A breathable hydrogel-based composite patch with reversible adhesion function and a preparation method thereof

Abstract

The application discloses a breathable hydrogel-based composite patch with reversible adhesion function and a preparation method thereof. The hydrogel-based composite patch is composed of a waterproof protective layer, a water absorption layer, a flow guide layer, an adhesion layer and a release paper layer in sequence, wherein the waterproof protective layer is a transparent polyurethane elastomer film, the water absorption layer is a sodium polyacrylate hydrogel, the flow guide layer is a non-woven fabric, the adhesion layer is dopamine and 7-carboxymethoxy-4-methyl coumarin double-graft modified chitosan, and a medicine component for relieving inflammation and pain and promoting blood circulation to remove blood stasis is loaded in the water absorption layer. The porous waterproof protective layer and the water absorption layer, and the water absorption layer and the flow guide layer are all bonded by using an acrylate adhesive; the flow guide layer and the release paper are connected by the adhesion capacity of the adhesion layer. The adhesion layer has reversible adhesion function in response to ultraviolet light, and the product has good ventilation capacity through selection of raw materials and structural design.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medical gel patch preparation, in particular to a breathable hydrogel-based composite patch with reversible adhesion function and a preparation method thereof. BACKGROUND

[0002] The patch is a long-standing plaster product, mainly used for the treatment of orthopedic diseases, such as rheumatic bone pain, cervical and lumbar pain, contusion and injury, hyperosteogeny, lumbar disc herniation, etc. Its main use form is to be pasted on the patient's affected area, relying on the skin absorption to play the drug effect, so as to achieve the purpose of relieving the pain of the patient. And the patch has become the first choice for many doctors or patients to treat orthopedic diseases due to its low toxicity and side effects, mild drug nature, strong site targeting, and convenient operation.

[0003] Traditional patches are mainly obtained by coating drug-containing glue on natural gauze, synthetic fiber, and polymeric film substrates. These traditional patch materials often have poor breathability, are prone to cause allergies, and have uncontrollable glue adhesion, resulting in glue residue on the skin or excessive adhesion force causing skin damage, etc. These problems seriously affect the patient's use experience. With the rapid development of today's society, people's pursuit of quality of life is getting higher and higher, and the treatment experience of medical treatment has also been higher. Therefore, how to solve the above problems of the patch is the main breakthrough point of the present application. SUMMARY

[0004] The purpose of the present application is to solve the problems of poor breathability, uncontrollable adhesion, and easy allergy of traditional patches. The present application independently designs the adhesion molecules and related molds, and provides a breathable hydrogel-based composite patch with reversible adhesion function and a preparation method thereof. The present application independently designs and synthesizes 7-carboxymethoxy-4-methyl coumarin grafted methacrylated gelatin and / or methacrylated chitosan molecules, and combines regional cutting and regional ultraviolet curing processes to successfully prepare a breathable hydrogel-based composite patch with reversible adhesion function, which is expected to promote the upgrading of traditional patches.

[0005] The present application adopts the following technical solutions:

[0006] A breathable hydrogel-based composite patch with reversible adhesion function, the composite patch is composed of a porous waterproof protective layer, a water absorption layer, a flow guide layer, an adhesion layer and a release paper layer from top to bottom, wherein the waterproof protective layer is a transparent polyurethane elastomer film, the water absorption layer is a polyacrylic acid sodium hydrogel, the flow guide layer is a non-woven fabric, and the adhesion layer is a dopamine and 7-carboxymethoxy-4-methyl coumarin double grafted modified chitosan, and the water absorption layer is loaded with blood-activating and stasis-removing, anti-inflammatory and analgesic drugs.

[0007] The specific preparation steps of the breathable hydrogel-based composite patch with reversible adhesion function are as follows:

[0008] 1) Using trace amount of potassium iodide as catalyst, 7-hydroxy-4-methyl coumarin is heated to reflux with bromoacetic acid and potassium carbonate ethanol solution for 15-25 hours, then the solution is cooled to room temperature, acidified and extracted with diethyl ether and water; after separation with a separatory funnel, the water phase is removed, and the organic phase is absorbed with magnesium sulfate, and the solvent is removed by rotary evaporation to obtain the desired product 7-carboxymethoxy-4-methyl coumarin (CM); then CM is grafted onto the amino group of dopamine-modified chitosan molecules (CS-DA) side chain, the specific steps are as follows: dopamine-modified chitosan (CS-DA) and CM are dissolved in DMSO / deionized water mixed solvent in a 50℃ water bath and in the dark, EDC and NHS are added for coupling reaction, and finally regenerated cellulose dialysis bag is used for dialysis, and after freeze-drying, dopamine and 7-carboxymethoxy-4-methyl coumarin double-grafted modified chitosan (CS-DA-CM) is obtained, which is stored in the dark and used as needed.

