CN-122005429-A - Medicine-carrying microneedle patch for inhibiting keloid hyperplasia and preparation method thereof

CN122005429ACN 122005429 ACN122005429 ACN 122005429ACN-122005429-A

Abstract

The invention belongs to the technical field of biomedical materials, and in particular relates to a drug-loaded microneedle patch for inhibiting keloid proliferation and a preparation method thereof, wherein the drug-loaded microneedle patch comprises, by weight, 100 parts of an antioxidant polymer carrier, 1-5 parts of 5-fluorouracil, 0.5-3 parts of triamcinolone acetonide, 1-4 parts of a cross-linking agent and 30-60 parts of a biocompatible polymer, the antioxidant polymer carrier consists of hyaluronic acid, ROS-responsive cross-linked bridge molecules and Prussian blue nano particles, the microneedle adopts a core-shell structure design, a shell layer loads quick-acting antiproliferative drug 5-fluorouracil, a core layer loads long-acting anti-inflammatory drug triamcinolone acetonide, and the crosslinking density of the core layer is higher than that of the shell layer, so that time-sharing release of the drug is realized, and the constructed drug-loaded microneedle patch can clear excessive active oxygen in response to a scar microenvironment and synergistically inhibit keloid proliferation.

Inventors

YANG YANLONG
GU JINGJING
XIE HAOYU

Assignees

中国人民解放军总医院海南医院

Dates

Publication Date: 20260512
Application Date: 20260325

Claims (6)

1. The drug-loaded microneedle patch for inhibiting keloid hyperplasia is characterized by comprising, by weight, 100 parts of an antioxidant polymer carrier, 1-5 parts of 5-fluorouracil, 0.5-3 parts of triamcinolone acetonide, 1-4 parts of a cross-linking agent and 30-60 parts of a biocompatible polymer; The drug-loaded microneedle patch adopts a core-shell structure design, wherein 5-fluorouracil is loaded on a shell layer, triamcinolone acetonide is loaded on a core layer; the antioxidant polymer carrier comprises the following raw materials of HA, ROS responsive cross-linked bridge molecules and PBNPs; the preparation method of the antioxidant polymer carrier comprises the following steps: S1, dissolving HA, activating by carboxyl, adding ROS (reactive oxygen species) responsive crosslinking bridge molecules into the HA activating solution to obtain a modified hyaluronic acid reaction solution, and dialyzing and drying to obtain modified hyaluronic acid; S2, dissolving modified hyaluronic acid to obtain modified hyaluronic acid solution, dispersing PBNPs, and performing ultrasonic treatment to obtain PBNPs dispersion; and S3, dripping PBNPs dispersion liquid into the modified hyaluronic acid solution to obtain a grafting reaction liquid, and centrifuging and drying to obtain the antioxidant polymer carrier.
2. A drug-loaded microneedle patch for inhibiting keloid proliferation according to claim 1, wherein the mass ratio of HA, ROS-responsive cross-linked bridge molecules and PBNPs is 8-12:2-4:1.
3. A drug-loaded microneedle patch for inhibiting keloid proliferation according to claim 2, wherein the ROS-responsive cross-linking bridge molecule is cystamine dihydrochloride or 3-aminophenylboronic acid.
4. A drug-loaded microneedle patch for inhibiting keloid proliferation according to claim 1, wherein the cross-linking agent is selected from any one of glutaraldehyde, genipin, or carbodiimide.
5. A drug-loaded microneedle patch for inhibiting keloid proliferation according to claim 1, wherein the biocompatible polymer is selected from at least one of polyvinyl alcohol, polyvinylpyrrolidone, polylactic acid-glycolic acid copolymer, and gelatin.
6. A method of preparing a drug-loaded microneedle patch for inhibiting keloid proliferation according to any one of claims 1 to 5, comprising the steps of: Step 1, respectively dividing an antioxidant polymer carrier and a cross-linking agent into two parts, wherein one part is used for a core layer, and the other part is used for a shell layer; Step 2, dissolving a first part of antioxidant polymer carrier to obtain a nuclear layer matrix solution, and adding triamcinolone acetonide and a first part of cross-linking agent into the matrix solution to obtain a nuclear layer drug-carrying solution; step 3, dissolving a second part of antioxidant polymer carrier to obtain a shell matrix solution, and adding 5-fluorouracil and a second part of cross-linking agent into the shell matrix solution to obtain a shell medicine carrying solution; step 4, injecting the shell drug-carrying solution into a microneedle mould, and degassing, centrifuging and drying to obtain a shell microneedle structure; step 5, injecting the core layer drug-carrying solution into the microneedle mould with the shell layer formed in the step 3, and obtaining a microneedle array through degassing, centrifuging, drying and demoulding; and 6, dissolving the biocompatible polymer to obtain a biocompatible polymer solution, pouring the biocompatible polymer solution on the back of the microneedle array, drying to obtain the drug-loaded microneedle patch, sterilizing and packaging to obtain the drug-loaded microneedle patch for inhibiting keloid proliferation.

