A hemostatic and analgesic cold compress and its preparation process

Abstract

The invention relates to the technical field of cold compresses, and discloses a hemostatic and analgesic cold compress and a preparation process thereof. The method comprises the following steps: adding chitosan and lauric acid into an ethanol solution, stirring and reacting for 3-4 hours to obtain lauric acid grafted chitosan; uniformly stirring a menthol-based polymer solution containing a benzaldehyde group in a side chain and a lauric acid grafted chitosan solution, adding composite ZIF-8B, vortexing, and obtaining a hydrogel matrix; coating the hydrogel matrix on a non-woven fabric, pressing a polyethylene film on the hydrogel matrix, cutting, curing, and packaging, and obtaining the cold compress.

Description

Technical Field

[0001] The invention relates to the technical field of cold compress patches, in particular to a hemostatic and analgesic cold compress patch and a preparation process thereof. Background Art

[0002] Cold compress is a product improved from the traditional cold compress method. It effectively removes heat and achieves local cooling through the vaporization of water content and natural cooling ingredients in polymer gel. The drug ingredients are combined with hydrogel and can quickly penetrate the fat layer and subcutaneous tissue to reach the lesion through hydration, playing the role of cold compress pain relief and sustained-release drug delivery.

[0003] Cold compresses can shrink local capillaries, reduce congestion, reduce the sensitivity of nerve endings and thus relieve pain. At the same time, they can reduce temperature and fever, reduce local blood flow, prevent the spread of inflammation and infection, promote the dissipation of body heat and help lower body temperature. In addition to analgesia, cold compresses also have an important application direction of hemostasis. However, the existing cold compresses are not ideal in terms of hemostasis. How to apply hemostasis and analgesia to the field of cold compresses at the same time is currently in urgent need of solution.

[0004] Therefore, it is of great significance to invent a cold compress patch for hemostasis and analgesia. Summary of the invention

[0005] The purpose of the present invention is to provide a hemostatic and analgesic cold compress patch and a preparation process thereof, so as to solve the problems raised in the above background technology.

[0006] In order to solve the above technical problems, the present invention provides the following technical solutions:

[0007] A preparation process of a hemostatic and analgesic cold compress: S1: Adding an arabic gum aqueous solution, N-isopropylacrylamide, sodium dodecyl sulfate, and N,N'-methylenebisacrylamide to deionized water in sequence and stirring evenly, adding ammonium persulfate and heating to 50-55°C under a nitrogen atmosphere to react for 4-4.5 hours, cooling, and purifying to obtain a temperature-sensitive composite wall material;

[0008] Further, the concentration of the gum arabic aqueous solution is 1wt%;

[0009] Furthermore, the mass ratio of gum arabic: N-isopropylacrylamide: sodium dodecyl sulfate is (0.1-0.2): (0.5-2): 0.05;

[0010] S2: adding menthol to isopropanol, heating to 55-60°C to dissolve, adding liquid paraffin, gelatin aqueous solution, isopropyl myristate, and emulsifier in sequence, keeping warm and emulsifying to obtain an emulsion; adding the thermosensitive composite wall material to the emulsion under stirring, stirring to react, adding ZIF-8, stirring to react, centrifuging, washing, and drying to obtain composite ZIF-8A;

[0011] Furthermore, the emulsifier is any one of Tween and Span;

[0012] Further, the concentration of the gelatin aqueous solution is 1wt%;

[0013] Furthermore, in the emulsion, the proportions of each component by mass are 10-12 parts of isopropyl alcohol, 42-71 parts of menthol, 4-6 parts of liquid paraffin, 2-8 parts of gelatin solution, 5-20 parts of isopropyl myristate, and 8-12 parts of emulsifier;

[0014] Furthermore, in the composite ZIF-8A, the mass ratio of the thermosensitive composite wall material: the emulsion: the ZIF-8 is (7-9): (1-3): (2-3);

[0015] S3: Add composite ZIF-8A to Tris-HCl buffer solution, disperse by ultrasonic, add dopamine-HCl solution, stir to react for 40-45h, centrifuge, wash, and obtain dopamine-modified ZIF-8; add dopamine-modified ZIF-8 to ethanol solution, disperse by ultrasonic, add curcumin solution, stir to react, centrifuge, wash, and dry to obtain composite ZIF-8B;