[0009] 2) The sodium polyacrylate gel dry powder is immersed in a certain amount of normal saline solution containing blood-activating and stasis-removing, anti-inflammatory and analgesic drug ingredients to obtain drug-loaded sodium polyacrylate hydrogel, realizing the loading of drugs in the water absorption layer.

[0010] 3) The waterproof protective layer is coated with adhesive, drug-loaded sodium polyacrylate hydrogel and adhesive in sequence, then covered with a drainage layer, and a semi-finished product is obtained by using a mold forming process, and the semi-finished product is punched by using an array type cutter to obtain a porous and breathable semi-finished product patch.

[0011] 4) Under the condition of light shielding, a shielding type porous mold is covered on the porous semi-finished product patch, the pores of the porous mold and the porous semi-finished product patch do not coincide, a certain concentration of CS-DA-CM solution is added into the pores of the shielding type porous mold and in-situ photocured by using ultraviolet light, then a release paper layer is covered after demolding, a light-proof packaging bag is used for packaging after irradiation sterilization, and a breathable hydrogel-based composite patch with reversible adhesion function is obtained.

[0012] Further, in step 1), the amounts of 7-hydroxy-4-methyl coumarin, bromoacetic acid, and potassium carbonate are 50-125 mmol / L, 250-350 mmol / L, and 75-125 mmol / L, respectively; in the grafting reaction of 7-carboxymethoxyl-4-methyl coumarin and CS-DA, the concentration of 7-carboxymethoxyl-4-methyl coumarin is 1-3 wt%; the viscosity average molecular weight of CS-DA is 200-600 thousand, the grafting degree of DA is 20-35%, and the concentration of CS-DA is 5-10 wt%; the ratio of DMSO / deionized water in the mixed solvent is 10 wt% DMSO / 90 wt% deionized water, the concentration of EDC is 0.025-0.06 wt%, the concentration of NHS is 0.04-0.08 wt%, the coupling reaction time is 12-48 hours, and the magnetic stirring speed is 200-500 rpm; and the deionized water is dialyzed for 5-7 days in the dark.

[0013] Further, in step 2), the anti-inflammatory and analgesic drug is one or more of non-steroidal anti-inflammatory drugs, flurbiprofen, and loxoprofen; the blood-activating and stasis-removing drug is one or more of musk, notoginseng, Szechuan lovage rhizome, Chinese galangal, Chinese red sandalwood, and raw meadowfoam; the weight ratio of the dry powder of sodium polyacrylate gel to normal saline is 1:2 to 1:4; and the amount of the above-mentioned drugs is about 1-5 wt% of the total mass of the dry powder of sodium polyacrylate gel and normal saline.

[0014] Further, in step 3), the adhesive is 5-15 wt% of an acrylate adhesive; the coating is performed using a doctor blade, the coating speed is 10 cm / s, and each layer is coated for 2 cycles; the structure of the array-type doctor blade includes a plurality of circular doctor blades with a diameter of 1-2 mm, and the circular doctor blades are arranged in parallel in the horizontal and vertical directions with a spacing of 5-15 mm; and the overall size of the array-type doctor blade is consistent with the size of the patch.

[0015] Further, in step 4), the shielding-type porous mold is in the form of a hollow cover plate, the diameter of the hollow circular holes on the mold is 5-7.5 mm, the hollow circular holes are arranged in parallel in the horizontal and vertical directions, and do not coincide with the holes generated on the patch using the array-type doctor blade mold in step 3); the thickness of the shielding-type porous mold is 0.75-1.5 mm; the concentration of the CS-DA-CM solution is 10-20 wt%, and the amount of the solution added to each hollow hole of the shielding-type porous mold is calculated according to the parameters; the wavelength of the ultraviolet light is greater than 300 nm, and the irradiation time is 5-10 minutes.

[0016] In the specific application of the patch, first, the non-light-transmitting packaging bag and release paper layer on the surface are torn off; then the patch is attached to the affected area to achieve good attachment to the affected area through dopamine. When the use period of the patch ends, a light source with a wavelength less than 280 nm is used for irradiation to make the adhesive layer change from a gel state to a solution state, so that the patch is easily peeled off, and the skin tissue of the affected area is not damaged.

