CN114732782A - Needle tip liquid, microneedle patch, and preparation method and application thereof - Google Patents

Abstract

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

Description

Needle point liquid, microneedle patch, preparation method and application thereof

Technical Field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a needle tip liquid, a microneedle patch, and preparation methods and applications thereof.

Background

According to the latest Global epidemiological studies "2016 Global Disease Burden research item (GBD)", the 10 diseases with the highest annual incidence rate of 2016, three of which are skin diseases, including pyoderma caused by bacterial infection, fungal dermatopathy caused by fungal infection and other skin and subcutaneous diseases. Skin diseases, particularly infectious skin diseases caused by bacteria and fungi, have become important problems affecting human health to a non-negligible extent.

The main reasons for the treatment of infectious skin diseases are as follows: directly acting on a skin target site; the local retention time is long, so that the effect of controlling symptoms can be better exerted; the absorption is less when being used externally, so that the adverse reaction of the system administration and the dysbacteriosis caused by the system administration can be avoided; fourthly, the dosage of antibiotics in a system can be reduced, and the economic burden of a patient is lightened; simple use mode and the like. However, the infectious skin diseases are caused by various pathogenic bacteria (bacteria or fungi), and even the possibility of mixed infection of various pathogenic bacteria exists, and in some regions, the infectious skin diseases caused by drug-resistant bacteria (such as methicillin-resistant staphylococcus aureus) are more than 50%. The traditional topical antibiotic preparations (such as erythromycin ointment, neomycin ointment and ofloxacin cream) have no ability of gathering at the infected part due to poor skin permeability, 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 attacks and also provides a barrier for drugs to enter the body. The stratum corneum (generally 10-15 μm) of the outermost layer of human epidermis is a major obstacle to transdermal drug penetration. The stratum corneum consists of dead keratinocytes and intracellular matrix, of which cholesterol, triglycerides and ceramides are the main constituents. The stratum corneum is dense in structure and highly lipophilic, and allows only a small amount of lipophilic drugs with molecular weight less than 500Da to permeate, which results in poor bioavailability and difficulty in achieving a therapeutic dose of many drugs administered through the skin.

The micro needle (Microneedle) drug delivery system can be used for improving the skin permeability of drugs (including small molecule drugs and biological macromolecule drugs), and has important significance for improving the in-vivo drug effect of the drugs. The micro-needle patch is formed by connecting a plurality of micro-needle heads with the needle length of 25-2000 mu m on a base in an array mode, and is a micro-invasion transdermal drug delivery mode combining the dual advantages of subcutaneous injection and skin patches. These microneedles have sufficient length and mechanical strength to penetrate the stratum corneum and underlying tissues of the skin by penetrating the microneedle patch into the skin, breaking the barrier to the drug, and delivering the drug directly into the epidermis or dermis, thereby increasing its permeability and accumulation at a specific site. Common microneedles are classified into solid microneedles, coated microneedles, hollow microneedles and soluble microneedles. The soluble micro-needle is generally prepared from a high molecular material which is dissolved or degraded biologically, and the structure of the soluble micro-needle is divided into a substrate layer which plays a role of supporting the micro-needle array and a needle point layer which is loaded with a medicament. After the microneedle array penetrates the skin, the drug is released into the skin as the needle tip dissolves. Different from the solid micro-needle composed of metal or silicon, the polymer of the soluble micro-needle can serve as a substrate and can wrap the drug, so that the drug loading of the micro-needle is increased. Therefore, the soluble microneedle has good tolerance, convenient use, good patient compliance and high drug loading capacity, and is a very potential, safe and convenient drug delivery mode.

Microneedles with antimicrobial activity can be used for topical treatment of skin infections, reducing the likelihood of skin infection due to puncture. In recent years, some attempts have been made to construct antibacterial microneedles. Gittard and the like prepare a series of microneedle patches with surfaces coated with silver films and gentamicin based on a two-photon polymerization-micro-molding technology. Boehm et al coated amphotericin B onto the surface of Gantrez 169 BF microneedles using piezo ink jet printing. Park et al wrap green tea extract into the tips of soluble microneedles to obtain microneedle patches with good antimicrobial activity for promoting wound infection skin healing. Caffarselsalvador et al used a soluble microneedle loaded with methylene blue to resist bacteria by photodynamic anti-bacterial chemotherapy. These works lay the foundation for the research of antibacterial microneedles, but the research of antibacterial microneedles is still far from sufficient due to the problems that antibiotics are easy to generate drug resistance, the antibacterial capability of antibacterial drugs is insufficient, the drug-loading rate of the method for coating antibacterial agents on the surfaces is low, and the like.

