Pharmaceutical composition for promoting wound healing as well as preparation method and application thereof

Abstract

The invention discloses a medicine composition for promoting wound healing as well as a preparation method and application thereof. The pharmaceutical composition comprises the following components in parts by weight: 1-10 parts of hemoglobin molecules, 1-5 parts of lipoic acid, 0.1-1 part of acetylcysteine and 40-80 parts of a solvent, the hemoglobin molecule comprises at least one cysteine moiety and at least one histidine moiety, where the cysteine moiety comprises an acetyl or ethylmaleoyl group and the histidine moiety comprises a benzimidazole derivative group. According to the invention, lipoic acid and acetylcysteine are jointly applied to the external pharmaceutical composition of hemoglobin molecules modified by acetyl or ethylmaleoyl and the like, and irritant reaction on skin after hemoglobin modification is effectively relieved through synergistic antioxidation and tissue protection effects; therefore, the safety and applicability of the pharmaceutical composition in skin wound treatment are improved, and the pharmaceutical composition is suitable for treatment of multiple types of wounds such as trauma, burn, postoperative wounds, ulcer wounds and the like.

Description

Technical Field

[0001] The present invention relates to the field of wound repair biotechnology, and in particular to a pharmaceutical composition for promoting wound healing, a preparation method thereof, and an application thereof. Background Art

[0002] Wound repair is a common yet challenging process in clinical medicine. Especially in complex wounds such as chronic wounds, burns, and diabetic foot, healing is often delayed due to tissue hypoxia, oxidative stress, and persistent inflammation. Numerous studies have demonstrated that oxygen plays a key role in tissue repair processes such as cell proliferation, angiogenesis, and collagen synthesis. However, traditional wound treatments, which primarily focus on antimicrobial, moisturizing, and sealing, are unable to fundamentally alleviate the hypoxic state in the wound microenvironment.

[0003] Hemoglobin is a natural oxygen-carrying protein that can reversibly bind to oxygen molecules and has been attempted to be developed as an artificial blood substitute or tissue oxygen carrier. However, traditional hemoglobin preparations have problems such as low oxygenation efficiency, poor stability, and easy oxidation conversion to methemoglobin (Met-Hb), which limit their application in topical wound treatment. At the same time, hemoglobin used alone may cause certain irritation or immune response to local tissues. In addition, the wound healing process is also accompanied by severe oxidative stress reactions. Excessive oxygen free radicals can easily inactivate hemoglobin, causing further damage to tissue cells and delaying the healing process.

[0004] Therefore, there is an urgent need for a new type of composite external-use pharmaceutical composition that can simultaneously improve the local hypoxic environment, relieve oxidative stress and reduce tissue irritation, so as to promote wound healing more efficiently and safely. Summary of the Invention

[0005] In view of the deficiencies in the prior art, the present invention provides a pharmaceutical composition for promoting wound healing, a preparation method thereof, and an application thereof.

[0006] The present invention provides a pharmaceutical composition for promoting wound healing, comprising the following components in parts by weight:

[0007] 1-10 parts of hemoglobin molecules, 1-5 parts of lipoic acid, 0.1-1 parts of acetylcysteine, and 40-80 parts of solvent;

[0008] The hemoglobin molecule includes at least one cysteine ​​moiety, wherein the cysteine ​​moiety includes an acetyl group or an ethylmaleoyl group; the hemoglobin molecule includes at least one cysteine ​​moiety and at least one histidine moiety, wherein the cysteine ​​moiety includes an acetyl group or an ethylmaleoyl group, and the histidine moiety includes a benzimidazole derivative group.

[0009] Benzimidazoles have a certain degree of hydrophobicity and aromaticity. After modifying hemoglobin molecules, they easily form π-π stacking interactions with skin barrier structures (such as keratin), causing mild inflammatory reactions or stinging, especially in open wounds. The present invention combines lipoic acid with acetylcysteine ​​to synergistically alleviate the irritation caused by hemoglobin molecules modified with benzimidazole derivatives. This can stabilize cell membrane structure, reduce lipid peroxidation, and alleviate irritation symptoms such as skin redness, swelling, and pain.

