Soluble microneedle patch and preparation method thereof

Abstract

The invention provides a soluble microneedle patch and a preparation method thereof, the soluble microneedle patch is composed of a needle tip and a substrate, the needle tip is formed by dissolving a drug and a biodegradable material which is soluble in water but insoluble in ethanol in water, then filling a needle cavity of a microneedle mold, and drying and curing. The substrate is formed by dissolving a biodegradable material which is soluble in water and ethanol in ethanol, then filling a microneedle mold containing a solidified needle tip with the biodegradable material, and drying and solidifying the microneedle mold, so that the soluble microneedle patch with only the needle tip carrying medicine is obtained. The needle tip material and the substrate material which are different in solubility are adopted, and polyethylene glycol and / or cyclodextrin are / is added into the substrate material, so that the problem that the substrate is wiredrawn and adheres to drugs is solved; acid is added into a needle tip solution, so that dissolution and absorption of the zolmitriptan medicine are promoted.

Description

[0001] This application claims the priority of the Chinese prior application, application number: 2023118207941, filing date December 27, 2023; all its contents are regarded as part of the present invention. Technical Field

[0002] The present invention belongs to the technical field of microneedles, and in particular, relates to a soluble microneedle patch and a preparation method thereof. Background Art

[0003] Migraine is a disease that seriously affects people's life experience and physical health. It is a common chronic neurovascular disease with symptoms of severe pulsating headache on one or both sides, which often occurs on one side of the head and lasts for more than 4-72 hours. It often recurs several times a month. It may be accompanied by symptoms such as nausea, vomiting, photophobia and phonophobia. It is the sixth most disabling disease.

[0004] Zolmitriptan is a selective 5-HTIB / ID receptor agonist. It can relieve and treat migraine by stimulating 5-HTIB / ID receptors on intracranial blood vessels (including arteriovenous anastomosis) and sympathetic nerves of the trigeminal nervous system, causing intracranial vasoconstriction and inhibiting the release of pro-inflammatory neuropeptides.

[0005] The currently available zolmitriptan drug formulations are oral tablets and nasal sprays. The problem with tablets is that they are slowly absorbed and slow to take effect, and generally take effect about 2 hours after taking the medicine. At the same time, during the attack of migraine, gastric effects (gastric retention, nausea, vomiting) may occur, further leading to poor oral absorption. Nasal sprays take effect quickly, about 15 minutes, but have an unpleasant odor. At the same time, when cluster migraine attacks, there is often nasal congestion and runny nose that affect the effect of intranasal delivery. Zosano Pharma Corporation in the United States has developed a titanium microneedle patch for zolmitriptan. The needles of the microneedle patch are coated with zolmitriptan, and then the microneedle patch is applied to the skin, such as the skin of the upper arm, and the microneedles are inserted into the skin, thereby delivering the drug on the needle body into the human body. The microneedle patch has the characteristics of painlessness, rapid onset, and bypassing the oral route. However, the microneedle patch is a titanium metal microneedle, which is expensive, and sharp waste will be generated after the microneedle patch is used, which poses a threat to the environment and may scratch other people.

[0006] Soluble microneedles do not require the use of metal microneedles, and their needle tips are completely absorbed through the skin, which is safer. However, existing soluble microneedles usually have the problem that drugs are difficult to be completely absorbed through the skin and are easily adsorbed by the microneedle substrate, making it difficult to accurately control the amount of drugs absorbed through the skin. Therefore, there is an urgent need to find a soluble microneedle patch that can enable the needle tip to carry drugs to be completely absorbed through the skin. Summary of the invention

[0007] In order to solve the above problems, the present invention provides a soluble microneedle patch and a preparation method thereof. The soluble microneedle patch is composed of a needle tip and a substrate. The needle tip is formed by dissolving a drug and a biodegradable material that is soluble in water but not ethanol in water, then filling the drug into the needle cavity of a microneedle mold, and drying and curing the drug. The substrate is formed by dissolving a biodegradable material that is soluble in both water and ethanol in ethanol, then filling the biodegradable material into a microneedle mold containing a cured needle tip, and drying and curing the biodegradable material to obtain a soluble microneedle patch with only the needle tip loaded with drug.

[0008] In one aspect, the present invention provides a soluble microneedle patch, comprising a needle tip and a substrate, wherein the needle tip comprises a biodegradable material soluble in water but insoluble in ethanol and a drug; and the substrate comprises a biodegradable material soluble in both water and ethanol.