The needle point has low drug-loading rate and is a main problem to be overcome by a transdermal drug delivery system of the soluble microneedle. The typical soluble microneedle tip layer is composed of a matrix high molecular material and a drug. As the main body of the needle point, the matrix high polymer material has better mechanical strength and is the basic guarantee that the microneedle patch can effectively pierce the skin. In order to ensure the basic mechanical property of the needle tip, the proportion of the medicine in the needle tip layer cannot be too large. Moreover, for some drugs (such as some hydrophobic drugs or protein drugs) with poor compatibility with needle tip substrate materials, if the dosage is too high, the drugs can be precipitated in the preparation or storage process of the needle tip of the soluble microneedle, so that the activity and the water solubility of the drugs are reduced.

Epsilon-polylysine is a polypeptide containing 25-30 lysine residues, has broad-spectrum antibacterial activity and also has certain mechanical properties. However, the microneedles prepared from pure epsilon-polylysine are brittle in texture and poor in mechanical property, and are difficult to puncture the stratum corneum of skin, and a certain amount of polymer auxiliary materials are required to be added and mixed with the microneedles to prepare the microneedles. If the content of the auxiliary materials is high, most space of the needle point of the microneedle can be occupied, and the enrichment of the antibacterial drugs on the needle point is reduced; if the content of the adjuvant is too low, the mechanical properties of the microneedle may be poor. Therefore, the construction of the microneedle with high drug loading and good mechanical property is a main technical problem for preparing the high-efficiency antibacterial soluble microneedle.

Disclosure of Invention

In view of the above, it is an object of the present invention to provide an efficient broad-spectrum antibacterial microneedle patch and a method for preparing the same. The efficient broad-spectrum antibacterial microneedle patch with high skin puncture rate and high needle point antibacterial active substance loading capacity is obtained by utilizing the characteristics that epsilon-polylysine has the mechanical property of a high polymer material and the broad-spectrum antibacterial activity of an antibacterial agent at the same time and matching with a small amount of other needle point matrix materials and the antibacterial agent.

The technical scheme for achieving the purpose is as follows.

A microneedle tip solution is prepared from a needle tip substrate material solution and a medicament, wherein the needle tip substrate solution contains 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 embodiments, the mass ratio of the epsilon-polylysine to the polyvinyl alcohol is 1:9 to 9:1, more preferably 3:7 to 7:3, and even more preferably 1:1.

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

The invention also provides a preparation method of the microneedle needle point liquid.

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

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

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

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 that the epsilon-polylysine has the mechanical property of a high polymer material and the broad-spectrum antibacterial activity of antibacterial active substances 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 puncture rate and high needle point antibacterial active substance loading capacity is obtained.

A microneedle patch comprises a substrate layer and a needle point layer loaded with a medicament, wherein the needle point layer is prepared from the microneedle needle point liquid.

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

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

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

obtaining the needle tip liquid according to the preparation method;

preparing a base layer solution, preferably, the base layer solution is configured as follows: polyvinylpyrrolidone was mixed in a ratio of 1: 2-1: 8(w: v) is dissolved in ethanol or water, more preferably 1: 3.8;

swelling overnight after uniformly stirring, fully and uniformly stirring again the next day, centrifuging and removing bubbles to obtain a base solution;

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

and (3) drying the microneedle female die, and peeling the microneedle to obtain the microneedle patch.

Another object of the present invention is to provide a use of the dissolvable microneedle patch described above for preparing a preparation for treating a skin disease.

The invention obtains the soluble microneedle tip substrate with antibacterial activity and good mechanical property by taking epsilon-polylysine (epsilon-PLL) as the main component of the tip substrate material and one of broad-spectrum antibacterial active substances and matching with the high molecular material polyvinyl alcohol (PVA). Researches find that the introduction of PVA is very important for improving the puncture rate of the microneedle, and the puncture rate of the antibacterial microneedle patch designed by the invention reaches more than 99%.

The invention also discovers that when epsilon-PLL and antibiotics such as doxycycline (Dox) are loaded together, the antibacterial spectrum of the prepared soluble microneedle patch is favorably expanded, even the synergistic effect is favorably exerted, the antibacterial activity of the microneedle in the body is further improved, and the microneedle patch is 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 amount, the total loading amount is more than 2319.1 mu g/tablet, wherein the loading amount of epsilon-PLL is 1869.3 mu g/tablet and the loading amount of Dox is 449.8 mu g/tablet.

Drawings

Figure 1 micrograph of dissolvable microneedle patch in example 1.

Figure 2 soluble microneedle patch skin penetration performance study in example 2.