[0010] In some embodiments, the mass ratio of the hemoglobin molecule to lipoic acid is (1-2):1. The disulfide ring structure contained in the lipoic acid molecular structure can rapidly scavenge free radical reactions initiated by metal ions or free iron on the surface of hemoglobin, thereby protecting skin cells and inhibiting lipid peroxidation. The present invention preferably compoundes the hemoglobin molecule and lipoic acid in a mass ratio of (1-2):1 to ensure that the antioxidant capacity is sufficient to match the potential oxidative burden of hemoglobin, prevent local oxidative stress accumulation, and form a stable pharmaceutical composition system while ensuring that its physical and chemical properties are suitable for transdermal absorption and tissue compatibility.

[0011] The present invention introduces two synergistic antioxidant components, lipoic acid and acetylcysteine, into the composition. On the one hand, they can directly remove excessive reactive oxygen species around the wound surface, and on the other hand, they can indirectly increase glutathione synthesis by providing a sulfhydryl donor, effectively alleviating oxidative stress, and facilitating inflammation control and tissue regeneration.

[0012] In some embodiments, the solvent is any one or more of water, physiological saline, and ethanol.

[0013] The present invention also provides a preparation comprising the pharmaceutical composition.

[0014] In some embodiments, the dosage form of the preparation is any one of a spray, an ointment, a gel, a cream, a patch, an emulsion, a paint, a foam, a hydrogel dressing, and a wound dressing.

[0015] In some embodiments, the spray further comprises 5 to 20 parts of a spray base, wherein the spray base is selected from one or more of a film-forming agent, a propellant, and a moisturizing agent.

[0016] In some embodiments, the film-forming agent is selected from any one or more of polyvinyl pyrrolidone, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, chitosan, gelatin, carbomer and hydroxypropyl cellulose.

[0017] In some embodiments, the propellant is selected from one or more of butane, isobutane, propane, 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, ethanol, and isopropanol.

[0018] The present invention also provides a method for preparing the pharmaceutical composition, comprising the following steps:

[0019] The modified hemoglobin molecule is dissolved in a buffer solution, lipoic acid and acetylcysteine ​​are added, and the mixture is continuously stirred. After the mixture is dissolved, a solvent is added to obtain the pharmaceutical composition.

[0020] In some embodiments, the buffer solution is any one of a phosphate buffer solution, a citric acid buffer solution, or an acetic acid buffer solution.

[0021] The present invention also provides use of the pharmaceutical composition in preparing a medicine for promoting wound healing and wound repair.

[0022] In some embodiments, the wound or injured surface is a burn, scald, soft tissue ulcer or long-term erosion.

[0023] In summary, compared with the prior art, the present invention achieves the following technical effects:

[0024] 1. The pharmaceutical composition of the present invention uses a hemoglobin molecule modified with a benzimidazole derivative as its main functional component, and has excellent oxygen binding and release capabilities. The oxygenation rate can quickly reach over 90% within 1 minute after exposure to air, significantly improving the hypoxic state of local tissues on the wound surface and promoting cell activity and tissue repair.

[0025] 2. The present invention combines lipoic acid and acetylcysteine ​​in an external-use pharmaceutical composition containing a hemoglobin molecule modified with a benzimidazole derivative. Through synergistic antioxidant and tissue protective effects, the irritation reaction to the skin caused by hemoglobin modification is effectively alleviated, thereby improving the safety and applicability of the drug in the treatment of skin wounds. The drug is suitable for the treatment of various types of wounds such as trauma, burns, and postoperative wounds.

[0026] 3. The pharmaceutical composition of the present invention is in the form of an aqueous solution with a simple formula and synergistic and compatible components. It can be prepared using conventional emulsification, mixing and filling processes, making it easy to industrialize. Stability studies have shown that the product has good stability and shows no obvious precipitation, stratification or component degradation within 12 months under room temperature and light-proof conditions. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for use in the embodiments. It should be understood that the following drawings only illustrate certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other relevant drawings can be obtained based on these drawings without paying any creative work.