[0017] Compared with the prior art, the present application has the following advantages:

[0018] 1) The composite dressing in the present application is composed of, from top to bottom, a transparent polyurethane elastomer film porous waterproof protective layer, a sodium polyacrylate hydrogel water absorption layer, a non-woven fabric flow guide layer, a dopamine and 7-carboxylic acid methoxy-4-methyl coumarin double-graft modified chitosan adhesion layer, and a release paper layer, and the water absorption layer is loaded with medicinal ingredients for promoting blood circulation and removing blood stasis, relieving inflammation and relieving pain; at the same time, the entire dressing is cut into a porous array by punching with a mold, and the adhesion layer is regionally and regularly arranged around the porous holes, and the above structure is independently designed according to the use requirements of the dressing, which is innovative.

[0019] 2) The waterproof protective layer, the water absorption layer, the flow guide layer, the adhesion layer and the release paper layer arranged from top to bottom in the composite dressing, as well as the holes cut by the mold, all play their specific roles: the waterproof protective layer is to avoid the loss of the medicinal ingredients inside the dressing caused by external water during use, and also to avoid the entry of external water into the wound to cause infection or scarring; the water absorption layer has the functions of loading medicine and absorbing tissue fluid exuded from the wound; the flow guide layer cooperates with the water absorption layer to guide the tissue fluid exuded from the wound, so that it is quickly absorbed, and the non-woven fabric also enhances the entire dressing to ensure the mechanical strength of the dressing; the adhesion layer is the medium for the adhesion of the skin and the dressing, which has the function of reversible wet adhesion, adheres in use, and detaches when the dressing needs to be replaced, which can reduce the secondary damage to the wound; the release paper layer protects the dressing from being damaged before use. In order to ensure the breathability of the dressing, it is processed by punching, and the position of the adhesion layer is arranged around the above-mentioned porous holes, which do not affect each other.

[0020] 3) The adhesion layer in the present application is composed of dopamine and 7-carboxylic acid methoxy-4-methyl coumarin double-graft modified chitosan molecules independently synthesized by the present application, and the above-mentioned molecules have the function of photo-crosslinking. When the above-mentioned molecules need to exhibit the function of ultraviolet crosslinking, only the dressing is covered with a porous mold, the solution containing the above-mentioned molecules is injected into the holes of the mold, and the gelation of the solution can be realized by irradiation with light with a wavelength greater than 300 nm, and at the same time the wet adhesion property is exhibited; when the dressing needs to be replaced or discarded, irradiation with a light source with a wavelength less than 280 nm can detach the adhesion. And the above-mentioned molecules are all biocompatible macromolecules, which have good biocompatibility and can ensure that there is no allergic reaction when directly contacting the affected area, and the arrayed regional arrangement of the adhesion layer increases the breathability and reduces the possibility of skin redness and allergy.

[0021] 4) The dopamine and 7-carboxylic acid methoxy-4-methyl coumarin double graft modified chitosan molecules are the first of the invention. The dopamine contributes to the wet adhesion performance; the 7-carboxylic acid methoxy-4-methyl coumarin can be crosslinked and decrosslinked under irradiation of light sources of different wavelengths (crosslinked at greater than 300 nm, and decrosslinked at less than 280 nm), thereby realizing gelation after irradiation of a light source of greater than 300 nm, and converting into a solution under irradiation of a light source of less than 280 nm at the gel layer level. At the material level, the solution is in-situ gelled after irradiation of a light source of greater than 300 nm, and simultaneously exhibits the wet adhesion performance after the gel is formed, realizing adhesion to the affected area. After irradiation of a light source of less than 280 nm, the gel converts into a solution, and the adhesion performance automatically disappears, realizing automatic peeling of the application.

[0022] 5) The water absorption layer of the application in the application simultaneously carries the drugs with anti-inflammatory and analgesic, blood-activating and stasis-removing functions, and can realize periodic release of the drugs through the sustained release of the sodium polyacrylate hydrogel, thereby achieving good effects. In addition, the water absorption layer can also guarantee the adhesion of the adhesion layer by absorbing the exudate of the wound tissue, and can realize good adhesion to the wound in a wet environment, thereby guaranteeing that the application does not fall off under normal activities of the human body.

[0023] 6) The application in the application can solve the problems of poor air permeability, uncontrollable adhesion, and easy allergy of traditional applications, and has great application prospects. BRIEF DESCRIPTION OF DRAWINGS

[0024] Figure 1 Structure diagram of the air-permeable hydrogel-based composite application with reversible adhesion function;

[0025] Figure 2 Structure diagram of the array type cutter (left) and the structure diagram of the shielding type mold (right) after the application is punched. DETAILED DESCRIPTION

[0026] The application is further described below in combination with specific examples.

