CN114732782B

CN114732782B - Needlepoint liquid, microneedle patch, and preparation methods and applications thereof

Info

Publication number: CN114732782B
Application number: CN202210259218.3A
Authority: CN
Inventors: 陆超; 罗芮; 吴传斌; 潘昕; 周桂玲; 权桂兰
Original assignee: Jinan University
Current assignee: Jinan University
Priority date: 2022-03-14
Filing date: 2022-03-14
Publication date: 2023-07-25
Anticipated expiration: 2042-03-14
Also published as: CN114732782A

Abstract

The invention discloses a microneedle tip liquid, a soluble microneedle patch prepared from the microneedle tip liquid, and a preparation method and application thereof. The microneedle tip is prepared from a tip matrix material and a drug, wherein the tip matrix material comprises epsilon-polylysine and polyvinyl alcohol. The prepared soluble microneedle has high drug loading (the total amount of antibacterial active ingredients reaches 2319.1 mug/tablet), and the needle tip strength of the microneedle is high, so that the skin penetration rate (penetration rate reaches 99%) of the microneedle can be greatly improved. The microneedle patch can be used for skin antibiosis and can be used for treating skin diseases.

Description

Needlepoint liquid, microneedle patch, and preparation methods and applications thereof

Technical Field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a needlepoint liquid, a microneedle patch, a preparation method and application thereof.

Background

According to the latest global epidemic statistics study "global disease burden study item of 2016 (Global Burden of Disease Study 2016, GBD)", 10 diseases with the highest incidence rate in 2016 are skin diseases, including pyoderma caused by bacterial infection, fungal skin diseases caused by fungal infection and other skin and subcutaneous diseases. Skin diseases, particularly infectious skin diseases caused by bacteria and fungi, have become an important issue that affects human health.

The external medicine treatment of the infectious dermatosis is mainly because: (1) directly acting on the target part of the skin; (2) the local residence time is long, so that the effect of controlling symptoms can be better exerted; (3) the external absorption is less, and adverse reaction of systemic administration, dysbacteriosis and the like caused by the adverse reaction can be avoided; (4) the system dosage of antibiotics can be reduced, and the economic burden of patients is lightened; (5) simple using mode and the like. However, the pathogenic bacteria (bacteria or fungi) of the infectious skin diseases are various, and even there is a possibility of mixed infection of a plurality of pathogenic bacteria, and in some areas, the infectious skin diseases caused by drug-resistant bacteria (such as methicillin-resistant staphylococcus aureus) are more high than 50%. Traditional topical antibiotic preparations (such as erythromycin ointment, neomycin ointment, ofloxacin cream, etc.) have poor skin permeability, do not have the capability of aggregating at the infected site, and have long curative effect and treatment period.

The skin is the largest organ of the human body, and serves as a barrier for the body against external attack, and also presents a barrier for the entry of drugs into the body. The stratum corneum, the outermost layer of the human epidermis (typically 10-15 μm), is the major obstacle to transdermal drug penetration. The stratum corneum consists of dead keratinocytes and intracellular matrix, cholesterol, triglycerides and ceramides being the major components of the intracellular matrix. The stratum corneum has compact structure and strong lipophilicity, only allows a small amount of lipophilic drugs with molecular weight less than 500Da to permeate, so that the drug effect dosage of many drugs is difficult to achieve by skin administration, and the bioavailability is low.