[0016] Further, the pH of the Tris-HCl buffer solution is 8.5;

[0017] Further, the concentration of the dopamine-HCl solution is 1 mg / mL;

[0018] Furthermore, in the dopamine-modified ZIF-8, the mass ratio of composite ZIF-8A:dopamine-HCl is (70-90):1;

[0019] Further, the concentration of the curcumin solution is 1 mg / mL;

[0020] Furthermore, in the composite ZIF-8B, the mass ratio of dopamine-modified ZIF-8:curcumin is (2-3):(1-1.5);

[0021] S4: Add menthol to dichloromethane, stir evenly, add triethylamine and 4-dimethylaminopyridine, stir evenly, add 2-bromoisobutyryl bromide under ice bath condition, react at room temperature for 12-14h, filter under reduced pressure, wash, separate, dry the organic phase, rotary evaporate, and vacuum dry to obtain a menthol-based initiator;

[0022] Further, the molar ratio of menthol: triethylamine: 4-dimethylaminopyridine: 2-bromoisobutyryl bromide is 1: (2-2.1): (2-2.1): (2-2.1);

[0023] S5: adding a menthol-based initiator, poly(ethylene glycol) methacrylate, and bipyridine to a methanol solution, stirring evenly, performing freeze-degasting treatment, adding cuprous bromide, performing freeze-degasting treatment again, heating the reaction system to 40-45° C. for 48-50 hours, cooling in an ice-water bath, connecting the reaction system to air, adding tetrahydrofuran to terminate the reaction, and purifying to obtain a menthol-based polymer;

[0024] Further, the molar ratio of the menthol-based initiator: poly(ethylene glycol) methacrylate: cuprous bromide: bipyridine is (1-2):(10-20):(1-2):(2-4);

[0025] Furthermore, the freeze-degassing treatment includes the following steps: placing the reaction system in liquid nitrogen for freeze-degassing for 5-6 minutes until the reaction system solidifies, evacuating the reaction system with a vacuum valve for 5-6 minutes, thawing the reaction system at room temperature, and simultaneously passing nitrogen into the reaction system until it is completely dissolved;

[0026] S6: Add menthol-based polymer and 4-dimethylaminopyridine to dichloromethane, stir evenly, add tetrahydrofuran solution of 4-formylbenzoic acid, add tetrahydrofuran solution of dicyclohexylcarbodiimide under nitrogen atmosphere, heat to 40-45° C. for 24-26 hours, purify, and obtain menthol-based polymer with benzaldehyde group on the side chain;

[0027] Further, the molar ratio of the menthol-based polymer: 4-dimethylaminopyridine: 4-formylbenzoic acid: dicyclohexylcarbodiimide is (1.3-1.95): (1-1.5): (8.75-13.12): (5-7.5);

[0028] S7: Add chitosan and lauric acid to an ethanol solution, stir and react for 3-4 hours to obtain lauric acid grafted chitosan; add a menthol-based polymer containing a benzaldehyde group on the side chain and lauric acid grafted chitosan to deionized water, add composite ZIF-8B, vortex to obtain a hydrogel matrix; coat the hydrogel matrix on a non-woven fabric, press a polyethylene film on the hydrogel matrix, cut, solidify, and package to obtain a cold compress.

[0029] Furthermore, in the lauric acid grafted chitosan, the mass ratio of chitosan:lauric acid is (1-2):(1-2);

[0030] Furthermore, in the hydrogel matrix, the mass ratio of menthol-based polymer containing benzaldehyde groups on the side chains: lauric acid grafted chitosan: composite ZIF-8B is 100:25:(1-5).

