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CN-122005426-A - Co-amorphous microneedle for treating alopecia and preparation method thereof

CN122005426ACN 122005426 ACN122005426 ACN 122005426ACN-122005426-A

Abstract

The invention belongs to the technical field of microneedles, and discloses a co-amorphous microneedle for treating alopecia and a preparation method thereof. The invention prepares the ketoconazole and the polythiooctanoic acid into [ ketoconazole ] [ polythiooctanoic acid ] co-amorphous compound, and further prepares the co-amorphous microneedle which takes the co-amorphous compound as a needle point and takes hyaluronic acid and glucan as a base. The invention enhances the skin permeability of ketoconazole through micro-needle administration, and accelerates the release and permeation of ketoconazole through in-situ melting after administration, thereby improving the external bioavailability of ketoconazole, and the prepared co-amorphous micro-particles have good synergy for external delivery of ketoconazole and alopecia treatment.

Inventors

  • XU YUEHONG
  • GUO SHIQI

Assignees

  • 中山大学

Dates

Publication Date
20260512
Application Date
20260311

Claims (10)

  1. 1. The co-amorphous microneedle comprises a needle tip and a base, and is characterized in that the needle tip is a [ ketoconazole ] [ polythiooctanoic acid ] co-amorphous compound, and the molar ratio of the ketoconazole to the lipoic acid is (4-8): 2-6.
  2. 2. The co-amorphous microneedle according to claim 1, wherein the polythiooctanoic acid is produced by thermal polymerization of lipoic acid at a temperature of 100 ℃ to 150 ℃.
  3. 3. The co-amorphous microneedle according to claim 1, wherein the preparation method of the [ ketoconazole ] [ polythiooctanoic acid ] co-amorphous composite comprises the steps of heating lipoic acid to obtain a polythiooctanoic acid liquid, adding ketoconazole into the polythiooctanoic acid liquid, continuously heating, uniformly mixing, and cooling to room temperature to obtain the [ ketoconazole ] [ polythiooctanoic acid ] co-amorphous composite.
  4. 4. The co-amorphous microneedle according to claim 1, wherein the base comprises hyaluronic acid and dextran.
  5. 5. The co-amorphous microneedle according to claim 4, wherein the mass ratio of hyaluronic acid to dextran is (1-3): 1.
  6. 6. The co-amorphous microneedle according to claim 4, wherein the hyaluronic acid comprises hyaluronic acid a having a molecular weight of 52 kDa and hyaluronic acid B having a molecular weight of 200 kDa to 400 kDa, and the mass ratio of hyaluronic acid a to hyaluronic acid B is (1-2): 1.
  7. 7. A method of making co-amorphous microneedles in any one of claims 1-6, comprising the steps of: (1) Heating and melting lipoic acid to obtain a poly lipoic acid liquid; (2) Adding ketoconazole into the polythiooctanoic acid liquid, continuously heating and melting, uniformly mixing, adding into a microneedle mould, and pouring to obtain a co-amorphous needlepoint; (3) Continuously adding the microneedle base solution into the microneedle mould, drying and demoulding to obtain the co-amorphous microneedle.
  8. 8. The method according to claim 7, wherein in the step (1) or (2), the heating temperature is 100 ℃ to 150 ℃.
  9. 9. The preparation method of the microneedle base solution according to claim 7, wherein in the step (3), the preparation method comprises dispersing hyaluronic acid and dextran in water, and swelling overnight at 0-4 ℃.
  10. 10. Use of the co-amorphous microneedle according to any one of claims 1-6 for the manufacture of a medicament for the treatment of hair loss.