The Microneedle (micro) drug delivery system can be used for improving the skin permeability of drugs (including micromolecular drugs and biomacromolecular drugs), and has important significance for improving the in vivo efficacy of the drugs. The micro needle patch is formed by connecting a plurality of micro needles with the length of 25-2000 mu m on a base in an array mode, and is a micro-invasion transdermal administration mode combining the advantages of subcutaneous injection and skin patch. These microneedles have sufficient length and mechanical strength to penetrate the stratum corneum and underlying tissue of the skin by penetrating the microneedle patch, breaking the barrier of the stratum corneum against the drug, and delivering the drug directly into the epidermis or dermis, thereby increasing its permeability and accumulation at specific sites. Common microneedles are classified into solid microneedles, coated microneedles, hollow microneedles, and soluble microneedles. The soluble microneedle is generally prepared from a polymer material which is biologically dissolved or degraded, and the structure is divided into a basal layer which plays a role of supporting the microneedle array and a needle tip layer which loads a drug. After the microneedle array penetrates the skin, the drug is released into the skin as the needle tip dissolves. Unlike solid microneedles composed of metal or silicon, the polymer of the soluble microneedles can not only act as a matrix, but also encapsulate the drug, increasing the drug loading of the microneedles. Therefore, the soluble microneedle has good tolerance, convenient use, good patient compliance and high drug loading, and is a potential, safe and convenient drug delivery mode.

Microneedles with antibacterial activity can be used to treat skin infections locally, reducing the likelihood of skin infection due to penetration. In recent years, attempts have been made to construct antimicrobial microneedles. Gittard et al prepared a series of microneedle patches with silver film and gentamicin coated on the surface based on two-photon polymerization-micro-molding technology. Boehm et al coated amphotericin B onto the surface of the microneedles of Gantrez 169 BF using a piezo ink jet printing process. Park et al encapsulate green tea extract into soluble microneedle tips to obtain microneedle patches with good antibacterial activity for promoting wound infected skin healing. Caffarelsalvador et al loaded methylene blue with soluble microneedles and sterilized by photodynamic antimicrobial chemotherapy. The work lays a foundation for the research of the antibacterial micro-needle, however, the research of the antibacterial micro-needle is far insufficient due to the problems of easy drug resistance of antibiotics, insufficient antibacterial capacity of antibacterial drugs, low drug loading rate of a method for coating the surface with the antibacterial agent and the like.

The low drug loading of the needle tip is a major problem to be overcome by the percutaneous drug delivery system of the soluble microneedle. The typical soluble microneedle tip layer is composed of a matrix polymer material and a drug. As the main body of the needle tip, the matrix polymer material has better mechanical strength, which is the basic guarantee that the microneedle patch can effectively pierce the skin. In order to ensure the basic mechanical properties of the needle tip, the proportion of the drug in the needle tip layer cannot be too large. Moreover, for some drugs (e.g., some hydrophobic drugs or protein drugs) that have poor compatibility with the needle tip matrix material, if the dosage is too high, the drug may precipitate during the preparation or storage of the soluble microneedle tips, resulting in reduced drug activity and water solubility.

Epsilon-polylysine is a polypeptide containing 25-30 lysine residues, has broad-spectrum antibacterial activity and also has certain mechanical properties. However, the micro-needle prepared by pure epsilon-polylysine has brittle texture and poor mechanical property, is difficult to puncture the skin horny layer, and needs to be mixed with certain polymer auxiliary materials to prepare the micro-needle. If the content of the auxiliary materials is high, the large space of the tip of the microneedle can be occupied, and the enrichment of the antibacterial drug on the tip is reduced; if the content of the auxiliary materials is too low, the mechanical properties of the micro-needle are poor. Therefore, the construction of the microneedle with high drug loading and good mechanical property is a main technical problem for preparing the efficient antibacterial soluble microneedle.

Disclosure of Invention

Based on the above, one of the purposes of the invention is to provide an efficient broad-spectrum antibacterial microneedle patch and a preparation method thereof. By utilizing the characteristics of epsilon-polylysine, which has the mechanical property of a high polymer material and the broad-spectrum antibacterial activity of an antibacterial agent, and matching with a small amount of other needle point matrix materials and the antibacterial agent, the high-efficiency broad-spectrum antibacterial microneedle patch with high skin penetration rate and high loading of the antibacterial active substances of the needle points is obtained.

The technical scheme for achieving the purpose is as follows.

The microneedle tip liquid is prepared from a tip matrix material solution and a drug, wherein the tip matrix solution comprises epsilon-polylysine and polyvinyl alcohol.