[0031] Compared with the prior art, the beneficial effects achieved by the present invention are:

[0032] The present invention uses gelatin as the inner wall material, the reaction product of gum arabic and N-isopropylacrylamide as the outer wall material, and diclofenac sodium diethylamine and menthol as the core material to prepare a thermosensitive microcapsule with a double-wall structure. By adding three compositions of isopropyl myristate, isopropyl alcohol and menthol in the emulsion as transdermal absorption enhancers, the transdermal absorption of the drug is promoted, and the cool and comfortable feeling of the skin can be increased, achieving the effects of anti-inflammatory, antipyretic and analgesic. The microcapsules are coated with a double-wall structure, and the release of the microcapsules is controlled by a thermosensitive effect. When the hydrogel matrix on the surface of the cold compress contacts the skin, the microcapsule environmental temperature is greater than 32°C, and the outer wall of the microcapsule becomes a porous structure and releases the encapsulated menthol. Low to medium concentrations of menthol can activate the main nociceptor TRPM8 to reduce mechanical allodynia and thermal hyperalgesia after nerve damage or chemical stimulation; at the same time, the skin heat taken away by the volatilization of the released menthol causes the environmental temperature to rise slowly, further achieving the effect of sustained release (temperature rise accelerates the disintegration of the wall material and accelerates the release of menthol). Different from the single-layer structure of traditional single-layer thermosensitive microcapsules (the reaction product of gum arabic and N-isopropylacrylamide is the wall material), when the ambient temperature is greater than 32°C, the encapsulated substance inside will be suddenly released. After 20 hours, the encapsulated substance content inside the traditional single-layer microcapsules is 40-50%, and the release rate will be further accelerated as the temperature rises; while the double-wall structure of the thermosensitive capsule of the present invention can avoid the sudden release of the encapsulated substance, and after 20 hours, the encapsulated substance inside the microcapsule can be greater than 60%, which greatly prolongs the anti-inflammatory, antipyretic and analgesic effects of the cold compress, and at the same time, avoids the occurrence of cold allodynia and TRPM8 sensitization-mediated cold hyperalgesia induced by higher concentrations of menthol.

[0033] The invention uses ZIF-8 to embed thermosensitive microcapsules, thereby improving the dispersibility of microcapsules in a matrix; and by treating ZIF-8 with dopamine, the hemostatic substance curcumin is loaded on ZIF-8 by utilizing the II-II bond effect, thereby preparing a composite ZIF-8 with hemostatic and analgesic effects; the pH value of a fresh acute wound is usually between 4 and 6, and when the composite ZIF-8 contacts the wound, the skeleton of ZIF-8 will rapidly disintegrate in an acidic environment, releasing the hemostatic substance curcumin and the thermosensitive microcapsules, and the curcumin cooperates with chitosan (using the electrostatic effect generated between the positively charged amino group of chitosan and the negatively charged erythrocyte cell membrane to cause erythrocyte agglutination, and sealing the wound by tissue adhesion to stop bleeding) and polydopamine (adhesion effect) to give the cold compress excellent antibacterial and hemostatic effects.

[0034] The invention prepares a menthol-based bromide initiator through an acylation reaction, initiates polymerization of a poly(ethylene glycol) methacrylate monomer to prepare a menthol-based polymer, reacts with 4-formylbenzoic acid to prepare a menthol-based polymer containing a benzaldehyde group on the side face, and finally grafts chitosan with lauric acid and modifies ZIF-8 with polydopamine, and prepares a hydrogel matrix through a Michael addition reaction; the hydrogel matrix is ​​coated on a non-woven fabric to prepare a cold compress with hemostatic, analgesic, antibacterial and anti-inflammatory effects. DETAILED DESCRIPTION

[0035] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. 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.

[0036] In the following examples, menthol was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.; ZIF-8CAS: 59061-53-9; poly(ethylene glycol) methacrylate Mn=500, purchased from Sigma-Aldrich (Shanghai) Trading Co., Ltd.; chitosan, deacetylation degree of 90.2%; and the remaining raw materials were commercially available.

