Processing technology of analgesic microneedle patch

Abstract

The invention discloses a processing technology of a pain-relieving microneedle patch, and relates to the technical field of microneedle patches, the processing technology is high in processing speed and short in time, and the preparation flexibility of the microneedle patch is improved; the demolding process is smooth, and the structural damage of the microneedle is reduced; the pain relieving effect is rapid and obvious. Lidocaine is a medicament with a good analgesic effect, and a physical channel beneficial to drug transmission can be generated on the surface of the skin when the microneedle pierces, so that the analgesic effect is enhanced. In order to further improve the transdermal effect of the medicine, lidocaine is coated in the nano-liposome, so that the tension of the medicine on the skin surface is reduced, the medicine transmission effect is improved, and the pain relieving effect is improved. Aminated polyvinyl alcohol is further added to further modify the lidocaine-containing nano-liposome, so that the dispersity of the lidocaine-containing nano-liposome is improved, and the pain relieving effect is enhanced.

Description

Technical Field

[0001] The invention relates to the technical field of microneedle patches, in particular to a processing technology for analgesic microneedle patches. Background Art

[0002] The pain-relieving microneedle patch is a new type of local pain treatment product, consisting of multiple tiny needles and drug carriers. The length of the microneedles is usually between tens of microns and several millimeters. The microneedle array is attached to the surface of the skin, allowing the drug to pass through the skin barrier to the target tissue, thereby relieving pain. Based on traditional analgesics, its pain-relieving microneedle patch has broken through the limitations of poor absorption of oral drugs and pain caused by injection needles. With its small needle puncture depth and high drug delivery efficiency, it has become an important development direction in the modern medical field.

[0003] However, the analgesic microneedle patch still faces some technical difficulties in the actual processing and production process. Currently commonly used microneedle materials include silicone, polymers, etc., but there are still certain difficulties in regulating the drug carrier design and release effect of these materials. The drug release rate of the analgesic microneedle patch is crucial to the therapeutic effect. Too fast or too slow release of the drug may affect the pain relief effect. How to accurately control the release rate of the drug and ensure that the drug effect is continuously released within a reasonable time has become a major challenge for current technology.

[0004] In order to solve the above problems, improve the drug release rate and enhance the analgesic effect, the present invention provides a processing technology for an analgesic microneedle patch. Summary of the invention

[0005] The purpose of the present invention is to provide a processing technology for a pain-relieving microneedle patch to solve the problems raised in the prior art.

[0006] To achieve the above object, the present invention provides the following technical solutions:

[0007] A processing technology for a pain-relieving microneedle patch comprises the following steps:

[0008] Step 1: Take polyvinyl alcohol and deionized water, stir evenly to obtain a polyvinyl alcohol aqueous solution, add the nanoliposome sol complex, stir evenly, and filter with a sterile filter membrane to obtain a polyvinyl alcohol mixed solution;

[0009] Step 2: taking a polydimethylsiloxane sub-mold and sterilizing it with high temperature and high pressure steam to obtain a pretreated polydimethylsiloxane sub-mold;

[0010] Step 3: Pour the polyvinyl alcohol mixture into the polydimethylsiloxane sub-mold, remove bubbles, place it at -20°C for 10-12 hours, take it out, and peel off the pretreated polydimethylsiloxane sub-mold at -5 to -2°C to obtain the analgesic microneedle patch.

[0011] More optimally, the polyvinyl alcohol mixed solution includes the following components, calculated by weight: 22-25 parts of polyvinyl alcohol, 580-600 parts of deionized water, and 2-2.5 parts of nanoliposome sol complex.

[0012] More optimally, the preparation method of the nanoliposome sol complex is: take silver nitrate and deionized water, stir evenly, add nanoliposomes containing lidocaine, stir evenly, add polyethylene glycol, heat to 55-60°C, stir for 1-2h, and obtain the nanoliposome sol complex.