In some of these embodiments, the drug is an antibacterial drug, more preferably a water-soluble antibacterial drug, and most preferably doxycycline hydrochloride.

In some of these embodiments, the mass ratio of epsilon-polylysine to polyvinyl alcohol is 1:9 to 9:1, more preferably 3:7 to 7:3, and even more preferably 1:1.

In some of these embodiments, the mass ratio of the drug to solute in the solution of the needle tip matrix material is from 1:1 to 1:100 (w: w), preferably from 1:2 to 1:32, more preferably 1:8.

The invention further provides a preparation method of the microneedle tip liquid.

A preparation method of microneedle tip liquid comprises the following steps: mixing the epsilon-polylysine solution and the polyvinyl alcohol solution according to the proportion of solutes in the solution, and heating at 70+/-5 ℃ until the epsilon-polylysine solution and the polyvinyl alcohol solution are completely dissolved to obtain a needle point matrix material solution;

adding the antibacterial drugs into PBS, heating and dissolving to prepare mother solution of 0.69g/mL, adding the drugs and solute in the needle point matrix material solution into the needle point matrix solution according to a proportion, and stirring and mixing at constant temperature to obtain the microneedle tip solution.

In some of these embodiments, the epsilon-polylysine solution is prepared by mixing epsilon-polylysine with water in a mixing ratio of 1:0.5 to 1:10 (w: v), more preferably 1:1.8, and/or the polyvinyl alcohol solution is prepared by mixing polyvinyl alcohol with water and then heating to dissolve, the mixing ratio being 1:0.5 to 1:10 (w: v), more preferably 1:1.8.

The invention aims at providing an efficient broad-spectrum antibacterial microneedle patch and a preparation method thereof. By utilizing the characteristics of epsilon-polylysine, which has the mechanical property of a high polymer material and the broad-spectrum antibacterial activity of an antibacterial active substance, and matching with a small amount of other needle point matrix materials and antibacterial drugs, the high-efficiency broad-spectrum antibacterial microneedle patch with high skin penetration rate and high loading of the antibacterial active substance of the needle point is obtained.

The microneedle patch comprises a basal layer and a needle tip layer loaded with a drug, wherein the needle tip layer is prepared from the microneedle needle tip liquid.

In some of these embodiments, the base layer is made of polyvinylpyrrolidone, more preferably, the base layer is made of polyvinylpyrrolidone k 90.

Another object of the present invention is to provide a method for preparing a soluble microneedle patch.

A method for preparing a soluble microneedle patch, comprising the steps of:

the needle tip liquid is obtained according to the preparation method;

a base layer solution is configured, preferably configured to: polyvinylpyrrolidone is prepared according to 1: 2-1: 8 (w: v) in ethanol or water, more preferably 1:3.8;

swelling overnight after stirring uniformly, fully stirring uniformly the next day, centrifuging to remove bubbles and obtaining a base solution;

adding the needle point liquid into a microneedle female die, centrifuging, scraping off redundant needle point liquid, centrifuging, drying, adding the base liquid, and centrifuging;

and drying the microneedle female die, and stripping the microneedle to obtain the product.

It is another object of the present invention to provide the use of the above-described soluble microneedle patch for the preparation of a dermatological formulation.

According to the invention, epsilon-polylysine (epsilon-PLL) is used as one of main components of a needle tip matrix material and a broad-spectrum antibacterial active substance, and is matched with a high polymer material polyvinyl alcohol (PVA) to obtain the soluble microneedle needle tip matrix with antibacterial activity and good mechanical property. The research shows that the introduction of PVA is very important for improving the puncture rate of the micro needle, and the puncture rate of the antibacterial micro needle patch designed by the invention reaches more than 99%.

The invention also researches and discovers that when antibiotics such as epsilon-PLL and doxycycline (Dox) are loaded together, the antibacterial spectrum of the prepared soluble microneedle patch is enlarged, even a synergistic effect is exerted, and the antibacterial activity of the microneedle in vivo is further improved, so that the soluble microneedle patch can be better applied to the treatment of skin diseases.

