DD248961A1 - METHOD FOR PRODUCING WOUND HEALING PROMOTIONAL PRAEPARATIONS - Google Patents

Abstract

Compsn. for stimulating healing of wounds contains the peptide Lys-Pro (I), or its derivs., as active ingredient, pref. at 1 microg-1 mg per ml or g. Pref. (I) derivs. are salts, protected analogues; or linear or cyclic peptides, and Pro can be replaced by picolinic acid; hydroxyproline; dehydroproline; beta-proline or prim. or sec. heterocyclic amines (esp. pyrrolidine or piperidine). Most pref. is N-(4-nitrobenzyloxy carbonyl)-Lys-Pro hydrochloride (Ia).

Description

Process for the preparation of wound healing preparations

Field of application of the invention;

The invention relates to a process for the production of wound-healing preparations containing the peptide Lys-Pro and its derivatives. These compounds stimulate the formation of granulation tissue and thus prepare the wound base for the subsequent epithelization process in skin and mucosal wounds or for self-skin transplantation. The preparations are suitable for direct or indirect local application in, on and on the wound. The invention makes it possible to have preparations available which promote and accelerate the wound-healing process efficiently and with high compatibility. The invention is suitable for use in medicine, veterinary medicine and cosmetics.

Chara kteristik the known technical solutions A number of pharmaceutical preparations with different active ingredients or drug combinations, which - brought near the wound or on wounds - an anti-inflammatory (DE-OS 2945 2395 US-PS 3965 260) or germ inhibiting or destroying (disinfectants, Antibiotics, sulfonamides) (HAUSCHILD, P .: Pharmacology and Fundamentals of Toxicology, VE3 Georg Shieaa Laipsig, 1973. 3 ¹ OHTH, W .; HEIiSCHLER, D; PiUISCDL, W »| General and Special Pharmacology and Soilcology, Bibliographisches Institut Mannheim, Vienna, Zurich, B »I * -7i3s-3nschaftsv3rlag, 1930), is known

furthermore, the possibility of covering wounds with IClab patches (DE-OS 2165 549 and 2443 180; DD-WP 102 078), with adsorbent granules (eg cellulose regenerate) or with synthetic skin substitutes (DE-OS 2708 822 and 2845 686) , which may optionally be impregnated with a suitable active ingredient (DD-WP 145 225). Although all listed preparations and the wound covering materials have a favorable influence on the V / undheilung by either inhibiting inflammatory processes depending on the type and quantity of the active ingredient, reduce contamination with pus pathogens, thwart or inhibit already entered into the wound pathogens or physical or Mode (shielding, secretion, prevention of dehydration, etc.) favorably influence the healing process, but in no case a specific immediate effect on the basic biological process of wound healing, namely the formation of the wound base filling granulation, unfolds.

However, the stimulation of Granulationsgewebsbildung by a crude extract from the brain of slaughter animals, which contains "IPibroblast Growth Pactor" activity and is suitable for the impregnation of wound dressing materials (DD-ICP 145 225). However, this brain raw extract has the disadvantage that he contains not only the active ingredient, but also accompanying proteins and other brain building and functional substances whose nature is unknown in detail and their share of production batch to production lot is changing, so that a sufficient chemical characterization of the preparation is not possible. Even in more heavily purged Porm allergic Fsbenreaktionsn be expected because of the close relationship to ITarvenmyelin with repeated application (GQSPODAROWICZ, D., Mol Cell Cell Biochem 25s 73, 1979) »

Finally, the antiinflammatory and wounding action of L-camosine (β-alanyl-L) is known.

Histidine) (Hagai, Κ ·, et al .: Arzneimittel-Forsch./Drug Ees 20, 1876, 1970; ITAGAI, K., T. YAlIAUE. Heterocycles Λ0 ± 277, 1978).

In intraperitoneal administration, experimental wounds and local wounds (ointment, lozenges) in humans could be favorably affected by tooth extraction in humans. However, extremely high doses (20 mg / kg rat intraperitoneally) are required for this purpose. This fact, together with findings of other authors (FITZPATRICK, D., H. PISHSR: Ped. Proc. 40, 3/2, 2514, 1981), according to which L-carnosine has no actual effect, but only a supplier of the amino acid histidine and thus of histamine causing cellular synthesis, the reason why this drug has not gained acceptance in medical practice.