[0037] Example 1: A preparation process of a hemostatic and analgesic cold compress: S1: 10g of gum arabic aqueous solution, 1g of N-isopropyl acrylamide, 0.05g of sodium dodecyl sulfate, and 0.05g of N,N'-methylenebisacrylamide are sequentially added into deionized water and stirred evenly. Under a nitrogen atmosphere, 0.05g of ammonium persulfate is added and heated to 50°C for 4h, cooled, and purified to obtain a temperature-sensitive composite wall material;

[0038] S2: Add 42g of menthol to 12g of isopropanol, heat to 55°C to dissolve, add 6g of liquid paraffin, 8g of gelatin aqueous solution, 20g of isopropyl myristate, and 12g of Tween 80 in sequence, and emulsify under heat preservation to obtain an emulsion; add 3g of the thermosensitive composite wall material to 7g of the emulsion under stirring, stir to react, add 2g of ZIF-8, stir to react, centrifuge, wash, and dry to obtain a composite ZIF-8A;

[0039] S3: Add 70g of composite ZIF-8A to Tris-HCl buffer solution, disperse by ultrasonic, add 1g of dopamine-HCl solution, stir and react for 40h, centrifuge, wash, and obtain dopamine-modified ZIF-8; add 2g of dopamine-modified ZIF-8 to ethanol solution, disperse by ultrasonic, add 1g of curcumin solution, stir and react, centrifuge, wash, and dry to obtain composite ZIF-8B;

[0040] S4: Add 2 mmol of menthol to dichloromethane, stir evenly, add 4 mmol of triethylamine and 4 mmol of 4-dimethylaminopyridine, stir evenly, add 4 mmol of 2-bromoisobutyryl bromide under ice bath condition, react at room temperature for 12 h, filter under reduced pressure, wash, separate, dry the organic phase, rotary evaporate, and vacuum dry to obtain a menthol-based initiator;

[0041] S5: 1 mmol of menthol-based initiator, 10 mmol of poly(ethylene glycol) methacrylate, and 2 mmol of bipyridine were added to a methanol solution, stirred evenly, and subjected to freeze-degassed treatment. 1 mmol of cuprous bromide was added, and the freeze-degassed treatment was performed again. The reaction system was heated to 40° C. for 48 h, cooled in an ice-water bath, the reaction system was connected to air, tetrahydrofuran was added to terminate the reaction, and purified to obtain a menthol-based polymer;

[0042] S6: 1.3 mmol of menthol-based polymer and 1 mmol of 4-dimethylaminopyridine were added to dichloromethane, stirred evenly, and 8.75 mmol of 4-formylbenzoic acid in tetrahydrofuran solution was added. Under nitrogen atmosphere, 5 mmol of dicyclohexylcarbodiimide in tetrahydrofuran solution was added, and the mixture was heated to 40° C. for 24 h, and purified to obtain a menthol-based polymer containing a benzaldehyde group on the side chain;

[0043] S7: Add 1g chitosan and 1g lauric acid to an ethanol solution, stir and react for 3h to obtain lauric acid grafted chitosan; add 100g menthol-based polymer containing benzaldehyde group in the side chain and 25g lauric acid grafted chitosan to deionized water, stir evenly, add 1g composite ZIF-8B, vortex to obtain a hydrogel matrix; coat the hydrogel matrix on a non-woven fabric, press a polyethylene film on the hydrogel matrix, cut, solidify, and package to obtain a cold compress.

[0044] Example 2: A process for preparing a hemostatic and analgesic cold compress: S2: Add 71g of menthol to 10g of isopropanol, heat to 55°C to dissolve, add 4g of liquid paraffin, 8g of gelatin aqueous solution, 5g of isopropyl myristate, and 8g of Tween 80 in sequence, and emulsify by heat preservation to obtain an emulsion; add 3g of the thermosensitive composite wall material to 7g of the emulsion under stirring, stir to react, add 2g of ZIF-8, stir to react, centrifuge, wash, and dry to obtain a composite ZIF-8A;

[0045] The remaining steps are the same as those in Example 1.

[0046] Example 3: A process for preparing a hemostatic and analgesic cold compress: S2: Add 56g of menthol to 10g of isopropanol, heat to 55°C to dissolve, add 4g of liquid paraffin, 8g of gelatin aqueous solution, 12g of isopropyl myristate, and 10g of Tween 80 in sequence, and emulsify by heat preservation to obtain an emulsion; add 3g of the thermosensitive composite wall material to 7g of the emulsion under stirring, stir to react, add 2g of ZIF-8, stir to react, centrifuge, wash, and dry to obtain a composite ZIF-8A;

[0047] The remaining steps are the same as those in Example 1.