[0028] Figure 1This is the change in the content of oxidized hemoglobin (Oxy-Hb) over time during the oxygenation process of hemoglobin molecules in air in Test Example 1 of the present invention. DETAILED DESCRIPTION

[0029] To help those skilled in the art better understand the present invention, the technical solutions in the embodiments of the present invention are clearly and completely described. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work should fall within the scope of protection of the present invention.

[0030] In a specific embodiment of the present invention, the pharmaceutical composition is applied in the form of a spray, which is easy to operate and suitable for rapid treatment of large or irregular wounds. However, it should be understood that the pharmaceutical composition provided by the present invention is not limited to a spray dosage form. Without departing from the essence of the present invention, technicians can prepare it into a variety of external dosage forms according to actual needs, including but not limited to ointments, gels, creams, patches, emulsions, paints, foams, hydrogel dressings, wound patches, etc. These dosage forms can better meet the needs of sustained drug release, local coverage, wound protection and patient compliance in different clinical situations. Therefore, the scope of protection of the present invention should include all suitable dosage forms for applying the composition to external treatment.

[0031] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. The materials and reagents used are all commercially available unless otherwise specified.

[0032] The preparation and identification of modified hemoglobin molecules are detailed in Patent No. ZL202411603238.3, Example 1.

[0033] Bovine hemoglobin molecule: Meilun Biotechnology, MB2760-1.

[0034] The preparation method of the pharmaceutical composition for promoting wound healing of the present invention is as follows:

[0035] (1) Solution preparation: Add hemoglobin molecules to physiological saline and stir and dissolve on a magnetic stirrer at a speed of 300-500 rpm. The temperature is controlled at 4-8°C to prevent protein denaturation.

[0036] (2) Add lipoic acid and acetylcysteine ​​to the above solution in sequence and continue stirring until all components are completely dissolved.

[0037] The above pharmaceutical composition was made into a spray for subsequent testing:

[0038] The spray base was added to the above mixture, and after continuing to stir evenly, physiological saline was added. Phytophosphate buffered saline (PBS, 0.01 mol / L) was used to control the pH in the range of 6.8 to 7.4.

[0039] The mixture was sterilized by filtration using a vacuum filtration apparatus and 0.22 μm PES.

[0040] Example 1

[0041] The pharmaceutical composition of this embodiment comprises the following components in parts by weight:

[0042] 5 parts of hemoglobin molecules, 3 parts of lipoic acid, 0.5 parts of acetylcysteine, 10 parts of vinylpyrrolidone, and 60 parts of normal saline.

[0043] Example 2

[0044] The pharmaceutical composition of this embodiment comprises the following components in parts by weight:

[0045] 1 part of hemoglobin molecule, 1 part of lipoic acid, 0.1 part of acetylcysteine, 2 parts of polyvinyl alcohol, 3 parts of propylene glycol, and 60 parts of normal saline.

[0046] Example 3

[0047] The pharmaceutical composition of this embodiment comprises the following components in parts by weight:

[0048] 10 parts of hemoglobin molecules, 5 parts of lipoic acid, 1 part of acetylcysteine, 2 parts of polyvinyl alcohol, 3 parts of propylene glycol, and 60 parts of normal saline.

[0049] Example 4

[0050] The pharmaceutical composition of this embodiment includes the following components in parts by weight: 3 parts of hemoglobin molecules, 5 parts of lipoic acid, 0.5 parts of acetylcysteine, 10 parts of vinylpyrrolidone, and 60 parts of normal saline.

[0051] Comparative Example 1

[0052] The pharmaceutical composition of this comparative example comprises the following components in parts by weight:

[0053] 5 parts of unmodified bovine hemoglobin molecules, 3 parts of lipoic acid, 0.5 parts of acetylcysteine, 10 parts of vinylpyrrolidone, and 60 parts of normal saline.

[0054] Comparative Example 2

[0055] The pharmaceutical composition of this comparative example comprises the following components in parts by weight:

[0056] 5 parts of hemoglobin molecule, 0.5 parts of acetylcysteine, 10 parts of vinylpyrrolidone, and 60 parts of normal saline.

[0057] Comparative Example 3

[0058] The pharmaceutical composition of this comparative example comprises the following components in parts by weight:

[0059] 5 parts of hemoglobin molecules, 3 parts of lipoic acid, 10 parts of vinyl pyrrolidone, and 60 parts of normal saline.