[0013] More optimally, the preparation method of the nanoliposome containing lidocaine is as follows: take chloroform and methanol, stir evenly to obtain solution A; take Tween 80 and phosphate buffer, stir evenly to obtain solution B; take soybean lecithin, cholesterol, amino polyvinyl alcohol, lidocaine, solution A, stir evenly, heat to 50-55°C, rotary evaporate for 60-70 minutes, add solution B, stir evenly at 50-55°C, and ultrasonicate for 10-12 minutes to obtain nanoliposome containing lidocaine.

[0014] More optimally, the preparation method of the amino polyvinyl alcohol is: take polyvinyl alcohol and dimethyl sulfoxide, stir at 60-65°C for 30-40 minutes, add triethylamine and succinic anhydride, react for 2-3 hours, add N-hydroxysuccinimide and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, react at 25-30°C for 40-45 minutes, add terminal amino hyperbranched polymer dropwise, stir for 22-24 hours, and obtain the amino polyvinyl alcohol.

[0015] More optimally, the preparation method of the amino-terminated hyperbranched polymer is: take methyl acrylate and methanol, stir evenly to obtain a methyl acrylate solution; take diethylenetriamine, cool to 0-1°C, add the methyl acrylate solution dropwise under nitrogen protection, react at 25-30°C for 4-5h, heat to 145-150°C, and react under reduced pressure for 3-4h to obtain an amino-terminated hyperbranched polymer.

[0016] More optimally, the mass ratio of the silver nitrate, deionized water, nanoliposomes containing lidocaine, and polyethylene glycol is (10-12):100:(12-13.5):(5.5-6).

[0017] More optimally, the mass ratio of the silver nitrate, deionized water, nanoliposomes containing lidocaine, and polyethylene glycol is 10:100:(12-13):5.5.

[0018] Compared with the prior art, the present invention has the following beneficial effects:

[0019] 1. The present invention provides a processing technology for a rapid analgesic microneedle patch, which has the following advantages: fast processing speed, short time, and improved flexibility in the preparation of microneedle patches; smooth demoulding process, reducing structural damage to the microneedles; rapid analgesic effect, and obvious analgesic effect.

[0020] 2. Lidocaine is a drug with good analgesic effect. The insertion of microneedles will produce physical channels on the skin surface that are conducive to drug transmission, thereby enhancing the analgesic effect. In order to further improve the transdermal effect of the drug, the present invention encapsulates lidocaine in nanoliposomes, uses soybean lecithin and cholesterol as the main materials of the nanoliposomes, reduces the tension of the drug on the skin surface, improves the drug transmission effect, and thus improves the analgesic effect.

[0021] 3. The present invention further modifies the nanoliposome containing lidocaine by adding amino polyvinyl alcohol, thereby improving the compatibility between the nanoliposome containing lidocaine and the polyvinyl alcohol aqueous solution matrix, improving the dispersibility of the nanoliposome containing lidocaine, and enhancing the analgesic effect. A large amount of amino groups can improve the delivery effect of analgesics and enhance the analgesic effect of analgesic microneedles. The present invention further modifies the nanoliposome containing lidocaine by using silver nitrate, thereby enhancing the antibacterial properties of the analgesic microneedle patch. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 This is a bright field image of the analgesic microneedle patch of Example 1 of the present invention;

[0023] Figure 2 This is a SEM image of the analgesic microneedle patch of Example 1 of the present invention;

[0024] Figure 3 This is the recovery condition of the analgesic microneedle patch of Experiment 2 of the present invention after removal. DETAILED DESCRIPTION

[0025] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0026] The sources and models of the substances involved in the present invention are not specifically limited, and illustratively include: polyethylene glycol: model: 807485, which can be purchased from Merck; soybean lecithin: model: S30869, which can be purchased from Shanghai Yuanye Biotechnology Co., Ltd.; polyvinyl alcohol: model: S30196, which can be purchased from Shanghai Yuanye Biotechnology Co., Ltd.

