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CN-121971365-A - Micro-needle patch loaded with minoxidil self-assembly body, preparation method and application

CN121971365ACN 121971365 ACN121971365 ACN 121971365ACN-121971365-A

Abstract

The invention discloses a microneedle patch for loading minoxidil self-assembly body, which comprises a back lining and a drug-loaded microneedle array attached to one side of the back lining, wherein the drug-loaded microneedle array is prepared from a minoxidil-ketoglutaric acid nano self-assembly body and a matrix, the minoxidil-ketoglutaric acid nano-assembly body is prepared from minoxidil and alpha-ketoglutaric acid through self-assembly reaction, and the molar ratio of minoxidil to alpha-ketoglutaric acid is 1:0.5-2. According to the invention, a physical penetration channel is created through the drug-loaded microneedle array, minoxidil and alpha-ketoglutaric acid are directly delivered to the dermis layer hair follicle enrichment region, the nanometer self-assembly optimizes the dissolution and diffusion behaviors of the minoxidil and the alpha-ketoglutaric acid in skin tissues, the two cooperatively realize the efficient and accurate delivery of the minoxidil to a target position, and simultaneously, the auxiliary effect of the alpha-ketoglutaric acid is utilized to enhance the hair growing effect, so that the nanometer self-assembly is suitable for preparing drugs for treating androgenetic alopecia.

Inventors

  • WU HAIBIN
  • SONG FENGLING
  • CHEN QIAN

Assignees

  • 杭州医学院

Dates

Publication Date
20260505
Application Date
20260114

Claims (10)

  1. 1. The micro-needle patch loaded with the minoxidil self-assembly comprises a back lining and a drug-loaded micro-needle array attached to one side of the back lining, and is characterized in that the drug-loaded micro-needle array is made of the minoxidil-ketoglutarate nano-self-assembly and a matrix; The nano self-assembly body of minoxidil-ketoglutaric acid is prepared by self-assembly reaction of minoxidil and alpha-ketoglutaric acid, and the molar ratio of minoxidil to alpha-ketoglutaric acid is 1:0.5-2.
  2. 2. The minoxidil self-assembly loaded microneedle patch of claim 1, wherein the minoxidil-ketoglutaric acid nano self-assembly has a particle size of 20-300 nm.
  3. 3. The minoxidil self-assembly loaded microneedle patch of claim 1, wherein said matrix is polyvinylpyrrolidone and sodium hyaluronate.
  4. 4. The minoxidil self-assembly loaded microneedle patch of claim 3, wherein the polyvinylpyrrolidone has a molecular weight of 1000-1500 kDa and the sodium hyaluronate has a molecular weight of 10-100 kDa.
  5. 5. The minoxidil self-assembly loaded microneedle patch of claim 1, wherein the drug-loaded microneedle array comprises minoxidil-ketoglutaric acid nano self-assembly, polyvinylpyrrolidone and sodium hyaluronate in a mass ratio of 5-15:50-70:20-35.
  6. 6. The minoxidil self-assembly loaded microneedle patch of claim 1, wherein the backing material is sodium carboxymethyl cellulose or polyvinyl alcohol.
  7. 7. The method for preparing the minoxidil self-assembly loaded microneedle patch according to any one of claims 1 to 6, comprising the steps of: (1) Respectively dissolving minoxidil and alpha-ketoglutaric acid in an organic solvent or water, respectively heating, mixing and stirring to form a self-assembled precursor solution, and performing dialysis replacement treatment on the self-assembled precursor solution to obtain aqueous dispersion of minoxidil-ketoglutaric acid nanometer self-assembly body; (2) Mixing the aqueous dispersion of the minoxidil-ketoglutarate nanometer self-assembly body obtained in the step (1) with polyvinylpyrrolidone and sodium hyaluronate, stirring for dissolution and vacuum defoaming to obtain microneedle tip slurry; (3) Pouring the microneedle tip slurry obtained in the step (2) into a microneedle mould, centrifuging, scraping off superfluous slurry on the surface, and drying and solidifying to form microneedle tips; (4) And (3) pouring the backing layer material solution onto the surface of the mould with the needlepoint formed in the step (3), centrifuging and drying again to form a backing layer, and demolding to obtain the microneedle patch loaded with the minoxidil self-assembly.
  8. 8. The method for preparing a minoxidil self-assembly loaded microneedle patch according to claim 7, wherein in the step (1), the organic solvent is at least one of dimethyl sulfoxide, N-dimethylformamide and tetrahydrofuran, the molecular weight cut-off is 500-3500 Da, and the total dialysis time is 24-48 hours.
  9. 9. The method for preparing a microneedle patch for supporting minoxidil self-assembly according to claim 7, wherein in the step (3), the height of the microneedle array is 50-600 μm, the bottom width is 50-500 μm, and the aspect ratio is 1-5:1 in the microneedle mould.
  10. 10. The use of a minoxidil self-assembly loaded microneedle patch according to any one of claims 1 to 6 in the manufacture of a medicament for the treatment of androgenetic alopecia.