[0060] Comparative Example 4

[0061] The pharmaceutical composition of this comparative example comprises the following components in parts by weight:

[0062] 5 parts of hemoglobin molecule, 10 parts of vinyl pyrrolidone, and 60 parts of normal saline.

[0063] Test Example 1: Hemoglobin molecule oxygenation curve analysis

[0064] This test example verifies whether the hemoglobin molecules used in this application can quickly combine with oxygen in the air and evaluates their oxygenation efficiency.

[0065] The content of oxyhemoglobin (Oxy-Hb) in the hemoglobin molecule used in this application was measured using a blood oxygen analyzer (GEM OPL) blood gas meter.

[0066] The results are as follows Figure 1 As shown, within 1 minute after the reaction started, the Oxy-Hb content rose rapidly, from an initial level of approximately 5% to over 90%. Thereafter, the Oxy-Hb content stabilized, maintaining a high level of 92% to 95%. Throughout the reaction, the methemoglobin (Met-Hb) content remained at a low level (<1%), with no significant increase. This indicates that hemoglobin did not undergo significant oxidative degradation, indicating that hemoglobin molecules can quickly bind to oxygen in the air and have a high oxygenation efficiency. This characteristic gives it a clear advantage in applications such as topical wound repair and oxygen supply to hypoxic tissues, verifying its functional reliability as an oxygen-carrying active ingredient.

[0067] Test Example 2 Long-term stability study of the composition

[0068] The physicochemical properties and active ingredient contents of the pharmaceutical compositions prepared in Examples 1 to 4 and Comparative Examples 1 to 4 were tested under different storage conditions.

[0069] Test conditions: temperature 6±2℃, relative humidity (RH) 60%±5%, time points: 0, 1, 3, 6, 12 months.

[0070] Test Method: Hemoglobin content is measured spectrophotometrically: Prepare a standard series of hemoglobin solutions of known concentrations ranging from 5 to 100 μg / mL. Accurately take 200 μL of the spray sample and dilute it to 1 mL with pure water. Measure the absorbance at 410 nm using a UV-Vis spectrophotometer. Substitute the absorbance into the curve to determine the concentration, and calculate the content retention rate (assuming the initial value is 100%).

[0071] The test results are shown in Table 1:

[0072] Table 1 Composition stability test results

[0073]

[0074]

[0075] As shown in Table 2, the pharmaceutical composition provided by the present invention was placed under normal temperature and dark conditions for 12 months, and the content of key functional components did not change significantly, indicating that the composition has good physicochemical stability. A comparative experiment found that in the composition without the addition of lipoic acid and acetylcysteine, the hemoglobin content retention rate was significantly reduced. This shows that the composite spray of the present invention has excellent long-term storage stability and ingredient activity retention ability, and is suitable for industrial production and clinical application needs.

[0076] Test Example 3 Skin Irritation Study

[0077] Thirty-six rabbits were randomly divided into eight experimental groups and one control group, with four rabbits in each group (two rabbits in each group with normal skin and two rabbits in each group with damaged skin). 24 hours before the experiment, the long hair on both sides of the rabbit's spine was trimmed with curved scissors. A depilatory agent was evenly applied to the depilatory area. After 5 minutes, the hair was gently removed with a glass rod. A cotton ball was dipped in warm water to wash away the depilatory agent and the shed hair (about 50 cm on each side). 2 A skin damage model was established in both the experimental and control groups by using a sterile needle to scratch the depilated area in a well-shaped pattern, preferably without bleeding. The experimental group rabbits were sprayed evenly with the sprays of Examples 1-4 and Comparative Examples 1-4 on the left depilated area, with the right side serving as a blank control. The control group rabbits were sprayed evenly with 0.9% sodium chloride injection on the left depilated area, with the right side serving as a blank control. Skin irritation reactions were observed and recorded 1, 24, and 72 hours after administration.