Object of the invention

The object of the invention is to provide preparations which, in the case of direct or indirect application to the wound area, excite and accelerate the primary step of the healing process of wounds, namely the formation of granulation tissue, and are clearly chemically defined with regard to the active substance contained are optionally combined with known active ingredients with supporting biological treatment and contain pharmaceutically suitable excipients for formulation, whereby an application to humans is possible and beyond known possibilities, the wound healing, especially the formation of granulation tissue, favorably influenced and thereby the Wound healing process is promoted overall.

Paris-grms ^ the J73 £ gji3 of the invention

The invention is dia object to develop methods for the production of preparations having wound healing efficacy demanding _9, the ζ ate the Grundpro represent 7 / undhe Settin g, namely, the formation of granulation tissue, stimulate. Ba

to become biologically active peptides, optionally or · earmarked supplemented by already known active ingredients defined impact quality - such. As antibiotics or sulfonamides - using chemically inert, common in pharmaceutics solvents and excipients brought into a form that allows the direct or indirect local application in the wound area ·

The object was achieved in that the peptide Lys-Pro, a partial sequence u.a. of the physiological regulatory peptide Substance P (OEHME, P., H. BIBNBRT, K. HECHT and J. BERGMAM: Substance P. In: OEHME, LÖWE, GÖRES: Contributions to the Drug Research, Issue 12, Academy-Industry-Complex "Drug Research", 1136 Berlin, Alfred-Kowalke-Str. 4), Lys-Pro derivatives, such as Lys-Pro salts, protected Lys-Pro derivatives and peptides with the sequence Lys-Pro - both linear and cyclic - and proline by Pipecolic acid, hydroxyproline, dehydroproline, β-proline, primary and secondary heterocyclic amines, especially pyrklidine or piperidine, may be substituted, as a carrier of a qualitatively new, namely the formation of granulation tissue stimulating, effect is used.

A preferred compound is IT-4-nitrobenzyloxycarbonyl-lysyl-proline hydrochloride, which is characterized in that a lysine derivative of the formula I

X-Lys £ ~Z (HO ₂ ) J- YI

with a proline derivative of the formula II

H-Pro-A II,

wherein

X is tert-butyloxycarbonyl, p-methoxybenzyloxycarbonyl, biphenylisopropylosycarbonyl, ^ - , «^ -dimethyl ^ S-dimethoxybansyloxycarbonyl, o-hitrophenylsulphenyl, 9-fluorenyl-

ra tyl or: y carb onyl

Ί for OH,? 3-tetrafluorophenyl, pantachlorophenyl, trichloroplianyl, p -litrophylnyl, IT-hydroxysuccinimide ester, hydrazone

ν 4 -j - ') J

zid

A is OH, methyl, ethyl, tert-butyl, phenyl, phenacyl ester

stent,

according to the coupling methods customary in peptide chemistry (compare W · WÜITSCH, Synthesis of Peptides in Houben-Feyl, Volume 15/11, Methods of Organic Chemistry, Ed. E. MÜLLER, Georg Thieme Verlag Stuttgart 1974) 11,11 -dicyclohexylcarbodiimide, NjN'-dicyclohezsylcarbodiimide / additive (preferably 1-hydroxybenzotriazole), mixed anhydride, activated esters, azide-linked and after purification of the corresponding dipeptide derivative by recrystallization or by Adsorbtionschromatographie on a silica gel column, the amino and Carbosylschutzgruppe with the usual Deblockierungsverfahren in peptide chemistry ( See E. WÜIISCH, supra), in particular by means of HCl / diosan, HCl / glacial acetic acid, trifluoroacetic acid, zinc / glacial acetic acid, piperidine or alkaline hydrolysis removed and the resulting dipeptide H-Lys ^ "* Z (iJOp) JP-Pro-OH preferred The peptide bond is preferably carried out via the active ester method by reacting U-tert-butylosycarbonyl-Hp-nitrobenzylosycarbonyl-lysi npentafluorophenyl ester with proline in the presence of an equivalent amount of triethylamine in dimethylformamide aspartate (10: 1). The reaction mixture is stirred at ⁰ ° C. for 1 h and at room temperature for 12 h, then poured into a KHSO 2 solution, and the crude product is extracted with ethyl acetate. The combined organic phases are washed with KHSO 4 solution and water and dried over Ha 2 SO 4. Each vaporizing the vinegar ester i. Vak. The thin-layer chromatography uniform product for the removal of H-iert.-butylosycarbonyl protecting group is treated for 40 minutes with 4.2 η HCl in diosan at room temperature and the resulting dipeptide H-LyS ^ fZ (HO ₂ ) JP-PrO-OH as H: / hydrochloride (R f: 3.9 in n-butanol / Eisassig / Jasser (4: 1: i) _s Rf; 5, β in n-butanol / glacial acetic acid /

