Microneedle transdermal drug delivery method for treating skin fibrosis

Abstract

The invention provides a microneedle transdermal drug delivery method for treating skin fibrosis, and relates to the field of microneedle drug delivery, the microneedle transdermal drug delivery method comprises the following steps: S100, preparing a sustained-release drug-loaded microneedle containing ethylenediamine tetraacetic acid (EDTA), the microneedle comprising a degradable matrix material and EDTA with a mass concentration of at least 0.5-10%; and S200, attaching the drug-loaded microneedle to a fibrosis skin area, and forming a microchannel through mechanical puncture. A drug channel directly reaching a focus is established through the microneedle transdermal drug delivery system (with adjustable needle length and array puncture), the transdermal efficiency is remarkably improved, it is ensured that the drug effectively permeates into the focus area, the problem of drug waste caused by cuticle obstruction of a traditional external preparation is solved, and the application prospect is wide. According to the present invention, by using the dual-ion targeting characteristic (Cu < 2 + > chelating to block the signal channel and Ca < 2 + > depolymerization to regulate collagen crosslinking) of EDTA, the upstream signal activation and downstream matrix reconstruction in the fibrosis process are synchronously inhibited, the multi-dimensional intervention mechanism is formed, and the treatment effect is significantly improved;

Description

Technical Field

[0001] The present invention relates to the field of microneedle drug delivery, and in particular to a microneedle transdermal drug delivery method for treating skin fibrosis. Background Art

[0002] Among existing methods for treating scar diseases using microneedles to deliver drugs, a typical approach is to use microneedles to deliver fluorouracil (5-FU) to prevent and treat hypertrophic scars. Fluorouracil is a drug primarily used to treat cancer, and its local injection is also commonly used to prevent and treat keloids, a first-line treatment option. Its mechanism of action is related to blocking the expression of the 2α1 type collagen gene mediated by transforming growth factor-β (TGF-β). Microneedle technology uses tiny needles to pierce the skin's stratum corneum barrier, rapidly establishing a large number of fine skin channels, allowing drugs to enter the subcutaneous tissue through these channels, thereby increasing drug penetration and absorption into the skin.

[0003] While microneedle-assisted fluorouracil therapy has shown some success in treating scar disorders, secondary skin fibrosis associated with scarring and connective tissue diseases remains a challenge in both internal and external medicine. Existing treatments, such as hormones and immunosuppressants, often struggle to achieve significant results, are costly, and can lead to complications such as infection and liver and kidney damage.

[0004] Therefore, we made improvements to this and proposed a microneedle transdermal drug delivery method for the treatment of skin fibrosis. Summary of the Invention

[0005] The purpose of the present invention is to address the problems raised by the current background technology.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides a microneedle transdermal drug delivery method for treating skin fibrosis to improve the above-mentioned problem.

[0007] The specific application is as follows:

[0008] The following steps are involved:

[0009] S100, preparing sustained-release drug-loaded microneedles containing ethylenediaminetetraacetic acid (EDTA), wherein the microneedles comprise a degradable matrix material and EDTA at a concentration of at least 0.5-10% by mass;

[0010] S200, attaching the drug-loaded microneedles to the fibrotic skin area and forming microchannels by mechanical puncture;

[0011] S300, through the dissolution or degradation of the matrix material triggered by body fluids, the sustained release of EDTA is achieved, with a release period of 6-72 hours;

[0012] S400 and EDTA inhibit the TGF-β1 / Smads pathway and collagen cross-linking by complexing copper ions and calcium ions in skin tissue, thereby inhibiting the fibrosis process.

[0013] As a preferred technical solution of the present application, the degradable matrix material is selected from at least one of hyaluronic acid, carboxymethyl cellulose, and polylactic acid-glycolic acid copolymer (PLGA), and the mass ratio of the matrix material to EDTA is 1:0.05 to 1:0.3.

[0014] As the preferred technical solution of this application, the microneedle body is a conical structure, the needle tip length is 200-800 μm, the base diameter is 50-150 μm, and the array density is 100-400 needles / cm 2 .