FIG. 3 skin penetration Rate of microneedle patches with different Epsilon-PLL and PVA ratios

FIG. 4 micrographs of 6 formulations screened with needle tip fluid adjuvant from example 1 (a) pure ε -PLL; (b) epsilon-PLL PVP k30 ═ 1: 1; (c) epsiloncpll: Dex 40 ═ 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

figure 5 micrograph of doxycycline hydrochloride co-loaded with antimicrobial peptide microneedles from example 3.

Fig. 6 shows drug loading of the doxycycline-loaded antimicrobial microneedle patch.

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

Detailed Description

The practice of the present invention will employ, unless otherwise indicated, molecular biology, pharmacology, and cell biology, which are within the skill of the art. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. The various chemicals 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. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.

The antibacterial active substances include antibacterial agents (antibacterial agents) and other substances having antibacterial activity. The antibacterial drugs generally refer to drugs with bactericidal or bacteriostatic activity, including various chemically synthesized drugs such as antibiotics, sulfonamides, imidazoles, nitroimidazoles, quinolones, and the like. The water-soluble antibacterial agent is one of antibacterial agents, and comprises doxycycline hydrochloride, gentamicin sulfate, kanamycin sulfate, streptomycin sulfate, tobramycin sulfate, neomycin sulfate, spectinomycin hydrochloride, sisomicin sulfate, micronomicin sulfate, amikacin sulfate, netilmicin sulfate, vancomycin hydrochloride, norvancomycin hydrochloride, teicoplanin, polymyxin A, polymyxin B, polymyxin C, polymyxin D, polymyxin E, methicillin sodium, oxacillin sodium, cloxacillin sodium, dicloxacillin sodium, ampicillin sodium, amoxicillin sodium, ampicillin sodium, ticarcillin sodium, pimecrin, cefotiam hydrochloride, cefotaxime sodium, ceftriaxone, cefepime sodium, cefmetazole sodium, cefazolin sodium, cefuroxime, cefepime, moxef, moxalactamide sodium, doxime, doxycycline hydrochloride, streptomycin sulfate, doxycycline sulfate, netin, meclocillin, teine, mecillin, doxycycline hydrochloride, doxycycline, mecillin, and a, Flomoxef sodium, clavulanate potassium, sulbactam sodium, tazobactam sodium, imipenem, meropenem, etc

epsilon-PLL is different from conventional antibacterial small molecule drugs. (1) The polymer has larger molecular weight, so the mechanical property is better. (2) The structure of the compound is rich in a large number of amino functional groups with good water solubility, so that 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 substrate material, and can be directly (or compounded with a small amount of other substrate materials) made into the microneedle 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 medicament on the microneedle tip layer, thereby improving the medicament-carrying capacity. In addition, the soluble microneedle patch constructed by epsilon-PLL has a large amount of amino, carbonyl and methylene in a needle point layer, and can provide multiple intermolecular interactions such as hydrogen bonds, static electricity and hydrophobic interaction for loading drugs. Therefore, the drug loading system is beneficial to loading other drugs with high efficiency and constructing a synergistic drug delivery system. However, although the solid epsilon-PLL has certain mechanical property, the material is brittle, a single molding cannot construct a soluble microneedle tip with sufficient mechanical property, and the skin puncture rate is low.

The epsilon-PLL based dissolvable microneedle patch of the present invention will be described in further detail with reference to the following specific examples and accompanying drawings, and it will be appreciated by those skilled in the art that the following descriptions are illustrative and not limiting, and should not be taken as limiting the scope of the invention.

The ε -PLL used in the following examples was purchased from Zheng State Poincha organisms.

PVA-103 was purchased from Shanghai Aladdin Biotechnology Ltd.

PVP k90 was purchased from BASF, germany.

Example 1

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

1. Preparation of microneedle negative mould

Placing a quadrangular pyramid-shaped metal microneedle male die (the height of microneedles is 1200 mu m, the width of the bottoms of the microneedles is 300 mu m, the distance between needle points is 800 mu m, and the number of the microneedles is 12 multiplied by 12) in absolute ethyl alcohol, carrying out ultrasonic treatment for 20 minutes, repeatedly cleaning, and placing the male die at room temperature until the surface of the male die is completely volatilized. 9mL of Polydimethylsiloxane (PDMS) and 0.9mL of curing agent (Dow Corning, USA) were mixed at a ratio of 10: 1 (w/w) and stirred uniformly, and air bubbles were removed under vacuum for about 10 minutes. The liquid PDMS with curing agent and without bubbles was slowly poured into the positive mold (6g), and then placed in a vacuum drying oven, and a vacuum pump was connected to degas for 45 minutes until no bubbles were present on the liquid surface. And (3) placing the male mold in an oven at 80 ℃ for curing for 2 hours, taking out the male mold after PDMS is completely solidified, and separating out the female mold after cooling.