In addition, the antibacterial microneedle patch designed by the invention has extremely high antibacterial active ingredient loading, and the total loading amount is more than 2319.1 mug/tablet, wherein the loading amount of epsilon-PLL is 1869.3 mug/tablet and the loading amount of Dox is 449.8 mug/tablet.

Drawings

Fig. 1 is a micrograph of a soluble microneedle patch of example 1.

Figure 2 skin penetration performance study of the soluble microneedle patch of example 2.

FIG. 3 skin penetration rate of microneedle patches with different epsilon-PLL and PVA ratios

FIG. 4 microscopic image of 6 prescriptions screened with tip fluid adjuvant in example 1 (a) pure ε -PLL; (b) epsilon-PLL PVP k30=1:1; (c) epsilon-PLL, dex40=1:1; (d) epsilon-PLL: PVP k30: PVA-103=45:45:10;

(e)ε-PLL:Dex 40:PVA-103＝45:45:10；(f)ε-PLL:PVA-103＝6:4

FIG. 5A microneedle micrograph of doxycycline hydrochloride co-loaded with antibacterial peptide of example 3.

Figure 6 drug loading of doxycycline-loaded antimicrobial microneedle patch.

FIG. 7 skin plot of the dorsal inflammation of mice in example 4. (a) a side view of the skin of a control mouse; (b) control group mice skin top view; (c) a skin tissue map of control mice; (d) a side view of the skin of the drug-loaded microneedle-treated group of mice; (e) a top view of the skin of the drug-loaded microneedle-treated group of mice; (f) skin tissue map of drug-loaded microneedle-treated mice.

Detailed Description

The practice of the present invention will employ, unless otherwise indicated, molecular biology, pharmacy, cell biology, which are within the skill of the art. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. The various chemicals commonly used in the examples are commercially available.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.

The antibacterial active substance includes antibacterial drug (antibacterial agents) and other substances having antibacterial activity. The antibacterial drug generally refers to a drug with bactericidal or bacteriostatic activity, and comprises various antibiotics, sulfonamides, imidazoles, nitroimidazoles, quinolones and other chemical synthetic drugs. The water-soluble antibacterial drug is one of antibacterial drugs, and comprises doxycycline hydrochloride, gentamicin sulfate, kanamycin sulfate, streptomycin sulfate, tobramycin sulfate, neomycin sulfate, spectinomycin hydrochloride, sisomicin sulfate, minoxidil sulfate, amikacin sulfate, netilmicin sulfate, vancomycin hydrochloride, norvancomycin hydrochloride, teicoplanin, polymyxin A, polymyxin B, polymyxin C, polymyxin D, polymyxin E, methicillin sodium, benzocillin sodium, cloxacillin sodium, dicloxacillin sodium, ampicillin sodium, amoxicillin sodium, ampicillin sodium, timacyllin sodium, pimelin, cefotiam hydrochloride, cefotaxime sodium, ceftriaxone, cefpiramide sodium, cefminox sodium, cefazolin sodium, cefuroxime sodium, ceftazidime, fluxazole sodium, ceftazidime, ceftizoxime sodium, ceftazidime, and the like

epsilon-PLL is different from conventional antimicrobial small molecule drugs. (1) The polymer has high molecular weight and high mechanical performance. (2) The structure is rich in a large amount of amino functional groups with good water solubility, so the water solubility is good. (3) The degradation product is mainly natural amino acid lysine, so the biodegradability is good. The epsilon-PLL with broad-spectrum antibacterial activity has the main structural characteristics of the traditional soluble microneedle tip matrix material, and can be directly (or composited with a small amount of other matrix materials) made into the tip layer of the microneedle patch. The new idea is beneficial to reducing the use amount of other matrix materials, and greatly improves the specific gravity of the medicine on the tip layer of the microneedle, thereby improving the medicine carrying amount. In addition, the soluble microneedle patch constructed by epsilon-PLL has a large number of amino groups, carbonyl groups and methylene groups in the needle tip layer, and can provide multiple intermolecular interactions such as hydrogen bonds, static electricity and hydrophobic effects for loading drugs. Therefore, the method is beneficial to efficiently loading other medicines and constructing a cooperative drug delivery system. However, although the solid epsilon-PLL has certain mechanical properties, the material is brittle, and the single molding can not construct the soluble microneedle tip with enough mechanical properties, so that the skin penetration rate is low.