[0009] Soluble microneedles are one of the means of drug delivery technology, and the therapeutic effect of drugs is often affected by the materials used to prepare the microneedles. For example, the drug may be adsorbed, precipitated or degraded by the microneedle material, resulting in inaccurate drug release. In view of the problem that drugs are easily adsorbed by the microneedle substrate, the present invention innovatively proposes to prepare soluble microneedles using needle tip materials and substrate materials with different solubilities. The needle tip material is a biodegradable material that is soluble in water but not in ethanol, and the substrate material is a biodegradable material that is soluble in both water and ethanol. During preparation, water is used to dissolve the needle tip material and the drug, and ethanol is used to dissolve the substrate material. Due to the different properties of the needle tip and the substrate material, the drug is precisely located at the needle tip without being adsorbed or adhered to the substrate, so that the loaded drug amount can be accurately released during use.

[0010] In some embodiments, the present invention experimentally verifies the necessity of preparing a soluble microneedle patch by dissolving the base material with ethanol. The results show that dissolving the base with ethanol and dissolving the needle tip material with water can well achieve needle tip drug loading; and the soluble microneedle patch obtained after the base solution dissolved with water and the needle tip are solidified, it can be observed from its appearance that the needle tip drug has partially diffused to the lower part of the needle and even on the base. The drug content of the needle tip and the base was further measured respectively, and the results showed that the base also contained a small amount of drug, but because only the needle tip drug can enter the skin to play a role when the soluble microneedle patch is used, dissolving the base material with water will cause the needle tip drug loading of the microneedle patch to decrease, and the therapeutic effect will be greatly reduced.

[0011] Furthermore, the biodegradable material that is soluble in water but insoluble in ethanol includes one or more of sodium hyaluronate, polyvinyl alcohol, dextran, and sodium carboxymethyl cellulose.

[0012] In some embodiments, the present invention also compares the effects of soluble microneedles prepared from four needle tip materials, sodium hyaluronate, polyvinyl alcohol, dextran or sodium carboxymethyl cellulose, respectively, and the base material in terms of drug loading and skin solubility. The results show that the soluble microneedles prepared from the four needle tip materials dissolved in water and the base material dissolved in ethanol can achieve precise needle tip drug loading, among which the microneedles prepared from sodium hyaluronate can pierce the skin well, and the needle tip drug can be well dissolved in the skin, while the drug solubility of the microneedles made of the other materials is average.

[0013] Furthermore, the biodegradable material that is soluble in both water and ethanol includes one or more of polyvinyl pyrrolidone, polyethylene glycol, and cyclodextrin.

[0014] Existing water-soluble microneedle patches generally use polyvinyl pyrrolidone to prepare the base material. Studies have shown that after the base is inserted into the body, the drug at the needle tip is easily adhered to the base due to the drawing properties of polyvinyl pyrrolidone, making it difficult for the drug to be completely absorbed by the body, thereby affecting the accuracy of the microneedle drug delivery dosage.

[0015] In some embodiments, the present invention can solve the problem of drug sticking to the microneedle substrate caused by polyvinyl pyrrolidone by adding polyethylene glycol and / or cyclodextrin to the substrate material, while also ensuring that the microneedle substrate has sufficient hardness so that the drug can be fully absorbed and the accuracy of the dosage can be ensured.

[0016] Furthermore, the drug includes zolmitriptan.

[0017] Furthermore, the needle tip also includes acid.

[0018] During the research process of the present invention, it was found that adding acid to the needle tip solution can promote the dissolution and absorption of zolmitriptan.

[0019] Furthermore, the acid includes one or more of citric acid, tartaric acid, maleic acid, hydrochloric acid, and acetic acid.

[0020] When the microneedle patch is used, the microneedles penetrate the skin, and then the needle tips dissolve in the skin, and the drugs in the needle tips also dissolve in the skin. The drugs are then absorbed by the abundant capillaries in the skin and distributed in the body to play a therapeutic role.

[0021] In another aspect, the present invention provides a zolmitriptan soluble microneedle patch.

[0022] The zolmitriptan soluble microneedle patch comprises a needle tip and a base.

[0023] The needle tip is composed of zolmitriptan, acid, and a biodegradable material that is soluble in water but insoluble in ethanol.

[0024] The acid includes: citric acid, tartaric acid, maleic acid, hydrochloric acid, and acetic acid.

[0025] The biodegradable material soluble in water but insoluble in ethanol includes one or more of sodium hyaluronate, polyvinyl alcohol, dextran, and sodium carboxymethyl cellulose.

[0026] The substrate comprises a biodegradable material that is soluble in both water and ethanol.

[0027] The biodegradable material soluble in both water and ethanol includes one or more of polyvinyl pyrrolidone, polyethylene glycol and cyclodextrin.