2. Preparation of tip liquid and base liquid

Epsilon-PLL (10g) was dissolved in 18mL of ultrapure water at a ratio (w/v) of 1:1.8 and shaken, and PVA-103 (10g) was dissolved in 18mL of ultrapure water at a ratio (w/v) of 1:1.8 and stirred, heated at 90 ℃ for 2 hours or more, and shaken periodically during the heating. The solution of ε -PLL and PVA-103 were mixed at a ratio of ε -PLL to PVA-103 of 1:1 (w/w) and then water-bathed at 70 ℃ for 1 hour.

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

3. Preparation of microneedle patch

Adding 250 μ L of needle point liquid into the microneedle female die, balancing, centrifuging (4000rpm,10min,0-10 deg.C), and filling the needle point liquid into the die. The excess tip liquid was removed with a clean spatula and then dried again by centrifugation (4000rpm,45min,20-30 ℃). PVP k90 base solution was added and centrifuged (4000rpm,45min,0-10 ℃). And (3) putting the microneedle female die into a drying box, and drying for more than 24 hours. The microneedle is peeled off, sealed, dried and stored.

The microneedles were gently removed from the mold to obtain needle-shaped perfect antimicrobial microneedle patches and observed with an optical microscope, as shown in fig. 1.

Example 2

Study of skin puncture Performance of antibiotic-free Epsilon-PLL/PVA-containing soluble microneedle Patches

The stratum corneum of rat skin was laid flat upward on a plate, fixed with a tack, and after depilation, the microneedle patch described in example 1 (epsilon-PLL: PVA-103 ═ 1:1) was inserted into the skin for 1 minute, stuck for 4 minutes, and then the microneedles were removed. Washing off melted microneedle liquid by using clear water, impregnating the surface of the skin with 4% (0.4g/10mL) trypan blue solution for a period of time (about 2 minutes), removing a coloring agent by using the clear water, pasting a background color by using an adhesive tape after wiping the surface dry, and observing the condition of a dyeing pore on the surface of the skin and the condition of the removed microneedle tip. (FIG. 2)

Fig. 2 shows that the soluble microneedle patch obtained by using the formulation of ∈ -PLL: PVA-103: 1 combines the hardness of ∈ -PLL and the toughness of the macromolecular material, has good mechanical strength, and has a puncture rate of 99% or more. Fig. 3 shows that the microneedle patch obtained the highest skin penetration rate using ∈ -PLL: PVA-103 ═ 1:1.

Example 3 comparison of microneedle patches constructed with different combinations of excipients

epsilon-PLL is selected as a main needle point matrix material, PVP, PVA or dextran (Dex 40) is used for improving the needle point performance, PVP K90 with the average molecular weight of 1300kDa is selected as a base layer material, and different soluble microneedle patches are constructed (other parameters refer to the preparation method of example 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 microneedles have nonuniform texture and high needle breakage rate, and when PVA-103 with a certain proportion is added into the prescription, the needle breakage rate of the prepared microneedles is greatly reduced; the micro-needle prepared by matching epsilon-PLL and PVA-103 has uniform texture and is completely transparent.

Example 4 preparation and characterization of doxycycline-loaded antimicrobial microneedles

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

Doxycycline hydrochloride (1.25g) was prepared as a 1.25: 1.8 (w/v) 1.8mL PBS buffer was added to make a high concentration solution, and the solution was washed with a 70 ℃ water bath until it was completely dissolved.

To PVP k90(10g) was added 1: 38mL of ethanol was added to a ratio (w/v) of 3.8 to dissolve, and the mixture was stirred with a spoon and swelled. The next day, the mixture was again homogenized, centrifuged at 2000rpm for 2 minutes to remove air bubbles, to obtain a base solution, and a syringe was added along the wall.

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

1. Preparation of microneedles

Adding 250 μ L of needle point liquid into the microneedle female die, balancing, centrifuging (4000rpm,10min,0-10 deg.C), and filling the needle point liquid into the die. Excess tip liquid was removed with a clean spatula and then re-dried by centrifugation (4000rpm,45min,20-30 ℃). PVP k90 base solution was added and centrifuged (4000rpm,45min,0-10 ℃). And (3) putting the microneedle female die into a drying box, and drying for more than 24 hours. The microneedle is peeled off, sealed, dried and stored.

