CN115518145A - Medicine for repairing skin defect, removing acne and/or removing wrinkles - Google Patents
Medicine for repairing skin defect, removing acne and/or removing wrinkles Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/195—Chemokines, e.g. RANTES
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1808—Epidermal growth factor [EGF] urogastrone
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1858—Platelet-derived growth factor [PDGF]
- A61K38/1866—Vascular endothelial growth factor [VEGF]
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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Abstract
The invention belongs to the field of medicines, and particularly relates to a medicine for repairing skin defects, removing acnes and/or wrinkles. The medicine is prepared from the following raw materials in parts by weight: 0.0025-100 parts of SDF-1, 0.00125-100 parts of VEGF and 0.01-100 parts of EGF. The medicine has good skin repairing effect, and can be used for removing acne and repairing wrinkle. As a preferred mode, the present invention allows better penetration of the cell growth factor into the skin by means of microneedle administration. The invention has good application prospect.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a medicine for repairing skin defects, removing acnes and/or wrinkles.
Background
Acne is a blockage of hair follicles due to a variety of causes, and is a common skin lesion. Wrinkles are another kind of skin injury caused by various reasons, are one of the most important characteristics of skin aging, are deepening of a primary line on the skin surface, and are clinical symptoms of subcutaneous fat reduction, water loss and wrinkle lines on the skin surface due to long-term effects of various endogenous and exogenous factors such as limb joint movement and long-term repeated traction of local subcutaneous muscles. The mechanism of the disease is mainly the research theories of genetics, free radical theory, supply deficiency theory, immune monitoring theory, endocrine hypofunction theory, protein synthesis error theory, photoaging theory and the like, and is essentially due to the result of physiological aging change or pathological function change of the skin tissue matrix structure.
The cell growth factor is combined with a cell surface specific receptor, propagates, grows and differentiates, promotes cell metabolism, enhances oxidation, can promote the rapid growth and propagation of cells related to skin injury, regulates the synthesis, secretion and decomposition of intercellular matrix, can promote the regeneration of stratum corneum cells, accelerates the repair of stratum corneum and matrix layers of the skin, and promotes the growth of skin cells of a human body. The Chinese patent application CN201811552858.3 as a raw material of cosmetics for removing freckles from skin and products thereof discloses that cell growth factors can be used in products related to skin repair.
The cell growth factor is difficult to directly permeate the skin, and the existing skin repair products are mostly in the forms of facial masks, ointments and the like, so that the existing medicines containing the cell growth factor are difficult to fully exert the effect of the cell growth factor on skin repair.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a medicine for repairing skin defects, removing acnes and/or wrinkles, and aims to prepare a cell growth factor into a micro-injection, and the treatment effect of the cell growth factor is fully exerted through micro-needle administration.
A medicine for repairing skin defects, removing acnes and/or wrinkles is prepared from the following raw materials in parts by weight:
0.0025 to 100 portions of SDF-1,
0.00125-100 parts of VEGF,
0.01-100 parts of EGF.
Preferably, the feed additive is prepared from the following raw materials in parts by weight:
0.0025 to 0.5 portion of SDF-1,
0.00125 to 0.05 portion of VEGF,
And 100 parts of EGF.
Preferably, the feed additive is prepared from the following raw materials in parts by weight:
0.5 portion of SDF-1,
VEGF 0.05 part,
And 100 parts of EGF.
Preferably, the medicament is a micro injection.
Preferably, the micro-needle curing agent is prepared by mixing the raw material and a micro-needle curing agent, wherein the weight ratio of the raw material to the micro-needle curing agent is as follows: (0.03-300): (0.03-300).
Preferably, the micro-needle curing agent is prepared by mixing the raw material and a micro-needle curing agent, wherein the weight ratio of the raw material to the micro-needle curing agent is as follows: 0.1:1-10:1.
Preferably, the microneedle solidifying agent is selected from hyaluronic acid.