[0048] Example 4: Preparation process of a hemostatic and analgesic cold compress: S7: Add 1g chitosan and 1g lauric acid to an ethanol solution, stir and react for 3h to obtain lauric acid grafted chitosan; add 100g menthol-based polymer containing benzaldehyde group in the side chain and 25g lauric acid grafted chitosan to deionized water, stir evenly, add 3g composite ZIF-8B, vortex to obtain a hydrogel matrix; coat the hydrogel matrix on a non-woven fabric, press a polyethylene film on the hydrogel matrix, cut, solidify and package to obtain a cold compress.

[0049] The remaining steps are the same as those in Example 3.

[0050] Example 5: Preparation process of a hemostatic and analgesic cold compress: S7: Add 1g chitosan and 1g lauric acid to an ethanol solution, stir and react for 3h to obtain lauric acid grafted chitosan; add 100g menthol-based polymer containing benzaldehyde group in the side chain and 25g lauric acid grafted chitosan to deionized water, stir evenly, add 5g composite ZIF-8B, vortex to obtain a hydrogel matrix; coat the hydrogel matrix on a non-woven fabric, press a polyethylene film on the hydrogel matrix, cut, solidify and package to obtain a cold compress.

[0051] The remaining steps are the same as those in Example 3.

[0052] Comparative Example 1: A process for preparing a hemostatic and analgesic cold compress: S2: Add 42g of menthol to 14g of isopropanol, heat to 55°C to dissolve, add 8g of liquid paraffin, 22g of isopropyl myristate, and 14g of Tween 80 in sequence, and emulsify under heat preservation to obtain an emulsion; add 3g of the thermosensitive composite wall material to 7g of the emulsion under stirring, stir to react, add 2g of ZIF-8, stir to react, centrifuge, wash, and dry to obtain a composite ZIF-8A;

[0053] The remaining steps are the same as those in Example 1.

[0054] Comparative Example 2: A preparation process of a hemostatic and analgesic cold compress: S1: 10g of arabic gum aqueous solution, 1g of N-isopropyl acrylamide, 0.05g of sodium dodecyl sulfate, and 0.05g of N,N'-methylenebisacrylamide are sequentially added into deionized water and stirred evenly. Under a nitrogen atmosphere, 0.05g of ammonium persulfate is added and heated to 50°C for 4h, cooled, and purified to obtain a temperature-sensitive composite wall material;

[0055] S2: Add 42g of menthol to 12g of isopropanol, heat to 55°C to dissolve, add 6g of liquid paraffin, 8g of gelatin aqueous solution, 20g of isopropyl myristate, and 12g of Tween 80 in sequence, and emulsify under heat preservation to obtain an emulsion; add 3g of the temperature-sensitive composite wall material to 7g of the emulsion under stirring, stir and react to obtain composite microcapsules;

[0056] S3: Add 2 mmol menthol to dichloromethane, stir evenly, add 4 mmol triethylamine and 4 mmol 4-dimethylaminopyridine, stir evenly, add 4 mmol 2-bromoisobutyryl bromide under ice bath condition, react at room temperature for 12 h, filter under reduced pressure, wash, separate, dry the organic phase, rotary evaporate, and vacuum dry to obtain a menthol-based initiator;

[0057] S4: 1 mmol of menthol-based initiator, 10 mmol of poly(ethylene glycol) methacrylate, and 2 mmol of bipyridine were added to a methanol solution, stirred evenly, and subjected to freeze-degassed treatment. 1 mmol of cuprous bromide was added, and the freeze-degassed treatment was performed again. The reaction system was heated to 40° C. for 48 h, cooled in an ice-water bath, the reaction system was connected to air, tetrahydrofuran was added to terminate the reaction, and purified to obtain a menthol-based polymer;

[0058] S5: 1.3 mmol of menthol-based polymer and 1 mmol of 4-dimethylaminopyridine were added to dichloromethane, stirred evenly, and 8.75 mmol of 4-formylbenzoic acid in tetrahydrofuran solution was added. Under nitrogen atmosphere, 5 mmol of dicyclohexylcarbodiimide in tetrahydrofuran solution was added, and the mixture was heated to 40° C. for 24 h, and purified to obtain a menthol-based polymer containing a benzaldehyde group on the side chain;