Description

Medicine-carrying microneedle patch for inhibiting keloid hyperplasia and preparation method thereof Technical Field The invention belongs to the technical field of biomedical materials, and in particular relates to a medicine-carrying microneedle patch for inhibiting keloid hyperplasia and a preparation method thereof. Background Keloids are a fibroproliferative disease secondary to skin injury, and are mainly characterized by excessive proliferation of fibroblasts and excessive deposition of extracellular matrix, which grow beyond the original wound boundary and are invasive, difficult to treat and high in recurrence rate. The existing pathological research shows that obvious oxidative stress microenvironment exists in the keloid tissues, and continuous high-level Reactive Oxygen Species (ROS) not only induce abnormal activation of fibroblasts, but also promote collagen synthesis and inhibit key pathological factors of apoptosis, and the regulation of the pathological microenvironment is often ignored by conventional treatment means. The current clinical methods for treating keloids mainly comprise surgical excision, radiotherapy, local drug injection and the like. Among them, intradermal injection of glucocorticoids (e.g., triamcinolone acetonide) and antimetabolites (e.g., 5-fluorouracil) is a well-recognized first-line treatment regimen. However, the traditional injection administration mode has a plurality of limitations that frequent injection brings severe pain and psychological fear to patients, so that compliance is poor, the liquid medicine is rapidly diffused in tissues, the maintenance time of local effective concentration is short, repeated treatment is required for a plurality of times, the injection dosage is difficult to accurately control, and adverse reactions such as skin atrophy, pigmentation and the like are easily caused. In addition, the simple injection of the medicine only can play pharmacological actions, can not actively improve the oxidative stress microenvironment which leads to scar hyperplasia, and is difficult to fundamentally block recurrence causes. In recent years, microneedle transdermal drug delivery systems have shown advantages in the treatment of local lesions due to their minimally invasive, painless and ability to break through the stratum corneum barrier. However, existing drug-loaded microneedles mostly adopt a single matrix material or a simple mixed drug-loaded structure, and lack a targeted design for pathological features of scars. On one hand, the traditional inert matrix has no microenvironment response capability and cannot clear excessive ROS at a focus part, and on the other hand, the single-structure microneedle is difficult to realize time sequence control release of multiple medicines and cannot meet the treatment time sequence difference requirement that an antiproliferative medicine needs to take effect quickly and an anti-inflammatory medicine needs to be maintained for a long time. Therefore, there is a need to develop a microneedle patch with multi-drug time-series release function that can respond to scar microenvironment to improve therapeutic effect and reduce recurrence rate. Disclosure of Invention Aiming at the technical problems, the invention provides the drug-loaded microneedle patch for inhibiting keloid hyperplasia and the preparation method thereof, and the drug-loaded microneedle patch can specifically respond to the high-activity oxygen microenvironment in keloid tissues, realize the time-series accurate release of drugs, and simultaneously have the functions of removing partial excessive ROS and remodelling the keloid microenvironment, so that the abnormal hyperplasia and fibrosis progress of the keloid are effectively inhibited. In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: The invention provides a drug-loaded microneedle patch for inhibiting keloid hyperplasia, which comprises the following raw materials, by weight, 100 parts of an antioxidant polymer carrier, 1-5 parts of 5-fluorouracil, 0.5-3 parts of triamcinolone acetonide, 1-4 parts of a cross-linking agent and 30-60 parts of a biocompatible polymer. Further, the antioxidant polymer carrier comprises the following raw materials of HA (hyaluronic acid) and ROS-responsive cross-linked bridge molecules PBNPs (Prussian blue nanoparticles) =8-12:2-4:1. Further, the ROS-responsive cross-linking bridge molecule is cystamine dihydrochloride or 3-aminophenylboronic acid. Further, the preparation method of the antioxidant polymer carrier comprises the following steps: S1, weighing HA, adding the HA into MES (2-morpholinoethanesulfonic acid) buffer solution, stirring until the mixture is uniform, obtaining HA solution, adding EDC and HCl (1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride) and NHS (N-hydroxysuccinimide) into the HA solution, performing carboxyl activation to obtain HA activated solution, weighing ROS-respon