A processing technology for pain-relieving microneedle patch

Abstract

The present invention discloses a processing technology for analgesic microneedle patches, which relates to the technical field of microneedle patches. The processing technology has a high processing speed and a short processing time, which improves the flexibility of microneedle patch preparation; the demoulding process is smooth, which reduces the structural damage of the microneedles; the analgesic effect is rapid and obvious. Lidocaine is a drug with a good analgesic effect. The insertion of microneedles will produce a physical channel on the skin surface that is 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, reduces the tension of the drug on the skin surface, improves the drug transmission effect, and thus improves the analgesic effect. The present invention also adds amino polyvinyl alcohol to further modify the nanoliposomes containing lidocaine, thereby improving the dispersibility of the nanoliposomes containing lidocaine and enhancing the analgesic effect.

Description

Technical Field

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

[0002] The analgesic microneedle patch is a novel topical pain treatment product composed of multiple tiny needles and a drug carrier. The microneedles, typically ranging from tens of microns to several millimeters in length, are attached to the skin surface, allowing the drug to pass through the skin barrier and reach the target tissue, thereby relieving pain. This analgesic microneedle patch, based on traditional analgesics, overcomes the limitations of oral medications, such as poor absorption and injection pain. With its minimal needle penetration depth and high drug delivery efficiency, it has become a key development in modern medicine.

[0003] However, the actual processing and production of analgesic microneedle patches still face some technical difficulties. Currently, commonly used microneedle materials include silicone and polymers, but there are still certain difficulties in regulating the drug carrier design and release effect of these materials. The drug release rate of analgesic microneedle patches 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 drug release rate 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 analgesic 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 them evenly to obtain a polyvinyl alcohol aqueous solution, add the nanoliposome sol complex, stir them evenly, and filter them through 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 mold, remove bubbles, place it at -20°C for 10-12 hours, take it out, and peel off the pretreated polydimethylsiloxane mold at -5 to -2°C to obtain the analgesic microneedle patch.

[0011] More optimally, the polyvinyl alcohol mixture 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 1-2 hours, and obtain the nanoliposome sol complex.

[0013] More optimally, the preparation method of the lidocaine-containing nanoliposomes 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, and 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 nanoliposomes containing lidocaine.

[0014] More optimally, the preparation method of the amino polyvinyl alcohol is as follows: polyvinyl alcohol and dimethyl sulfoxide are stirred at 60-65°C for 30-40 minutes, triethylamine and succinic anhydride are added, and the reaction is carried out for 2-3 hours. N-hydroxysuccinimide and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added, and the reaction is carried out at 25-30°C for 40-45 minutes. The amino-terminated hyperbranched polymer is added dropwise, and the mixture is stirred for 22-24 hours to obtain the amino polyvinyl alcohol.

[0015] More optimally, the preparation method of the amino-terminated hyperbranched polymer is as follows: take methyl acrylate and methanol, stir them evenly to obtain a methyl acrylate solution; take diethylenetriamine, cool it to 0-1°C, add the methyl acrylate solution dropwise under nitrogen protection, react at 25-30°C for 4-5 hours, heat it to 145-150°C, and react under reduced pressure for 3-4 hours to obtain the 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 and short time, which improves the flexibility of microneedle patch preparation; smooth demoulding process, which reduces structural damage to the microneedles; rapid analgesic effect and obvious analgesic effect.

[0020] 2. Lidocaine is a drug with excellent analgesic effects. Microneedle penetration creates physical pathways on the skin surface that facilitate drug delivery, enhancing the analgesic effect. To further enhance drug transdermal delivery, the present invention encapsulates lidocaine in nanoliposomes, using soy lecithin and cholesterol as the primary materials. This reduces drug tension on the skin surface, improves drug delivery, and thus enhances analgesic efficacy.

[0021] 3. The present invention further modifies the lidocaine-containing nanoliposomes by adding amino-polyvinyl alcohol, improving the compatibility between the lidocaine-containing nanoliposomes and the polyvinyl alcohol aqueous solution matrix, increasing the dispersibility of the lidocaine-containing nanoliposomes, and enhancing the analgesic effect. The abundant amino groups in the nanoliposomes enhance the delivery of the analgesic drug, thereby strengthening the analgesic effect of the analgesic microneedle. The present invention also further modifies the lidocaine-containing nanoliposomes using silver nitrate, 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 of the analgesic microneedle patch of Experiment 2 of the present invention after removal. DETAILED DESCRIPTION