VTasser / Essigester (1: 1: 1: I) ₃ on silica gel periplatate ₁ '. ,,)! -; ^, / «.._,', 22 - _ ^ ς A ß s: 1. V / assep7

characterized. Granules, solutions, emulsions, suspensions and aerosols are suitable as preferred preparations. Solutions and emulsions may contain, in addition to the active ingredient (s), the customary carriers, such as solvents and solubilizers. The solvents used may be, in particular, water or lower alcohols lower glycols such as propylene glycol and 1,3-butylene glycol may be used. As a solubilizer can serve compounds from the series of polyglycols, which may still be mixed with oils or with glycerol.

Suspensions may contain, in addition to the active ingredient (s), the usual excipients, such as liquid diluents (eg, water, ethanol, propylene glycol) and suspending agents, as long as they are tolerated by the wound. According to the invention, the active ingredient is used as an additive to cosmetics. In aftershave for skin treatment after wet shaving, it serves to heal set cut injuries or existing other types of skin wounds. In the form of a cosmetic pencil, it enables the targeted treatment of small-area skin wounds of various origins. As a component of toothpastes, it exerts a healing effect on existing gingival wounds. As an additive to mouth and gargle water inflammatory-ulcerous mucosal defects in the mouth and throat, for example in the course of viral diseases, are favorably influenced by him. This applies equally to the local treatment of such changes in animals, ζ. B. in the course of virus anther or certain metabolic disorders.

Another indication is the treatment and conditioning of large-area skin wounds, z. As surgically set wounds, for the preparation of a plastic cover, the ulcus cruris or of firebrands. Here, after the base has been cleaned, the formation of granulation particles is promoted and promoted by impregnating wound dressing material, for example synthetic rubber foam tape, T7ia SYspur-dsrraj, with the active ingredient or physically.

Slightly acting granules, such as the compounded cellulose regenerate deshisan, are mixed with the active ingredient.

According to the invention, the preparation contains the granulation tissue-forming active ingredient in concentrations between 10 and 100 / μg per ml or g.

The meaning of the invention results from the fact that by means of the active compound according to the invention alone or its optional combination with another common active ingredient with different point of attack and with non-toxic, inert, pharmaceutically suitable excipients preparations can be prepared which are useful both in medicine for the requirement of Healing of wounds, in particular those with severe tissue defects, in which the triggering, stimulation and enhancement of the Granulationsgewebsbildung for the healing process of crucial importance and are sometimes simultaneously inhibiting influences on unpleasant companion Prose, such as suppuration to be exercised and in the cosmetics Improvement of the quality of effect and quantity of relevant products for the skin and Zahnbzw. Gum care.

The invention will be explained in more detail with reference to embodiments.

embodiments List of abbreviations

PG wet weight PG % percentage change in wet weight TG dry weight TG % percentage change in dry weight TZ number of animals

ζ The rates of increase in the weight of clown and dry weights can be significantly secured in the t-test according to STUDBSTT.

Example 1:

Application of the Active Ingredient Lys / "* Z (HOp) _7-Pro.HCl in Aqueous Solution to the Rat Wound Healing Model According to RUDAS

Polyvinyl rings with a base diameter of 19 mm are implanted below the dorsal skin of 2-month-old rats with a body weight of 220 to 270 g under sterile conditions (test according to RUDiIS, modified according to BECK, WIEGERS-HAUSSlT and JUlIG, Acta bio. IJ _x (1964)). The ring lies on the pascis of the back muscles. On the day of the operation, 1.0 ml of sterile isotonic saline (control) is administered weekly. applied the same amount of saline with the active ingredients contained therein. The wound of the dorsal skin above the ring is then closed. On the 2nd or the 2nd, 4th and 6th day postoperative (p.op.), repeated injections are made through the skin into the ring, with 0.2 ml of sterile, isotonic saline solution each containing 20 % of the day of surgery given amount of active ingredient are administered. In the Pail of the control is an injection of 0.2 ml saline without active ingredient.