[0027] Embodiment 1: A processing technology for a pain-relieving microneedle patch comprises the following steps:

[0028] Step 1: Preparation of amination polyvinyl alcohol:

[0029] S1: 80 mL of methyl acrylate and 200 mL of methanol were stirred evenly to obtain a methyl acrylate solution; 125 mL of diethylenetriamine was taken, cooled to 0°C, and the methyl acrylate solution was added dropwise under nitrogen protection, reacted at 27°C for 4.5 hours, heated to 148°C, and reacted under reduced pressure for 3.5 hours to obtain an amino-terminated hyperbranched polymer;

[0030] S2: Take 10g polyvinyl alcohol and 200mL dimethyl sulfoxide, stir at 62°C for 35min, add 0.45mL triethylamine and 1.5g succinic anhydride, react for 2.5h, add 1.1g N-hydroxysuccinimide and 2g 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, react at 28°C for 42min, add 45mL terminal amino hyperbranched polymer dropwise, stir for 23h, and obtain amino polyvinyl alcohol;

[0031] Step 2: Preparation of nanoliposomes containing lidocaine:

[0032] Take 25 mL of chloroform and 25 mL of methanol, stir evenly to obtain solution A; take 0.1 g of Tween 80 and 50 mL of phosphate buffer, stir evenly to obtain solution B; take 10 g of soybean lecithin, 2 g of cholesterol, 2 g of amino polyvinyl alcohol, 0.5 g of lidocaine, and 50 mL of solution A, stir evenly, heat to 52°C, rotary evaporate for 65 min, add solution B, stir evenly at 52°C, and ultrasonicate for 11 min to obtain nanoliposomes containing lidocaine;

[0033] Step 3: Preparation of nanoliposome sol complex:

[0034] Take 10 g of silver nitrate and 100 mL of deionized water, stir evenly, add 12 g of nanoliposomes containing lidocaine, stir evenly, add 5.5 g of polyethylene glycol, heat to 58 ° C, stir for 1.5 h, and obtain a nanoliposome sol complex;

[0035] Step 4: Preparation of polyvinyl alcohol mixed solution:

[0036] Take polyvinyl alcohol and deionized water, stir evenly to obtain a polyvinyl alcohol aqueous solution, add the nanoliposome sol complex, stir evenly, and filter with a sterile filter membrane to obtain a polyvinyl alcohol mixed solution;

[0037] The polyvinyl alcohol mixed solution includes the following components, calculated by weight: 23 parts of polyvinyl alcohol, 590 parts of deionized water, and 2.2 parts of nanoliposome sol complex;

[0038] Step 5: Preparation of analgesic microneedle patch:

[0039] S1: taking a polydimethylsiloxane sub-mold and sterilizing it with high temperature and high pressure steam to obtain a pretreated polydimethylsiloxane sub-mold;

[0040] S2: pouring the polyvinyl alcohol mixed solution into the polydimethylsiloxane sub-mold, removing bubbles, placing it at -20°C for 11 hours, taking it out, and peeling off the pretreated polydimethylsiloxane sub-mold at -3°C to obtain the analgesic microneedle patch;

[0041] The analgesic microneedle patch has 10×10 microneedles, a total of 100 microneedles, a needle height of 820 μm, a needle base width of 300 μm, and a needle center spacing of 700 μm.

[0042] Embodiment 2: A processing technology for a pain-relieving microneedle patch comprises the following steps:

[0043] Step 1: Preparation of amination polyvinyl alcohol:

[0044] S1: 80 mL of methyl acrylate and 200 mL of methanol were stirred evenly to obtain a methyl acrylate solution; 125 mL of diethylenetriamine was taken, cooled to 0°C, and the methyl acrylate solution was added dropwise under nitrogen protection, and the reaction was carried out at 25°C for 4 hours, and the temperature was raised to 145°C and the reaction was carried out under reduced pressure for 3 hours to obtain an amino-terminated hyperbranched polymer;

[0045] S2: Take 10g polyvinyl alcohol and 200mL dimethyl sulfoxide, stir at 60°C for 30min, add 0.45mL triethylamine and 1.5g succinic anhydride, react for 2h, add 1.1g N-hydroxysuccinimide and 2g 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, react at 25°C for 40min, add 45mL terminal amino hyperbranched polymer dropwise, stir for 22h, and obtain amino polyvinyl alcohol;