[0025] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. 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 making creative efforts 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 particularly 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] Example 1: A processing technology for analgesic microneedle patch, comprising 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 to obtain a methyl acrylate solution; 125 mL of diethylenetriamine was cooled to 0°C, and the methyl acrylate solution was added dropwise under nitrogen protection. The mixture was reacted at 27°C for 4.5 hours, and then the temperature was raised to 148°C and the reaction was carried out under reduced pressure for 3.5 hours to obtain an amino-terminated hyperbranched polymer;

[0030] S2: 10 g of polyvinyl alcohol and 200 mL of dimethyl sulfoxide were stirred at 62°C for 35 min, 0.45 mL of triethylamine and 1.5 g of succinic anhydride were added, and the mixture was reacted for 2.5 h. 1.1 g of N-hydroxysuccinimide and 2 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added, and the mixture was reacted at 28°C for 42 min. 45 mL of an amino-terminated hyperbranched polymer was added dropwise, and the mixture was stirred for 23 h to obtain amino-polyvinyl alcohol.

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

[0032] Take 25 mL of chloroform and 25 mL of methanol and stir evenly to obtain solution A; take 0.1 g of Tween 80 and 50 mL of phosphate buffer and 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 and stir evenly, heat to 52°C, and rotary evaporate for 65 minutes, then add solution B, stir evenly at 52°C, and sonicate for 11 minutes 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, and stir for 1.5 h to obtain a nanoliposome sol complex;

[0035] Step 4: Preparation of polyvinyl alcohol mixture:

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

[0037] The polyvinyl alcohol mixture 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: Take a polydimethylsiloxane sub-mold and sterilize it with high temperature and high pressure steam to obtain a pretreated polydimethylsiloxane sub-mold;

[0040] S2: Pour the polyvinyl alcohol mixture into the polydimethylsiloxane mold, remove bubbles, place it at -20°C for 11 hours, remove it, and peel off the pretreated polydimethylsiloxane mold at -3°C to obtain the analgesic microneedle patch;

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

[0042] Example 2: A processing technology for analgesic microneedle patch, comprising 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 to obtain a methyl acrylate solution; 125 mL of diethylenetriamine was cooled to 0°C, and the methyl acrylate solution was added dropwise under nitrogen protection. The mixture was reacted at 25°C for 4 h, and then the temperature was raised to 145°C and the reaction was carried out under reduced pressure for 3 h to obtain an amino-terminated hyperbranched polymer;

[0045] S2: 10 g of polyvinyl alcohol and 200 mL of dimethyl sulfoxide were stirred at 60°C for 30 min, 0.45 mL of triethylamine and 1.5 g of succinic anhydride were added, and the mixture was reacted for 2 h. 1.1 g of N-hydroxysuccinimide and 2 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added, and the mixture was reacted at 25°C for 40 min. 45 mL of an amino-terminated hyperbranched polymer was added dropwise, and the mixture was stirred for 22 h to obtain amino-polyvinyl alcohol.

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

[0047] Take 25 mL of chloroform and 25 mL of methanol and stir evenly to obtain solution A; take 0.1 g of Tween 80 and 50 mL of phosphate buffer and 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 and stir evenly, heat to 50°C, and rotary evaporate for 60 minutes, then add solution B, stir evenly at 50°C, and sonicate for 10 minutes 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, and stir for 1 hour to obtain a nanoliposome sol complex;

[0050] Step 4: Preparation of polyvinyl alcohol mixture:

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

[0052] The polyvinyl alcohol mixture comprises 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: Take a polydimethylsiloxane sub-mold and sterilize it with high temperature and high pressure steam to obtain a pretreated polydimethylsiloxane sub-mold;

[0055] S2: Pour the polyvinyl alcohol mixture into the polydimethylsiloxane mold, remove bubbles, place it at -20°C for 10 hours, remove it, and peel off the pretreated polydimethylsiloxane mold at -5°C to obtain the analgesic microneedle patch;

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

[0057] Example 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 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. The mixture was reacted at 30°C for 5 h, and then heated to 150°C and reacted under reduced pressure for 4 h to obtain an amino-terminated hyperbranched polymer;

[0060] S2: 10 g of polyvinyl alcohol and 200 mL of dimethyl sulfoxide were stirred at 65°C for 40 min, 0.45 mL of triethylamine and 1.5 g of succinic anhydride were added, and the mixture was reacted for 3 h. 1.1 g of N-hydroxysuccinimide and 2 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added, and the mixture was reacted at 30°C for 45 min. 45 mL of an amino-terminated hyperbranched polymer was added dropwise, and the mixture was stirred for 24 h to obtain amino-polyvinyl alcohol.