[0028] On the other hand, the present invention provides a method for preparing the soluble microneedle patch as described above, comprising the following steps:

[0029] S1: Use water to prepare the tip solution and ethanol to prepare the base solution;

[0030] S2: needle tip solution is passed through a microneedle mold to prepare a needle tip;

[0031] S3: The substrate solution is passed through a microneedle mold to prepare a substrate.

[0032] The present invention also discloses a method for preparing a soluble microneedle patch with quantitative drug loading at the needle tip, wherein the soluble microneedle is composed of a needle tip and a substrate. The needle tip is a water-soluble drug or a water-insoluble drug that is soluble in water by solubilization means and a biodegradable material that is soluble in water but not ethanol is dissolved in water, and then quantitatively filled into the needle cavity of the microneedle mold using a dispensing machine, and dried and solidified to form; the substrate is a biodegradable material that is soluble in both water and ethanol, dissolved in ethanol, and then filled into the microneedle mold containing the solidified needle tip, and dried and solidified to form a microneedle patch with only the needle tip loaded with drug.

[0033] Furthermore, the method comprises the following steps:

[0034] (1) Use water to prepare the tip solution and use ethanol to prepare the base solution.

[0035] (2) Load the needle tip solution into a dispensing machine, and use the dispensing machine to quantitatively spray the needle tip solution into each needle cavity of the microneedle mold.

[0036] (3) The mold sprayed with the needle tip solution is placed in a dryer to dry and solidify to form a needle tip.

[0037] (4) Pour the base solution onto the mold containing the needle tip, and then vacuum or centrifuge to fill the needle cavity with the base solution.

[0038] (5) The mold containing the solution is placed in a dryer for drying, curing, and demolding to obtain a microneedle patch.

[0039] In another aspect, the present invention provides a use of an acid for preparing an agent for improving the absorption effect of a zolmitriptan soluble microneedle patch, wherein the acid comprises one or more of citric acid, tartaric acid, maleic acid, hydrochloric acid, and acetic acid.

[0040] In another aspect, the present invention provides use of polyethylene glycol for preparing a microneedle substrate for promoting drug release from the needle tip of a soluble microneedle patch.

[0041] The present invention has the following beneficial effects:

[0042] 1. The microneedle patch is administered transdermally, avoiding the shortcomings of oral and nasal sprays;

[0043] 2. The microneedle patch provided by the present invention uses needle tip materials and base materials with different solubility, and water is used to dissolve the needle tip material and ethanol is used to dissolve the base material, respectively, so as to achieve complete drug loading of the needle tip and improve the utilization effect of the drug;

[0044] 3. By adding polyethylene glycol and / or cyclodextrin to the base material of the soluble microneedle patch, the problem of drug adhesion on the microneedle base caused by polyvinyl pyrrolidone can be solved. At the same time, the microneedle base can be guaranteed to have sufficient hardness so that the drug can be fully absorbed and the dosage can be accurately guaranteed.

[0045] 4. Adding acid to the needle tip solution of the zolmitriptan soluble microneedle patch can promote the dissolution and absorption of zolmitriptan.

[0046] 6. The zolmitriptan soluble microneedle patch prepared by the present invention only carries the drug at the needle tip. When used, the needle tip dissolves in the skin, ensuring the consistency of each drug administration. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 A is the appearance of the zolmitriptan microneedle patch prepared in Example 1;

[0048] Figure 1 B is the appearance of the zolmitriptan microneedle patch prepared in Example 2;

[0049] Figure 1 C is the appearance of the zolmitriptan microneedle patch prepared in Example 3;

[0050] Figure 1 D is the appearance of the zolmitriptan microneedle patch prepared in Example 4;

[0051] Figure 1 E is the appearance of the zolmitriptan microneedle patch prepared in Example 6;

[0052] Figure 1F is the appearance of the zolmitriptan microneedle patch prepared in Comparative Example 1;

[0053] Figure 2 This is a working diagram of a voltage jet dispensing machine;

[0054] Figure 3 A is the skin condition of rats after being pierced with the zolmitriptan microneedle patch prepared in Example 1;

[0055] Figure 3 B is the dissolution of the zolmitriptan microneedle patch prepared in Example 1 after piercing the rat skin for 10 minutes. DETAILED DESCRIPTION

[0056] The present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be pointed out that the embodiments described below are intended to facilitate the understanding of the present invention and do not have any limiting effect on the present invention.

