A soluble microneedle loaded with an ester drug, and a preparation method and application thereof

Abstract

The application discloses a preparation method of soluble microneedles loaded with ester drugs, and comprises the following steps: dissolving microneedle matrix material A in water to obtain an aqueous solution; dissolving microneedle matrix material B and ester drugs in an organic solvent to obtain an organic solution; mixing the aqueous solution and the organic solution, and removing air bubbles to obtain a microneedle solution; and forming the microneedle solution in a mold and demolding to obtain the soluble microneedles loaded with ester drugs; wherein the solubility of the microneedle matrix material A in water is greater than that in the organic solvent; and the solubility of the microneedle matrix material B in the organic solvent is greater than that in water. The method solves the problems that ester drugs are difficult to be transdermally administered in microneedles, the solubility of ester drugs in water is low, ester drugs are prone to hydrolysis, and it is difficult to prepare soluble microneedles with high drug loading and low transdermal administration efficiency. The application also discloses microneedles prepared by the preparation method and microneedle patches containing the microneedles.

Description

Technical Field

[0001] This invention relates to the field of biomedical materials. More specifically, it relates to a soluble microneedle loaded with an ester drug, its preparation method, and its application. Background Technology

[0002] Transdermal drug delivery refers to the delivery of drugs through the skin to the dermis or bloodstream, thereby exerting local or systemic therapeutic effects. Transdermal drug delivery has many advantages, such as avoiding the first-pass effect, reducing fluctuations in blood drug concentration, high local targeting, and good patient compliance. However, the biggest obstacle to transdermal drug delivery is the stratum corneum of the skin, a natural barrier that most drugs cannot easily cross. Esters are a general term for fats, lipids, and their derivatives. Fats and lipids with specific physiological and pharmacological effects are called ester drugs. A common characteristic of ester drugs is their low solubility in aqueous solutions and high solubility in organic solvents; therefore, the drug loading capacity of ester drugs in hydrogels is relatively low. Ester drugs can have a larger drug loading capacity in creams or patches, but due to the barrier effect of the stratum corneum, ester drugs loaded in patches or creams are difficult to deliver transdermally. Furthermore, ester drugs are prone to hydrolysis under high temperature and humidity conditions, which also poses difficulties for the production and storage of ester drug formulations. Summary of the Invention

[0003] To address the aforementioned problems, the present invention aims to provide a microneedle loaded with ester drugs, its preparation method, and its application, thereby at least solving the problems of the difficulty in transdermal administration of ester drugs in microneedles and the low solubility and easy hydrolysis of ester drugs in water in soluble microneedles, making it difficult to obtain soluble microneedles with high drug loading and low transdermal administration efficiency.

[0004] In one aspect, the present invention provides a method for preparing soluble microneedles loaded with ester drugs, comprising the following steps:

[0005] Microneedle matrix material A was dissolved in water to obtain an aqueous solution;

[0006] Microneedle matrix material B and ester drugs are dissolved in an organic solvent to obtain an organic solution;

[0007] The aqueous solution was mixed with an organic solution, and the air bubbles were removed to obtain a microneedle solution.

[0008] The microneedle solution was molded in a mold and then demolded to obtain the soluble microneedles loaded with the ester drug.

[0009] in:

[0010] The microneedle matrix material A has a higher solubility in water than in organic solvents;

[0011] The microneedle matrix material B has a higher solubility in organic solvents than in water.

[0012] To address the problem of low solubility of ester drugs in water, which makes it difficult to fabricate water-soluble microneedles with high drug loading, this invention employs different matrix materials with varying solubilities in water and organic solvents, each dissolved in a different solvent. The organic solvent increases the solubility of ester drugs, thereby improving the drug loading per unit area of ​​the microneedles. Water dissolves the biocompatible microneedle matrix material and reduces the drying time or temperature of the microneedles.

[0013] The microneedles prepared by this method have high transdermal drug delivery efficiency for esters. The loaded esters can effectively penetrate the stratum corneum of the skin, allowing the esters to pass directly through the barrier of the stratum corneum. They have the advantages of low therapeutic dose, high drug utilization rate, and convenient use by patients.

[0014] Furthermore, the organic solvent is selected from organic solvents with low boiling points and high solubility and low hydrolysis rate for the ester drug.

[0015] Furthermore, the organic solvent is selected from one or more of N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), and tripropylene glycol monomethyl ether (TPM).

[0016] Furthermore, both microneedle matrix material A and microneedle matrix material B exhibit good compatibility with the ester drug. Good compatibility also means low hydrolysis rate.

[0017] Furthermore, the microneedle matrix material A is selected from one or more of polyvinyl alcohol (PVA), hydroxyethyl cellulose (HEC), hyaluronic acid (HA), and sodium carboxymethyl cellulose (CMC).