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

[0062] Take 25 mL of chloroform and 25 mL of methanol and stir evenly to obtain solution A; take 0.1 g of Tween 80 and 50 mL of phosphate buffer and 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 and stir evenly, heat to 55°C, and rotary evaporate for 70 minutes, then add solution B, stir evenly at 55°C, and sonicate for 12 minutes 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, and stir for 2 h to obtain a nanoliposome sol complex;

[0065] Step 4: Preparation of polyvinyl alcohol mixture:

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

[0067] The polyvinyl alcohol mixture 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: Take a polydimethylsiloxane sub-mold and sterilize it with high temperature and high pressure steam to obtain a pretreated polydimethylsiloxane sub-mold;

[0070] S2: Pour the polyvinyl alcohol mixture into the polydimethylsiloxane mold, remove bubbles, place it at -20°C for 12 hours, remove it, and peel off the pretreated polydimethylsiloxane mold at -2°C to obtain the analgesic microneedle patch;

[0071] The analgesic microneedle patch has 100 microneedles (10×10), with 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 and stir evenly to obtain solution A; take 0.1 g of Tween 80 and 50 mL of phosphate buffer and stir evenly to obtain solution B; take 10 g of soy lecithin, 2 g of cholesterol, 0.5 g of lidocaine and 50 mL of solution A and stir evenly, heat to 52°C, and rotary evaporate for 65 minutes, then add solution B, stir evenly at 52°C, and sonicate for 11 minutes 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, and stir for 1.5 h to obtain a nanoliposome sol complex;

[0077] Step 3: Preparation of polyvinyl alcohol mixture:

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

[0079] The polyvinyl alcohol mixture 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: Take a polydimethylsiloxane sub-mold and sterilize it with high temperature and high pressure steam to obtain a pretreated polydimethylsiloxane sub-mold;

[0082] S2: Pour the polyvinyl alcohol mixture into the polydimethylsiloxane mold, remove bubbles, place it at -20°C for 11 hours, remove it, and peel off the pretreated polydimethylsiloxane mold at -3°C to obtain the analgesic microneedle patch;

[0083] The analgesic microneedle patch has 100 microneedles (10×10), with 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 in Example 1:

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

[0086] Take 25 mL of chloroform and 25 mL of methanol and stir evenly to obtain solution A; take 0.1 g of Tween 80 and 50 mL of phosphate buffer and stir evenly to obtain solution B; take 10 g of soy lecithin, 2 g of cholesterol, 2 g of polyvinyl alcohol, 0.5 g of lidocaine and 50 mL of solution A and stir evenly, heat to 52°C, and rotary evaporate for 65 minutes, then add solution B, stir evenly at 52°C, and sonicate for 11 minutes 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, and stir for 1.5 h to obtain a nanoliposome sol complex;

[0089] Step 3: Preparation of polyvinyl alcohol mixture:

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

[0091] The polyvinyl alcohol mixture 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: Take a polydimethylsiloxane sub-mold and sterilize it with high temperature and high pressure steam to obtain a pretreated polydimethylsiloxane sub-mold;

[0094] S2: Pour the polyvinyl alcohol mixture into the polydimethylsiloxane mold, remove bubbles, place it at -20°C for 11 hours, remove it, and peel off the pretreated polydimethylsiloxane mold at -3°C to obtain the analgesic microneedle patch;

[0095] The analgesic microneedle patch has 100 microneedles (10×10), with 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, and stir for 1.5 h to obtain a lidocaine sol complex;

[0099] Step 2: Preparation of polyvinyl alcohol mixture:

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

[0101] The polyvinyl alcohol mixture 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: Take a polydimethylsiloxane sub-mold and sterilize it with high temperature and high pressure steam to obtain a pretreated polydimethylsiloxane sub-mold;

[0104] S2: Pour the polyvinyl alcohol mixture into the polydimethylsiloxane mold, remove bubbles, place it at -20°C for 11 hours, remove it, and peel off the pretreated polydimethylsiloxane mold at -3°C to obtain the analgesic microneedle patch;

[0105] The analgesic microneedle patch has 100 microneedles (10×10), with 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] Establishment of an acute pain model in mice: A 0.9% acetic acid solution was prepared and sterilized by filtration through a 220 μm sterile filter membrane. A 10 mg / kg dose of acetic acid was injected intraperitoneally into mice to establish an acute pain model. The pain intensity was quantified, the analgesic ability of the microneedle patch after application was tested, and its transdermal drug delivery efficacy was evaluated. Twenty-four hours before the patch experiment, the abdominal skin of the mice was depilated. After anesthesia with isoflurane, the analgesic microneedle patches prepared in Examples 1-3 and Comparative Examples 1-3 were applied to the abdomen of the mice and pressure was maintained for 2 minutes.