The epsilon PLL-based soluble microneedle patches of the present invention will be described in further detail below with reference to specific examples and figures, and it should be understood by those skilled in the art that the following descriptions are illustrative and not limiting, and should not be construed as limiting the scope of the present invention.

The epsilon-PLL used in the examples below was purchased from Bonnetaver, zhengzhou.

PVA-103 was purchased from Shanghai Ala Biochemical technologies Co., ltd.

PVP k90 was purchased from BASF, germany.

Example 1

Preparation and characterization of antibiotic-free epsilon-PLL/PVA soluble microneedle patches

1. Preparation of microneedle female mould

The square pyramid-shaped metal microneedle male mould (the height of the microneedle is 1200 mu m, the width of the bottom is 300 mu m, the distance between needle tips is 800 mu m, the number of the microneedle is 12 multiplied by 12) is placed in absolute ethyl alcohol, ultrasonic treatment is carried out for 20 minutes, and after repeated cleaning, the male mould is placed at room temperature until the ethyl alcohol on the surface of the male mould is completely volatilized. 9mL of Polydimethylsiloxane (PDMS) and 0.9mL of a curing agent (Dow Corning Co., U.S.A.) were mixed and stirred uniformly at a ratio (w/w) of 10:1, and the bubbles were removed in vacuo for about 10 minutes. The curing agent-containing liquid PDMS with bubbles removed was slowly poured into a male mold (6 g) and then placed in a vacuum oven, which was degassed by connecting a vacuum pump for 45 minutes until the surface of the liquid was bubble free. The male mold is placed in an oven at 80 ℃ for solidification for 2 hours, after PDMS is completely solidified, the male mold is taken out, and after cooling, the female mold is separated.

2. Preparation of needle tip liquid and base liquid

The epsilon-PLL (10 g) was dissolved in 18mL of ultrapure water at a ratio (w/v) of 1:1.8, and then shaken well, and the PVA-103 (10 g) was stirred after adding 18mL of ultrapure water at a ratio (w/v) of 1:1.8, heated at 90℃for 2 hours or more, and shaken well at regular time during heating. After mixing the epsilon-PLL solution and PVA-103 solution in a ratio (w/w) of epsilon-PLL to PVA-103=1:1, the mixture was subjected to a water bath at 70 ℃ for 1 hour.

To PVP k90 (10 g) was added 38mL of ethanol at a ratio (w/v) of 1:3.8, dissolved, stirred well with a spoon and swollen. The next day is fully stirred, the mixture is centrifuged at 2000rpm for 2 minutes to remove bubbles, the supernatant is taken to obtain a base solution, and the base solution is added into a syringe along the wall.

3. Preparation of microneedle patch

Taking 250 mu L of needlepoint liquid, adding the needlepoint liquid into a microneedle female die, balancing, and centrifuging (4000 rpm,10min,0-10 ℃) to fill the mould with the needlepoint liquid. Excess tip solution was removed with a clean spatula and then dried again by centrifugation (4000 rpm,45min,20-30 ℃). PVP k90 base solution was added and centrifuged (4000 rpm,45min,0-10 ℃ C.). And (5) placing the microneedle female die into a drying box, and drying for more than 24 hours. And (5) stripping the micropins, sealing, drying and storing.

The microneedles were gently removed from the mold to obtain a needle-type intact antimicrobial microneedle patch and observed with an optical microscope, as shown in fig. 1.