[0018] Furthermore, the microneedle matrix material B is selected from one or more of polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), highly substituted hydroxypropyl cellulose (HHPC), and ethyl cellulose (EC).

[0019] Furthermore, the soluble microneedles loaded with ester drugs contain 5-50 wt% ester drugs by weight percentage.

[0020] The amount of matrix material added needs to be determined based on the microneedle's puncture capability and the hydrolysis rate of aspirin within the microneedle. Higher matrix material content results in better microneedle puncture capability, but also a higher hydrolysis rate of aspirin within the microneedle. Therefore, a minimum amount of matrix material should be used while ensuring the microneedle can puncture the skin.

[0021] For example, when the ester drug is aspirin, the microneedle matrix material A is PVA and the microneedle matrix material B is PVP. The microneedle solution contains 5-20 wt% ester drug, 15-25 wt% PVA, 5-15 wt% PVP, 20-50 wt% water and 20-40 wt% organic solvent.

[0022] For example, when the ester drug is dabigatran mesylate, the microneedle matrix material A is HEC and the microneedle matrix material B is HPMC. The microneedle solution contains 10-20 wt% ester drug, 5-10 wt% HEC, 20-30 wt% HPMC, 30-50 wt% water and 20-40 wt% organic solvent.

[0023] Furthermore, the mold is made of polydimethylsiloxane (PDMS).

[0024] Furthermore, the method for molding the microneedle solution in a mold includes:

[0025] The microneedle solution is injected into the mold, and a vacuum is drawn to force the solution at the needle tip into the needle hole unit, which is then dried.

[0026] Furthermore, the drying method is in the form of heated air supply.

[0027] Furthermore, the method for molding the microneedle solution in a mold includes:

[0028] The microneedle solution was injected into the mold, and a vacuum of 0.1 MPa was applied for 10 minutes to encourage the solution at the needle tip to enter the needle hole unit. The mold was then dried in a forced-air drying oven at 60°C for 25 hours.

[0029] On the other hand, the present invention provides soluble microneedles loaded with ester drugs prepared by the preparation method described above.

[0030] In another aspect, the present invention provides a microneedle patch comprising soluble microneedles as described above and a backing bonded to the soluble microneedles.

[0031] Furthermore, the microneedle patch also includes a protective film located on the outer surface of the microneedle.

[0032] The beneficial effects of this invention are as follows:

[0033] The method for preparing soluble microneedles loaded with ester drugs provided by this invention significantly reduces the hydrolysis of ester drugs and increases the drug loading per unit area by selecting different microneedle matrix materials and using different solvents for dissolution. Furthermore, this invention employs molding technology to fabricate the ester-loaded microneedles and utilizes a microneedle array mold to prepare microneedle patches. This method is simple, low-cost, suitable for mass production, and highly practical. Attached Figure Description

[0034] The specific embodiments of the present invention will be described in further detail below with reference to the accompanying drawings.

[0035] Figure 1 The hydrolysis rate of aspirin in microneedles is shown. Among them, the solutions for preparing microneedles in A, B, and C contain 20% aspirin, 15% PVA, 22.5% water, and the organic solvents are DMA, NMP, and DMSO, respectively, with a total content of 42.5% for organic solvents and PVP. The solution for preparing microneedles in D contains 15% PVA, 10% PVP, 22.5% water, and a total content of 52.5% for aspirin and DMA.

[0036] Figure 2 A stereomicroscopic image of the aspirin microneedles prepared in Example 2 is shown.

[0037] Figure 3 The pharmacokinetic curves of aspirin microneedles in rats are shown.

[0038] Figure 4 The results show the plasma thromboxane B2 concentrations in rats before and after administration for 7 consecutive days.

[0039] Figure 5 A: Dissolution of microneedle tips in the abdominal skin of male ICR mice (scale bar = 200 μm). B: Change in tip height over time with microneedle application on the abdominal skin of male ICR mice. C: Optical microscopic image of the abdominal skin of male ICR mice after microneedling (scale bar = 2 mm). D: Optical microscopic image of the dorsal skin of male Japanese white rabbits after microneedling. Black dashed circles indicate areas where aspirin-free microneedles were applied. Red dashed circles indicate areas where microneedles containing 6 mg / tablet aspirin were applied (scale bar = 10 mm). Detailed Implementation

[0040] To more clearly illustrate the present invention, the following description, in conjunction with preferred embodiments and accompanying drawings, further explains the invention. Similar components in the drawings are indicated by the same reference numerals. Those skilled in the art should understand that the specific description below is illustrative rather than restrictive and should not be construed as limiting the scope of protection of the present invention.