On days 3 and 7 post-operative the quantitative recovery of the newly formed garanulation tissue (wound tissue) in the ring is carried out by preparatory removal of the paspe. Thereafter, the weight of the tissue is determined by means of a torsion balance. Dia dry weights are determined after extraction of the water by two 24-hour storage in ether and 43 hours-3 drying at 56 ⁰ C (HEUMAFiI and LOGALI,

Effect of different doses of LyS ^ Z (NO ₉ ) J7 ~ Pr ο · HCl per ml of isotonic saline; £ æ] 2 ^{c- 1} l of cesium (l ¹ G) and dry weights (tg) of water content of granules ion sgev / eb e

* "* - - 2 _months old rats 3 days post operations!

Control PG /% 7 125 »2 ± 5.6 TG /% 7 11.9 * 0.5 H ₂ O % 90.4 * 0.3 TZ 21 PG % 100 tg £ 100

Effect of different doses of Ly3 ^ ~ Z (lJ0 ₂ ) _ _M 7 ~ Pro "HCl per ml of isotonic saline

ffabelle_2 ^ Wet and dry weights and water content of granulation tissue 2 months "" old 7 days post surgery!

5 / ug / ml 7, 8th 50 / Ug / ml i 3, 2 100 / Ug / ml 34.2 500 / Ug / ml 14 2 125.0 * 0 8th 231.4 ± 1, 5 188.6 * 3.4 209.6 2, 1 12.6 * O, 6 24.5 + O, 7 18.8 * 0.4 21.3 + O, 7 89.8 ± 89.4 89.8 * 89.8 ± 6 7 ,8th 7 7 99.8 184 , 9 150.6 167 , 4 105.9 205 158.0 179 , 0

Control 5 / μg / ral 5C

PG /% 7 162.2 * 9.9 260.7 * 21.2 235 ', O * 9.7

^{fJ? G} Z% 7 14.7 * 1.1 27.4 * 2.3 26.6 * 1.6

H ₂ O % 90.9 * 0.3 89.4 - 0.4 88.7 * 0.3

TZ 9 7

FG % 100 160.7 144.9

TZ % 100 186.4 181.0

100 / Ug / ral 2 500 / Ug / ml 5 , 0 242.8 * 20, 2 223.6 + 0 , 6 24.9 * 2, 4 -26.3 ± 0 3 89.4 * 0, 88.2 7 7 149.7 137 , 9 169.4 179 , 0

10 J. Biol. Chem. 184, 299 (195O)).

Example 2:

Use of the active substance for the impregnation of synthetic

Skin replacement.

From the synthetic skin replacement "SYSpur-derm" (manufacturer: TEB Synthesewerk Schwarzheide / DDR) discs of 13 ram diameter are punched under sterile conditions with a sharp punch. These discs are placed in either sterile, isotonic saline (0.14 M) (control) or in sterile, isotonic saline to which 50 / Ug Lys-Pro / ml is added. The fluid intake per disc is about 0.07 ml and the Lys-Pro content accordingly about 5 / ug.

Polyvinyl rings (test according to RUDAS, cf Example 1) are again implanted under the sterile skin of the approximately 2-month-old male rats weighing 230 to 270 g. The drug-free or drug-impregnated "SYSpur-derm" discs are placed on the pas of the back muscles during surgery inside the rings. They cover the largest part of the wound and adhere to the pas- sage.The wound over the ring is then closed with skin clips.3 and 7 days after the operation (p.op.), the quantitative extraction of the granulation tissue or wound tissue newly formed in the ring takes place (see Example 1) For this purpose, first each "SYSpur-derm" scaffold is lifted off the granulation tissue and the granulation tissue itself is prepared from the JPaszie.The further processing is carried out in the manner described in example 1. The following experimental groups were formed: group 1 3 Taga p. Op. SYSpur-derm-Scheiben-Kon-

trolls (with sterile isotonic saline)

Group 2 3 days ρ. ορ. Impregnated "SYSpur-derm" -

Slices (as described above)

Group 3 7 days p. op. SYSpur-derm-Seheiben-Kontrol-

Ie (with sterile isotonic saline) Group 4 7 days P op. Impregnated "SYSpur-derm"

Slices (as described above)

Wound healing disorders did not occur frequently. In three animals, infection was due to biting off of wound closure. These animals were eliminated from the trial. 7 days p. On the other hand, the "SYSpur-derm" slices were firmly attached to the newly formed granulation tissue, and at the time of their withdrawal they appeared stronger after 7 days than after 3 days. op. punctate bleeding of the wound.

