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CN-120478261-B - Soluble microneedle for treating hypertrophic scar and preparation method and application thereof

CN120478261BCN 120478261 BCN120478261 BCN 120478261BCN-120478261-B

Abstract

The invention belongs to the technical field of biomedical technology, and discloses a soluble microneedle for treating a hyperplastic scar, and a preparation method and application thereof. The invention obtains sulfonated hyaluronic acid by modifying hyaluronic acid, and obtains sulfonated hyaluronic acid-D-borneol solid dispersion after blending, rotary steaming and freeze-drying with a natural permeation promoter D-borneol with anti-inflammatory activity, and then loads the solid dispersion into a microneedle to obtain the soluble microneedle with the function of treating the hypertrophic scar. The method improves the bioavailability and biocompatibility of the D-borneol, loads the D-borneol into the micro needle, and can penetrate compact scar tissues to achieve the purpose of deeply delivering medicines under the double penetration promotion of the micro needle and the D-borneol while maximally exerting the anti-inflammatory and fibroblast migration inhibition capabilities of the solid dispersion. The invention provides a safe and efficient novel transdermal drug delivery system for treating the hyperplastic scar, and has wide clinical application prospect and market value.

Inventors

  • SU JIANYU
  • WANG ZIZHEN
  • FAN PENGHUI
  • HOU YUCHAO

Assignees

  • 华南理工大学
  • 华工新颜(深圳)科技有限公司

Dates

Publication Date
20260508
Application Date
20250514

Claims (10)

  1. 1. A method for preparing a soluble microneedle for treating a hypertrophic scar, comprising the steps of: S1, preparing sulfonated hyaluronic acid, namely firstly mixing the hyaluronic acid with an ammonium salt solution to obtain modified fat-soluble hyaluronic acid, then adding a sulfonation reagent under the condition of inert gas and ice bath to react, then adding water to terminate the reaction, adding an alkaline solution to adjust the pH value, adding an organic solvent to precipitate, performing solid-liquid separation, dissolving the obtained solid with water, and then dialyzing to obtain SHA; S2, preparing a sulfonated hyaluronic acid-dextroborneol solid dispersion, namely uniformly mixing dextroborneol and SHA prepared in the step S1 in an organic solvent, removing the organic solvent by rotary evaporation, and freeze-drying to obtain the solid dispersion; s3, preparing a needle layer solution, namely uniformly mixing a needle forming material with water to obtain a solution A, uniformly mixing the solid dispersion obtained in the step S2 with water to obtain a solution B, and mixing the solution A and the solution B to obtain the needle layer solution, wherein the dosage of each component is as follows, by mass volume, 5-15% of the needle forming material, 5-15% of the solid dispersion, and the balance of water; S4, preparing a backing layer solution, namely uniformly mixing a soluble polymer and water to obtain a solution C, and uniformly mixing the solution C with a needle forming material solution, wherein the dosage of each component is as follows, 3-7% of the soluble polymer, 8-12% of the needle forming material and the balance of water in terms of mass-volume ratio; S5, preparing a microneedle: A. Adding the needle body layer solution prepared in the step S3 into a microneedle female die, filling the microneedle female die with the needle body layer solution, scraping off redundant feed liquid, and drying and solidifying the needle body layer solution to form a microneedle body layer; B. And (3) adding the backing layer solution prepared in the step (S4) onto the microneedle body layer in the step (A), connecting the needle body layer with the backing layer, and drying the whole microneedle to obtain the soluble microneedle for treating the hyperplastic scar.
  2. 2. A method of preparing soluble microneedles for use in the treatment of hypertrophic scars according to claim 1, characterized in that: the molecular weight of the hyaluronic acid in the step S1 is 5000-70000 Da; the ammonium salt in the step S1 is tetrabutylammonium hydroxide; The sulfonation reagent in the step S1 is sulfur trioxide-pyridine; the needle body shaping material in the step S3 is at least one of polyvinylpyrrolidone K30 and polyvinylpyrrolidone K90; the soluble polymer in the step S4 is polyvinyl alcohol.
  3. 3. A method of preparing soluble microneedles for use in the treatment of hypertrophic scars according to claim 1, characterized in that: the inert gas in the step S1 is nitrogen; the alkaline solution in step S1 is selected from sodium hydroxide solution; The organic solvent in the step S1 is absolute ethyl alcohol; the organic solvent in the step S2 is ethanol solution.
  4. 4. A method of preparing soluble microneedles for use in the treatment of hypertrophic scars according to claim 1, characterized in that: The pH value in the step S1 is 8-8.5; the SHA and the D-borneol in the step S2 are proportioned according to the mass ratio of 1:1-1.1; the solution A and the solution B in the step S3 are proportioned according to the volume ratio of 0.5-1.5:1; And (3) proportioning the needle body shaping material solution and the solution C in the step (S4) according to the volume ratio of 0.5-1.5:1.
  5. 5. A method of preparing soluble microneedles for use in the treatment of hypertrophic scars according to claim 1, characterized in that: The reaction time in the step S1 is 1-2 h; the specification of the dialysis bag in the dialysis in the step S1 is 3000-3500 Da; The dialysis time in the step S1 is 24-48 hours; the spin steaming condition in the step S2 is that the temperature is 30-50 ℃ and the rotating speed is 100-150 r/min.
  6. 6. A method of preparing soluble microneedles for use in the treatment of hypertrophic scars according to claim 1, characterized in that: The number of times of precipitation in the step S1 is 3; the solid-liquid separation mode in the step S1 is centrifugation; The soluble polymer and water in the step S4 are uniformly mixed and prepared by dissolving the soluble polymer in water under the heating condition to obtain a soluble polymer aqueous solution; the mode of filling the microneedle female mold in the step S5A is vacuum treatment; the drying condition in the step S5A is that the temperature is 25-40 ℃ and the drying is carried out until the drying is solidified; the manner of connecting the needle layer and the backing layer in the step S5B is vacuum treatment; the drying condition in the step S5B is 25-40 ℃ drying to solidification.
  7. 7. The method of preparing soluble microneedles for use in treating a hypertrophic scar according to claim 6, wherein: the centrifugation condition is 6000-10000 r/min for 5-15 min; the vacuum treatment condition is that the vacuum is pumped for 15-20 min under the environment that the vacuum degree is-0.09 to-0.1 MPa; the drying condition in the step S5A is that the temperature is 25-40 ℃ and the drying time is 4-5 hours; and the drying condition in the step S5B is 25-40 ℃ for 18-24 hours.
  8. 8. A soluble microneedle for treating hypertrophic scars, which is obtained by the preparation method according to any one of claims 1 to 7.
  9. 9. Use of the soluble microneedle for treating hypertrophic scars of claim 8 in the preparation of a medicament for treating hypertrophic scars.
  10. 10. The use of the soluble microneedle for treating hypertrophic scar according to claim 9, wherein the drug is a drug for inhibiting inflammatory factor expression and inhibiting excessive proliferation and migration of fibroblast.

