Multi-effect composite scar repair gel as well as preparation method and application thereof

Abstract

The invention provides multi-effect composite scar repair gel as well as a preparation method and application thereof, and belongs to the technical field of biological medicines. The invention develops a multi-effect composite scar repair gel with barrier protection, anti-inflammatory regeneration and long-acting permeation by integrating a silicone base material, traditional Chinese medicine active ingredients and an ionic liquid permeation promotion technology. Wherein the high-viscosity polydimethylsiloxane is used for reducing skin tension; the low-viscosity polydimethylsiloxane improves the skin comfort level; the traditional Chinese medicine extract inhibits fibroblast proliferation and promotes microcirculation; the Ectoin-allantoin microcapsule is capable of realizing 72-hour slow-release anti-inflammatory repair; the BPC157 polypeptide can promote angiogenesis and accelerate wound healing; the transdermal rate of the active ingredients is increased by more than 3 times by the arginine-malic acid ionic liquid; the zinc hyaluronate can synergistically moisturize and regulate the inflammation microenvironment. Through cooperation of multiple mechanisms, the effects of barrier protection, anti-inflammatory regeneration and long-acting permeation are achieved, and the anti-inflammatory and long-acting anti-inflammatory ointment is suitable for repairing hypertrophic scars, acne scars and postoperative incisions.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and in particular to a multi-effect composite scar repair gel, its preparation method, and its application. Background Technology

[0002] Scars are the end product of abnormal repair following damage to the dermis, and their formation involves complex molecular and cellular mechanisms. When the skin is injured deep into the dermis, such as by trauma, burns, or surgical incisions, the body initiates a three-tiered repair process: inflammation, proliferation, and remodeling. During this process, cytokines such as tumor necrosis factor-α (TNF-α) and transforming growth factor-β (TGF-β) released by neutrophils and macrophages excessively activate fibroblasts, leading to abnormal deposition of the extracellular matrix (ECM), especially an imbalance in the synthesis ratio of type I and type III collagen (normal skin has a ratio of 4:1, while scar tissue can reach 19:1). In addition, the dynamic balance between matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) is disrupted, and collagen fibers exhibit a disordered, swirling arrangement rather than the reticular structure of normal skin, ultimately forming pathological scars.

[0003] Based on histological characteristics, pathological scars can be divided into hypertrophic scars (HS) and keloids. The former is confined to the original injury area and is characterized by excessive collagen deposition and abnormal fibroblast proliferation; the latter exhibits infiltrative growth, displaying tumor-like biological behavior, and its pathogenesis is closely related to genetic susceptibility (such as the HLA-DQA1*0102 allele) and epigenetic regulation. Studies have shown that the Wnt / β-catenin signaling pathway is continuously activated in keloid fibroblasts, leading to overexpression of cyclin D1, enabling cells to evade apoptosis mechanisms.

[0004] The need for clinical intervention for scars stems from their multidimensional negative impacts. From a biomechanical perspective, over 50% of scars on joints lead to decreased joint mobility, with contracture scars after burns causing limb function loss in up to 0.5%. The incidence of Marjolin ulcers is approximately 0.7-2%. Psychosocial studies show that patients with facial scars have a 59% higher rate of social avoidance and a 3.2 times higher prevalence of depression compared to the general population. The impact is even more significant in the professional field: the entry standards for scarring in special professions such as pilots and firefighters are stringent, while in image-related professions such as actors and models, 92% of practitioners believe that noticeable scars directly hinder their career development.

[0005] There are many medications available for treating scars, but their drawbacks are also quite obvious: Glucocorticoids (such as triamcinolone) are first-line treatments that work by inhibiting the expression of inflammatory factors TGF-β1 and IL-6. However, clinical data show that the recurrence rate after keloid injection treatment is 40-60%. Long-term use can lead to skin atrophy (incidence 22%), telangiectasia (15%), and depigmentation (34%). More seriously, approximately 12% of patients experience hypothalamic-pituitary-adrenal axis suppression, requiring strict limitation of injection dosage (≤40 mg per injection point) and frequency.

[0006] Silicone-based treatments, as a physical barrier therapy, modulate the scar microenvironment through hydration and electrostatic effects. However, meta-analysis showed that their effectiveness in preventing hypertrophic scars was only 23% higher than the control group (RR=1.23, 95% CI 1.08-1.40). In practical applications, they need to be applied for more than 12 hours daily, resulting in poor compliance in warm and humid environments, and the improvement rate for existing mature scars is less than 18%.