As shown in fig. 5, the experimental results showed that the antibacterial microneedle loaded with doxycycline had a good needle shape, delamination of the tip layer and the basal layer was significant, and there was substantially no air bubbles in the needle. The calculation shows that the micro-needle has high drug loading of the antibacterial active ingredient, 449.8 mu g/tablet of doxycycline and 1869.3 mu g/tablet of epsilon-PLL, and the total amount of the antibacterial active ingredient is as high as 2319.1 mu g/tablet (figure 6)

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

ICR mice were anesthetized by intraperitoneal injection of 0.2mL of 1% sodium pentobarbital (50mg/kg), and then the mice were injected subcutaneously into the back with 100. mu.L of 1X 10 sodium pentobarbital⁸CFU/mL MRSA suspension, and marking the injection position. In the control group, 100L of PBS solution with the pH value of 7.4 is injected subcutaneously at the back of the mouse after 2h of sterilization (the injection part is the same as the sterilization part), and after 24h of sterilization, the drug-carrying microneedle described in example 4 is inserted into the back infection part of the mouse, pressed for 1 min, and removed after 10 min. After 48h, the mice were sacrificed and the skin of the inflammation site was excised to observe the abscess condition. (results see FIG. 7).

The experimental result shows that compared with a control group, the subcutaneous tissue of the mouse treated by the drug-loaded microneedle treatment group has no pustule and no obvious red swelling, which indicates that the drug-loaded antibacterial microneedle can exert obvious in-vivo antibacterial activity. In addition, the top view and the side view of the skin of the mouse with the drug-loaded microneedle treatment group show that the needle hole generated by the puncture of the microneedle is not obvious, which indicates that the soluble microneedle treatment is a safe and reliable minimally invasive technology.

The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims (10)

1. The microneedle tip solution is characterized by being prepared from a needle tip substrate material solution and a medicament, wherein the needle tip substrate material solution contains epsilon-polylysine and polyvinyl alcohol, and the mass ratio of the epsilon-polylysine to the polyvinyl alcohol is 1: 9-9: 1.

2. The microneedle tip fluid according to claim 1, wherein the drug is an antibacterial drug, more preferably a water-soluble antibacterial drug.

3. A microneedle tip solution according to claim 1, wherein said tip matrix material solution is formed by mixing epsilon-polylysine and polyvinyl alcohol, and the mass ratio of epsilon-polylysine to polyvinyl alcohol is 3: 7-7: 3, more preferably 1:1.

4. A microneedle tip fluid according to claim 1, wherein the mass ratio of the drug to the solute in the tip matrix material solution is 1: 1-1: 100(w: w), preferably 1: 2-1: 32, more preferably 1: 8.

5. A method for preparing the microneedle tip fluid according to any one of claims 1 to 4, comprising the steps of: mixing the epsilon-polylysine solution and the polyvinyl alcohol solution according to the proportion of solute in the solution, and heating at 70 +/-5 ℃ until the solutions are completely dissolved to obtain a needle tip matrix material solution;

and adding the antibacterial drug into PBS, heating and dissolving to prepare a mother solution, adding the mother solution into the needle point matrix solution according to the proportion of the drug to the solute in the needle point matrix material solution, and uniformly stirring at constant temperature to obtain the microneedle needle point solution.

6. The method according to claim 5, wherein the solution of epsilon-polylysine 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 solution of polyvinyl alcohol is prepared by mixing polyvinyl alcohol with water and dissolving the mixture by heating in a mixing ratio of 1:0.5 to 1:10(w: v), more preferably 1: 1.8.

7. A microneedle patch is characterized by comprising a substrate layer and a needle point layer loaded with a medicament, wherein the needle point layer is prepared from the microneedle needle point liquid of any one of claims 1 to 3, and the medicament is preferably an antibacterial medicament, more preferably a water-soluble antibacterial medicament.

8. A microneedle patch according to claim 7, wherein said base layer is made of polyvinylpyrrolidone, more preferably, said base layer is made of polyvinylpyrrolidone k 90.

9. A method for preparing a microneedle patch is characterized by comprising the following steps:

obtaining the needle tip liquid according to the preparation method of claim 5;

preparing a base layer solution, preferably, the base layer solution is prepared by: polyvinylpyrrolidone the ratio of 1: 2-1: 8(w: v) is dissolved in ethanol or water, more preferably 1: 3.8;

swelling overnight after uniformly stirring, fully and uniformly stirring again the next day, centrifuging and removing bubbles to obtain a base solution;

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

and (3) drying the microneedle female die, and peeling the microneedle to obtain the microneedle patch.

10. Use of the microneedle patch of claim 7 or 8 for preparing a preparation for treating a skin disease.

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