Table 3t Assay Results 3 Days p. op.

Group 1 group "2 increase control impregnated %

Dampweights138 ± 15.9 187 - 13.9 35.5 ^{x <>} (mg)

Dry Weights 13.5 - 1 ^ 7 17.6 ± 1.0 30.4 ^ (mg)

Animal number 9 10

Table 4j Test results 7 days p. op.

Group 3 Group 4 increase control impregnated %

Dampweights 140 - 10.7 169 - 7.2 21,7 ³ ^ (mg)

Dry matter / density 1β, 2 -1,1 18,6 * 0,6 14,8 (mg)

Animal number 11 13

The rates of increase in pat and dry weights could be secured in the t-test according to Student significant (s). The lower rates of increase compared to the results after repeated administration of active ingredient (sialia example 1), insbasonsra in rattan 7 Tags p. op. shall be explained by kleinara amounts of the active ingredient per zugefügtan disc (under 5yug).

from Lys-Pro »2HBr

 The procedure corresponds to that under Example 1.

' Effect of different doses of Lys-Pro * 2HBr per ml of isotonic solution.

Moisture and dry weights as well as water content of granulation tissue of 2-month-old rats 3 days postoperative

Control 50 / μg / ml 500 / μg / ml

FG 125.2 - 5.6 170.7 * 8.7x ⁾ 193.6 ± 20.3x ⁾

TG 11.9 * 0.5 16.6 ^x 1.5 ^x) 18.7 + 2.0 ^x)

H ₂ O 90.4 * 0.3 90.3 * 0.7 90.3 ± 0.2

TZ 21 7 7

I ¹ G ^f / 5 100 136.3 154.6

TG % 100 139.5 157.1

Table ^ t _- Effect of different doses of Lys-Pro * 2HBr per ml of isotonic solution.

Wet and dry weights as well as water content of granulation tissue 2 months

old rats 7 days postoperatively control 50 / ug / ral

PG 132.5 ± 6.9 184.2 ± 13.5 ^x)

TG 13.6 ± 1.1 25.4 ± 1.9 ^X)

H ₂ O 89.6 ± 0.7 85.7 t 1.7

TZ 10 6

PG% 100 139.0

TG % 100 186.8

500 Yug / ml 10 , 4 4 ^X > 186 0 ± 2, ,8th 8. ^X 25 4 ± 2, 1 85 9 ± 5 140 186th

Beispiel_4 ". Testing of Lys (Z) -Pro

The procedure corresponds to that under Example 1.

Titration of different doses of Lys (Z) -Pro ml of isotonic saline.

Wet and dry weights and water content of granulation tissue 2 months old rats 3 days postoperationeni

3d Control « 2 * 5, , 6 5 ₄ 4 10 / Ug / ml 14 ,8th 5 20 / ug / ml ,8th x) 40 / ug / ml 3 I ¹ G 1 25 9 * 0, , 5 121j 4 ^x) 147 , 5 * 2, , 5 3 206 7 * 17 3 χ) 187.5 * 15, 1 TG 11 4 * O ₅ 3 9 ^4X) 14 ,1 * O, 8th 16 5 * 2 ,8th 12.1 * 1, 6 ² ^ H ₂ O 90, 21 92 90 , 6 * 92 7 * 1 93.5 * 0, TZ 100 6 6 4 PG % 100 117 165.1 149.8 TG % V / MPACT different 118 138.7 101.7 • table 8th: ,, ug / ml cans from Lys (Z) -Pro ml isotonic saline , 0 * 6, A * 0, , 1 * 0, 5 96.6 79.0

Wet and dry weights and water content of granulation tissue of 2-month-old rats 7 days postoperations!

control

PG 162 2 ± 9 , 9 121 , 0 * 11 1 χ) 119 , 5 * 1 3, 0 ² ^ ¹ 114, 0 ± 11 2 x) 125 ± 12 0 i) TG 14 7 * 1 ,1 13 1 ± 1, 1 11 ,8th* 0 8th 12 6 ± 1, 2 13 ,1 * 1, 5 H ₂ O 90, 9 * 0 3 89 1 ± O, 4 χ) 90 , 0 * O, 6 88 9 * O, 3 x) 89 , 6 * O, 4 χ) TZ 9 5 6 5 6 PG % 100 74.6 73.7 70.3 77.1 TG % 100 89.1 80.3 85.7 89.1

Tasting of the tetrapeptide SP ^ '"" 4J The procedure corresponds to that under example

( 1-4.}

i. Effect of different doses of SP ^v ^ ' per ml of isotonic saline.