[0027] Example 1:

[0028] 1) 13.6 mmol 7-hydroxy-4-methylcoumarin, 56.8 mmol bromoacetic acid, 25.2 mmol potassium carbonate were added in sequence to 220 ml ethanol solution with 0.003 mmol potassium iodide as catalyst, heated to reflux for 22 hours, then the solution was cooled to room temperature, acidified and extracted with diethyl ether and water; after separation with a separatory funnel, the water phase was removed, and the organic phase was absorbed with magnesium sulfate, and the solvent was removed by rotary evaporation to obtain the desired product 7-carboxymethoxy-4-methylcoumarin (CM), product purity > 97.6%, yield 64%; 2 wt% 7-carboxymethoxy-4-methylcoumarin and 10 wt% CS-DA were dissolved in 10 wt% DMSO / 90 wt% deionized water mixed solvent in a 50°C water bath and in the dark, 0.03 wt% EDC and 0.06 wt% NHS were added under magnetic stirring at 400 rpm for coupling reaction for 24 hours, and finally dialysis was performed using a regenerated cellulose dialysis bag with a molecular weight of 3000, and after 7 days, CS-DA-CM was obtained by freeze-drying, and was stored in the dark until use. 2) Musk, Panax notoginseng, flurbiprofen, and red sandalwood were dispersed in physiological saline, and the above mixed solution was mixed with sodium polyacrylate gel powder at a ratio of 2:1, and the solution was absorbed by the sodium polyacrylate, to obtain a water-absorbed layer with a total drug content of about 3 wt% of the water-absorbed sodium polyacrylate gel.

[0029] 3) The transparent polyurethane waterproof protective layer was coated with an acrylate adhesive, the drug-loaded sodium polyacrylate hydrogel prepared in step 2), and an acrylate adhesive in sequence at a rate of 10 cm / s, the acrylate adhesive concentration was 7 wt%, and each layer was coated 2 times; then a non-woven fabric flow guide layer was covered; then a semi-finished product was obtained using a compression molding process, and an array type cutting tool (a circular cutting tool with a diameter of 1 mm was arranged in parallel in the horizontal and vertical directions, and the cutting tools were spaced 10 mm apart) was used to punch the semi-finished product to obtain a porous and breathable semi-finished product patch; 4) under light shielding conditions, a shielding type porous mold (mold thickness 1 mm, hollow circular hole 5 mm, hollow hole arranged in parallel in the horizontal and vertical directions) was covered on the porous semi-finished product patch, the holes of the porous mold and the porous semi-finished product patch did not coincide, and then 10 wt% CS-DA-CM PBS solution was added to the holes of the shielding type porous mold and in situ photocured using 405 nm ultraviolet light for 5 minutes, then a release paper layer was covered after demolding, a light-proof packaging bag was used for packaging, and then sterilized by irradiation, to obtain a breathable hydrogel-based composite patch with reversible adhesion function.

[0030] The prepared patch has an adhesion strength of 32.4 kPa, and after irradiation by a light source with a wavelength less than 280 nm, the gel becomes a solution. The patch can achieve absorption of water droplets on the attached surface in 30 s. Using a semi-permeable membrane model (the semi-permeable membrane as an intermediate layer, the outside as the patch, and the inside as the PBS solution), the drug release of the patch on the surface of human skin is simulated, and 41.2% of the drug can be released in 12 hours.

[0031] Example 2:

[0032] 1) 13.6 mmol of 7-hydroxy-4-methylcoumarin, 56.8 mmol of bromoacetic acid, and 25.2 mmol of potassium carbonate were sequentially added to 220 ml of ethanol solution with 0.003 mmol of potassium iodide as catalyst, and heated to reflux for 22 hours. Then the solution was cooled to room temperature, acidified, and then extracted with diethyl ether and water. After separation with a separatory funnel, the water phase was removed, and the organic phase was absorbed by magnesium sulfate to remove water. The solvent was removed by rotary evaporation to obtain the desired product 7-carboxymethoxy-4-methylcoumarin (CM), with a purity of >97.6% and a yield of 64%. 2 wt% of 7-carboxymethoxy-4-methylcoumarin and 10 wt% of CS-DA were dissolved in 10 wt% DMSO / 90 wt% deionized water mixed solvent under the conditions of 50°C water bath and light shielding. Under the condition of magnetic stirring at 400 rpm, 0.03 wt% of EDC and 0.06 wt% of NHS were added for coupling reaction for 24 hours. Finally, CS-DA-CM was obtained by dialysis using a regenerated cellulose dialysis bag with a molecular weight of 3000, and then freeze-dried after 7 days. It was stored in the dark and used as needed. 2) Musk, Panax notoginseng, flurbiprofen, and red sandalwood were dispersed in physiological saline. The above mixed solution was mixed with sodium polyacrylate gel powder at a ratio of 2:1. The solution was absorbed by sodium polyacrylate to obtain a water-absorbed layer with a total drug content of about 3 wt% of the water-absorbed sodium polyacrylate gel.