[0041] Examples 1-6

[0042] aspirin-loaded microneedles

[0043] The hydrolysis rate of aspirin in microneedles increases with the content of PVP and PVA in the formulation. To ensure the punctureability of the microneedles, the content of PVP or PVA should be minimized. The boiling point and content of the organic solvent in the formulation also affect the hydrolysis rate of aspirin in microneedles. An ideal solvent should have a low boiling point and high solubility for aspirin. Among DMA, NMP, and DMSO, DMA is the most suitable solvent for preparing aspirin microneedles. DMA has the least impact on aspirin hydrolysis, and aspirin has high solubility in DMA. The drying temperature of the microneedle solution needs to be selected based on the formulation. Higher drying temperatures result in shorter microneedle preparation times, but also higher aspirin hydrolysis rates. The aspirin content in the microneedles also affects the hydrolysis rate. Lower aspirin concentrations in the microneedle solution lead to higher aspirin hydrolysis rates in the prepared microneedles. Dilute solutions require longer heating and drying times, resulting in higher hydrolysis rates.

[0044] In this embodiment, the factors causing aspirin hydrolysis in the solution used to fabricate microneedles were investigated. The hydrolysis of aspirin in solution is mainly related to the solvent, the type and concentration of the matrix material, and the concentration of aspirin. The hydrolysis rate of aspirin in microneedles is related to the drying temperature, such as... Figure 1 As shown in AC, the solutions A, B, and C used to prepare microneedles contain 20% aspirin, 15% PVA, 22.5% water, and organic solvents DMA, NMP, and DMSO, respectively. The total content of organic solvents and PVP is 42.5%. It can be seen that within a certain temperature range, the hydrolysis rate of aspirin increases with increasing temperature.

[0045] Figure 1 Figure D shows the hydrolysis rate of aspirin at 60°C when microneedles were prepared using a microneedle raw material with a solution containing 15% PVA, 10% PVP, 22.5% water, and a total content of 52.5% aspirin and DMA. It can be seen that the hydrolysis rate of aspirin gradually decreases with increasing aspirin content in the microneedles. Microneedles containing high aspirin loading exhibit higher stability.

[0046] The raw material composition of the microneedles in Examples 1-6 is shown in Table 1 below. The preparation method of the soluble microneedles loaded with ester drugs includes the following steps:

[0047] (1) Microneedle solution preparation

[0048] Add a certain amount of ultrapure water to a centrifuge tube, weigh a certain amount of PVA using an electronic balance and add it to the tube. Place the tube in an oven and heat at 90°C to dissolve. After complete dissolution, remove the tube and cool to room temperature. Separately, add a certain amount of DMA to a centrifuge tube, add aspirin and PVP, and stir until completely dissolved. After complete dissolution, mix the aqueous solution and organic solution and stir thoroughly. Centrifuge at 5000 rpm for 5 minutes to remove air bubbles, thus obtaining a microneedle solution containing aspirin. The mass fractions of aspirin, PVP, PVA, water, and DMA are 5-20%, 5-15%, 15-25%, 20-50%, and 20-40%, respectively.

[0049] (2) Preparation of microneedles

[0050] The microneedle solution was injected into a cleaned and dried PDMS mold, and a vacuum of 0.1 MPa was applied for 10 minutes to encourage the solution to enter the needle tip cells. The mold was then dried in a forced-air drying oven at 60°C for 25 hours. After complete drying, the mold was removed to obtain the aspirin-containing microneedle patch.

[0051] The properties of the prepared microneedles are shown in Table 1.

[0052] Table 1

[0053]

[0054] The stereomicroscopic images of the aspirin microneedles obtained in Example 2 above are as follows: Figure 2 As shown, the aspirin microneedles are transparent overall, with sharp needles and uniform needle height.

[0055] After 7 days of continuous administration, the pharmacokinetic study of aspirin microneedles was conducted by measuring the concentration of salicylic acid in rat plasma before and after administration. The results are as follows: Figure 3 As shown. The 2.5mg aspirin microneedle patch is the microneedle patch prepared in Example 2, and the 1.25mg aspirin microneedle patch is half the size of the microneedle patch prepared in Example 2. Oral aspirin reaches peak salicylic acid plasma concentration after 2 hours. Transdermal microneedle administration reaches peak salicylic acid plasma concentration after 8 hours. Salicylic acid plasma concentrations gradually decrease after reaching their respective peak levels. Microneedle administration results in more stable plasma drug concentrations, which is beneficial for reducing the toxic side effects of aspirin. There is no significant difference in plasma drug concentration between 8 hours and 24 hours after microneedle application within 24 hours.

[0056] The efficacy of aspirin microneedles was evaluated by measuring plasma thromboxane B2 concentrations in rats before and after administration, following 7 days of continuous administration. Results are as follows: Figure 4As shown in the figure. The control group represents the thromboxane B2 concentration in the plasma of healthy rats. Aspirin microneedles, at a dosage of 1.25 mg, achieve the same efficacy as 2.5 mg aspirin administered orally. That is, in this embodiment, good efficacy is still achieved even with a smaller drug-loaded aspirin microneedle patch.