Wet and dry weights and water content of granulation tissue 2 months old rats 3 days postoperative

3d control sp

I ¹ G 125.2 ± 5.6 TG 11.9 ± 0.5 H ₂ O 90.4 - 0.3 TZ 21 PG% 100 TG % 100

5 / ug / ml 24 3 ₉ x) ¹⁰ z 'Ug / ml 57 ,8th 9 x) 50 / Ug / ml 9 ± 27.1 ^x) 100 / Ug / ml 30 6 ^4X) 200 7 ± 2, , 7 6 ³ ^ 344 0 ± 2, , 0 1 χ) 342 9 ^± 3,5 ^x) 371.4 ± 2, 3 2 ³ ^ 21 , ± 5 O, 43 2 ± O, 4 37, 0 ± 0.4x ⁾ 39.9 ± O, 4 ^x) 89 .2 ± 88 9 ± 89 7 _y 89.1 ± 7 7 273, 9 7 160 274 318 5 296 18O ₁ 363, 335

(1-4Λ Table IQ ^ Irrespective of doses of SP ^V ^ ^J per ml of isotonic saline.

Wet and dry weights and water content of granulation tissue of 2-month-old rats 7 days postoperatively

control

m 162.2 ± 9.9 209.2 t _Uf5 ^x) 290.7 ± 24.9 ^ 256.7 ^± 21.2 ^x)

TG 14.7 ± 1.1 24.0 ± 1.8 ^x) 33.3 ^± 2.9 ^x) 31.6 ± 2.9 ^x)

H ₂ O 90.9 ^± 0.3 88.3 ± 1.2 88.5 ± 0.5 ^x) 87.6 ± 0.7 ^x)

TZ 9 6 7

I ¹ G % 100 128.9 179.2 158.3

TG % 100 163.3 226.5 215.0

Example 6:

Histological-morphometric studies for the detection of the angiogenesis-promoting effect of Lys / ~Z (IJO ₂ ) _J- Pro »HCl A differential count of the total number of cells (% γ (Ρ subdivided according to the number of cell nuclei of the fibroblasts (% _C fjig) was obtained on histological sections , Granulozyten (^ jjq _C ) of the round cells (Έ _ΎΧΌη ) and endothelial cells (IT ™ -) at a hundredfold magnification in Ölimmersion and with a Okularnetsmikrometer performed (P · BUITTROCK: ZbI general Pathol., And general pathol Anat , 124 (1930) 48-59) The results are shown in Table 11. The control animals were rats treated with isotonic saline, the numbers of which were set equal to 100 % , resulting in a significant increase in the number of endothelial cell nuclei of the capillaries. The procedure of treatment corresponds to Example 1.

Table 11: Percentage Change in the Number of Nuclei

Controls were set equal to 100 % .

Wound Age: 3 days ρ. ου. 500 / ug / ml 7 days P. OO. 500 / ug / ml Treatment: Repeated gift of 108 Lys / "Z (HO ₂ ) _7-Pro · HCl 85 50yug / ml 117 SOyUg / ml 66 % VC 96 24 95 86 OTC% 95 67 71 73 ¹ ITGC 99 292 85 148 % RC 61 90 ¹¹ HEC 230 174

With the aid of the point counting method (Buntrock et al .: Exper. Pathol. 21 (1982) 62-67), the percentage volume of capillaries (W ",, ->), subdivided into endothelial cells (W ^), SMothelsell cores (TVV ^ ), (TT ^ _n) on the one hand and the capillary lumen (W _n ^ _x) andersrseita bestirsit .Endothelzellzytoplasma ". Dia controls Trurden again with

140 157 200 300 155 185 192 266 214 274 260 409 127 142 157 193 109 114 230 374

set at 100%.

The results are shown in Table 12.

Table 12: Horphometry of the capillaries

Wundalter: 3 days p. op. 7 days p. op "

Treatment: Repeated Gift of Lys / * Z (II0 ₂ ) _7-Pro

HCl

50 / ug / ml 500 / ug / ml 50, ug / ml 500 / ug / ml

⁷⁷ CAP

⁷⁷ UEC

⁷⁷ CYT

⁷⁷ QAFL

This suggests that angiogenesis-requiring repression by the dipeptide Lys / ~ z (iI0p) _7-Pro * HCl can be considered as the cause of increased granulation tissue formation and accelerated wound healing.