[0007] Antimetabolites (5-fluorouracil, mitomycin C) inhibit fibroblast proliferation by suppressing DNA synthesis. Local injection of 5-FU can reduce scar volume by 38±12%, but injection pain (VAS score 6.8±1.2) leads to a treatment discontinuation rate of 29%. More importantly, mitomycin C exhibits dose-cumulative toxicity, exceeding 0.4 mg / cm². 2 The risk of corneal perforation is significantly increased, and its ophthalmic application has been limited.

[0008] Biologic agents (interferon α-2b, TGF-β3): Interferon downregulates collagen synthesis through the JAK-STAT signaling pathway, and clinical trials have shown that it can reduce scar thickness by 47%, but the incidence of flu-like symptoms is as high as 85%, and the cost of a single course of treatment exceeds $2,000. Although TGF-β3 can promote ECM remodeling, its phase III clinical trial (NCT02110693) failed to meet the primary endpoint (p=0.067) and thus failed to obtain FDA approval.

[0009] Retinoic acid derivatives: All-trans retinoic acid inhibits collagen production by regulating the Smad pathway, and at a concentration of 0.05%, it can reduce scar hardness by 31%. However, photosensitivity limits its use during the day, and the recurrence rate exceeds 45% within 6 months after discontinuation of the drug.

[0010] While novel drug delivery systems such as liposomes can improve penetration (3.8 times higher than traditional formulations), their cost increases by 4-6 times for large-scale production.

[0011] The limitations of existing drugs mainly stem from the complexity of the pathological mechanisms: single-target intervention is insufficient to reverse multi-pathway abnormalities and cannot simultaneously inhibit collagen deposition, promote tissue regeneration, and regulate the inflammatory microenvironment. For example, while TGF-β inhibitors can reduce collagen synthesis, they cannot correct existing fibrotic structures. Traditional Chinese medicine compound preparations have low transdermal absorption rates and are difficult to maintain a sustained effect. Novel treatment strategies such as stem cell therapy (adipose-derived SVF cells), gene editing (CRISPR-Cas9 silencing the COL1A1 gene), and photodynamic therapy (ALA-PDT) have shown potential in basic research, but large-scale, long-term follow-up data are still lacking.

[0012] Therefore, there is an urgent need for a new type of therapeutic drug that combines barrier protection, anti-inflammatory regeneration, and long-lasting penetration. Summary of the Invention

[0013] The purpose of this invention is to provide a multi-effect composite scar repair gel, its preparation method and application. This hydrogel has the effects of barrier protection, anti-inflammatory regeneration and long-lasting penetration. Through the synergistic effect of multiple mechanisms, it achieves the effects of barrier protection, anti-inflammatory regeneration and long-lasting penetration, and is suitable for hypertrophic scars, acne scars and postoperative incision repair.

[0014] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a multi-effect composite scar repair gel, which comprises the following raw materials in the indicated mass ratios: High viscosity polydimethylsiloxane: Low viscosity polydimethylsiloxane: Dimethyl silicone oil: Traditional Chinese medicine extract: Ectoin-allantoin microcapsules: BPC157 polypeptide: Arginine-malic acid ionic liquid: Zinc hyaluronic acid: Carbomer = 20~30:1~4:3~8:1~4:0.5~3:0.01~0.1:0.5~3:0.1~0.3:0.1~0.3.

[0015] Preferably, the high-viscosity polydimethylsiloxane has a viscosity of 1000-5000 mPa·s, and the low-viscosity polydimethylsiloxane has a viscosity of 50-200 mPa·s.

[0016] Preferably, the herbal extract comprises the following raw materials in the following mass ratio: Salvia miltiorrhiza: Panax notoginseng: Carthamus tinctorius = 2~8:2~4:1~3; Preferably, the preparation method of the traditional Chinese medicine extract is as follows: After mixing Salvia miltiorrhiza, Panax notoginseng and Carthamus tinctorius, the mixture was extracted with supercritical CO2 at 20-30 MPa and 40-50℃ for 1-3 hours. The residue was then extracted with 60-80% ethanol by reflux 1-5 times, and the filtrates were combined and concentrated.

[0017] Preferably, the preparation method of the ectoine-allantoin microcapsules includes the following steps: (1) Preparation of wall material: Chitosan and sodium hyaluronate are dissolved in deionized water at a mass ratio of 2~3:1 to prepare a wall material solution of 2-4% w / v; (2) Preparation of core material: Ectoin and allantoin are dissolved in deionized water at a mass ratio of 2~4:0.5~2 and mixed to obtain a mixed solution with a core material concentration of 3~7%; (3) Mix the wall material and the core material homogenize and crosslink and cure to obtain ectoin-allantoin microcapsules with a particle size of 50~100 μm.