Example 2

Skin penetration performance study of antibiotic-free epsilon-PLL/PVA soluble microneedle patches

The stratum corneum of the mouse skin was spread up on a plate, fixed with a tack, and after depilation, the microneedle patch (epsilon-PLL: PVA-103=1:1) described in example 1 was inserted into the skin for 1 minute, applied for 4 minutes, and then the microneedle was removed. The melted microneedle liquid was washed off with clean water, the skin surface was stained with 4% (0.4 g/10 mL) trypan blue solution for a period of time (about 2 minutes), the stain was removed with clean water, the background color was removed with tape after wiping, and the skin surface was observed for the condition of stained pinholes and the condition of removed microneedle tips. (FIG. 2)

In fig. 2, it is shown that the soluble microneedle patch obtained by adopting the prescription of epsilon-PLL (polyvinyl alcohol-phase locked loop) PVA-103=1:1 combines the hardness of epsilon-PLL and the toughness of macromolecular material, has good mechanical strength, and the puncture rate is more than 99%. Figure 3 shows that the highest skin penetration rate was achieved with the microneedle patch using epsilon PLL with PVA-103=1:1.

Example 3 comparison of microneedle patches constructed with different adjuvant combinations

epsilon-PLL is selected as a main needle tip matrix material, PVP, PVA or dextran (Dex 40) is used for improving the needle tip performance, PVP K90 with the average molecular weight of 1300kDa is selected as a basal layer material, and different soluble microneedle patches are constructed (other parameters refer to the preparation method of the embodiment 1). The experimental results are shown in fig. 4, and the quality of the prepared microneedles is different when epsilon-PLL is matched with different auxiliary materials in different proportions. When epsilon-PLL is used alone or matched with PVP k30 and Dex 40 alone, the prepared micro-needle has nonuniform texture and high breaking rate, and when PVA-103 with a certain proportion is added in a prescription, the breaking rate of the prepared micro-needle is greatly reduced; the micro-needle prepared by matching the epsilon-PLL and the PVA-103 has uniform texture and is completely transparent.

Example 4 preparation and characterization of doxycycline-loaded antimicrobial microneedles

The epsilon-PLL (5 g) was dissolved in 9mL of ultrapure water at a ratio (w/v) of 1:1.8, and then shaken well, and the PVA-103 (5 g) was stirred after 9mL of ultrapure water was added at a ratio (w/v) of 1:1.8, heated at 90℃for 2 hours or more, and shaken well at regular time during heating.

Doxycycline hydrochloride (1.25 g) as 1.25:1.8 (w/v) and 1.8mL of PBS buffer were added to prepare a high concentration solution, which was completely dissolved in a water bath at 70 ℃.

In PVP k90 (10 g) at 1:3.8 (w/v) was dissolved in 38mL of ethanol, stirred well with a spoon and swollen. The next day is fully stirred, centrifuged at 2000rpm for 2 minutes to remove bubbles, thus obtaining a base solution, and the base solution is added into a syringe along the wall.

According to the following steps of 1:1 (w/w) mixing the epsilon-PLL solution and the PVA-103 solution uniformly, then adding the doxycycline hydrochloride high-concentration solution (the mass ratio of epsilon-PLL to doxycycline is 4:1) in proportion when the mixture is hot after water bath at 70 ℃ for 1 hour, continuing the water bath for 1 hour, and removing bubbles by ultrasonic treatment for 5 minutes to obtain the needle tip solution.