[0033] 3) On the surface of the transparent polyurethane waterproof protective layer, the acrylic adhesive, the drug-loaded polyacrylate sodium hydrogel prepared in step 2), and the acrylic adhesive were coated in turn at a rate of 10 cm / s using a doctor blade, the concentration of the acrylic adhesive was 7 wt%, each layer was coated 2 times, and then a non-woven fabric flow guide layer was covered. A semi-finished product was obtained using a molding process, and the semi-finished product was punched using an array type cutting tool (a circular cutting tool with a diameter of 1 mm was arranged in parallel in the horizontal and vertical directions, and the cutting tools were spaced 10 mm apart on the left and right), to obtain a porous and breathable semi-finished product dressing; 4) Under light shielding conditions, a shielding type porous mold (mold thickness 1 mm, hollow circular hole 5 mm, hollow hole arranged in parallel in the horizontal and vertical directions) was covered on the porous semi-finished product dressing, the porous mold and the pores of the porous semi-finished product dressing did not coincide, a 20 wt% CS-DA-CM PBS solution was added to the pores of the shielding type porous mold, and in-situ light curing was performed using a light source greater than 300 nm for 5 minutes, after demolding, a release paper layer was covered, a light-proof packaging bag was used for packaging, and then radiation sterilization was performed, to obtain a breathable hydrogel-based composite dressing with reversible adhesion function.

[0034] The dressing prepared by the above process has an increased CS-DA-CM concentration compared to Example 1, the adhesion strength is 37.9 kPa, and after irradiation with a light source with a wavelength less than 280 nm, the gel becomes a solution. The dressing can absorb water droplets on the attached surface in 30 s; using a semi-permeable membrane model (the semi-permeable membrane as the intermediate layer, the outside as the dressing, and the inside as the PBS solution) to simulate the drug release of the dressing on the surface of the human skin, 39.7% of the drug can be released in 12 hours.

[0035] Example 3:

[0036] 1) 13.6 mmol 7-hydroxy-4-methylcoumarin, 56.8 mmol bromoacetic acid, 25.2 mmol potassium carbonate were added in sequence to 220 ml ethanol solution with 0.003 mmol potassium iodide as catalyst, heated to reflux for 22 hours, then the solution was cooled to room temperature, acidified and extracted with diethyl ether and water; after separation with a separatory funnel, the water phase was removed, and the organic phase was absorbed with magnesium sulfate to remove water, and the solvent was removed by rotary evaporation to obtain the desired product 7-carboxymethoxy-4-methylcoumarin (CM), product purity > 97.6%, yield 64%; 2 wt% 7-carboxymethoxy-4-methylcoumarin and 10 wt% CS-DA were dissolved in 10 wt% DMSO / 90 wt% deionized water mixed solvent in a 50°C water bath and in the dark, 0.03 wt% EDC and 0.06 wt% NHS were added under magnetic stirring at 400 rpm for coupling reaction for 24 hours, and finally dialysis was performed using a regenerated cellulose dialysis bag with a molecular weight of 3000, and after 7 days of dialysis, CS-DA-CM was obtained by freeze-drying, and was stored in the dark until use. 2) Musk, panax notoginseng, flurbiprofen, and red sandalwood were dispersed in physiological saline, and the above mixed solution was mixed with sodium polyacrylate gel powder at a ratio of 2:1, and the solution was absorbed by sodium polyacrylate to obtain a water-absorbed layer with a total drug content of about 5 wt% of the water-absorbed sodium polyacrylate gel.

[0037] 3) The transparent polyurethane waterproof protective layer was coated with acrylate adhesive, drug-loaded sodium polyacrylate hydrogel prepared in step 2), acrylate adhesive, and a non-woven fabric flow guide layer in sequence at a speed of 10 cm / s, the concentration of acrylate adhesive was 7 wt%, and each layer was coated twice. Then a semi-finished product was obtained using a molding process, and an array type cutter (with circular cutters with a diameter of 1 mm arranged in parallel in the horizontal and vertical directions, and the cutters were spaced 10 mm apart) was used to punch holes in the semi-finished product to obtain a porous and breathable semi-finished product patch;

[0038] 4) Under light shielding conditions, a shielding type porous mold (mold thickness 1 mm, hollow circular holes 5 mm, hollow holes arranged in parallel in the horizontal and vertical directions) was covered on the porous semi-finished product patch, the holes of the porous mold and the porous semi-finished product patch did not coincide, and then 10 wt% CS-DA-CM PBS solution was added to the holes of the shielding type porous mold and in situ photocured using ultraviolet light greater than 300 nm for 5 minutes, and after demolding, a release paper layer was covered, a light-proof packaging bag was used for packaging, and then sterilized by irradiation to obtain a breathable hydrogel-based composite patch with reversible adhesion function.