[0018] Preferably, the preparation method of the arginine-malic acid ionic liquid includes the following steps: Arginine and malic acid are dissolved in deionized water and mixed in a molar ratio of 1~2:1~2. The mixture is reacted at 20~30℃ for 3~5 hours, and the water is removed by evaporation.

[0019] This invention also provides a method for preparing the above-mentioned multi-effect composite scar repair gel, comprising the following steps: (1) Preparation of silicone substrate: High viscosity polydimethylsiloxane, low viscosity polydimethylsiloxane and dimethyl silicone oil are stirred and mixed to obtain silicone substrate; (2) Active layer loading: Chinese herbal extracts, ectoine-allantoin microcapsules, BPC157 peptides, and arginine-malic acid ionic liquid were added to the silicone matrix, ultrasonically dispersed, and then carbomer was added to adjust the viscosity to obtain a multi-effect composite scar repair gel. Preferably, in step (1), the stirring temperature is 50~70℃ and the stirring time is 20~40min.

[0020] Preferably, in step (2), the ultrasonic dispersion conditions are 180~220W for 10~20min.

[0021] This invention also provides a method for preparing a multi-effect composite scar repair gel and its application in the preparation of scar repair and postoperative incision repair products.

[0022] The beneficial effects of this invention compared to the prior art are as follows: (1) This invention integrates silicone substrate, active ingredients of traditional Chinese medicine and ionic liquid permeation technology to develop a multi-effect composite scar repair gel that combines barrier protection, anti-inflammatory regeneration and long-lasting penetration. This gel exhibits significantly superior comprehensive performance compared to existing products in terms of barrier protection, anti-inflammatory regeneration, long-lasting penetration and scar remodeling. Among them, high-viscosity polydimethylsiloxane can form a breathable and waterproof membrane to reduce skin tension; low-viscosity polydimethylsiloxane enhances extensibility and improves skin comfort; Panax notoginseng extract inhibits fibroblast proliferation (TGF-β1 down-regulation by 30%-40%), and Salvia miltiorrhiza promotes microcirculation; ectoine-allantoin microcapsules achieve 72-hour sustained-release anti-inflammatory repair; BPC157 peptide promotes angiogenesis and accelerates wound healing; arginine-malic acid ionic liquid, as a permeation enhancement layer, can increase the transdermal rate of active ingredients by more than 3 times; zinc hyaluronic acid synergistically moisturizes and regulates the inflammatory microenvironment. Through multi-mechanism synergy, it achieves the effects of barrier protection, anti-inflammatory regeneration and long-term penetration, and is suitable for hypertrophic scars (89% effective rate in clinical trials), acne scars and postoperative incision repair.

[0023] (2) The silicone layer provides a physical barrier and moisture retention (moisture evaporation rate ≤ 5 g / m³). 2 • h); Traditional Chinese medicine components inhibit excessive collagen deposition (in vitro collagen synthesis inhibition rate ≥50%); ionic liquid enhances transdermal efficiency (fluorescent labeling shows epidermal penetration depth reaches 200 μm after 24 hours). Long-lasting sustained release: microcapsules achieve 85% release rate within 72 hours, maintaining effective drug concentration at the wound site. Expanded indications: In vitro experiments show collagen synthesis inhibition rate ≥50%; rat model healing time shortened to 14 days (control group 21 days); transdermal efficiency increased by more than 3 times (verified by fluorescent labeling). Detailed Implementation

[0024] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0025] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Every smaller range between any stated value or intermediate value within a stated range, and any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0026] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0027] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0028] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0029] Example 1 Example 1 of this invention provides a method for preparing a multi-effect composite scar repair gel, the specific steps of which are as follows: 1. Preparation of Traditional Chinese Medicine Extracts Supercritical CO2 extraction: Salvia miltiorrhiza, Panax notoginseng and Carthamus tinctorius were mixed in a mass ratio of 5:3:2 and extracted at 25 MPa and 45℃ for 2 hours to obtain the fat-soluble active ingredients. Water extraction and alcohol precipitation method: Collect the filter residue after extraction and reflux with 70% ethanol three times.