[0057] Example 1: Preparation of Zolmitriptan Soluble Microneedle Patch

[0058] The composition of the zolmitriptan soluble microneedle is shown in Table 1 below:

[0059] Table 1 Composition ratio of zolmitriptan soluble microneedles

[0060]

[0061] (1) Preparation of needle tip solution:

[0062] 1) Take 2.24 g of citric acid (purchased from Shanghai MacLean Biochemical Technology Co., Ltd., C13792946) and add 2 ml of ultrapure water, stir to dissolve, and obtain a citric acid aqueous solution.

[0063] 2) Add 2.80 g of zolmitriptan (purchased from Shanghai Huyuan Pharmaceutical Co., Ltd., D0120033A) to the citric acid aqueous solution, stir and dissolve to obtain a zolmitriptan aqueous solution.

[0064] 3) Add 1.12 g of sodium hyaluronate (purchased from Bloomage Biotech Co., Ltd., 19122143) to the zolmitriptan aqueous solution, stir and dissolve to obtain a needle tip solution.

[0065] 4) Weigh 37.2 mg of carmine (Shanghai Dyestuff Research Institute Co., Ltd., 10121017) and add it to the above needle tip solution for dyeing.

[0066] (2) Preparation of base solution:

[0067] Weigh 9 g of PVPK60 (purchased from Shanghai Yien Chemical Technology Co., Ltd., R096806) and add it to a 50 ml centrifuge tube, add 30 ml of anhydrous ethanol, stir in a 50° C. water bath for 1 h to dissolve, and obtain a PVPK60 substrate solution.

[0068] (3) Preparation of soluble microneedles:

[0069] 1) Pipette 1 ml of the needle tip solution into the dispenser tube, use the dispenser to spray the needle tip solution into each needle cavity of the microneedle mold in a quantitative manner, and then place it in a dryer for 10 minutes at 25°C / 40% RH to solidify and shape the needle tip.

[0070] 2) Pipette 2 ml of the above-mentioned base solution into the microneedle mold containing the needle tip, and fill the needle cavity with the solution by vacuum or centrifugation. Dry in a desiccator for 10 hours, drying conditions: 25°C / 40% RH, solidify and shape, demould, and obtain a microneedle patch of zolmitriptan loaded with drug only on the needle tip, such as Figure 1 As shown in A.

[0071] Example 2: Preparation of Zolmitriptan Soluble Microneedle Patch

[0072] The composition of the zolmitriptan soluble microneedle is shown in Table 2 below:

[0073] Table 2 Composition ratio of zolmitriptan soluble microneedles

[0074]

[0075] (1) Preparation of needle tip solution:

[0076] 1) Weigh 2.24 g of citric acid, add 2 ml of ultrapure water, stir to dissolve, and obtain a citric acid aqueous solution.

[0077] 2) Add 2.80 g of zolmitriptan in the above proportion to the citric acid aqueous solution, stir and dissolve, to obtain a zolmitriptan aqueous solution.

[0078] 3) 1.12 g of sodium carboxymethyl cellulose (purchased from Shanghai Aladdin Biochemical Technology Co., Ltd., L2023204) with the above ratio was added to the zolmitriptan aqueous solution, and the mixture was stirred to dissolve to obtain a needle tip solution.

[0079] 4) Weigh 37.2 mg of carmine and add it to the needle tip solution for dyeing.

[0080] (2) Preparation of base solution:

[0081] Weigh 9 g of PVPK60 and add it to a 50 ml centrifuge tube, add 30 ml of anhydrous ethanol, and stir in a 50°C water bath for 1 h to dissolve to obtain a PVPK60 substrate solution.

[0082] (3) The preparation method of soluble microneedles is the same as that of Example 1 to obtain a microneedle patch such as Figure 1 As shown in B.

[0083] Example 3: Preparation of Zolmitriptan Soluble Microneedle Patch

[0084] The composition of the zolmitriptan soluble microneedle is shown in Table 3 below:

[0085] Table 3 Composition ratio of zolmitriptan soluble microneedle

[0086]

[0087] (1) Preparation of needle tip solution:

[0088] 1) Weigh 2.24 g of citric acid, add 2 ml of ultrapure water, stir to dissolve, and obtain a citric acid aqueous solution.

[0089] 2) Add 2.80 g of zolmitriptan in the above proportion to the citric acid aqueous solution, stir and dissolve, to obtain a zolmitriptan aqueous solution.

[0090] 3) 1.12 g of dextran (purchased from Shanghai Yien Chemical Technology Co., Ltd., R162986-100 g) with the above ratio was added to the zolmitriptan aqueous solution, and the mixture was stirred to dissolve to obtain a needle tip solution.

[0091] 4) Weigh 37.2 mg of carmine and add it to the needle tip solution for dyeing.