[0039] The patch prepared by the above process has increased drug loading compared to Example 1, and has an adhesive strength of 31.8 kPa. After irradiation with a light source having a wavelength of less than 280 nm, the gel becomes a solution. The patch can achieve absorption of water droplets on the attached surface in 30 s. Using a semi-permeable membrane model (the semi-permeable membrane as the intermediate layer, the outside as the patch, and the inside as the PBS solution), the drug release of the patch on the surface of the human skin is simulated, and 36.4% of the drug can be released in 12 hours.

[0040] Example 4:

[0041] 1) 0.003 mmol of potassium iodide was used as a catalyst, 13.6 mmol of 7-hydroxy-4-methyl coumarin was added to 56.8 mmol of bromoacetic acid, 25.2 mmol of potassium carbonate, and 220 ml of ethanol solution was heated to reflux for 22 hours, then the solution was cooled to room temperature, acidified and extracted with ether and water; after separation with a separatory funnel, the water phase was removed, and the organic phase was absorbed with magnesium sulfate to remove water, and the solvent was removed by rotary evaporation to obtain the desired product 7-carboxymethoxy-4-methyl coumarin (CM), with a purity of >97.6% and a yield of 64%; 2 wt% of 7-carboxymethoxy-4-methyl coumarin and 10 wt% of CS-DA were dissolved in 10 wt% DMSO / 90 wt% deionized water mixed solvent at 50°C water bath and in the dark, under the condition of magnetic stirring at 400 rpm, 0.03 wt% of EDC and 0.06 wt% of NHS were added for coupling reaction for 24 hours, and finally the product was dialyzed using a regenerated cellulose dialysis bag with a molecular weight of 3000, and after 7 days of freeze-drying, CS-DA-CM was obtained, which was stored in the dark and used as needed. 2) musk, panax notoginseng, flurbiprofen, and red sandalwood were dispersed in physiological saline, and the above mixed solution was mixed with sodium polyacrylate gel powder at a ratio of 4:1, and the solution was absorbed by sodium polyacrylate to obtain a water-absorbed layer with a total drug content of about 3 wt% of the water-absorbed sodium polyacrylate gel.

[0042] 3) On the surface of the transparent polyurethane waterproof protective layer, the acrylic adhesive, the drug-loaded poly (sodium acrylate) hydrogel prepared in step 2), and the acrylic adhesive were coated in turn using a doctor blade at a speed of 10 cm / s, 2 coats for each layer, and the concentration of the acrylic adhesive was 7 wt%; then a non-woven fabric flow guide layer was covered. A semi-finished product was obtained using a compression molding process, and the semi-finished product was punched using an array type cutter (circular cutters with a diameter of 1 mm were arranged in parallel in the transverse and longitudinal directions, and the cutters were spaced 10 mm apart on the left and right) to obtain a porous and breathable semi-finished product dressing; 4) Under light shielding conditions, a shielding type porous mold (mold thickness 1 mm, hollow circular holes 5 mm, hollow holes arranged in parallel in the transverse and longitudinal directions) was covered on the porous semi-finished product dressing, the holes of the porous mold and the porous semi-finished product dressing did not coincide, and then a 10 wt% CS-DA-CM PBS solution was added to the holes of the shielding type porous mold. Using ultraviolet light greater than 300 nm, in-situ photopolymerization was performed for 5 minutes, a release paper layer was covered after demolding, a light-proof packaging bag was used for packaging, and then radiation sterilization was performed, thereby obtaining a breathable hydrogel-based composite dressing with reversible adhesion function.

[0043] The dressing prepared by the above process has an increased amount of water-absorbing layer poly (sodium acrylate) compared to Example 1, and the adhesion strength is 33.7 kPa. After irradiation with a light source with a wavelength less than 280 nm, the gel becomes a solution. The dressing can absorb water droplets on the attached surface in 30 s. Using a semi-permeable membrane model (the semi-permeable membrane as the intermediate layer, the outside as the dressing, and the inside as the PBS solution), the drug release of the dressing on the surface of the human skin was simulated, and 35.6% of the drug was released in 12 hours.