Description

Co-amorphous microneedle for treating alopecia and preparation method thereof Technical Field The invention relates to the technical field of microneedles, in particular to a co-amorphous microneedle for treating alopecia and a preparation method thereof. Background Hair plays an important role in sensory function, provides thermal and physical insulation, and imparts societal cultural characteristics to humans. The generation of hair involves cycles of growth, shedding and replacement, with about 50-100 hairs per day shed as part of normal physiological balance. Unwanted hair loss is a clinical condition that occurs when the number of degenerative hair exceeds that of hair regrowth. Alopecia is a very common disease that slowly, involuntarily, brings emotional stress to people. Although oral and topical ketoconazole is widely used as a broad spectrum antifungal, there is evidence that the use of ketoconazole shampoos can treat male pattern alopecia. In the chinese guide for diagnosis and treatment of androgenetic alopecia (2023 edition), ketoconazole is considered to be clinically useful as an androgen synthesis inhibitor in the coming years. It has been proposed that ketoconazole may interfere with the dihydrotestosterone pathway. Ketoconazole can inhibit the binding of 5α -reductase to sex hormone binding globulin and also can bind directly to androgen receptor in humans. This interfering effect and the potential reduction in dihydrotestosterone levels may explain the role of ketoconazole in the treatment of androgenic alopecia. The antibacterial and anti-inflammatory properties of ketoconazole may also be responsible for its use in the treatment of such alopecia. As a broad-spectrum antifungal agent, ketoconazole can inhibit the growth of various common dermatophytes and yeasts, and is helpful for reducing fungus colonization and peripheral inflammation. In some populations androgenic alopecia may result from the presence of lipophilic microorganisms in the follicular unit. These microorganisms trigger inflammation and immunomodulation reactions, ultimately leading to hair loss, and thus ketoconazole may also act similarly to the treatment of androgenic alopecia, i.e. by reducing the number of microorganisms and the associated inflammation. However, although ketoconazole may be applied to clinical treatment of androgenic alopecia in the next few years, there are still problems to be overcome in application to treatment of androgenic alopecia. First, the currently commercially available forms of ketoconazole external preparations include lotions, creams, gels, foams, etc., which are liquid preparations or semisolid preparations, and ketoconazole in a solution state has a problem of poor long-term stability due to oxidation. Second, ketoconazole has a molecular weight of 531.44 Da and poor transdermal penetration, which limits the bioavailability of current ketoconazole external preparations. Therefore, there is a need to develop a ketoconazole external preparation with good stability and strong transdermal penetration capability, and provide a new way for clinical treatment of alopecia. Disclosure of Invention The invention aims to overcome the defects of the prior art and provide a co-amorphous microneedle for treating alopecia and a preparation method thereof. In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: In a first aspect, the invention provides a co-amorphous microneedle comprising a needle tip and a base, wherein the needle tip is a [ ketoconazole ] [ polythiooctanoic acid ] co-amorphous compound, and the molar ratio of the ketoconazole to the lipoic acid is (4-8): 2-6. The co-amorphous complex of the present invention is a single amorphous phase complex formed by amorphizing a mixture of ketoconazole and lipoic acid. The melting temperature of the co-amorphous composite is varied by the molar ratio of the two components in the particular co-amorphous composite. The co-amorphous compound with melting temperature higher than room temperature and lower than intradermal temperature is used as a needle point to prepare the microneedle patch, so as to obtain the co-amorphous microneedle with in-situ melting capability. The co-amorphous microneedle can inhibit oxidation of ketoconazole, improve long-term stability, improve transdermal penetration capacity of ketoconazole, increase bioavailability of external administration, and has the advantages of convenient administration, quick drug release and good skin penetration effect. As a preferred embodiment of the co-amorphous microneedle, the poly lipoic acid is prepared by heating and polymerizing lipoic acid, wherein the heating temperature is 100-150 ℃. Preferably, the temperature of the heating is in the range of values of any one or both of 100 ℃, 110 ℃, 120 ℃, 130 ℃, 140 ℃, 150 ℃. The preparation method of the [ ketoconazole ] [ polythiooctanoic acid ] co-amorphous compound comprises the steps of he