[0092] (2) Preparation of base solution:

[0093] Weigh 9 g of PVPK60 and add it to a 50 ml centrifuge tube, add 30 ml of anhydrous ethanol, and stir in a 50°C water bath for 1 h to dissolve to obtain a PVPK60 substrate solution.

[0094] (3) The preparation method of soluble microneedles is the same as that of Example 1 to obtain a microneedle patch such as Figure 1 As shown in C.

[0095] Example 4: Preparation of Zolmitriptan Soluble Microneedle Patch

[0096] The composition of the zolmitriptan soluble microneedle is shown in Table 4 below:

[0097] Table 4 Composition ratio of zolmitriptan soluble microneedle

[0098]

[0099] (1) Preparation of needle tip solution:

[0100] 1) Weigh 2.24 g of citric acid, add 2 ml of ultrapure water, stir to dissolve, and obtain a citric acid aqueous solution.

[0101] 2) Add 2.80 g of zolmitriptan in the above proportion to the citric acid aqueous solution, stir and dissolve, to obtain a zolmitriptan aqueous solution.

[0102] 3) 1.12 g of polyvinyl alcohol (purchased from Sigma-Aldrich (Shanghai) Trading Co., Ltd., MKCJ5322) with the above ratio was added to the zolmitriptan aqueous solution, and the mixture was stirred to dissolve to obtain a needle tip solution.

[0103] 4) Weigh 37.2 mg of carmine and add it to the needle tip solution for dyeing.

[0104] (2) Preparation of base solution:

[0105] Weigh 9 g of PVPK60 and add it to a 50 ml centrifuge tube, add 30 ml of anhydrous ethanol, and stir in a 50°C water bath for 1 h to dissolve to obtain a PVPK60 substrate solution.

[0106] (3) The preparation method of soluble microneedles is the same as that of Example 1 to obtain a microneedle patch such as Figure 1 As shown in D.

[0107] Example 5: Preparation of Zolmitriptan Soluble Microneedle Patch

[0108] The composition of the zolmitriptan soluble microneedle is shown in Table 5 below:

[0109] Table 5 Composition ratio of zolmitriptan soluble microneedle

[0110]

[0111] (1) Preparation of needle tip solution:

[0112] 1) Weigh 2.24 g of tartaric acid (purchased from Shanghai MacLean Biochemical Technology Co., Ltd., C13946057) and add 2 ml of ultrapure water, stir to dissolve, and obtain a tartaric acid aqueous solution.

[0113] 2) Add 2.80 g of zolmitriptan in the above proportion to the tartaric acid aqueous solution, stir and dissolve, to obtain a zolmitriptan aqueous solution.

[0114] 3) Add 1.12 g of sodium hyaluronate in the above proportion to the zolmitriptan aqueous solution, stir and dissolve to obtain a needle tip solution.

[0115] 4) Weigh 37.2 mg of carmine and add it to the needle tip solution for dyeing.

[0116] (2) Preparation of base solution:

[0117] Weigh 9 g of PVPK60 and add it to a 50 ml centrifuge tube, add 30 ml of anhydrous ethanol, and stir in a 50°C water bath for 1 h to dissolve to obtain a PVPK60 substrate solution.

[0118] (3) The preparation method of soluble microneedles is the same as that in Example 1.

[0119] Example 6: Preparation of Zolmitriptan Soluble Microneedle Patch

[0120] The composition of the zolmitriptan soluble microneedle is shown in Table 6 below:

[0121] Table 6 Composition ratio of zolmitriptan soluble microneedle

[0122]

[0123] (1) Preparation of needle tip solution:

[0124] 1) Weigh 2.24 g of citric acid, add 2 ml of ultrapure water, stir to dissolve, and obtain a citric acid aqueous solution.

[0125] 2) Add 2.80 g of zolmitriptan in the above proportion to the citric acid aqueous solution, stir and dissolve, to obtain a zolmitriptan aqueous solution.

[0126] 3) Add 1.12 g of sodium hyaluronate in the above proportion to the zolmitriptan aqueous solution, stir and dissolve to obtain a needle tip solution.

[0127] 4) Weigh 37.2 mg of carmine and add it to the needle tip solution for dyeing.

[0128] (2) Preparation of base solution:

[0129] 2.7 g of PVPK60 and 6.3 g of PEG4000 (purchased from Shandong Ruisheng Pharmaceutical Excipients Co., Ltd., PQ20220401) were weighed according to the ratio, added into a 50 ml centrifuge tube, 30 ml of anhydrous ethanol was added, and stirred in a 50°C water bath for 1 h to dissolve, to obtain a PVPK60 and PEG4000 base solution.