[0046] Step 2: Preparation of nanoliposomes containing lidocaine:

[0047] Take 25 mL of chloroform and 25 mL of methanol, stir evenly to obtain solution A; take 0.1 g of Tween 80 and 50 mL of phosphate buffer, stir evenly to obtain solution B; take 10 g of soybean lecithin, 2 g of cholesterol, 2 g of amino polyvinyl alcohol, 0.5 g of lidocaine, and 50 mL of solution A, stir evenly, heat to 50°C, rotary evaporate for 60 min, add solution B, stir evenly at 50°C, and ultrasonicate for 10 min to obtain nanoliposomes containing lidocaine;

[0048] Step 3: Preparation of nanoliposome sol complex:

[0049] Take 10 g of silver nitrate and 100 mL of deionized water, stir evenly, add 12 g of nanoliposomes containing lidocaine, stir evenly, add 5.5 g of polyethylene glycol, heat to 55 ° C, stir for 1 h, and obtain a nanoliposome sol complex;

[0050] Step 4: Preparation of polyvinyl alcohol mixed solution:

[0051] Take polyvinyl alcohol and deionized water, stir evenly to obtain a polyvinyl alcohol aqueous solution, add the nanoliposome sol complex, stir evenly, and filter with a sterile filter membrane to obtain a polyvinyl alcohol mixed solution;

[0052] The polyvinyl alcohol mixed solution includes the following components, calculated by weight: 22 parts of polyvinyl alcohol, 580 parts of deionized water, and 2 parts of nanoliposome sol complex;

[0053] Step 5: Preparation of analgesic microneedle patch:

[0054] S1: taking a polydimethylsiloxane sub-mold and sterilizing it with high temperature and high pressure steam to obtain a pretreated polydimethylsiloxane sub-mold;

[0055] S2: pouring the polyvinyl alcohol mixed solution into the polydimethylsiloxane sub-mold, removing bubbles, placing it at -20°C for 10 hours, taking it out, and peeling off the pretreated polydimethylsiloxane sub-mold at -5°C to obtain the analgesic microneedle patch;

[0056] The analgesic microneedle patch has 10×10 microneedles, a total of 100 microneedles, a needle height of 820 μm, a needle base width of 300 μm, and a needle center spacing of 700 μm.

[0057] Embodiment 3: A processing technology for analgesic microneedle patch, comprising the following steps:

[0058] Step 1: Preparation of amination polyvinyl alcohol:

[0059] S1: 80 mL of methyl acrylate and 200 mL of methanol were stirred evenly to obtain a methyl acrylate solution; 125 mL of diethylenetriamine was taken, cooled to 1°C, and the methyl acrylate solution was added dropwise under nitrogen protection, and the reaction was carried out at 30°C for 5 h, and the temperature was raised to 150°C and the reaction was carried out under reduced pressure for 4 h to obtain an amino-terminated hyperbranched polymer;

[0060] S2: Take 10g polyvinyl alcohol and 200mL dimethyl sulfoxide, stir at 65°C for 40min, add 0.45mL triethylamine and 1.5g succinic anhydride, react for 3h, add 1.1g N-hydroxysuccinimide and 2g 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, react at 30°C for 45min, add 45mL terminal amino hyperbranched polymer dropwise, stir for 24h, and obtain amino polyvinyl alcohol;

[0061] Step 2: Preparation of nanoliposomes containing lidocaine:

[0062] Take 25 mL of chloroform and 25 mL of methanol, stir evenly to obtain solution A; take 0.1 g of Tween 80 and 50 mL of phosphate buffer, stir evenly to obtain solution B; take 10 g of soybean lecithin, 2 g of cholesterol, 2 g of amino polyvinyl alcohol, 0.5 g of lidocaine, and 50 mL of solution A, stir evenly, heat to 55°C, rotary evaporate for 70 min, add solution B, stir evenly at 55°C, and ultrasonicate for 12 min to obtain nanoliposomes containing lidocaine;