[0015] As a preferred technical solution of the present application, the microneedles are prepared by freeze-drying technology in step S100, including the following sub-steps:

[0016] S101, mixing EDTA with a matrix material solution and injecting the mixture into a mold;

[0017] S102, pre-freeze at -20°C to -80°C for 4-12 hours;

[0018] S103, vacuum drying to remove ice crystals and form drug-loaded microneedles with a porous structure.

[0019] As a preferred technical solution of the present application, the release kinetics of EDTA in step S300 satisfies the Higuchi model, and the cumulative release amount in 24 hours is ≥80%.

[0020] As a preferred technical solution of the present application, the method further includes pre-treating the fibrotic area before step S400, wherein the pre-treatment is selected from at least one of the following:

[0021] A. Use low-intensity focused ultrasound (LIFU) to enhance skin permeability;

[0022] B. Apply a weakly acidic buffer solution with a pH of 5.0-6.5 topically.

[0023] A sustained-release drug-loaded microneedle patch for treating skin fibrosis, comprising:

[0024] a base layer made of a biodegradable material;

[0025] A microneedle array arranged on a substrate, wherein the microneedles contain an effective amount of EDTA and a sustained-release excipient;

[0026] a peelable protective film covering the microneedle array;

[0027] The sustained-release excipient is poloxamer 407 with temperature-sensitive response characteristics, which undergoes a sol-gel phase transition at 32-37°C.

[0028] As a preferred technical solution of the present application, the surface of the microneedle is coated with mesoporous silica nanoparticles with a mesopore diameter of 2-10 nm, and EDTA is loaded in the pores of the nanoparticles by chemical bonding.

[0029] As a preferred technical solution of this application, the edge of the base layer is provided with a pressure-sensitive adhesive layer with an adhesive force of 0.5-2.0 N / cm 2 , and sodium chloride particles are dispersed in the adhesive layer to enhance the durability of the attachment.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] In the scheme of this application:

[0032] 1. Through the microneedle transdermal drug delivery system (adjustable needle length, array puncture), a drug channel directly reaching the lesion is established, which significantly improves the transdermal efficiency and ensures that the drug effectively penetrates into the lesion area, overcoming the drug waste problem caused by the stratum corneum barrier of traditional topical preparations. By utilizing the dual ion targeting properties of EDTA (chelated Cu 2 + Block signaling pathways, depolymerize Ca 2 + regulating collagen cross-linking), simultaneously inhibiting upstream signal activation and downstream matrix remodeling in the fibrosis process, forming a multi-dimensional intervention mechanism, significantly improving treatment efficacy. The sustained-release system design combining thermosensitive materials and biodegradable matrices prolongs the duration of drug action at the lesion site, reduces the burden of frequent medication for patients, and improves treatment compliance. Local controlled-release technology limits the scope of drug action, and the use of biocompatible substrates effectively avoids side effects such as hypocalcemia and organ damage caused by traditional systemic administration, significantly improving treatment safety. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 Schematic diagram of the microneedle transdermal drug delivery method for treating skin fibrosis provided in this application. DETAILED DESCRIPTION

[0034] In order to enable those skilled in the art to better understand the solutions of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts should fall within the scope of protection of the present invention.

[0035] In order to enable those skilled in the art to better understand the solutions of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings.

[0036] It should be noted that, in the absence of conflict, the embodiments of the present invention and the features and technical solutions therein may be combined with each other.

[0037] It should be noted that similar reference numerals and letters denote similar items in the following drawings, and therefore, once an item is defined in one drawing, it does not need to be further defined or explained in subsequent drawings.

[0038] Example 1, please refer to Figure 1 , a microneedle transdermal drug delivery method for treating skin fibrosis, comprising the following steps:

[0039] S100, preparing sustained-release drug-loaded microneedles containing ethylenediaminetetraacetic acid (EDTA), wherein the microneedles comprise a degradable matrix material and at least 0.5-10% by mass concentration of EDTA, PLGA (molecular weight 15 kDa) and hyaluronic acid (1% w / v) are mixed in a ratio of 7:3, and EDTA disodium salt is added to a final concentration of 5%;

[0040] Freeze drying process:

[0041] Pre-freezing: -40℃ / 6h, vacuum degree 10Pa

[0042] Gradient temperature increase: -20℃→25℃ / 24h, to maintain directional growth of ice crystals;