[0130] (3) The preparation method of soluble microneedles is the same as that of Example 1 to obtain a microneedle patch such as Figure 1 As shown in E.

[0131] Example 7: Preparation of Zolmitriptan Soluble Microneedle Patch

[0132] The composition of the zolmitriptan soluble microneedle is shown in Table 7 below:

[0133] Table 7 Composition ratio of zolmitriptan soluble microneedle

[0134]

[0135]

[0136] (1) Preparation of needle tip solution:

[0137] 1) Weigh 2.24 g of citric acid, add 2 ml of ultrapure water, stir to dissolve, and obtain a citric acid aqueous solution.

[0138] 2) Add 2.80 g of zolmitriptan in the above proportion to the citric acid aqueous solution, stir and dissolve, to obtain a zolmitriptan aqueous solution.

[0139] 3) Add 1.12 g of sodium hyaluronate in the above proportion to the zolmitriptan aqueous solution, stir and dissolve to obtain a needle tip solution.

[0140] 4) Weigh 37.2 mg of carmine and add it to the needle tip solution for dyeing.

[0141] (2) Preparation of base solution:

[0142] 2.7 g of PVPK60 and 6.3 g of cyclodextrin (purchased from Shanghai Aladdin Biochemical Technology Co., Ltd., C2125158) were weighed according to the ratio, added into a 50 ml centrifuge tube, 30 ml of anhydrous ethanol was added, and stirred in a 50°C water bath for 1 h to dissolve, thereby obtaining a PVPK60 and PEG4000 base solution.

[0143] (3) The preparation method of soluble microneedles is the same as that in Example 1.

[0144] Example 8: Preparation of Zolmitriptan Soluble Microneedle Patch

[0145] The composition of the zolmitriptan soluble microneedle is shown in Table 8 below:

[0146] Table 8 Composition ratio of zolmitriptan soluble microneedle

[0147]

[0148] (1) Preparation of needle tip solution:

[0149] 1) Weigh 2.24 g of citric acid, add 2 ml of ultrapure water, stir to dissolve, and obtain a citric acid aqueous solution.

[0150] 2) Add 2.80 g of zolmitriptan in the above proportion to the citric acid aqueous solution, stir and dissolve, to obtain a zolmitriptan aqueous solution.

[0151] 3) Add 1.12 g of sodium hyaluronate in the above proportion to the zolmitriptan aqueous solution, stir and dissolve to obtain a needle tip solution.

[0152] 4) Weigh 37.2 mg of carmine and add it to the needle tip solution for dyeing.

[0153] (2) Preparation of base solution:

[0154] According to the ratio, 2.7 g of PVPK60, 3.15 g of PEG4000 and 3.15 g of cyclodextrin were weighed and added into a 50 ml centrifuge tube. 30 ml of anhydrous ethanol was added and stirred in a 50°C water bath for 1 h to dissolve to obtain a PVPK60, PEG4000 and cyclodextrin base solution.

[0155] (3) The preparation method of soluble microneedles is the same as that in Example 1.

[0156] Comparative Example 1: Preparation of Zolmitriptan Soluble Microneedle Patch

[0157] The composition of the zolmitriptan soluble microneedle is shown in Table 9 below:

[0158] Table 9 Composition ratio of zolmitriptan soluble microneedle

[0159]

[0160] (1) Preparation of needle tip solution:

[0161] 1) Weigh 2.24 g of citric acid, add 2 ml of ultrapure water, stir to dissolve, and obtain a citric acid aqueous solution.

[0162] 2) Add 2.80 g of zolmitriptan in the above proportion to the citric acid aqueous solution, stir and dissolve, to obtain a zolmitriptan aqueous solution.

[0163] 3) Add 1.12 g of sodium hyaluronate in the above proportion to the zolmitriptan aqueous solution, stir and dissolve to obtain a needle tip solution.

[0164] 4) Weigh 37.2 mg of carmine and add it to the needle tip solution for dyeing.

[0165] (2) Preparation of base solution:

[0166] Weigh 9 g of PVPK60 and add it to a 50 ml centrifuge tube, add 30 ml of ultrapure water, and stir in a 50°C water bath for 1 h to dissolve to obtain a PVPK60 substrate solution.

[0167] (3) Preparation of soluble microneedles:

[0168] 1) Pipette 2 ml of the needle tip solution into a dispensing tube, use a dispensing machine to spray the needle tip solution into each needle cavity of the microneedle mold in a quantitative manner, and then place it in a dryer for 20 minutes at 25°C 40RH to solidify and shape the needle tip.