[0059] S6: Add 1g chitosan and 1g lauric acid to an ethanol solution, stir and react for 3h to obtain lauric acid grafted chitosan; add 100g menthol-based polymer containing benzaldehyde group in the side chain and 25g lauric acid grafted chitosan to deionized water, stir evenly, add 1.5g composite microcapsule and 0.5 curcumin solution, vortex to obtain a hydrogel matrix; coat the hydrogel matrix on a non-woven fabric, press a polyethylene film on the hydrogel matrix, cut, solidify and package to obtain a cold compress.

[0060] Comparative Example 3: Preparation process of a hemostatic and analgesic cold compress: S1: 10g of gum arabic aqueous solution, 1g of N-isopropyl acrylamide, 0.05g of sodium dodecyl sulfate, and 0.05g of N,N'-methylenebisacrylamide are sequentially added into deionized water and stirred evenly. Under a nitrogen atmosphere, 0.05g of ammonium persulfate is added and heated to 50°C for 4h, cooled, purified, and a temperature-sensitive composite wall material is obtained;

[0061] S2: Add 42g of menthol to 12g of isopropanol, heat to 55°C to dissolve, add 6g of liquid paraffin, 8g of gelatin aqueous solution, 20g of isopropyl myristate, and 12g of Tween 80 in sequence, and emulsify under heat preservation to obtain an emulsion; add 3g of the thermosensitive composite wall material to 7g of the emulsion under stirring, stir to react, add 2g of ZIF-8, stir to react, centrifuge, wash, and dry to obtain a composite ZIF-8A;

[0062] S3: Add 70g of composite ZIF-8A to Tris-HCl buffer solution, disperse by ultrasonic, add 1g of dopamine-HCl solution, stir and react for 40h, centrifuge, wash, and obtain dopamine-modified ZIF-8; add 2g of dopamine-modified ZIF-8 to ethanol solution, disperse by ultrasonic, add 1g of curcumin solution, stir and react, centrifuge, wash, and dry to obtain composite ZIF-8B;

[0063] S4: Add 2 mmol of menthol to dichloromethane, stir evenly, add 4 mmol of triethylamine and 4 mmol of 4-dimethylaminopyridine, stir evenly, add 4 mmol of 2-bromoisobutyryl bromide under ice bath condition, react at room temperature for 12 h, filter under reduced pressure, wash, separate, dry the organic phase, rotary evaporate, and vacuum dry to obtain a menthol-based initiator;

[0064] S5: 1 mmol of menthol-based initiator, 10 mmol of poly(ethylene glycol) methacrylate, and 2 mmol of bipyridine were added to a methanol solution, stirred evenly, and subjected to freeze-degassed treatment. 1 mmol of cuprous bromide was added, and the freeze-degassed treatment was performed again. The reaction system was heated to 40° C. for 48 h, cooled in an ice-water bath, the reaction system was connected to air, tetrahydrofuran was added to terminate the reaction, and purified to obtain a menthol-based polymer;

[0065] S6: 1.3 mmol of menthol-based polymer and 1 mmol of 4-dimethylaminopyridine were added to dichloromethane, stirred evenly, and 8.75 mmol of 4-formylbenzoic acid in tetrahydrofuran solution was added. Under nitrogen atmosphere, 5 mmol of dicyclohexylcarbodiimide in tetrahydrofuran solution was added, and the mixture was heated to 40° C. for 24 h, and purified to obtain a menthol-based polymer containing a benzaldehyde group on the side chain;

[0066] S7: Add 1g chitosan and 1g lauric acid to an ethanol solution, stir and react for 3h to obtain lauric acid grafted chitosan; add 100g menthol-based polymer containing benzaldehyde group in the side chain and 25g lauric acid grafted chitosan to deionized water, stir evenly, add 7g composite ZIF-8B, vortex to obtain a hydrogel matrix; coat the hydrogel matrix on a non-woven fabric, press a polyethylene film on the hydrogel matrix, cut, solidify, and package to obtain a cold compress.