The invention also provides a preparation method of the medicine, which comprises the following steps:
step 1, mixing the raw materials with a microneedle curing agent to prepare microneedles;
and 2, fixing the microneedle to prepare the microneedle patch.
The invention takes three cell growth factors of SDF-1, VEGF and EGF as active ingredients. The proliferation and differentiation characteristics of the stem cells are utilized to attract the stem cells to the damaged part (also called homing), so that a better tissue repair effect can be generated. Cell growth factors, including SDF-1, VEGF, are important factors for attracting stem cell homing, for attracting CXCR4+/VEGFR1+ pluripotent stem cells to the site of injury, as shown in fig. 5. EGF is used for promoting differentiation and proliferation of cells, and can accelerate granulation tissue generation and epithelial cell proliferation of wound surface. The three cell growth factors are compounded to play a role in repairing, and have the effects of removing acnes and wrinkles. As a preferred scheme, the three cell growth factors are prepared into a micro-injection, when the micro-injection is administered, along with the dissolution of a curing agent, the drug enters the epidermis to form high concentration locally, and stem cells enter tissues in a reverse concentration gradient manner, so that the treatment effect can be effectively improved.
It will be apparent that various other modifications, substitutions and alterations can be made in the present invention without departing from the basic technical concept of the invention as described above, according to the common technical knowledge and common practice in the field.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
Fig. 1 is a schematic illustration of a microneedle agent and its administration;
FIG. 2 is a graph showing the skin repairing effect of the animals in Experimental example 1.
FIG. 3 is a graph showing that the acne marks were apparently disappeared after two weeks by the patient in Experimental example 2.
FIG. 4 shows the results of the animal experiments in Experimental example 3.
FIG. 5 shows the results of animal immunofluorescence in Experimental example 4, wherein yellow arrows indicate CXCR4+/VEGFR1+ pluripotent stem cells.
Detailed Description
The reagents and materials used in the following examples and experimental examples are commercially available ones without specific reference.
EXAMPLE 1 medicament for repairing skin defects, removing acne and/or wrinkles
Adding 2g carbomer into 80ml distilled water, stirring to make it fully swell, adding 2.7g triethanolamine under stirring, and making into hydrogel matrix. And dissolving SDF-1, VEGF and EGF in 2ml of water, adding into the gel matrix under stirring, adding distilled water to 100g, and stirring. The final concentration of the three cell growth factors is SDF-1 ng/g, VEGF 2.5ng/g and EGF200ug/g.
The drug prepared in this example was a transparent semisolid gel.
EXAMPLE 2 medicament for repairing skin defects, removing acne and/or wrinkles
The preparation method of this example is the same as that of example 1, except that the amounts and ratios of the raw materials are adjusted so that the final concentrations of the three cell growth factors are: SDF-1 100ng/g, VEGF25ng/g and EGF200ug/g.
EXAMPLE 3 medicament for repairing skin defects, removing acne and/or wrinkles
The preparation method of this example is the same as that of example 1, except that the amounts and ratios of the raw materials are adjusted so that the final concentrations of the three cell growth factors are: SDF-1 1000ng/g, VEGF 100ng/g and EGF200ug/g.
Example 4 medicament for repairing skin defects, removing acne and/or wrinkles
The raw materials used and the ratio in this example were the same as in example 3, and SDF-1 ug, VEGF0.1ug and EGF200ug were dissolved in 1ml of water. In order to break through the natural barrier effect of the stratum corneum of the skin and increase the skin administration permeation efficiency, the raw materials are mixed with 100mg of Hyaluronic Acid (HA), and a drug-carrying solution is dripped on a Polydimethylsiloxane (PDMS) microneedle template to prepare the top end of a microneedle; then 100mg/mL HA solution without raw materials is dripped on the surface of the microneedle mould to prepare a microneedle patch, and a plurality of microneedles are synthesized into a soft transdermal drug delivery microneedle patch as shown in figure 1.
The advantageous effects of the present invention will be further described below by experiments.