[0043] S200, attaching the drug-loaded microneedles to the fibrotic skin area and forming microchannels by mechanical puncture;

[0044] S300, through the dissolution or degradation of the matrix material triggered by body fluids, the sustained release of EDTA is achieved, with a release period of 6-72 hours;

[0045] S400 and EDTA inhibit the TGF-β1 / Smads pathway and collagen cross-linking by complexing copper and calcium ions in skin tissue, thereby inhibiting the fibrosis process;

[0046] The dual-ion targeting mechanism synergistically enhances efficacy; the sustained-release technology prolongs the duration of local drug action; and the microneedle puncture breaks through the stratum corneum barrier to improve drug bioavailability.

[0047] The degradable matrix material is selected from at least one of hyaluronic acid, carboxymethyl cellulose, and polylactic acid-glycolic acid copolymer (PLGA), and the mass ratio of the matrix material to EDTA is 1:0.05 to 1:0.3. The biocompatible material reduces skin irritation, and the specific ratio optimizes drug loading and release rate.

[0048] The microneedle body is a conical structure, the needle tip length is 200-800 μm, the base diameter is 50-150 μm, and the array density is 100-400 needles / cm 2 , taking into account the skin penetration depth and painless operation requirements, the array density is adapted to the fibrosis area in different parts.

[0049] In step S100, microneedles are prepared by freeze-drying technology, including the following sub-steps:

[0050] S101, mixing EDTA with a matrix material solution and injecting the mixture into a mold;

[0051] S102, pre-freeze at -20°C to -80°C for 4-12 hours;

[0052] S103, vacuum drying to remove ice crystals and form drug-loaded microneedles with a porous structure.

[0053] The freeze-drying process forms a porous structure, which accelerates body fluid penetration and drug release.

[0054] The release kinetics of EDTA in step S300 meets the Higuchi model, and the cumulative release amount in 24 hours is ≥80%, which is in line with the classic drug release law and ensures that the therapeutic dose is controllable.

[0055] The method further includes pre-treating the fibrotic area before step S400, wherein the pre-treatment is selected from at least one of the following:

[0056] A. Use low-intensity focused ultrasound (LIFU) to enhance skin permeability;

[0057] B. Apply a weakly acidic buffer solution with a pH of 5.0-6.5 topically.

[0058] Pretreatment synergistically improves drug penetration efficiency, and the buffer regulates the skin microenvironment to stabilize EDTA activity.

[0059] A sustained-release drug-loaded microneedle patch for treating skin fibrosis, comprising:

[0060] a base layer made of a biodegradable material;

[0061] A microneedle array arranged on a substrate, wherein the microneedles contain an effective amount of EDTA and a sustained-release excipient;

[0062] a peelable protective film covering the microneedle array;

[0063] The sustained-release excipient is poloxamer 407 with temperature-sensitive response characteristics, which undergoes a sol-gel phase transition at 32-37°C.

[0064] Thermosensitive materials enable body temperature-triggered drug release, avoiding excessive local concentrations caused by the burst effect.

[0065] The surface of the microneedle is coated with mesoporous silica nanoparticles with a mesopore diameter of 2-10 nm, and EDTA is loaded in the pores of the nanoparticles through chemical bonding.

[0066] Nanocarriers improve the stability of EDTA and prevent oxidative degradation.

[0067] Multiple mechanisms synergistically fight fibrosis and reduce the dosage and toxic side effects of single drugs.

[0068] The edge of the base layer is provided with a pressure-sensitive adhesive layer with an adhesive force of 0.5-2.0 N / cm 2 The adhesive layer contains sodium chloride particles to enhance the durability of the patch and optimize the mechanical compatibility between the patch and the skin to prevent it from falling off during treatment.

[0069] In the present invention, unless otherwise specified or limited, the terms "installed," "connected," "connect," "fixed," etc. should be understood in a broad sense. For example, they can refer to fixed connection, detachable connection, or integration; mechanical connection, electrical connection, or communication; direct connection or indirect connection through an intermediate medium; internal communication between two elements or interaction between two elements, unless otherwise specified. Those skilled in the art will understand the specific meanings of the above terms in the present invention based on specific circumstances.

