CS276270B6 - Preparation for local therapy of cutaneous and mucosal lesions - Google Patents

Abstract

The solution relates to a local device treatment of skin and mucosal lesions, for example burns, abrasions, pressure sores, non-specific inflammatory or uterine inflammation a suppository based on a physiologically inert carrier and at least one active agent promoting and / or accelerating the healing of the lesion The principle lies in being as effective the substance contains cyclo (L-alanyl-1-amino-1-cyclopentanecarbonyl) with an optional ingredient one or more other active ingredients. As a physiologically inert nostrils he has proven himself biocompatible collagen material at type I collagen.

Description

The invention relates to a composition for the topical therapy of skin and mucosal lesions, for example burns, abrasions, pressure ulcers or non-specific intestinal inflammations, certain skin diseases, such as eczema, if not too widespread, as well as those caused by an organic defect, for example shin ulcers. . Said skin lesions or diseases occur relatively often and form a common part of medical care in both outpatient and clinical practice.

Thus, the obvious requirement is, especially in urgent cases, the possibility of a quick and simple intervention, by which an appropriate treatment of the skin lesion is carried out, and which is followed by a reliable and, if possible, rapid therapeutic effect. This means having a suitable treatment available.

Many types of agents for the topical therapy of skin and mucous membrane lesions are known from the technical and patent literature, as well as from advertising materials from various manufacturers, the simplest of which are, for example, sticky patches with pads, sometimes impregnated with active ingredients, most often hemostatics or antimicrobials; for the treatment of mucosal lesions, a suppository and / or microenema formulations are suitable. Physiologically inert porous carriers of various natural, synthetic or semi-synthetic materials are often used for the local therapy of large-scale skin lesions.

In general, for the treatment of the described skin and mucosal lesions, a therapeutic agent is required which allows, by simple intervention, the application of a substance which promotes the growth of healthy cells and facilitates the regeneration of damaged cells. In addition, it is often expedient to combine a substance with the mentioned properties with a carrier which is chemically and physiologically inert to allow homogeneous incorporation of the active ingredient, at least one or more therapeutically active substances.

The spirocyclic dipeptide cyclo (L-alanyl-1-amino-1-cyclopentanecarbonyl) of formula I was selected for the composition as a substance that promotes and / or accelerates the local therapy of skin and mucosal lesions.

(I), in which regenerative action on cells of tissues damaged by endogenous factors has previously been experimentally determined. This substance is non-toxic and has no pathophysiological side effects (A0 No. 231 237).

After experimental verification, a biocompatible collagen material, prepared by a special procedure from animal tendons, with new properties which distinguishes it from other similar known products on the basis, was chosen as the basic carrier for the active ingredient in the composition.

CS 276270 B2 collagen base and which is non-pyrogenic, non-antigenic and partially absorbable (AO No. 269 196).

The invention therefore relates to a composition for the topical therapy of skin and mucosal lesions, for example burns, abrasions or pressure ulcers, consisting of a physiologically inert sterilizable porous absorbent carrier, optionally at least limited absorbable, and at least one active substance promoting and / or accelerating lesion healing; The essence of this composition is that it contains cyclo (L-alanyl-1-amino-1-cyclopentanecarbonyl) of the formula I as an active ingredient promoting and / or accelerating the healing of the lesion.

(I), in a concentration of 0.05 to 5.00% by weight, based on the weight of the carrier of the type biocompatible collagen material based on collagen type I. The preparation may also optionally contain an additive of one or more antimicrobially active substances and / or one or more inhibitors. proteases and / or local anesthetics and / or deodorants.

The composition according to the invention contains said substances in the form of a homogenized dispersion, either in the whole mass of the carrier or only in a part thereof, in particular in the one which comes into contact with the lesion and its immediate surroundings. It is expedient if the composition is available with several concentrations of active substance in the form of suspensions and / or plates in different sizes and thicknesses and / or suppositories. Other possible ingredients are selected according to the nature and severity of the skin lesion to be treated, resp. treated.

The composition according to the invention is usually stored in plastic film packages, preferably sealed or welded, optionally combined with paper and / or aluminum foil, which are sparingly permeable to gases and liquids, for example polyethylene or at least translucent, but this is not absolutely necessary. and / or in suitably shaped plastic containers for use as microclimates. The microbial safety of the composition according to the invention can be ensured, for example, by radiation sterilization and / or, for example, by acetic acid. · ·

For some purposes, the composition according to the invention can also be stored in a suitable container also in a moist state (plate), i.e. impregnated with a solution of the active substance. · '

As already mentioned above, other known natural and / or synthetic materials can be used as carriers for the desired properties, which are shape-adaptable and which can be formed, for example, as foam, sponge, fleece, woven or nonwoven fabric or unreinforced laminate. . ·· - '

As a particularly preferred carrier, the carrier is made of a biocompatible collagen material which contains exclusively type I collagen obtained according to MS. A0 No. 269 196.