Experimental example 1 skin repair Effect on animals
1. Experimental methods
New Zealand rabbits were divided into a product group (using the drug of example 1), a control group (without any drug), and a commercially available drug (recombinant human epidermal growth factor gel, guilin Huanworu Gene pharmaceutical Co., ltd.). After 4 x 4cm of skin was excised from the backs of rabbits, healing of the skin was observed every 3-5 days using different drugs (either micro-injections were applied to the wounds or the drugs were applied to the wounds).
2. Results of the experiment
Wounds healed in 3 groups of animals 55 days after skin excision, however, in both the control group and the commercially available drug group, giant fibrous connective tissue appeared (indicated by red arrows), and the skin structure was intact and appendages developed normally using this patent. The skin is cut along the box to make a pathological section. Microscopically, the neonatal skin of the experimental animals had not only normal stratum corneum (fig. 2C, shown by red open triangles) but also newly formed sebaceous glands (fig. 2C, shown by cyan triangles) and hair follicles (fig. 2C, shown by blue triangles). While the other two groups of animals seen only giant fibrous connective tissue (fig. 2A, B, shown by red triangles) without any skin appendage structures (fig. 2A, B, shown by green arrows).
The experiments show that the medicine has good skin repairing effect.
Experimental example 2 acne removing Effect study
1. Experimental methods
The study included 28 patients with acne who used the medication of example 4 at 2 times per day for a treatment period of 2-5 days.
And the efficacy was analyzed with the following criteria:
2. results of the experiment
The efficacy results are shown in the following table:
| conclusion | Number of examples | ％ |
| Complete recovery | 25 | 89.3％ |
| Discontent withIntention to | 1 | 3.6％ |
| Is completely ineffective | 2 | 7.1％ |
The comparative graph of the treatment effect of the typical case is shown in FIG. 3.
The experimental results show that the effective rate of the medicine reaches 89.3%, and the medicine has a good treatment effect.
Experimental example 3 formulation optimization experiment
1. Experimental method
1. Animal modeling
SPF grade 2.5-3kg New Zealand rabbits were used as experimental animals, and were divided into control group (without any drug), and experimental group (inventive group). After the rabbits were anesthetized with 0.5% sodium pentobarbital by intravenous injection at the ear margin at a dose of 6 ml/kg, the backs of the rabbits were excised at 4 × 4cm of skin, and then the wounds were each dressed with different drugs, and the healing of the skin was observed every 3-5 days.
2. Method of treatment
The animal wounds were treated with the drugs prepared in example 1, example 2 and example 3, and the drugs were applied by spreading on the wounds.
2. Results of the experiment
The drug of example 1 was used in the first and second batches of animals as shown in figure 4. After use, the following findings are: the animal skin after defect grows more rapidly, but is still unsatisfactory, and has no significant difference compared with a control group. Fortunately, however, the growing skin is mostly capable of hair growth with insignificant wound shrinkage, suggesting that these drugs still play a very important role.
The drug of example 2 was used for the third batch of animals. The results showed that the wound was evenly covered with multiple layers of cells within 3-5 days of the skin incision. The skin can quickly mature within 10 days, basically heals within 25 days, and the wound surface can grow hair within 35 days. This obvious disadvantage: when the skin heals to the most central position, a piece of skin still cannot become normal skin, and scars are formed; in the later stages, the skin still has contractures; horn-like scars were still visible.
The drug of example 3 was used in the fourth batch of animals. As a result, it was found that complete coverage of the wound surface was achieved in 24 to 48 hours, and the cells near the skin were completely changed into skin cells around the wound in 10 days, with the edge growing about 1cm. The wound surface is replaced by the whole skin within 20 days, and scars are not obvious. The skin grown for 25 days had already had hair growth, leaving only 0.1cm in the central position. The growing skin has already had hair growth, and the central site has healed all together.