[0078] Irritation evaluation: Observe the degree of erythema (including eschar) and edema. ① Erythema reaction: No erythema = 0 points; barely visible erythema = 1 point; moderate erythema = 2 points; severe erythema = 3 points; purple-red erythema with eschar formation = 4 points. ② Edema reaction: No edema = 0 points; barely visible edema = 1 point; skin bulge with clear outline = 2 points; edema bulge of approximately 1 cm and extending to a larger area = 4 points.

[0079] Irritation score = (total score of erythema reaction + total score of edema reaction) / number of animals in each group. A irritation score of <0.5 indicates no irritation; 2.0 indicates mild irritation; 6 indicates moderate irritation; and >6 indicates strong irritation.

[0080] The results are shown in Table 2:

[0081] Table 2 Results of the rabbit skin irritation test with hemoglobin spray

[0082]

[0083]

[0084] As shown in Table 1, the combination of lipoic acid and acetylcysteine ​​was added to Examples 1 to 4 of the present invention, which significantly reduced the irritation of the spray to the skin. The irritation score was less than 0.5, and no adverse reactions such as obvious erythema and peeling were observed. In the comparative example, lipoic acid and acetylcysteine ​​were not added, or components of unmodified hemoglobin were used, and the irritation score was significantly increased. Some samples showed irritation such as erythema and peeling. The results show that the addition of lipoic acid and acetylcysteine ​​to the spray has the effects of synergistic antioxidant, stabilizing membrane structure, and inhibiting inflammatory response, thereby significantly improving skin irritation and enhancing its application safety in wound repair and topical medicine.

[0085] Test Example 4: Analysis of Oxygen Carrying Capacity of Hemoglobin Spray

[0086] The blood oximeter was used for detection (GEM OPL) and calibrated with yellow and orange optical calibration sheets respectively.

[0087] Oxygen-carrying sample testing is carried out according to the GEM OPL operating instructions. The specific steps are as follows: use a 1mL syringe to draw an appropriate amount of sample, insert the front end of the syringe into the test piece, keep the test piece tilted at approximately 45°, and evenly inject the sample into the test piece until the sample reaches the vent position of the test piece. Keep the syringe connected to the test piece and insert it into the GEM OPL slot. Select according to the prompts on the instrument display.

[0088] The results are shown in Table 3:

[0089] Table 3 GEM OPL blood gas analysis results

[0090]

[0091]

[0092] The results are shown in Table 3. Compared with Comparative Examples 1 to 4, Examples 1 to 4 generally have a higher proportion of oxygenated hemoglobin, indicating that the compound lipoic acid and acetylcysteine ​​can effectively maintain the oxygen binding capacity of hemoglobin. Among them, the combination of synergistic antioxidant components in Examples 1 and 3 has the best effect. At the same time, the presence of high-concentration hemoglobin also brings higher total Hb value and oxygenation rate. In Comparative Example 1, unmodified hemoglobin is used, and the content of methemoglobin is the highest, indicating that its stability and functionality are the worst.

[0093] Test Example 5: Bacterial Endotoxin Detection

[0094] Endotoxin detection was performed using the Limulus amebocyte lysate (LAL) microgel method according to the product instructions (sensitivity 0.125 EU / mL, Fuzhou Xinbei Biochemical Industry Co., Ltd.). The specific steps are as follows:

[0095] First, prepare the endotoxin standard solution with endotoxin test water to obtain an endotoxin standard solution with 2 times the sensitivity, then dilute the sample with endotoxin test water, and prepare the test sample positive control at the same time. Next, dissolve the horseshoe crab reagent, mix well and add it to the inspection tube: add the endotoxin standard solution to the positive control tube, add the endotoxin test water to the negative control tube, and add the diluted sample to the test sample tube. Then seal the tube mouth, place it vertically in a 37°C constant temperature water bath, and keep warm for 1 hour. Result judgment: Take the inspection tube out of the constant temperature water bath, slowly turn it upside down 180°. If a gel is formed in the tube, and the gel does not deform and does not slide off the tube wall, it is positive; if no gel is formed or the formed gel is not strong, deforms, and slides off the tube wall, it is negative. The results are shown in Table 4:

[0096] Table 4 Endotoxin detection of sprays promoting wound healing

[0097]

[0098]