[0067] Experiment: Experiment on sustained release of hydrogel matrix: Healthy mice weighing about 20g were selected, and the hydrogel matrix was applied to the right auricle of the mice at a rate of 0.1g / mouse. After 20 hours, the percentage of residual menthol content in the microcapsules was analyzed by headspace gas chromatography.

[0068] Analgesic effect experiment: Select healthy mice weighing about 20g, adjust the temperature of the hot plate pain meter to 55℃, place the mice on the hot plate to measure the pain threshold of each mouse (the time from the mouse touching the hot plate to licking the hind foot), and select mice with a time between 5-30s as qualified mice; set up a blank control group, an embodiment group, and a comparative group; measure the normal pain threshold of each group of mice according to the same method as the pain threshold before administration. Apply physiological saline (blank group) and hydrogel matrix 0.2g / mouse to the 4 soles of each group of mice respectively; set an interval of 15min after external application, and measure the pain threshold of each group of mice according to the same method. The pain threshold is calculated as 60s. If the mice still have no reaction after 60s, take out the mice and discard them.

[0069] Hemostatic effect experiment: rabbits weighing about 2kg were selected, and after anesthesia, they were fixed on the operating table in a supine position. An abdominal incision was made to expose and fix the liver. The liver tissue of 1cm×1cm×1cm was removed from the liver lobe using surgical scissors. After wiping off the spurted blood, 1g of hydrogel matrix was immediately applied to the wound area, and pressed with a 200g weight for 1min. The hemostatic effect was observed after 1min. Hemostasis was stopped when there was no bleeding. If there was still bleeding, the hydrogel matrix was continued to be applied and pressure was applied. The observation was made every 30s. If the bleeding did not stop for more than 3min, the hemostasis time was recorded as >3min. The coating material of the blank control group was starch. Two hemostatic test experiments were performed on each rabbit.

[0070] Table 1 Hydrogel matrix microcapsule sustained release performance data table

[0071]

[0072]

[0073] Conclusion: The double-walled microcapsules used in the present invention have excellent sustained-release effect.

[0074] Table 2 Cold compress hemostasis / analgesia performance data table

[0075]

[0076] Conclusion: The cold compress prepared by the present invention has excellent hemostatic and analgesic effects.

[0077] Comparative Example 1 did not use double-walled microcapsules, resulting in rapid early release of the encapsulated substance, too high a concentration of menthol, an early pain threshold, and reduced analgesic effect;

[0078] Comparative Example 2 did not use ZIF-8 loading, resulting in reduced dispersibility of microcapsules and curcumin, leading to reduced hemostatic and analgesic effects;

[0079] In comparative example 3, excessive amount of composite ZIF-8B was added, resulting in excessive concentration of menthol release, early pain threshold, and reduced analgesic effect.

[0080] Finally, it should be noted that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A preparation process of a hemostatic and analgesic cold compress patch, characterized in that: The following steps are involved: Add chitosan and lauric acid to an ethanol solution, stir and react for 3-4 hours to obtain lauric acid grafted chitosan; add a menthol-based polymer containing a benzaldehyde group on the side chain and lauric acid grafted chitosan to deionized water, stir evenly, add composite ZIF-8B, vortex to obtain a hydrogel matrix; coat the hydrogel matrix on a non-woven fabric, press a polyethylene film on the hydrogel matrix, cut, solidify, and package to obtain a cold compress; The preparation method of ZIF-8B comprises the following steps: The composite ZIF-8A was added to a Tris-HCl buffer solution, ultrasonically dispersed, and a dopamine-HCl solution was added. The mixture was stirred for reaction for 40-45 hours, centrifuged, and washed to obtain dopamine-modified ZIF-8. The dopamine-modified ZIF-8 was added to an ethanol solution, ultrasonically dispersed, and a curcumin solution was added. The mixture was stirred for reaction, centrifuged, washed, and dried to obtain a composite ZIF-8B. In the dopamine-modified ZIF-8, the mass ratio of composite ZIF-8A: dopamine-HCl is (70-90): 1; in the composite ZIF-8B, the mass ratio of dopamine-modified ZIF-8: curcumin is (2-3): (1-1.5); The preparation method of ZIF-8A comprises the following steps: Add menthol to isopropanol, heat to 55-60°C to dissolve, add liquid paraffin, gelatin aqueous solution, isopropyl myristate, and emulsifier in sequence, keep warm and emulsify to obtain an emulsion; add the temperature-sensitive composite wall material to the emulsion under stirring, stir to react, add ZIF-8, stir to react, centrifuge, wash, and dry to obtain composite ZIF-8A; In the emulsion, the proportions of each component by mass are 10-12 parts of isopropanol, 42-71 parts of menthol, 4-6 parts of liquid paraffin, 2-8 parts of gelatin solution, 5-20 parts of isopropyl myristate, and 8-12 parts of emulsifier; in the composite ZIF-8A, the mass ratio of the temperature-sensitive composite wall material: emulsion: ZIF-8 is (7-9):(1-3):(2-3); The preparation method of the temperature-sensitive composite wall material comprises the following steps: The gum arabic aqueous solution, N-isopropyl acrylamide, sodium dodecyl sulfate, and N,N'-methylenebisacrylamide are sequentially added into deionized water and stirred evenly. Under a nitrogen atmosphere, ammonium persulfate is added and heated to 50-55°C for reaction for 4-4.5 hours. The mixture is cooled and purified to obtain a temperature-sensitive composite wall material. The mass ratio of the gum arabic: N-isopropylacrylamide: sodium dodecyl sulfate is (0.1-0.2): (0.5-2): 0.