CS 276270 02

Since the collagen carrier, by its physicochemical structure, forms a high molecular weight carrier in which the compound of the formula I is bound by a physical bond, a perforated effect of the composition according to the invention can also be expected. Of applying the components of the composition according to the invention been achieved in that the application area above ^j satisfactory results which would clearly demonstrate the advantages of their use. Therefore, combinations were sought and, surprisingly, with a carrier based on collagen material in the form of foam and felt, surprising results were also obtained, especially in that both components were well tolerated and that significant potentiation of effects was found, although only additive effect was expected. resp. the effect of only one component, i.e. the substance of formula I; this could be applied in a lower concentration than in combination with a carrier conventional, e.g. a gel.

It follows from the above that a new high effect has been achieved in the composition according to the invention, which could not be clearly deduced from the known properties of the starting components.

In common practice (in a medical facility or in a home treatment), the composition according to the invention is applied to the damaged area of the skin, lightly transported with a bandage, preferably airtight, and left in place, e.g. for occasional check-ups, for the time necessary for healing, resp. healing the lesion, or replacing or replacing it, if desired, with a composition of the invention of a different composition. Suppositories and / or microclimates that can be used in some non-specific intestinal inflammations, ulcus recti, are conveniently inserted into the rectum. Another advantageous application of suppositories is in gynecology in outpatient cervical surgery. All of these procedures require the rapid healing of diseased or surgically injured tissue. The mutual combination of the regenerative component (active substance of the formula I) and the collagen carrier as a hemostyptic component positively potentiates the healing effect.

In the following, several possible compositions of the composition according to the invention for typical indications are given by way of illustration, without, however, all possibilities being exhausted. At the same time, the results of the treatment of several cases in comparison with the current procedure are presented.

The experiments were performed on 13 rats weighing 400-450 g, male, Wistar. The skin defect was performed on skin deprived of hair on the back. The size of the defect was determined by a metal tube with sharp edges 1.8 cm in diameter (cork boring). To this extent, the skin and subcutaneous tissue were removed. In the vast majority of cases, no major bleeding was observed. A slightly larger collagen plate with the active substance of the formula I, or without four stitches, was then attached to the defect. The size of the defect was evaluated. caliper; the results were then processed statistically. The plates were changed three times during the 14 day experiment. In the group with active substance I the average area of the skin defect was only 58% compared to the control group (100 °). ·. ·

The collagen plates with active substance I have a gray layer on the surface of the skin defect, and later also an uneven surface, finely granulated and well perfused. However, in the control group, the skin defect is red in color, bleeding and below skin level. Skin defects treated with collagen plate with active substance I were characterized by positive growth of granulation tissue and to a lesser extent by epithelialization of the skin defect. If the plate covered the skin with the hair removed, it also showed a beneficial effect on hair growth. ·

CS 276270 B2. . . 2

Evaluation of collagen platelets (reduction of skin defect area in cm)

Control

0.75

0.44

1.49

1.25

1.96

1.13

7.02: δ = 1.17 and 0.49 cm ² t = 2.8 p 0.02

Active substance of formula I

0.5

0.24

0.3

0.76

0.35

1.09

0.28 ₊ 9

3.52: 7 = 0.50 - 0.29 cm

Chemical composition of the components listed in the working examples under the trade names:

Slovásol 2430:

Alkyl polyglycol ether (HLB 12-18)

Slovanik M 640:

Mixed copolymer of propylene oxide and ethylene oxide

Witepsol H 15; Witepsol W 35;

Neutral fat (mixture of triglycerides of natural vegetable fatty acids with a chain length of C ^ Carbopol 940:

Polyacfyclic acid *

Cremophor EL:

Polyoxyethylene ricinoleate

Keltrol B-1495:

Polysaccharide

Polysorbate 20:

Tween 20 (polyethylene sorbitan monoleurate)

Freon 12:

Difluorodichloroethane

AI pin base:

Neutral fat is a mixture of glycerol esters of saturated fatty acids with the chains C ^ _Q - Ο ^ θ.

Freon 114:

Tetrafluorodichloroethane

CS 276270 B2

Example 1

Burn Treatment

The collagen material in the form of an open foam is saturated with an aqueous suspension of the substance of formula I in a concentration of 3% by weight, dried in a stream of filtered air at a temperature of not more than 50 ° C, cut into 8 x 12 cm rectangles, placed between two polyethylene films and sealed. . It is sterilized by gamma radiation.

Example 2

A product for the treatment of abrasions

The collagen material in the form of a felt about 5 mm thick, saturated with a suspension of the compound of formula I as in Example I and 0.5 ml of procaine hydrochloride solution, is dried with physiological saline after drying and is continued as in Example 1.