[0063] Step 3: Preparation of nanoliposome sol complex:

[0064] Take 10 g of silver nitrate and 100 mL of deionized water, stir evenly, add 12 g of nanoliposomes containing lidocaine, stir evenly, add 5.5 g of polyethylene glycol, heat to 60 ° C, stir for 2 h, and obtain a nanoliposome sol complex;

[0065] Step 4: Preparation of polyvinyl alcohol mixed solution:

[0066] Take polyvinyl alcohol and deionized water, stir evenly to obtain a polyvinyl alcohol aqueous solution, add the nanoliposome sol complex, stir evenly, and filter with a sterile filter membrane to obtain a polyvinyl alcohol mixed solution;

[0067] The polyvinyl alcohol mixed solution includes the following components, calculated by weight: 25 parts of polyvinyl alcohol, 600 parts of deionized water, and 2.5 parts of nanoliposome sol complex;

[0068] Step 5: Preparation of analgesic microneedle patch:

[0069] S1: taking a polydimethylsiloxane sub-mold and sterilizing it with high temperature and high pressure steam to obtain a pretreated polydimethylsiloxane sub-mold;

[0070] S2: pouring the polyvinyl alcohol mixed solution into the polydimethylsiloxane sub-mold, removing bubbles, placing it at -20°C for 12 hours, taking it out, and peeling off the pretreated polydimethylsiloxane sub-mold at -2°C to obtain the analgesic microneedle patch;

[0071] The analgesic microneedle patch has 10×10 microneedles, a total of 100 microneedles, a needle height of 820 μm, a needle base width of 300 μm, and a needle center spacing of 700 μm.

[0072] Comparative Example 1: Aminated polyvinyl alcohol was not added to the nanoliposomes containing lidocaine, and the rest was the same as in Example 1:

[0073] Step 1: Preparation of nanoliposomes containing lidocaine:

[0074] Take 25 mL of chloroform and 25 mL of methanol, stir evenly to obtain solution A; take 0.1 g of Tween 80 and 50 mL of phosphate buffer, stir evenly to obtain solution B; take 10 g of soybean lecithin, 2 g of cholesterol, 0.5 g of lidocaine, and 50 mL of solution A, stir evenly, heat to 52°C, rotary evaporate for 65 min, add solution B, stir evenly at 52°C, and ultrasonicate for 11 min to obtain nanoliposomes containing lidocaine;

[0075] Step 2: Preparation of nanoliposome sol complex:

[0076] Take 10 g of silver nitrate and 100 mL of deionized water, stir evenly, add 12 g of nanoliposomes containing lidocaine, stir evenly, add 5.5 g of polyethylene glycol, heat to 58 ° C, stir for 1.5 h, and obtain a nanoliposome sol complex;

[0077] Step 3: Preparation of polyvinyl alcohol mixed solution:

[0078] Take polyvinyl alcohol and deionized water, stir evenly to obtain a polyvinyl alcohol aqueous solution, add the nanoliposome sol complex, stir evenly, and filter with a sterile filter membrane to obtain a polyvinyl alcohol mixed solution;

[0079] The polyvinyl alcohol mixed solution includes the following components, calculated by weight: 23 parts of polyvinyl alcohol, 590 parts of deionized water, and 2.2 parts of nanoliposome sol complex;

[0080] Step 4: Preparation of analgesic microneedle patch:

[0081] S1: taking a polydimethylsiloxane sub-mold and sterilizing it with high temperature and high pressure steam to obtain a pretreated polydimethylsiloxane sub-mold;

[0082] S2: pouring the polyvinyl alcohol mixed solution into the polydimethylsiloxane sub-mold, removing bubbles, placing it at -20°C for 11 hours, taking it out, and peeling off the pretreated polydimethylsiloxane sub-mold at -3°C to obtain the analgesic microneedle patch;

[0083] The analgesic microneedle patch has 10×10 microneedles, a total of 100 microneedles, a needle height of 820 μm, a needle base width of 300 μm, and a needle center spacing of 700 μm.