Based on SDF-1 ng/g and VEGF 2.5ng/g of example 1, the dosage proportion and dosage unit of example 1 are changed. In order to make the medicine fully exert the efficacy function, the medicine concentration of blood plasma should reach VEGF:100-500pg/ml; SDF-1:1-2ng/ml. Example 2SDF-1 100ng/g VEGF25ng/g was performed because SDF-1 is the primary cell that initiates stem cell mobilization. If 2g of drug is applied to the wound, and if all the drug is absorbed, the plasma drug concentration will reach: VEGF = (25 × 2)/(2.5 × 80) =0.25ng/ml, blood =250pg/ml, approximately doubling the concentration of blood. SDF = (100 × 2)/(2.5 × 80) =1ng/ml blood =1000pg/ml, and approximately doubles the blood concentration. However, only 1/4 of the drug is absorbed, and the blood concentration can be increased only by about 1/4, which is difficult to achieve the purpose of starting stem cells and only can attract the stem cells to the wound. That is, the stem cells that are attracted are already present in the blood. If the wound is too big and the bone marrow needs to be started to secrete stem cells, the concentration of the medicine needs to be increased to 5-10 times, and the SDF-1 of example 3 is 1000ng/g, the VEGF is 100ng/g and the EGF is 200ug/g.
The above results indicate that the therapeutic effect of the drug of example 3 is superior to that of the drugs of examples 1 and 2.
Experimental example 4
1. Experimental methods
After the animals were anesthetized, the injured tissue was fixed by soaking in 10% paraformaldehyde for 24h, dehydrated with 30% sucrose for 3 days, and frozen sections with a thickness of 10 μm were prepared using a freezing microtome. And (3) marking the co-staining condition of CXCR4 and VEGFR1 receptors and DAPI by using a fluorescence double-labeling method.
2. Results of the experiment
The result of immunofluorescence staining shows that CXCR4+/VEGFR1+ pluripotent stem cells at the damaged part of the tissue are increased after the medicine in the embodiment 3 is used, and the SDF-1 and the VEGF in the product can attract the CXCR4+/VEGFR1+ pluripotent stem cells to reach the damaged part.
The embodiments of the present invention can show that the present invention provides a micro-injection solution with cell growth factor as active ingredient, which can better penetrate into skin by micro-needle administration. The medicine disclosed by the invention has a good skin repairing effect, can better remove acnes and repair wrinkles, and has a good application prospect.
Claims (8)
1. A medicine for repairing skin defects, removing acnes and/or wrinkles is characterized by being prepared from the following raw materials in parts by weight:
0.0025 to 100 portions of SDF-1,
0.00125-100 parts of VEGF,
0.01-100 parts of EGF.
2. The medicament of claim 1, wherein: the traditional Chinese medicine composition is prepared from the following raw materials in parts by weight:
0.0025 to 0.5 portion of SDF-1,
0.00125 to 0.05 portion of VEGF,
And 100 parts of EGF.
3. The medicament of claim 2, wherein: the traditional Chinese medicine composition is prepared from the following raw materials in parts by weight:
0.5 part of SDF-1,
VEGF 0.05 part,
And 100 parts of EGF.
4. A medicament as claimed in any one of claims 1 to 3, characterized in that: the medicine is micro injection.
5. The medicament of claim 4, wherein: the micro-needle curing agent is prepared by mixing the raw materials with a micro-needle curing agent, wherein the weight ratio of the raw materials to the micro-needle curing agent is as follows: (0.03-300): (0.03-300).
6. The medicament of claim 5, wherein: the micro-needle curing agent is prepared by mixing the raw materials with a micro-needle curing agent, wherein the weight ratio of the raw materials to the micro-needle curing agent is as follows: 0.1:1-10:1.
7. The medicament of claim 5, wherein: the microneedle solidifying agent is selected from hyaluronic acid.
8. A process for the preparation of a medicament as claimed in any one of claims 1 to 7, comprising the steps of:
step 1, mixing the raw materials with a microneedle curing agent to prepare microneedles;
and 2, fixing the microneedle to prepare the microneedle patch.
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