[0057] The dissolution of the microneedles (microneedle patch obtained in Example 2) in the skin of ICR mice was observed under a microscope (e.g.) Figure 5 As shown in Figure A). The implanted microneedles gradually dissolve over time. Within 60 minutes, the height of the microneedle tips decreased by 80.89% (as shown in Figure A). Figure 5 (As shown in Figure B). Before microneedling, the abdominal skin of the ICR mice was smooth and intact. After microneedling was applied and left in place for 10 minutes, a row of micropores appeared on the skin. After the microneedles were removed, the micropores on the skin gradually healed over time. Under a microscope, the skin fully recovered within 60 minutes. Figure 5 (As shown in C). Skin irritation from microneedling was observed by applying microneedles to the skin of a Japanese white rabbit's back. Mild erythema was observed at the application site of the microneedles. No edema or crusting was observed. The erythema was caused by localized micro-injuries from the microneedle tips piercing the skin. Under a microscope, the erythema on the skin completely healed within 24 hours. There was no significant difference in skin irritation between microneedles containing aspirin and those without. Figure 5 (As shown in D). This demonstrates that aspirin delivered via microneedles does not irritate the skin. Microneedles improve the transdermal delivery rate of aspirin while ensuring the safety of administration.

[0058] Examples 7-12

[0059] Microneedles loaded with dabigatran methanesulfonate

[0060] The raw material composition of the microneedle is shown in Table 2 below, and the preparation of the microneedle includes the following steps:

[0061] (1) Microneedle solution preparation

[0062] Add a certain amount of ultrapure water to a centrifuge tube, weigh a certain amount of HEC using an electronic balance, and add it to the tube. Stir thoroughly until completely dissolved. Separately, add a certain amount of DMSO to a centrifuge tube, along with dabigatran methanesulfonate and HPMC, and stir until completely dissolved. After complete dissolution, mix the aqueous and organic solutions and stir thoroughly. Centrifuge at 5000 rpm for 5 minutes to remove air bubbles, thus obtaining a microneedle solution containing dabigatran methanesulfonate. The specific formulation is shown in Table 1.

[0063] (2) Preparation of microneedles by adding samples

[0064] The microneedle solution was injected into a cleaned and dried PDMS mold, and a vacuum of 0.1 MPa was applied for 10 minutes to encourage the solution to enter the pinhole units. The mold was then dried in a forced-air drying oven at 60°C for 30 hours. After complete drying, the mold was removed to obtain the microneedle patch containing dabigatran methanesulfonate.

[0065] Table 2. Formulation composition of products containing HPMC and HEC microneedles

[0066]

[0067]

[0068] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the implementation of the present invention. For those skilled in the art, other variations or modifications can be made based on the above description. It is impossible to exhaustively list all the implementation methods here. All obvious variations or modifications derived from the technical solutions of the present invention are still within the protection scope of the present invention.

Claims

1. A method for preparing soluble microneedles loaded with ester drugs, characterized in that, It consists of the following steps: Microneedle matrix material A was dissolved in water to obtain an aqueous solution; Microneedle matrix material B and ester drugs are dissolved in an organic solvent to obtain an organic solution; The aqueous solution was mixed with an organic solution, and the air bubbles were removed to obtain a microneedle solution. The microneedle solution was molded in a mold and then demolded to obtain the soluble microneedles loaded with the ester drug. in: The microneedle matrix material A has a higher solubility in water than in organic solvents; The microneedle matrix material B has a higher solubility in organic solvents than in water; The organic solvent is selected from one or more of N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, and tripropylene glycol monomethyl ether; The ester drug is aspirin, microneedle matrix material A is PVA, microneedle matrix material B is PVP, and the microneedle solution contains 5-20 wt% ester drug, 15-25 wt% PVA, 5-15 wt% PVP, 20-50 wt% water, and 20-40 wt% organic solvent; or The ester drug is dabigatran mesylate, microneedle matrix material A is HEC, microneedle matrix material B is HPMC, and the microneedle solution contains 20wt% ester drug, 10wt% HPMC, 20wt% HEC, 30wt% water and 20wt% organic solvent.

2. The preparation method according to claim 1, characterized in that, The mold is made of dimethylsiloxane.

3. The preparation method according to claim 1, characterized in that, The method for molding the microneedle solution in a mold includes: The microneedle solution is injected into the mold, and a vacuum is drawn to force the solution at the needle tip into the needle hole unit, which is then dried.

4. Soluble microneedles loaded with ester drugs prepared by the preparation method according to any one of claims 1-3.

5. A microneedle patch, characterized in that, Includes the soluble microneedles as described in claim 4 and a backing material bonded to the soluble microneedles.

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