[0084] Comparative Example 2: Polyvinyl alcohol was used instead of amino polyvinyl alcohol, and the rest was the same as Example 1:

[0085] Step 1: Preparation of nanoliposomes containing lidocaine:

[0086] Take 25 mL of chloroform and 25 mL of methanol, stir evenly to obtain solution A; take 0.1 g of Tween 80 and 50 mL of phosphate buffer, stir evenly to obtain solution B; take 10 g of soybean lecithin, 2 g of cholesterol, 2 g of polyvinyl alcohol, 0.5 g of lidocaine, and 50 mL of solution A, stir evenly, heat to 52°C, rotary evaporate for 65 min, add solution B, stir evenly at 52°C, and ultrasonicate for 11 min to obtain nanoliposomes containing lidocaine;

[0087] Step 2: Preparation of nanoliposome sol complex:

[0088] Take 10 g of silver nitrate and 100 mL of deionized water, stir evenly, add 12 g of nanoliposomes containing lidocaine, stir evenly, add 5.5 g of polyethylene glycol, heat to 58 ° C, stir for 1.5 h, and obtain a nanoliposome sol complex;

[0089] Step 3: Preparation of polyvinyl alcohol mixed solution:

[0090] Take polyvinyl alcohol and deionized water, stir evenly to obtain a polyvinyl alcohol aqueous solution, add the nanoliposome sol complex, stir evenly, and filter with a sterile filter membrane to obtain a polyvinyl alcohol mixed solution;

[0091] The polyvinyl alcohol mixed solution includes the following components, calculated by weight: 23 parts of polyvinyl alcohol, 590 parts of deionized water, and 2.2 parts of nanoliposome sol complex;

[0092] Step 4: Preparation of analgesic microneedle patch:

[0093] S1: taking a polydimethylsiloxane sub-mold and sterilizing it with high temperature and high pressure steam to obtain a pretreated polydimethylsiloxane sub-mold;

[0094] S2: pouring the polyvinyl alcohol mixed solution into the polydimethylsiloxane sub-mold, removing bubbles, placing it at -20°C for 11 hours, taking it out, and peeling off the pretreated polydimethylsiloxane sub-mold at -3°C to obtain the analgesic microneedle patch;

[0095] The analgesic microneedle patch has 10×10 microneedles, a total of 100 microneedles, a needle height of 820 μm, a needle base width of 300 μm, and a needle center spacing of 700 μm.

[0096] Comparative Example 3: No nanoliposomes were added, and the rest was the same as Example 1:

[0097] Step 1: Preparation of nanoliposome sol complex:

[0098] Take 10 g of silver nitrate and 100 mL of deionized water, stir evenly, add 12 g of lidocaine, stir evenly, add 5.5 g of polyethylene glycol, heat to 58 ° C, stir for 1.5 h, and obtain lidocaine sol complex;

[0099] Step 2: Preparation of polyvinyl alcohol mixed solution:

[0100] Take polyvinyl alcohol and deionized water, stir evenly to obtain a polyvinyl alcohol aqueous solution, add the nanoliposome sol complex, stir evenly, and filter with a sterile filter membrane to obtain a polyvinyl alcohol mixed solution;

[0101] The polyvinyl alcohol mixed solution includes the following components, calculated by weight: 23 parts of polyvinyl alcohol, 590 parts of deionized water, and 2.2 parts of lidocaine sol complex;

[0102] Step 3: Preparation of analgesic microneedle patch:

[0103] S1: taking a polydimethylsiloxane sub-mold and sterilizing it with high temperature and high pressure steam to obtain a pretreated polydimethylsiloxane sub-mold;

[0104] S2: pouring the polyvinyl alcohol mixed solution into the polydimethylsiloxane sub-mold, removing bubbles, placing it at -20°C for 11 hours, taking it out, and peeling off the pretreated polydimethylsiloxane sub-mold at -3°C to obtain the analgesic microneedle patch;

[0105] The analgesic microneedle patch has 10×10 microneedles, a total of 100 microneedles, a needle height of 820 μm, a needle base width of 300 μm, and a needle center spacing of 700 μm.