[0044] Example 5:

[0045] 1) 13.6 mmol of 7-hydroxy-4-methyl coumarin, 56.8 mmol of bromoacetic acid, and 25.2 mmol of potassium carbonate were sequentially added to 220 ml of ethanol solution with 0.003 mmol of potassium iodide as catalyst, heated to reflux for 22 hours, then cooled to room temperature, acidified, and extracted with ether and water; after separation using a separatory funnel, the water phase was removed, and the organic phase was absorbed with magnesium sulfate to remove water, and the solvent was removed by rotary evaporation to obtain the desired product 7-carboxymethoxy-4-methyl coumarin (CM), with a purity of >97.6% and a yield of 64%; 2 wt% of 7-carboxymethoxy-4-methyl coumarin and 10 wt% of CS-DA were dissolved in a 10 wt% DMSO / 90 wt% deionized water mixed solvent under a water bath at 50°C and in the dark, and 0.03 wt% of EDC and 0.06 wt% of NHS were added for coupling reaction under magnetic stirring at 400 rpm for 24 hours. Finally, CS-DA-CM was obtained by dialysis using a regenerated cellulose dialysis bag with a molecular weight of 3000, and freeze-drying after 7 days. It was stored in the dark and used as needed.

[0046] 2) Disperse musk, notoginseng, flurbiprofen, and red sandalwood in physiological saline, mix the above mixture solution with sodium polyacrylate gel powder at a ratio of 2:1, the solution is absorbed by sodium polyacrylate, and a water-absorbing layer with a total drug content of about 3wt% of the water-absorbed sodium polyacrylate gel is obtained.

[0047] 3) Apply the acrylate adhesive, the drug-loaded sodium polyacrylate hydrogel prepared in step 2), and the acrylate adhesive in sequence on the surface of the transparent polyurethane waterproof protective layer at a rate of 10 cm / s, each layer is coated 2 times, and the concentration of the acrylate adhesive is 7wt%; then cover the non-woven fabric flow guide layer. Use a molding process to obtain a semi-finished product, and use an array type cutter (with circular cutters with a diameter of 2mm arranged in parallel in the horizontal and vertical directions, and the cutters are spaced 7mm apart) to punch the semi-finished product to obtain a porous and breathable semi-finished product patch;

[0048] 4) Under light shielding conditions, use a shielding type porous mold (mold thickness 1.5mm, hollow circular hole 5mm, hollow hole arranged in parallel in the horizontal and vertical directions), cover the porous semi-finished product patch, the pores of the porous mold and the porous semi-finished product patch do not coincide, then add 10wt% CS-DA-CM PBS solution to the pores of the shielding type porous mold, use ultraviolet light greater than 300nm for in-situ photocuring for 5 minutes, cover the release paper layer after demolding, use an opaque packaging bag for packaging, and then irradiate for sterilization, to obtain a breathable hydrogel-based composite patch with reversible adhesion function.

[0049] The patch prepared by the above process has an increased cutter pore size of the array type cutter mold, a reduced cutter spacing distance, and an increased thickness of the adhesive layer. The adhesion strength is 31.8kPa, and the gel becomes a solution after irradiation with a light source with a wavelength less than 280nm. The patch can absorb water droplets on the attached surface in 30s; using a semi-permeable membrane model (semi-permeable membrane as the middle layer, outside the patch, and inside the PBS solution) to simulate the drug release of the patch on the surface of the human skin, 36.1% of the drug can be released in 12 hours. Compared with example 1, the skin on the back of the mouse in example 5 has less redness after being attached for 12h, and the experimental mice in example 5 do not have obvious conditions after eating the back patch.

Claims

1. A breathable hydrogel-based composite patch with reversible adhesive function, characterized by: The composite patch comprises, in sequence, a porous waterproof protective layer, a water-absorbing layer, a flow guide layer, an adhesive layer, and a release paper layer, wherein the waterproof protective layer is a transparent polyurethane elastomer film, the water-absorbing layer is a sodium polyacrylate hydrogel, the flow guide layer is a non-woven fabric, and the adhesive layer is dopamine and 7-carboxymethoxyl-4-methyl coumarin double-graft modified chitosan, and the water-absorbing layer is loaded with drugs for promoting blood circulation and removing blood stasis, relieving inflammation and pain.

2. The breathable hydrogel-based composite patch with reversible adhesive function according to claim 1, wherein: The adhesive fixation of the adhesive layer and the flow guide layer is achieved by using a regional light curing process.

3. The breathable hydrogel-based composite patch with reversible adhesive function according to claim 1, wherein: The patch has reversible adhesion function. When the adhesive layer is cured by ultraviolet light with a wavelength greater than 300 nm, the patch has adhesion ability. When it is necessary to replace or remove the patch, the patch can be detached by irradiation with a light source with a wavelength less than 280 nm.