[0108] To verify the analgesic effect of the analgesic microneedle patch, a blank control group was set up. This group served as the pain group and received no treatment. A pain model was established 5 minutes after patch application, and the number of curling, stretching, and abdominal contractions in the mice was recorded starting from the 10th minute. By comparing the number of pain episodes within 1 hour, the analgesic effect of the drug-loaded patch group was analyzed. The data obtained are shown below:

[0109] Number of pains (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 pain episodes 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. The dispersibility of the nanoliposomes containing lidocaine in the polyvinyl alcohol aqueous solution matrix is ​​poor, and the analgesic effect is deteriorated. Comparative Example 2 uses polyvinyl alcohol instead of amino polyvinyl alcohol, and the hydrophilicity is deteriorated, the delivery effect of the analgesic drug is deteriorated, and the analgesic effect of the analgesic microneedle is deteriorated. Comparative Example 3 does not add nanoliposomes, the delivery effect of the analgesic drug is deteriorated, and the analgesic effect of the analgesic microneedle is deteriorated. Examples 1 to 3 of the present invention encapsulate lidocaine in nanoliposomes, and use soybean lecithin and cholesterol as the main materials of the nanoliposomes, which reduces the tension of the drug on the skin surface, improves the drug transmission effect, and thus improves the analgesic effect. The present 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 irritation 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 pressed on the mouse abdomen 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 delivery and destroy the skin structure. Therefore, the microneedle patch was attached to the skin surface of mice to evaluate the irritation of the mouse skin caused by the microneedle attachment. 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 attachment of the microneedles did not cause redness or swelling of the skin or cause 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 invention can be embodied in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as illustrative and non-restrictive, and the scope of the invention is defined by the appended claims rather than the foregoing description, and it is intended that all variations that come within the meaning and range of equivalents of the claims be embraced therein.

Claims

1. A processing technology for analgesic microneedle patch, characterized by: The following steps are involved: Step 1: Take polyvinyl alcohol and deionized water, stir them evenly to obtain a polyvinyl alcohol aqueous solution, add the nanoliposome sol complex, stir them evenly, and filter them through 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 mold, remove bubbles, place it at -20°C for 10-12 hours, take it out, and peel off the pretreated polydimethylsiloxane mold at -5 to -2°C to obtain the analgesic microneedle patch; The preparation method of the nanoliposome sol complex is as follows: silver nitrate and deionized water are mixed evenly, nanoliposomes containing lidocaine are added, the mixture is mixed evenly, polyethylene glycol is added, the mixture is heated to 55-60° C., and the mixture is stirred for 1-2 hours to obtain the nanoliposome sol complex; 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, and 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 nanoliposomes containing lidocaine.

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 1, characterized in that: The preparation method of the amino polyvinyl alcohol comprises the following steps: taking polyvinyl alcohol and dimethyl sulfoxide, stirring at 60-65° C. for 30-40 minutes, adding triethylamine and succinic anhydride, reacting for 2-3 hours, adding N-hydroxysuccinimide and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, reacting at 25-30° C. for 40-45 minutes, adding dropwise an amino-terminated hyperbranched polymer, and stirring for 22-24 hours to obtain the amino polyvinyl alcohol.

4. The processing technology of the analgesic microneedle patch according to claim 3, characterized in that: The preparation method of the amino-terminated hyperbranched polymer comprises the following steps: taking methyl acrylate and methanol, stirring them uniformly to obtain a methyl acrylate solution; taking diethylenetriamine, cooling it to 0-1°C, adding the methyl acrylate solution dropwise under nitrogen protection, reacting at 25-30°C for 4-5 hours, heating it to 145-150°C, and reacting it under reduced pressure for 3-4 hours to obtain the amino-terminated hyperbranched polymer.

5. The processing technology of the analgesic microneedle patch according to claim 1, 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).

6. The processing technology of the analgesic microneedle patch according to claim 5, 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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