[0169] 2) Add the above-mentioned base solution to the microneedle mold containing the needle tip, and fill the needle cavity with the solution by vacuum or centrifugation. Dry in a dryer for 10 hours, drying conditions: 25°C / 40% RH, solidify and shape, demold, and obtain a zolmitriptan microneedle patch, such as Figure 1 As shown in F.

[0170] Comparative Example 2: Preparation of Zolmitriptan Soluble Microneedle Patch

[0171] The composition of the zolmitriptan soluble microneedle is shown in Table 10 below:

[0172] Table 10 Composition ratio of zolmitriptan soluble microneedle

[0173]

[0174] (1) Preparation of needle tip solution:

[0175] 1) Weigh 2.80 g of zolmitriptan, add 2 ml of ultrapure water, stir and dissolve to obtain a zolmitriptan aqueous solution.

[0176] 2) Add 3.36 g of sodium hyaluronate in the above proportion to the zolmitriptan aqueous solution, stir and dissolve, and obtain a needle tip solution.

[0177] 3) Weigh 37.2 mg of carmine and add it to the needle tip solution for dyeing.

[0178] (2) Preparation of base solution:

[0179] Weigh 9 g of PVPK60 and add it to a 50 ml centrifuge tube, add 30 ml of anhydrous ethanol, stir in a 50°C water bath for 1 h to dissolve, and obtain a PVPK60 substrate solution.

[0180] (3) The preparation method of soluble microneedles is the same as that in Example 1.

[0181] Example 9: Appearance of microneedle patch

[0182] from Figure 1 A~ Figure 1 From the appearance of the microneedles prepared by F, it can be seen that these prescription compositions can be solidified to form microneedles, and the microneedles of Examples 1-4 and 6 can well achieve needle tip drug loading. However, in Comparative Example 1, it can be seen that the needle tip drug partially diffuses to the lower part of the needle, and even to the substrate, so it is difficult to achieve needle tip drug loading by dissolving the substrate material with water.

[0183] Example 10: Determination of drug loading consistency of microneedle patches

[0184] Three microneedle patches prepared in Examples 1 to 8 and Comparative Examples 1 to 2 were taken, and the content of zolmitriptan in each patch was determined using high performance liquid chromatography. The results are as follows:

[0185] Table 11 Drug loading of soluble microneedle patches prepared by different methods

[0186]

[0187] From the results, it can be seen that microneedle patches with consistent content can be prepared by using a voltage jet dispenser. Figure 2 This is a working diagram of the voltage jet dispensing machine.

[0188] In order to further compare the prepared microneedle patches of Examples 1 to 8 and Comparative Examples 1 to 2, whether the drug content is completely loaded by the needle tip and does not adhere to the substrate. In this example, one piece of each of the prepared microneedle patches with an equal drug loading (1.66 mg) was taken, and the needle tip was dissolved in the gelatin by pressing the microneedle to the gelatin surface, thereby disconnecting from the substrate. The content of zolmitriptan in each part was determined by high performance liquid chromatography, and the results are shown in Table 12.

[0189] Table 12 Drug loading in different parts of soluble microneedle patches prepared by different methods

[0190]

[0191] As shown in the results of Table 12, the soluble microneedle patch prepared according to the method of Example 8 can completely realize the needle tip drug loading, and there is no drug precipitation in the base part, while the microneedle patch obtained by the method of Comparative Example 1 contains about one-third of the drug in the base part. The reason is that the needle tip and the base material are both water-soluble, which causes the drug to easily diffuse into the base, thereby reducing the drug loading of the needle tip. At the same time, there is also a trace of drug retention in the base part of the microneedle patch of Examples 1 to 7 and Comparative Example 2, and the amount of drug adhered to the base part of Examples 6 and 7 is less. The reason may be that polyvinyl pyrrolidone has the performance of drawing, which makes it easy to adhere the drug of the needle tip to the base. Adding polyethylene glycol (Example 6) or cyclodextrin (Example 7) to the base solution can reduce the ability of polyvinyl pyrrolidone to draw and adhere, and adding polyethylene glycol and cyclodextrin (Example 8) can solve this problem well. Therefore, it is preferred that soluble microneedles prepared by zolmitriptan, citric acid, sodium hyaluronate, polyvinyl pyrrolidone, polyethylene glycol and cyclodextrin.

[0192] Example 11: Effect and dissolution of microneedle patch on rat skin

[0193] SD rats were taken, the back hair was removed, and three microneedles prepared in Examples 1 to 8 and Comparative Examples 1 to 2 were respectively taken out and inserted into the depilated back skin. The skin was pressed for 1 min, and the three microneedles were removed 5 min, 10 min and 15 min after being inserted into the skin, respectively. The skin was stained with methylene blue to facilitate observation of the punctured holes, skin condition and microneedle dissolution.