1. Preparation of microneedles

As shown in fig. 5, the experimental results showed that the antimicrobial microneedle loaded with doxycycline had good needle shape, the delamination of the needle tip layer and the basal layer was remarkable, and there was substantially no air bubble in the needle. The calculation shows that the micro-needle has high antibacterial active ingredient carrying capacity, contains 449.8 mug/tablet of doxycycline and 1869.3 mug/tablet of epsilon-PLL, and has the total amount of the antibacterial active ingredient up to 2319.1 mug/tablet (figure 6)

Example 5 epsilon-PLL and doxycycline co-loaded soluble microneedle patch in vivo antibacterial activity evaluation method was performed as follows:

ICR mice were anesthetized with 0.2mL of 1% sodium pentobarbital (50 mg/kg) and injected subcutaneously at the back with 100. Mu.L of 1X 10 ⁸ CFU/mL MRSA bacterial liquid, and marks the injection position. The control group subcutaneously injected 100L of PBS solution with pH value of 7.4 at the back of the mice after 2h of sterilization (injection site is the same as that of sterilization), the drug-loaded microneedle described in example 4 was inserted into the back infection site of the mice after 24h of sterilization, pressed for 1 minute, and removed after 10 minutes. After 48 hours, the mice are sacrificed, and the skin at the inflammation part is sheared to observe abscess. (see FIG. 7 for results).

Experimental results show that compared with a control group, the mice treated by the drug-loaded microneedle treatment group basically have no pustules and no obvious red swelling under the skin, which indicates that the drug-loaded antimicrobial microneedle can exert remarkable in-vivo antimicrobial activity. In addition, the top view and the side view of the skin of the mice in the drug-loaded microneedle therapy group show that pinholes generated by microneedle penetration are not obvious, which indicates that the soluble microneedle therapy is a safe and reliable minimally invasive technology.

The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.

Claims

1. The microneedle patch is characterized by comprising a basal layer and a needle tip layer loaded with a drug, wherein the needle tip layer is prepared from microneedle needle tip liquid, the microneedle needle tip liquid is prepared from a needle tip matrix material solution and the drug, and the drug is doxycycline hydrochloride; the matrix material in the needle tip matrix material solution isPolylysine and polyvinyl alcohol, where->The mass ratio of the polylysine to the polyvinyl alcohol is 3:7-7:3, the polyvinyl alcohol is PVA-103, and the mass ratio of the drug to the solute in the needle point matrix material solution is 1:2-1:32; the substrate layer is prepared from polyvinylpyrrolidone.

2. The microneedle patch of claim 1, wherein the microneedle patchThe mass ratio of the polylysine to the polyvinyl alcohol is 1:1.

3. The microneedle patch of claim 1, wherein the mass ratio of the drug to solute in the solution of the needle tip matrix material is 1:8.

4. A microneedle patch according to any one of claims 1 to 3, wherein the base layer is made of polyvinylpyrrolidone k 90.

5. A method of preparing a microneedle patch according to any one of claims 1 to 4, comprising the steps of:

preparing the needle tip liquid: the saidMixing the polylysine solution and the polyvinyl alcohol solution according to the proportion of solutes in the solution, and heating at 70+/-5 ℃ until the polylysine solution and the polyvinyl alcohol solution are completely dissolved to obtain a needle point matrix material solution; adding the antibacterial drugs into PBS, heating and dissolving to prepare mother liquor, adding the mother liquor into the needle point matrix solution according to the proportion of the drugs and solutes in the needle point matrix material solution, and stirring and mixing at constant temperature to obtain microneedle tip liquid;

polyvinylpyrrolidone at g/mL 1: 2-1: 8 adding ethanol or water in proportion for dissolving, and stirring uniformly

Swelling overnight, stirring thoroughly the next day, centrifuging to remove bubbles to obtain base solution;

6. The method of claim 5, wherein the base layer solution is formulated with vinylpyrrolidone at g/mL of 1:3.8, ethanol or water is added for dissolution.

7. The method of claim 5, wherein the steps ofPolylysine solution, from->The polylysine is prepared by mixing with water, and the mixing ratio is 1:0.5-1:10 according to g/mL; and/or the polyvinyl alcohol solution is prepared by mixing polyvinyl alcohol with water and then heating and dissolving, and the mixing ratio is 1:0.5-1:10 according to g/mL.

8. Use of the microneedle patch of any one of claims 1-4 in the preparation of a formulation for treating skin disorders.