[0099] The results in Table 4 show that, from the bacterial endotoxin test results, the spray products of each embodiment of the present invention and the comparative example did not form gel under the detection conditions of the Limulus amebocyte lysate microgel method (sensitivity 0.125EU / mL), and were judged to be negative, indicating that the endotoxin content in the product is low, meeting the injection standard specified in the pharmacopoeia (less than 0.5EU / mL), and is suitable for high safety requirements such as external use or transdermal absorption. Test Example 6 Hemoglobin spray promotes healing in a full-thickness skin wound model in mice

[0100] (1) Animal Model Establishment: BALB / c, 6- to 8-week-old female mice were anesthetized, their backs shaved, and disinfected with 75% ethanol. Two symmetrical full-thickness skin defects (deep into the muscular layer) were created using a sterile 8 mm round hole punch. Each mouse was randomly divided into two groups: an experimental group (sprayed with the spray prepared in Example 1) and a control group (sprayed with PBS solution, pH 7.4), with 6 mice in each group.

[0101] (2) Drug treatment: Spray the wound area once a day, about 100 μL each time, and let it dry naturally after spraying. The treatment cycle continues until the wound is completely healed (about 10 to 14 days)

[0102] (3) Wound healing was recorded every 2 days, and the wound area was measured using ImageJ software to calculate the healing rate.

[0103] (4) The results are shown in Table 5:

[0104] Table 5 The efficacy of hemoglobin spray on wound healing in mice

[0105] Detection indicators Control group (PBS) Example 1 Wound residual area on day 3 (%) 85.6±4.2 58.3±2.9** Residual wound area on day 7 (%) 46.7±5.0 18.2±3.1** Complete healing time (days) 13.8±1.1 8.6±0.7**

[0106] Note: All data are expressed as mean ± standard deviation (Mean ± SD), and statistical analysis was performed using a two-sided t-test.

[0107] The results are shown in Table 5. After being treated with the spray prepared in Example 1 of the present application, the healing time of the mouse wounds was significantly shortened, indicating that the pharmaceutical composition of the present invention can significantly improve the healing effect of the mouse wounds.

[0108] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A pharmaceutical composition for promoting wound healing, characterized in that: In parts by weight, it comprises the following components: 1-10 parts of hemoglobin molecules, 1-5 parts of lipoic acid, 0.1-1 parts of acetylcysteine, and 40-80 parts of solvent; The hemoglobin molecule comprises at least one cysteine ​​moiety and at least one histidine moiety, wherein the cysteine ​​moiety comprises an acetyl group or an ethylmaleyl group and the histidine moiety comprises a benzimidazole derivative group.

2. The pharmaceutical composition according to claim 1, characterized in that The mass ratio of the hemoglobin molecule to the lipoic acid is (1-2):

1.

3. The pharmaceutical composition according to claim 1, characterized in that The solvent is any one or more of water, physiological saline and ethanol.

4. A preparation, characterized in that The preparation comprises the pharmaceutical composition according to any one of claims 1 to 3.

5. The preparation according to claim 4, characterized in that The dosage form of the preparation is any one of a spray, an ointment, a gel, a cream, a patch, an emulsion, a paint, a foam, a hydrogel dressing and a wound patch.

6. The preparation according to claim 5, characterized in that The spray further comprises 5 to 20 parts of a spray base, and the spray base is selected from one or more of a film-forming agent, a propellant and a moisturizing agent.

7. The preparation according to claim 5, characterized in that The film-forming agent is selected from any one or more of polyvinyl pyrrolidone, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, chitosan, gelatin, carbomer and hydroxypropyl cellulose.

8. The method for preparing the pharmaceutical composition according to any one of claims 1 to 3, characterized in that: The steps include: The modified hemoglobin molecule is dissolved in a buffer solution, lipoic acid and acetylcysteine ​​are added, and the mixture is continuously stirred. After the mixture is dissolved, a solvent is added to obtain the pharmaceutical composition.

9. The preparation method according to claim 8, characterized in that The buffer solution is any one of a phosphate buffer solution, a citric acid buffer solution or an acetic acid buffer solution.

10. Use of the pharmaceutical composition according to any one of claims 1 to 3 in the preparation of a medicament for promoting wound healing and wound repair.

Images