Description

Soluble microneedle for treating hypertrophic scar and preparation method and application thereof Technical Field The invention belongs to the technical field of biomedical technology, and in particular relates to a soluble microneedle for treating a hyperplastic scar, and a preparation method and application thereof. Background The Hypertrophic Scar (HS), also known as a raised scar, is secondary to surgical wounds and burns, and is a skin tissue fibrosis lesion caused by pathological healing of wounds after wound healing. More than 1 million people worldwide scar from surgery or trauma, with the number of hypertrophic scars accounting for 15%. The clinical symptoms of the traditional Chinese medicine are irregular uplift, itching and pain discomfort, and the traditional Chinese medicine has three pain points of high morbidity, complex pathogenesis, high treatment difficulty and the like, and the inhibition of the generation of the hyperplastic scar is still the current research hot spot. Scar formation is divided into three phases, namely an inflammatory phase, a proliferation phase and a remodeling phase. Inflammatory cells migrate to a wound surface to release inflammatory factors in an inflammatory stage, the inflammatory factors directly or indirectly cause proliferation of fibroblast (HSF), excessive proliferation and migration of the fibroblast are caused by release of a large amount of transforming growth factors TGF-beta in the proliferation stage, so that collagen-based extracellular matrix (ECM) is promoted to be deposited in a large amount, and the excessive accumulated ECM is difficult to be absorbed or remodeled by an organism in time in a remodelling stage, so that the ECM and the HSF are connected to generate fibrosis lesions. The tissue of the hypertrophic scar is therefore characterized by inflammatory cell infiltration, and a large deposition of fibroblasts and extracellular matrix. Therefore, how to reduce the content of inflammatory factors and regulate the excessive proliferation and migration of fibroblast is an important link for inhibiting scar hyperplasia. Three treatment methods commonly used in clinic at present are that the oral administration is mainly based on anti-inflammatory drugs, only plays a role in relieving symptoms, and has the gastrointestinal first pass effect of the drugs; although the application of the drug can regulate the collagen arrangement and reduce pigmentation, the traditional transdermal method has low drug permeability due to dense scar tissue, and the intralesional injection of corticosteroid in the drug-mechanical combination therapy is the most common and effective method since 1960, can penetrate dense scar tissue to achieve the release of drug in the dermis layer, but the long-term injection of corticosteroid can cause pain, skin atrophy, pigmentation, and require multiple injections by doctors, which is expensive, and this treatment method causes negative emotion to the patient. Thus, there is a need for a safe and efficient drug and drug-potentiating delivery system for treating hypertrophic scars. Disclosure of Invention The primary aim of the invention is to overcome the defects and shortcomings of the prior art and provide a preparation method of a soluble microneedle for treating hyperplastic scars. It is another object of the present invention to provide a soluble microneedle with therapeutic proliferative scars obtained by the above preparation method. It is a further object of the present invention to provide the use of the above-described soluble microneedle with a therapeutic proliferative scar. The invention aims at realizing the following technical scheme that the preparation method of the soluble microneedle for treating the hyperplastic scar comprises the following steps: S1, preparing Sulfonated Hyaluronic Acid (SHA), namely firstly mixing hyaluronic acid with an ammonium salt solution to obtain modified fat-soluble hyaluronic acid, then adding a sulfonation reagent to react under the condition of inert gas and ice bath, then adding water to terminate the reaction, adding an alkaline solution to adjust the pH value, adding an organic solvent to precipitate, performing solid-liquid separation, dissolving the obtained solid with water, and dialyzing to obtain SHA; S2, preparing sulfonated hyaluronic acid-dextroborneol solid dispersion (SHA-NB-SD), namely uniformly mixing dextroborneol (NB) and SHA prepared in the step S1 in an organic solvent, removing the organic solvent by rotary evaporation, and freeze-drying to obtain a solid dispersion; S3, preparing a needle layer solution, namely uniformly mixing a needle forming material with water to obtain a solution A, uniformly mixing the solid dispersion obtained in the step S2 with water to obtain a solution B, and mixing the solution A and the solution B to obtain the needle layer solution, wherein the dosage of each component is as follows, in terms of mass (g) volume (mL) ratio, 5-15