 120 The dried product is put into paper filter-bags and then sealed between aluminum foils. The product is sterilied by irradiation or the whole operation is carried out under aseptic conditions.

Example 6 A polyurethane foam sponge sheet, which is suitable for wound covering, is soaked by a 5% by weight solution of cimetidine in 96% ethanol. The sheets are dried at a temperature below 40 0 C and then cut into pieces of the desired size. The sterilization is carried out by irradiation or by using ethylene oxide; or the whole operation is performed under aseptic 12 conditions.

The product obtained contains 25 mg/drmn 2 of cimetidine.

Example 7 According to the process described in Example 6, a grey plain cotton cloth sheet is soaked by a solution containing 10% by weight of cimetidine, then cut into pieces of the desired size and an adhesive plaster is 10 prepared which is useful for a rapid dressing.

The product obtained contains 50 mg/din of cimetidine.

*4 00. Example 8 5 of an acrylic acid polymer are swollen under germ-poor conditions in 500 g. of sterile distilled water containing 1.5 g. of methyl 4-hydroxy-benzoote and, after adding 5 g. of 30% by weight sodium hydroxide solution, it is stirred until a uniform gel is obtained. To the gel obtained 1 g. of cimetidine hydrochloride dissolved in 300 g. of sterile distilled water is added, then the gel is made up to 1000 9. with sterile distilled water. The composition is packaogd in tubes in a known manner.

The product obtained contains U.1' by weiUht of cimntidine.

13 Example 9 1 g. of water-soluble chlorophyll is homogenized with 998 g. of a dextran grain polymer cross-linked with epichlorohydrin (grain size: 120 to 320 To the homogenate, a solution containing 5 g. of cimetidine in 200 ml. of 96% ethanol is added and the mixture is stirred at room temperature for 2 hours. The product is dried at a temperature below 60 °C while stirring. The I. dried product is packaged in spraying boxes and 10 sterilized by using a 20 kGy dose of gamma-irradiation.

The product obtained contains 0,5% by weight of cimetidine.

15 2.5 g. of fat-soluble chlorophyll are homogenized' in a melt containing 268,5 g. of Macrogol 400, 20 g. of Maorogol 1540 and 29 g, of Polysorbae 80. The melt is cooled to 30 oC and 660 g. f a dextran grain polymer crss-linked with epichlorohydrin (grain size: 40 to 120 /um) and saturated with 20 g. of cimetidine as described in Example 1, are distributed therein under stirring, The paste obtained is suitably filled in 10 g.

portions into polyethy1ane-mouited aluminum foil bags and then sterilized by using a 20 kGy dose-of gamma- -irradiation.

The product obtained contains 1.98' by weight of cimetidine.

Li 13a Comparative Example No. 1 The wound healing activity of the compositions Jcording to the invention was studied by the test methods of Limski et al (1974) and Rovee et al (1975), i.e. by the so-called skin excise in full thickness method, which is suitable for studying the influence on human burn and traumatic wounds. As test animal guinea pigs were used, the following test materials were involved: 1) dextran grain polymer impregnated with cimetidine; 2) an injectable solution containing cimetidine; 3) dextran grain polymer as reference material; 4) physiological saline as control material.

The test results are as follows: The wounds of the animals treated with dextran S: 15 grain polymer impregnated with cimetidine were entirely sticked at their lips on the second day, the formation of the germinating tissues at the basis of the wound is substantial, they cover the basis of the wound up to 80% on the fourth day and as of the fifth day the wounds are healed through formation of scurf.

In the case of the animals treated with the dextran grain polymer the sticking of the lips of the wound was detecta'ble only on the third day, the formation of germinating tissues is substantially slower and the 25 formation of scurf can be detected only on the 3ixth day, before the germinating tissues entirely cover the basis of the wound.

The wounds of the animals treated with the injectable solution containing cimetidine and physiological saline reacted substantially in the same way. The sticking of the lips of the wounds started as of the fourth day, the formation of germinating tissues can be detected on the seventh or eighth day. Formation of scurf cannot be detected at all.

-1R,% Thus, one can summarj!,ze that in in vivo tests cimetidine alone, in the form of a solution, cannot influence substantially the wound healing. At the same time the dextran grain polymer impregnated vwith cimetidine accelerates substantially the wound healing, even in comparison to dextran grain polymer alone.

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Claims (4)

1. Pharmaceutical composition promoting the wound healing, which comprises 0.1 to 15% by weight of H-1 and/or H-2 receptor-blocking antihistamine as active ingredient on a solid, suitably porous hygroscopic carrier which is useful for covering wounds and injuries.

2. A composition as claimed in claim 1, which comprises 0.1 to 5.0% by weight of H-1 and/or H-2 receptor- blocking antihistamine.

3. A composition as claimed in claim 1 or claim 2, which comprises cimetidine or ranitidine as active ingredient.

4. A composition as claimed in any one of claims 1 to 3, wherein the solid, suitably porous hygroscopic carrier is a hydrophilic polymer. A composition as claimed in any one of claims 1 to 4, wherein the solid, suitably porous hygroscopic carrier is 0000 a dextran grain polymer cross-linked with epichloro hydrin or cyclodextrin. o *o 0000 DATED this 9th day of April, 1991. BIOGAL GYOYSZERGYAR 0 0 WATERMARK PATENT ATTORNEYS 2ND FLOOR "THE ATRIUM", 290 BURWOOD ROAD, HAWTHORN, VIC. 3122. AUSTRALIA Melb Pisk 10/1.44 MG M W