05.

2. The preparation process of the hemostatic and analgesic cold compress according to claim 1, characterized in that: In the lauric acid grafted chitosan, the mass ratio of chitosan: lauric acid is (1-2):(1-2); in the hydrogel matrix, the mass ratio of menthol-based polymer containing benzaldehyde groups on the side chains: lauric acid grafted chitosan: composite ZIF-8B is 100:25:(1-5).

3. The preparation process of the hemostatic and analgesic cold compress according to claim 1, characterized in that: The method for preparing the menthol-based polymer containing benzaldehyde groups on the side chains comprises the following steps: Step (1): add menthol to dichloromethane, stir evenly, add triethylamine and 4-dimethylaminopyridine, stir evenly, add 2-bromoisobutyryl bromide under ice bath condition, react at room temperature for 12-14h, filter under reduced pressure, wash, separate, dry the organic phase, rotary evaporate, and vacuum dry to obtain a menthol-based initiator; Step (2): adding a menthol-based initiator, poly(ethylene glycol) methacrylate, and bipyridine to a methanol solution, stirring evenly, performing freeze-degasting treatment, adding cuprous bromide, performing freeze-degasting treatment again, heating the reaction system to 40-45° C. for 48-50 hours, cooling in an ice-water bath, connecting the reaction system to air, adding tetrahydrofuran to terminate the reaction, and purifying to obtain a menthol-based polymer; Step (3): Add menthol-based polymer and 4-dimethylaminopyridine to dichloromethane, stir evenly, add a tetrahydrofuran solution of 4-formylbenzoic acid, add a tetrahydrofuran solution of dicyclohexylcarbodiimide under a nitrogen atmosphere, heat to 40-45° C. and react for 24-26 hours, purify, and obtain a menthol-based polymer containing a benzaldehyde group on the side chain.

4. The preparation process of the hemostatic and analgesic cold compress according to claim 3, characterized in that: In the menthol-based initiator, the molar ratio of menthol: triethylamine: 4-dimethylaminopyridine: 2-bromoisobutyryl bromide is 1: (2-2.1): (2-2.1): (2-2.1); in the menthol-based polymer, the molar ratio of menthol-based initiator: poly (ethylene glycol) methacrylate: cuprous bromide: bipyridine is (1-2): (10-20): (1-2): (2-4); in the menthol-based polymer containing benzaldehyde groups in the side chain, the molar ratio of menthol-based polymer: 4-dimethylaminopyridine: 4-formylbenzoic acid: dicyclohexylcarbodiimide is (1.3-1.95): (1-1.5): (8.75-13.12): (5-7.5).

5. A cold compress patch prepared according to the preparation process of a hemostatic and analgesic cold compress patch according to any one of claims 1 to 4.

Images