[0106] Experiment 1:

[0107] Constructing an acute pain model in mice: Prepare a 0.9% acetic acid solution, filter and sterilize it with a 220μm sterile filter membrane, and inject it intraperitoneally into mice at a dose of 10mg / kg to construct an acute pain model, quantify the degree of pain, test the analgesic ability of the microneedle patch after attachment, and evaluate its transdermal drug delivery effect. The abdominal skin of the mice was depilated 24h before the patch experiment. After the mice were anesthetized with isoflurane, the analgesic microneedle patches prepared in Examples 1-3 and Comparative Examples 1-3 were attached to the abdomen of the mice and kept pressed for 2min.

[0108] In order to verify the analgesic effect of the analgesic microneedle patch, a blank control group was set up. The blank control group was the pain group and no treatment was given. The pain model was constructed 5 minutes after the patch was attached, and the number of curling, stretching, and abdominal contraction of the mice was recorded from the 10th minute. By comparing the number of pains within 1 hour, the analgesic effect of the drug-loaded patch group was analyzed. The data obtained are as follows:

[0109] Pain frequency (1h) Blank control group 172 times Example 1 2 times Example 2 2 times Example 3 1 time Comparative Example 1 18 times Comparative Example 2 7 times Comparative Example 3 30 times

[0110] Conclusion: From the comparison of the data in the table, it can be seen that the mice in the blank control group were not treated, and the number of pains in the mice within 30 minutes was as high as 92 times. Comparative Example 1 does not add amino polyvinyl alcohol to the nanoliposomes containing lidocaine, and the dispersibility of the nanoliposomes containing lidocaine in the polyvinyl alcohol aqueous solution matrix is ​​poor, and the analgesic effect is poor. Comparative Example 2 uses polyvinyl alcohol instead of amino polyvinyl alcohol, and the hydrophilicity is poor, the delivery effect of the analgesic drug is poor, and the analgesic effect of the analgesic microneedle is poor. Comparative Example 3 does not add nanoliposomes, the delivery effect of the analgesic drug is poor, and the analgesic effect of the analgesic microneedle is poor. Examples 1 to 3 of the present invention encapsulate lidocaine in nanoliposomes, use soybean lecithin and cholesterol as the main materials of nanoliposomes, reduce the tension of the drug on the skin surface, improve the drug transmission effect, and thus improve the analgesic effect. The invention further adds amino polyvinyl alcohol to further modify the nano liposome containing lidocaine, thereby improving the compatibility between the nano liposome containing lidocaine and the polyvinyl alcohol aqueous solution matrix, improving the dispersibility of the nano liposome containing lidocaine, and enhancing the analgesic effect.

[0111] Experiment 2:

[0112] In order to study the stimulation of the pain-relieving microneedle patch on the skin, the patch was attached to the abdomen of the mouse and the skin condition of the mouse was observed after it was removed. After the mouse was anesthetized with isoflurane, the pain-relieving microneedle patch was continuously pressed on the abdomen of the mouse for 2 minutes. After the patch was removed, the skin was immediately photographed and the skin condition was recorded within 30 minutes to observe the recovery of the mouse skin. Figure 3 shown.

[0113] Conclusion: The penetration of microneedles will create physical channels on the skin surface that are conducive to drug transmission and destroy the skin structure. Therefore, the microneedle patch was attached to the surface of mouse skin to evaluate the irritation of the microneedle attachment on the mouse skin. Figure 3 As shown, the physical channels left by the microneedles on the surface of mouse skin can heal over time. After removing the microneedle patch, the skin can recover within 30 minutes, and the microneedle attachment did not cause skin redness or swelling or irreversible damage to the skin.