[0070] Obviously, the embodiments described above are only some embodiments of the present invention, rather than all embodiments. The preferred embodiments of the present invention are given in the accompanying drawings, but they do not limit the patent scope of the present invention. The present invention can be implemented in many different forms. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive. Although the present invention has been described in detail with reference to the aforementioned embodiments, for those skilled in the art, it is still possible to modify the technical solutions described in the aforementioned specific embodiments, or to make equivalent replacements for some of the technical features therein. Any equivalent structure made using the contents of the present invention specification and drawings, directly or indirectly used in other related technical fields, is also within the scope of patent protection of the present invention.

Claims

1. A microneedle transdermal drug delivery method for treating skin fibrosis, characterized in that: The following steps are involved: S100, preparing sustained-release drug-loaded microneedles containing ethylenediaminetetraacetic acid (EDTA), wherein the microneedles comprise a degradable matrix material and EDTA at a concentration of at least 0.5-10% by mass; S200, attaching the drug-loaded microneedles to the fibrotic skin area and forming microchannels by mechanical puncture; S300, through the dissolution or degradation of the matrix material triggered by body fluids, the sustained release of EDTA is achieved, with a release period of 6-72 hours; S400 and EDTA inhibit the TGF-β1 / Smads pathway and collagen cross-linking by complexing copper ions and calcium ions in skin tissue, thereby inhibiting the fibrosis process.

2. A microneedle transdermal drug delivery method for treating skin fibrosis according to claim 1, characterized in that: The degradable matrix material is selected from at least one of hyaluronic acid, carboxymethyl cellulose, and polylactic acid-glycolic acid copolymer (PLGA), and the mass ratio of the matrix material to EDTA is 1:0.05 to 1:0.

3.

3. A microneedle transdermal drug delivery method for treating skin fibrosis according to claim 2, characterized in that: The microneedle body is a conical structure, the needle tip length is 200-800 μm, the base diameter is 50-150 μm, and the array density is 100-400 needles / cm 2 .

4. A microneedle transdermal drug delivery method for treating skin fibrosis according to claim 3, characterized in that: In step S100, microneedles are prepared by freeze-drying technology, including the following sub-steps: S101, mixing EDTA with a matrix material solution and injecting the mixture into a mold; S102, pre-freeze at -20°C to -80°C for 4-12 hours; S103, vacuum drying to remove ice crystals and form drug-loaded microneedles with a porous structure.

5. The microneedle transdermal drug delivery method for treating skin fibrosis according to claim 4, characterized in that: The release kinetics of EDTA in step S300 meets the Higuchi model, and the cumulative release amount in 24 hours is ≥80%.

6. The microneedle transdermal drug delivery method for treating skin fibrosis according to claim 5, characterized in that: The method further includes pre-treating the fibrotic area before step S400, wherein the pre-treatment is selected from at least one of the following: A. Use low-intensity focused ultrasound (LIFU) to enhance skin permeability; B. Apply a weakly acidic buffer solution with a pH of 5.0-6.5 topically.

7. A sustained-release drug-loaded microneedle patch for treating skin fibrosis, used in the microneedle transdermal drug delivery method for treating skin fibrosis as claimed in claim 6, characterized in that: include: a base layer made of a biodegradable material; A microneedle array arranged on a substrate, wherein the microneedles contain an effective amount of EDTA and a sustained-release excipient; a peelable protective film covering the microneedle array; The sustained-release excipient is poloxamer 407 with temperature-sensitive response characteristics, which undergoes a sol-gel phase transition at 32-37°C.

8. The sustained-release drug-loaded microneedle patch for treating skin fibrosis according to claim 7, characterized in that: The surface of the microneedle is coated with mesoporous silica nanoparticles with a mesopore diameter of 2-10 nm, and EDTA is loaded in the pores of the nanoparticles through chemical bonding.

9. The sustained-release drug-loaded microneedle patch for treating skin fibrosis according to claim 8, characterized in that: The edge of the base layer is provided with a pressure-sensitive adhesive layer with an adhesive force of 0.5-2.0 N / cm 2 , and sodium chloride particles are dispersed in the adhesive layer to enhance the durability of the attachment.

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