4. The method of claim 1, wherein the preparation method of the breathable hydrogel-based composite patch having a reversible adhesive function is characterized by, The steps are as follows: 1) Using trace potassium iodide as a catalyst, 7-hydroxy-4-methyl coumarin is heated to reflux with bromoacetic acid and potassium carbonate in ethanol solution for 15-25 hours, then the solution is cooled to room temperature, acidified, and then extracted with diethyl ether and water; after separation with a separatory funnel, the water phase is removed, and the organic phase is absorbed with magnesium sulfate to remove water, and the solvent is removed by rotary evaporation to obtain 7-carboxymethoxyl-4-methyl coumarin CM; then CM is grafted to the amino group of the dopamine modified chitosan molecule CS-DA side chain, and the specific steps are as follows: in a 50°C water bath and in the dark, CS-DA and CM are dissolved in a DMSO / deionized water mixed solvent, then EDC and NHS are added for coupling reaction, and finally regenerated cellulose dialysis bags are used for dialysis, and after freeze-drying, dopamine and 7-carboxymethoxyl-4-methyl coumarin double-graft modified chitosan CS-DA-CM is obtained, which is stored in the dark; 2) The sodium polyacrylate gel dry powder is immersed in a physiological saline solution containing blood circulation promoting and stasis removing, inflammation relieving and pain relieving drug components to obtain a drug-loaded sodium polyacrylate hydrogel, achieving drug loading in the water-absorbing layer; 3) A glue is coated on the surface of the waterproof protective layer, followed by drug-loaded sodium polyacrylate hydrogel and glue, and then the flow guide layer is covered, a semi-finished product is obtained by using a mold forming process, and the semi-finished product is punched by using an array type cutter to obtain a porous and breathable semi-finished product patch; 4) Under light shielding conditions, a shielding type porous mold is covered on the porous semi-finished product patch, the pores of the porous mold and the porous semi-finished product patch do not coincide, then the CS-DA-CM solution is added to the pores of the shielding type porous mold and in-situ light cured by using ultraviolet light, the release paper layer is covered after demolding, the package bag is sealed after irradiation sterilization, and a breathable hydrogel-based composite patch with reversible adhesion function is obtained.

5. The method of claim 4, wherein the method is characterized by: In step 1), the concentrations of 7-hydroxy-4-methyl coumarin, bromoacetic acid and potassium carbonate in the ethanol solution are 50-125 mmol / L, 250-350 mmol / L and 75-125 mmol / L, respectively; in the grafting reaction of 7-carboxymethoxyl-4-methyl coumarin and CS-DA, the concentration of 7-carboxymethoxyl-4-methyl coumarin is 1-3 wt%, the viscosity average molecular weight of CS-DA is 200-600 million, the grafting degree of DA is 20-35%, the concentration of DMSO / deionized water mixed solvent is 10 wt% DMSO / 90 wt% deionized water, the concentration of EDC is 0.025-0.06 wt%, the concentration of NHS is 0.04-0.08 wt%, the coupling reaction time is 12-48 hours, and the magnetic stirring speed is 200-500 rpm; dialysis is performed using a regenerated cellulose dialysis bag, and the dialysis is performed in deionized water for 5-7 days in the dark.

6. The method of claim 4, wherein the method is characterized by: In step 2), the anti-inflammatory and analgesic drug is one or more of non-steroidal anti-inflammatory drugs, flurbiprofen and loxoprofen; the blood-activating and stasis-removing drug is one or more of musk, notoginseng, chuanxiong, wulingzhi, suomu and shengpuhuang; the weight ratio of sodium polyacrylate gel dry powder to normal saline is 1:2-4; and the amount of the drug is 1-5 wt% of the total mass of the sodium polyacrylate gel dry powder and normal saline.

7. The method of claim 4, wherein the method is characterized by: In step 3), the adhesive is 5-15 wt% of an acrylate adhesive; a doctor blade is used for coating, the coating speed is 10 cm / s, and each layer is coated twice; the structure of the array type cutter is that a plurality of circular cutters with a diameter of 1-2 mm are arranged in a horizontal and vertical parallel manner with a spacing of 5-15 mm; and the overall size of the array type cutter is consistent with the size of the patch.

8. The method of claim 4, wherein the method is characterized by: In step 4), the shielding type porous mold is in the form of a hollow cover plate, the diameter of the hollow circular holes on the mold is 5-7.5 mm, the hollow circular holes are arranged in a horizontal and vertical parallel manner, and do not coincide with the holes generated on the patch by using the array type cutter in step 3); the thickness of the shielding type porous mold is 0.75-1.5 mm; the concentration of the CS-DA-CM solution is 10-20 wt%, and the solution addition amount of each hollow hole of the shielding type porous mold is calculated according to the parameters; the wavelength of the ultraviolet light is greater than 300 nm, and the irradiation time is 5-10 minutes.

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