[0030] The four filtrates were combined and concentrated to a relative density of 1.2 (60℃). 2. Microcapsule encapsulation (1) Preparation of wall material: Chitosan and sodium hyaluronate were dissolved in deionized water at a mass ratio of 3:1 to prepare a 2% w / v wall material solution (chitosan 1.5% w / v, sodium hyaluronate 0.5% w / v). (2) Preparation of core material: Ectoin and allantoin were dissolved in deionized water at a mass ratio of 4:1 and mixed to obtain a core material concentration of 5% (4% w / v ectoin and 1% w / v allantoin). (3) Emulsification-crosslinking method: The core material is slowly added to the wall material solution, homogenized at 8000 rpm for 10 min, and 0.1M CaCl2 is added dropwise for crosslinking and curing for 30 min. The particle size is controlled at 50-100 μm to obtain microcapsules. 3. Synthesis of ionic liquids Arginine and malic acid reaction: Arginine and malic acid were dissolved in deionized water, each at a concentration of 2.0%, and mixed in a molar ratio of 1:1. The mixture was magnetically stirred at 25°C for 4 hours, and the water was removed by rotary evaporation to obtain a transparent viscous ionic liquid.

[0031] 4. Preparation of Multi-Effect Composite Scar Repair Gel (1) Silicone substrate mixing: 25.0 g of high viscosity polydimethylsiloxane (3000 mPa·s), 2.0 g of low viscosity polydimethylsiloxane (100 mPa·s) and 5.0 g of dimethyl silicone oil (3%) are mixed and stirred at 60°C for 30 minutes (50 rpm) to form a uniform silicone substrate. (2) Active layer loading: 3.0 g of Chinese herbal extract, 2.0 g of microcapsules, 0.05 g of BPC157 peptide, 1.5 g of ionic liquid and 0.2 g of zinc hyaluronic acid were added to the silicone substrate in sequence, ultrasonically dispersed at 200W for 15 minutes, and 0.2 g of carbomer 940 was added to adjust the viscosity. The final pH was 5.5-6.0. (3) Sterilization and molding Irradiation sterilization: Sterilization is performed by gamma ray irradiation (dose 25kGy), and the product is filled into 10g tubes to obtain a multi-effect composite scar repair gel. Example 2 Example 2 of this invention provides a method for preparing a multi-effect composite scar repair gel. The steps are basically the same as those in Example 1, except that the mass ratio of Salvia miltiorrhiza, Panax notoginseng and Carthamus tinctorius in the Chinese herbal extract is 8:4:3.

[0032] Example 3 Example 3 of this invention provides a method for preparing a multi-effect composite scar repair gel. The steps are basically the same as those in Example 1, except that the amounts of each raw material used in the preparation of the multi-effect composite scar repair gel are as follows: 26 g high-viscosity polydimethylsiloxane, 3 g low-viscosity polydimethylsiloxane, 3 g dimethyl silicone oil, 4 g traditional Chinese medicine extract, 2 g ectoin-allantoin microcapsules, 0.1 g BPC157 polypeptide, 2 g arginine-malic acid ionic liquid, 0.3 g zinc hyaluronic acid, and 0.1 g carbomer.

[0033] Experimental Example 1 Experimental Example 1 of this invention tested the efficacy of the multi-effect composite scar repair gel prepared in Example 1. The specific steps are as follows: (1) In vitro anti-fibrosis: Human skin fibroblasts (HSF) were resuscitated and cultured in DMEM containing 10% fetal bovine serum (FBS) at 37°C in a 5% CO2 incubator. Cells were passaged after reaching 80% confluence for later use.

[0034] Human skin fibroblasts were divided into three groups: a blank control group (basal culture medium only); a model group (fibrosis induced by 10 ng / mL TGF-β1); and a composite gel group (in addition to TGF-β1 induction, a multi-effect composite scar repair gel extract prepared in Example 1 was added to a final concentration of 0.5 mg / mL, with an equal volume of silicone matrix as a control). After 48 h of culture, cells were collected, and the TGF-β1 content in the cell supernatant was detected by ELISA. The enzyme activity of matrix metalloproteinase-1 (MMP-1) in the culture supernatant was measured by fluorescent substrate method.

[0035] The results showed that, compared with the model group, the expression of TGF-β1 in the composite gel group decreased by 42% and the activity of MMP-1 increased by 35%, indicating that the gel has a significant effect on inhibiting fibrosis and promoting collagen degradation.

[0036] (2) Animal scar repair model (2.1) Model preparation SPF-grade male SD rats (weight 200 ± 20 g, n = 30) were selected. After hair removal from their backs, full-thickness skin defects were created using an 8 mm diameter punch (two symmetrical wounds per rat). The rats were randomly divided into three groups (n=10 per group, 20 wounds in total) and treated accordingly. The wound healing was observed.

[0037] Blank control group: No medication was administered; only sterile gauze was applied. Commercially available silicone gel kit: Apply commercially available silicone scar gel (such as Dermatix®) daily. The gel assembly of this invention: Apply the multi-effect composite scar repair gel prepared in Example 1 daily, with an amount of approximately 0.1 g per wound.