Example 7:

Wound healing shaving water

By mixing of ethanol, astringents, bacteriostatic substances, fragrances, by addition of 0.0001 to 0.1 % Lys-Pro or its derivatives

salubrious shaving waters.

Example 8;

Wound healing toothpastes

Wound-healing toothpastes are prepared by mixing cleaning bodies, foaming agents, palette retention agents, flavorings, preservatives, thickening agents and adding 0.0001 to 0.1 % of Lys-Pro or its derivatives.

BeisOJel 9; V / and healing-promoting oral vein / or Gurgel waters

By mixing of ethanol, flavorings and with addition

From 0.0001 to 0.1 % Lys-Pro or its derivatives are prepared mouth and / or Gurgel waters that promote the healing of mucosal wounds in the mouth and throat.

Example 10: Wound treatment sticks

By mixing lipstick bases and 0.0001 to 0.1 % Lys-Pro or its derivatives, wound treatment sticks are made.

Example 11:

Wound-healing bandage dressing material, preferably plastic soft foam tape, either in industrial production, beispielswei se via a system of parallel spray nozzles, before given to a 5 x 10 "to 5 x " \ Q molar, sterile, aqueous-based Lys Pro or. Lys-Pro derivative solution soaked in strips, dried and sterile packaged or immersed in the hospital immediately prior to use in an equally concentrated germ-free Lys-Pro or Ly3-Pro derivative solution and placed directly on the wound surface.

Example 12:

Wound healing strain s wound powder

Adsorbent wound powder, preferably compounded

Cellulose regenerate, with Lys-Pro or Lys-Pro-Derivat-! Prockensub punch in the preferred ratio of 1: 100 to

1: 10 000 offset and mixed.

Claims (9)

invention claim 1. A process for the preparation of wound healing preparations, characterized in that the peptide Lys-Pro and its derivatives are added in preferred concentrations of 1 / ug to 1 mg per ml or g as effective components. 2. Method according to item 1, characterized in that as active components Lys-Pro and its derivatives, in particular their salts, protected Lys-Pro derivatives and peptides with the sequence Lys-Pro, both linear and cyclic, are added and in which Proline may be replaced by picolinic acid, hydroxyproline, dehydroproline, ß ~ proline, primary and secondary heterocyclic amines, in particular pyrrolidine or piperidine. * -3 -5 with a 5 x 10 to 5 x 10 molar, sterile, aqueous Lys-Pro or Lys-Pro derivative solution soaked strips, dried and sterile packaged or in the hospital immediately before .Awendung in an equally concentrated germ-free Lys-Pro or Lys-Pro derivative solution immersed and placed directly on the wound surfaces. 3 · Method according to item 1 and 2, characterized in that. that on the basis of ethanol, astringents, bacteriostatic substances, perfumes and with the addition of 0.0001 to 0.1 % Lys-Pro or its derivatives wound healing shaving waters are produced. 4. The method according to item 1 and 2, characterized in that on the basis of cleaning articles, foaming agents, humectants, flavorings, preservatives, thickeners and with the addition of 0.0001 to 0.1 % Lys-Pro or its derivatives toothpastes are prepared that exert a healing effect on gum sores. 5. The method according to item 1 and 2, characterized in that on the basis of ethanol, flavorings and with the addition of 0.0001 to 0.1 % Lys-Pro or its derivatives oral and / or Gurgeiwässer be prepared, the Promote healing of mucosal wounds in the mouth and throat. 6. The method according to item 1 "and 2, characterized in that on the basis of lipstick base with the addition of 0.001 to 0.1 % Lys- ro or its derivatives, a wound treatment pen is produced. 7. The method according to item 1 and 2, characterized in that bandage material, preferably plastic flexible foam band, either in industrial production, for example via a system of parallel spray nozzles, preferred 8. The method according to item 1 and 2, characterized in that from adsorbing wound powder, preferably compounded cellulose regenerate, with Lys-Pro or Lys-Pro derivative dry substance in the preferred ratio of 1: 100 to 1: 10 000 by mixing a wound healing wound powder is prepared. 9. The method according to item 1 and 2, characterized in that as an effective component preferably Έ -4-Hitrobenzyloxycarbonyl-lysyl-proline hydrochloride, H-Lys ^ ~ Z (3Op) __ 7-Pro-OH'HCl, is used.