Example 3

Means for the treatment of leg ulcers

The procedure is as in Example 1, except that a synthetic pancreatic elastase inhibitor, glutaryl-L-alanyl-t-alanyl-L-alanine ethylamide, in the form of the sodium salt, is additionally added in a concentration of 1% by weight, and the procedure is followed. as shown in Example 1.

Attachment á

A product for the treatment of the cervix

The collagen material in the form of an open foam is saturated with an aqueous suspension of the compound of formula 1 in a concentration of 2% by weight, peracetic acid is added in a concentration of 0.001% by weight. The suspension is concentrated (max. It is then dried in a stream of filtered air, sandwiched between polyethylene films and sealed.

Example 1 and d 5

Means for the treatment of non-specific intestinal inflammations (microclysis)

The procedure of Example 4 is followed, except that the resulting suspension is not dried but filled directly into plastic containers with a volume of 50 to 70 ml and adjusted with an applicator attachment. The product is intended for single application.

Example 6

Cervical treatment agent (Vaginal suppositories)

Active substance of formula I .... ..... 0.500 g Slovasol 2430 0.120 Slovanik M 640 0.060 Cholesterol acetate 0.030 Suppository base A 1 2,140 th most common

Slovanik M 640 and Slovasol 2430 are added to suppository base A 1 melted at 50 ° C and cholesterol acetate is added with stirring. The active compound of the formula I is stirred in the melt at a temperature of 45 [deg.] C. and, after homogenization, the suppository is poured into 3 g molds.

v *

CS 276270 B2 6

Example 7

Cervical treatment agent (Vaginal suppositories)

Active substance of formula I Pure type I collagen Slovasol 2430 Slovanik M 640 0.300 g 0.300 0.120 0.060 Cholesterol acetate Suppository base A I 0.030 2,040 th most common For rosehip base A 2430 and cholesterol mixing 1 melted at 50 ° C, Slovanik M 640 and Slovasol ol acetate were added. At a temperature of 45 ° C, dust is stirred in the melt. mixture of active substance and co-forms. type I lag and after homogenisation the suppository is poured into 3 g

Example 8

The treatment agent does not sleep digital intestinal inflammation (Rectal suppositories) Active substance of formula I 0.25 g Monoglyceride C Cocoa oil Propylene glycol 0.1 1.66 0.02 In the melt of conical z pours into rosehip molds. On this basis, the active compound of the formula I is homogenized and the suppository is dissolved

Example 9 The treatment agent does not sleep specific intestinal inflammation (Rectal suppositories) ₍ Active substance of formula I Pure type I collagen Oxycellulose Sojalecithin Witepsol H 15 Witepsol W 35 0.25 g 0.25 ' 0.25 0.015 0.67 0.67 The molten Witepsols flowed. After thorough homogenization at 40 ° C, Sojalecithin is added and a mixture of dusts is poured into suppositories.

Example 10

Vaginal gel (Microclimate)

Active substance of formula I Pure type I collagen Methylparaben Propylparaben Edtan disodium Propylene glycol Triethanolamine 2.5 g. 2.5 0.14 0.06 0.05 5.00 1.00 Carbopol 940 Cremophor EL Distilled water 1.00 2.00 85.75

CS 276270 B2

A suspension of Carbopol in water with dissolved parahens at room temperature (20 ° C) was neutralized with triethanolamine. Disodium edetate is dissolved in propylene glycol at 60 ° C. This solution was cooled and dissolved in Cremophor EL. In this way. The active compound of the formula I and the type I collagen are mixed with the resulting solution. The homogeneous suspension is mixed in portions into the gel base. The gel is homogenized in a homogenizer under vacuum.

Example

Vaginal foam (Microclimate)

Active substance of formula I Pure collagen type I Lactic acid Polysaccharide B-14 ^ 5 Propylene glycol Polysorbate 20 Cetyl alcohol Sorbic acid Methyl paraben Dest. vodaFreon 12/114

1.25 g

1.25

0.05

0.35

5.62

0.30

0.70

0.045

0.045

28.41

7.0

The active ingredient and collagen are suspended in the aerosol foam concentrate. This base is topped up with propellant after closing the aerosol can.

Claims (2)

PATENTS A composition for the topical therapy of skin and mucosal lesions, for example burns, abrasions or pressure ulcers, consisting of a physiologically inert sterilizable porous absorbent carrier, optionally at least sparingly absorbable and at least one active substance promoting and / or accelerating lesion healing, characterized in that the active substance promoting and / or accelerating the healing of the lesion contains cyclo (L-alanyl-1-amino-1-cyclopentanecarbonyl) of the formula I CS 276270 B2 in a concentration of 0.05 to 5.00% by weight, based on the weight of a carrier of the type biocompatible collagen material based on collagen type I. 2. A composition according to claim 1, characterized in that it contains an additive of one or more antimicrobially active substances and / or one or more protease inhibitors and / or a local anesthetic and / or deodorant.