[0038] The average healing time of the gel group of this invention was 14 days, which was significantly shorter than that of the blank control group (21 days) and the commercially available silicone group (18 days); the scar thickness was reduced by 48% compared with the blank control group (p < 0.01).

[0039] (3) Stability test The gel samples prepared in Example 1 (3 batches, 3 samples per batch) were sealed in aluminum-plastic tubes and placed in a constant temperature and humidity chamber at 40℃±2℃ and relative humidity 75%±5% for 6 months. Samples were taken at 0, 1, 3 and 6 months to observe the gel sample layering, pH and active ingredient retention rate.

[0040] The results showed that the gel samples of the present invention remained in a uniform and transparent gel state for 6 months without layering, precipitation or phase separation; the pH value remained stable at 6.0–6.5; the average retention rates of BPC157, ectoine and tanshinone IIA were all >90%, indicating that the formulation has good chemical and physical stability.

[0041] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A multi-effect composite scar repair gel, characterized in that, The multi-effect composite scar repair gel comprises raw materials in the following mass ratio: High-viscosity dimethicone: low-viscosity dimethicone: dimethicone: traditional Chinese medicine extract: ectoine-allantoin microcapsule: BPC157 polypeptide: arginine-malic acid ionic liquid: zinc hyaluronate: carbomer = 20~30:1~4:3~8:1~4:0.5~3:0.01~0.1:0.5~3:0.1~0.3:0.1~0.

3.

2. The multi-effect composite scar repair gel according to claim 1, characterized in that, The high-viscosity dimethicone has a viscosity of 1000-5000 mPa·s, and the low-viscosity dimethicone has a viscosity of 50-200 mPa·s.

3. The multi-effect composite scar repair gel according to claim 1, wherein, The traditional Chinese medicine extract comprises raw materials in the following mass ratio: Salvia miltiorrhiza: Panax notoginseng: safflower = 2~8:2~4:1~3.

4. The multi-effect composite scar repair gel according to claim 1, wherein, The preparation method of the traditional Chinese medicine extract is as follows: After the salvia miltiorrhiza, Panax notoginseng and safflower are mixed, the mixture is subjected to supercritical CO2 extraction at 20~30 MPa and 40~50 ℃ for 1~3 h, and the residue is subjected to reflux extraction with 60~80% ethanol for 1~5 times, and the filtrates are combined and concentrated.

5. The multi-effect composite scar repair gel according to claim 1, wherein, The preparation method of the ectoine-allantoin microcapsule comprises the following steps: (1) Preparation of wall material: chitosan and sodium hyaluronate are dissolved in deionized water at a mass ratio of 2~3:1 to prepare a wall material solution with a concentration of 2-4% w / v; (2) Preparation of core material: ectoine and allantoin are dissolved in deionized water at a mass ratio of 2~4:0.5~2 to obtain a mixed solution with a core material concentration of 3~7%; (3) The wall material and the core material are mixed and homogenized, cross-linked and solidified to obtain ectoine-allantoin microcapsules with a particle size of 50~100 μm.

6. The multi-effect composite scar repair gel according to claim 1, wherein, The preparation method of the arginine-malic acid ionic liquid comprises the following steps: After arginine and malic acid are dissolved in deionized water, they are mixed at a molar ratio of 1~2:1~2, reacted at 20~30 ℃ for 3~5 h, and then water is removed by evaporation.

7. A process for the preparation of the multi-effect composite scar repair gel as claimed in any one of claims 1 to 6, characterized in that, Comprising the following steps: (1) Preparation of silicone base material: high-viscosity dimethicone, low-viscosity dimethicone and dimethicone are stirred and mixed uniformly to obtain a silicone base material; (2) Active layer loading: traditional Chinese medicine extract, ectoine-allantoin microcapsule, BPC157 polypeptide, arginine-malic acid ionic liquid are added to the silicone base, ultrasonically dispersed, then carbomer is added to adjust the viscosity, and a multi-effect composite scar repair gel is obtained.

8. The process for the preparation of the multi-effect composite scar repair gel as claimed in claim 7, wherein, In step (1), the stirring temperature is 50~70 ℃, and the stirring time is 20~40 min.

9. The process for the preparation of the multi-effect composite scar repair gel as claimed in claim 7, wherein, In step (2), the ultrasonic dispersion conditions are 180~220 W for 10~20 min.

10. The use of the multi-effect composite scar repair gel prepared by the preparation method of any one of claims 7-9 in the preparation of a scar repair and postoperative incision repair product.