[0194] The results show that the microneedles prepared in Comparative Example 2 did not completely dissolve the drugs after being removed at 15 minutes, while the microneedles and drugs in Examples 1-8 and Comparative Example 1 were fully dissolved at 10 minutes. The reason is that acid was added to the needle tip solution of Examples 1-8 and Comparative Example 1, and the acid can promote the dissolution and absorption of zolmitriptan. Among them, it was observed that most of the drugs in the microneedle tips of Examples 1-4, 6-8 were dissolved at 5 minutes, while the drug in Example 5 began to dissolve at 5 minutes, indicating that adding citric acid to the needle tip to promote the dissolution of zolmitriptan is more effective. In addition, it was also found in the research process of the present invention that the microneedle tips prepared by maleic acid, hydrochloric acid or acetic acid were not as effective as citric acid in promoting the dissolution of zolmitriptan. Therefore, adding citric acid to the needle tip to promote the dissolution of zolmitriptan is the best.

[0195] Among them, the microneedle patches prepared in Examples 1 and 6-8 can pierce the skin well, and the needle tip drug can be well dissolved in the skin. Figure 3 As shown, the microneedle of Example 1 has been fully dissolved at 10 minutes, indicating that the microneedle prepared by sodium hyaluronate has good solubility and hardness. The microneedle prepared by polyethylene glycol (Example 4) has too high hardness. Although it can provide good puncture force, it may also cause microneedle breakage or poor comfort when piercing the skin during use; the microneedles of two needle tip materials, dextran and sodium carboxymethyl cellulose (Examples 2 and 3), have low hardness, and the solubility of the drug is general during use, and the amount of drug loaded cannot be fully utilized. Since the microneedle tip prepared by Example 8 has a better drug loading effect, the present embodiment preferably uses soluble microneedles prepared by zolmitriptan, citric acid, sodium hyaluronate, polyvinylpyrrolidone, polyethylene glycol and cyclodextrin.

[0196] The embodiments of the present invention are described in detail above, but the present invention is not limited to the above embodiments, and various changes can be made within the knowledge scope of ordinary technicians in the relevant technical field without departing from the purpose of the present invention.

Claims

1. A soluble microneedle patch, characterized in that: The invention comprises a needle tip and a substrate. The needle tip comprises a biodegradable material soluble in water but insoluble in ethanol and a drug; and the substrate comprises a biodegradable material soluble in both water and ethanol.

2. The soluble microneedle patch according to claim 1, characterized in that: The biodegradable material soluble in water but insoluble in ethanol includes one or more of sodium hyaluronate, polyvinyl alcohol, dextran, and sodium carboxymethyl cellulose.

3. The soluble microneedle patch according to claim 2, characterized in that: The biodegradable material soluble in both water and ethanol includes one or more of polyvinyl pyrrolidone, polyethylene glycol, and cyclodextrin.

4. The soluble microneedle patch according to claim 3, characterized in that: The drugs include zolmitriptan.

5. The soluble microneedle patch according to claim 4, characterized in that: The tip also includes an acid.

6. The soluble microneedle patch according to claim 5, characterized in that: The acid includes one or more of citric acid, tartaric acid, maleic acid, hydrochloric acid and acetic acid.

7. The method for preparing the soluble microneedle patch according to any one of claims 1 to 6, characterized in that: The following steps are involved: S1: Use water to prepare the tip solution and ethanol to prepare the base solution; S2: needle tip solution is passed through a microneedle mold to prepare a needle tip; S3: The substrate solution is passed through a microneedle mold to prepare a substrate.

8. The preparation method according to claim 7, characterized in that: The following steps are involved: (1) Use water to prepare the tip solution and use ethanol to prepare the base solution. (2) Load the needle tip solution into a dispensing machine, and use the dispensing machine to quantitatively spray the needle tip solution into each needle cavity of the microneedle mold. (3) The mold sprayed with the needle tip solution is placed in a dryer to dry and solidify to form a needle tip. (4) Pour the base solution onto the mold containing the needle tip, and then vacuum or centrifuge to fill the needle cavity with the base solution. (5) The mold containing the solution is placed in a dryer for drying, curing, and demolding to obtain a microneedle patch.

9. Use of an acid for preparing an agent for improving the absorption effect of a zolmitriptan soluble microneedle patch, characterized in that: The acid includes one or more of citric acid, tartaric acid, maleic acid, hydrochloric acid and acetic acid.

10. Use of polyethylene glycol for preparing a microneedle substrate for promoting drug release from the needle tip of a soluble microneedle patch.

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