Description

Micro-needle patch loaded with minoxidil self-assembly body, preparation method and application Technical Field The invention relates to the field of transdermal drug delivery systems, in particular to a microneedle patch loaded with minoxidil self-assembly, a preparation method and application. Background Androgenic alopecia (AGA) is one of the most common progressive hair-reducing diseases affecting millions of men and women worldwide, placing a significant burden on the mental health and quality of life of the patient. The pathological mechanism is mainly related to genetic factors and the actions of androgens, in particular Dihydrotestosterone (DHT), on susceptible hair follicles. DHT causes hair follicle miniaturization, shortening of anagen phase, lengthening of telogen phase, and gradual transition of the end hair to a fine, soft vellus hair. Currently, the first line of drugs approved by the FDA in the united states for the treatment of AGA include oral finasteride and topical minoxidil. Minoxidil as a potassium channel opener and vasodilator has not been completely elucidated, and it is thought that it is possible to exert its effects by (1) directly opening potassium channels, hyperpolarizing cell membranes, promoting proliferation and differentiation of hair follicle epithelial cells, (2) stimulating hair papilla cells to produce Vascular Endothelial Growth Factor (VEGF), promoting generation of capillary blood vessels around hair follicles and local blood circulation, improving nutrition supply to hair follicles, (3) prolonging the growing period of hair follicles, and possibly reactivating hair follicles in telogen period into growing period. Although minoxidil has been used clinically for decades, its existing external preparations (mainly tinctures and foams) have obvious limitations, severely restricting its efficacy and patient compliance. First, extremely low transdermal penetration efficiency is a core bottleneck, the stratum corneum is a high-efficiency physical barrier, minoxidil itself has poor transdermal properties, most of the drug (usually more than 98%) stays on the skin surface, it is difficult to penetrate and reach deep hair follicle targets, the dermal papilla layer, resulting in extremely low bioavailability (often less than 2%). Secondly, the drug solubility is limited, and the minoxidil has low solubility in water, which limits the development and application of the minoxidil in high-concentration water-based preparations. Further, local adverse reactions frequently occur, and commercial preparations often contain propylene glycol with high concentration as a permeation enhancer and a solvent, which are liable to cause irritation symptoms such as contact dermatitis, scalp dryness, itching, desquamation and the like, which are main causes of drug withdrawal for patients. Finally, the traditional dosage form is inconvenient to use, the liquid preparation is easy to flow, the facial hair is possibly caused, and after the traditional dosage form is used, the hair is greasy, the appearance is affected, and the medication willingness of a patient is reduced. To overcome the above-mentioned obstacles, microneedle technology has been attracting attention as an innovative transdermal drug delivery platform. The microneedle array consists of tens to hundreds of micrometer-sized (usually 50-1000 mu m in length) needle points, can penetrate through a stratum corneum in a minimally invasive and painless mode and directly deliver drugs to a dermis layer, and can quickly absorb tissue fluid and dissolve a water-soluble matrix after penetrating into skin to realize in-situ release of the drugs. The method can greatly improve the bioavailability of the medicine, avoid the first pass effect, and remarkably improve the compliance of patients without using chemical permeation promoters. However, simply physically mixing minoxidil with a microneedle matrix material (e.g., polyvinylpyrrolidone PVP, sodium hyaluronate HA) remains a challenge. The low solubility of minoxidil and potential crystallization tendency in hydrophilic matrix may cause problems such as uneven drug loading of the microneedle, incomplete drug release, etc., which affect the final therapeutic effect. Alpha-ketoglutarate (AKG) is an important intermediate metabolite in the tricarboxylic acid cycle. In recent years, research has found that it has important roles in cellular energy metabolism, collagen synthesis, antioxidation and the like. More research shows that AKG can provide support for hair follicle regeneration by improving energy metabolism microenvironment around hair follicle （Chai Min, et al. Stimulation of Hair Growth by Small Molecules that Activate Autophagy. Cell Rep. 2019, 27(12):3413-3421.e3. doi: 10.1016/j.celrep.2019.05.070. ）. In the field of pharmacy, the molecular self-assembly technology provides a new strategy for improving the performance of insoluble drugs. The solubility, stability and biological mem