[0114] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above and that the present invention can be implemented in other specific forms without departing from the spirit or essential features of the present invention. Therefore, the embodiments should be considered exemplary and non-restrictive in all respects, and the scope of the present invention is defined by the appended claims rather than the above description, and it is intended that all changes falling within the meaning and scope of the equivalent elements of the claims be included in the present invention.

Claims

1. A processing technology for a pain-relieving microneedle patch, characterized in that: The following steps are involved: Step 1: Take polyvinyl alcohol and deionized water, stir evenly to obtain a polyvinyl alcohol aqueous solution, add the nanoliposome sol complex, stir evenly, and filter with a sterile filter membrane to obtain a polyvinyl alcohol mixed solution; Step 2: taking a polydimethylsiloxane sub-mold and sterilizing it with high temperature and high pressure steam to obtain a pretreated polydimethylsiloxane sub-mold; Step 3: Pour the polyvinyl alcohol mixture into the polydimethylsiloxane sub-mold, remove bubbles, place it at -20°C for 10-12 hours, take it out, and peel off the pretreated polydimethylsiloxane sub-mold at -5 to -2°C to obtain the analgesic microneedle patch.

2. The processing technology of the analgesic microneedle patch according to claim 1, characterized in that: The polyvinyl alcohol mixed solution comprises the following components, calculated by weight: 22-25 parts of polyvinyl alcohol, 580-600 parts of deionized water, and 2-2.5 parts of nano-liposome sol complex.

3. The processing technology of the analgesic microneedle patch according to claim 2, characterized in that: The preparation method of the nanoliposome sol complex is as follows: take silver nitrate and deionized water, stir evenly, add nanoliposomes containing lidocaine, stir evenly, add polyethylene glycol, heat to 55-60° C., stir for 1-2 hours, and obtain the nanoliposome sol complex.

4. The processing technology of the analgesic microneedle patch according to claim 3, characterized in that: The preparation method of the nano liposome containing lidocaine comprises the following steps: taking chloroform and methanol, stirring evenly to obtain solution A; taking Tween 80 and phosphate buffer, stirring evenly to obtain solution B; taking soybean lecithin, cholesterol, amino polyvinyl alcohol, lidocaine and solution A, stirring evenly, heating to 50-55° C., rotary evaporation for 60-70 minutes, adding solution B, stirring evenly at 50-55° C., and ultrasonicating for 10-12 minutes to obtain nano liposome containing lidocaine.

5. The processing technology of the analgesic microneedle patch according to claim 4, characterized in that: The preparation method of the amino polyvinyl alcohol is as follows: polyvinyl alcohol and dimethyl sulfoxide are taken, stirred at 60-65° C. for 30-40 minutes, triethylamine and succinic anhydride are added, reacted for 2-3 hours, N-hydroxysuccinimide and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added, reacted at 25-30° C. for 40-45 minutes, and an amino-terminated hyperbranched polymer is added dropwise, stirred for 22-24 hours, to obtain the amino polyvinyl alcohol.

6. The processing technology of the analgesic microneedle patch according to claim 5, characterized in that: The preparation method of the amino-terminated hyperbranched polymer is as follows: methyl acrylate and methanol are taken and stirred evenly to obtain a methyl acrylate solution; diethylenetriamine is taken and cooled to 0-1° C., the methyl acrylate solution is added dropwise under nitrogen protection, the reaction is carried out at 25-30° C. for 4-5 hours, the temperature is raised to 145-150° C., and the reaction is carried out under reduced pressure for 3-4 hours to obtain the amino-terminated hyperbranched polymer.

7. The processing technology of the analgesic microneedle patch according to claim 3, characterized in that: The mass ratio of the silver nitrate, deionized water, lidocaine-containing nanoliposomes, and polyethylene glycol is (10-12):100:(12-13.5):(5.5-6).

8. The processing technology of the analgesic microneedle patch according to claim 7, characterized in that: The mass ratio of the silver nitrate, deionized water, the nanoliposome containing lidocaine and polyethylene glycol is 10:100:(12-13):5.5.

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