Long-acting controlled-release medical composite membrane and preparation method thereof

Abstract

The invention provides a long-acting controlled-release medical composite membrane and a preparation method thereof. The preparation method of the composite membrane comprises the following steps: limiting surface modification of the membrane; preparing a microgel aqueous phase dispersion liquid; the viscosity of the microgel water-phase dispersion liquid is improved, and the structure is strengthened; preparing a low-density net stent structural body: dissolving Arabic gum in water, heating, pouring menthol, valerian root extract, sorbitol ester, gelatin and cell exosome, and stirring until dissolving to form a functional coating solution; taking polyvinyl alcohol, a surfactant, polylactic acid, epoxidized soybean oil, carboxymethyl cellulose, water and glycerol, mixing, uniformly stirring, and fully mixing with the functional coating liquid to obtain a low-density net bracket structural body; and packaging the pressure control groove. According to the invention, long-acting stable release of the medicine can be realized, and the promotion effect on wound healing is obviously enhanced. The preparation method is relatively simple, low in cost and beneficial to large-scale production and clinical application, and has wide market prospects and social value.

Description

Technical Field

[0001] The present invention belongs to the technical field of medical composite membranes, and particularly relates to a long-acting controlled-release medical composite membrane and a preparation method thereof. Background Art

[0002] In the medical field, the application of medical composite membranes is becoming increasingly widespread, especially playing an important role in drug controlled release, tissue repair, etc. However, there are many deficiencies in existing medical composite membranes.

[0003] The controlled-release effect of existing medical composite membranes is often not ideal, and it is difficult to achieve long-term and stable release of drugs. This may be due to the unreasonable structure design of the membrane, which cannot effectively control the diffusion rate and release time of drug molecules. The pressure transmission control performance of some composite membranes is poor, and it is impossible to accurately adjust the speed and amount of drug release according to actual needs, thus affecting the treatment effect.

[0004] In addition, the effect of existing medical composite membranes in promoting wound healing is also not satisfactory. Some composite membranes cannot provide a suitable microenvironment, which is not conducive to cell proliferation and migration, and affects the tissue repair and regeneration process. There are also some composite membranes with insufficient or low bioactive components, which cannot effectively stimulate cells to secrete growth factors, thus slowing down the wound healing rate. Summary of the Invention

[0005] Aiming at the deficiencies of the existing technology, the purpose of the present invention is to provide a long-acting controlled-release medical composite membrane and a preparation method thereof.

[0006] To achieve the above purpose, the solution of the present invention is as follows:

[0007] A long-acting controlled-release medical composite membrane includes a composite membrane main body and a microchannel transfer layer arranged at the bottom of the composite membrane main body. The composite membrane main body is sequentially divided into a low-density through-net support structure layer, a gel-state pressure transmission control layer, and a restricted membrane pressure transmission control layer from the inside to the outside. The preparation method of the long-acting controlled-release medical composite membrane includes the following steps:

[0008] Step 1: Surface modification of the restricted membrane

[0009] Blow hydrochloric acid gas on the polyurethane restricted membrane for treatment;

[0010] Step 2: Preparation of the microgel aqueous dispersion

[0011] Add a swellable hydrogel to water to form a microgel aqueous dispersion;

[0012] Step 3: Viscosity increase and structure strengthening of the microgel aqueous dispersion

[0013] The aqueous dispersion of microgels is uniformly dispersed and fixed on the surface of the modified restrictive membrane, and UV irradiation is continuously carried out to form a gel-state pressure transmission control layer;

[0014] Step 4: Prepare a low-density network scaffold structure:

[0015] Dissolve gum arabic in water, heat it, pour in menthol, valerian root extract, sorbitan ester, gelatin, and extracellular vesicles, and stir until dissolved to form a functional coating solution; the valerian root extract is an acetone extract of valerian root;

[0016] Take polyvinyl alcohol, surfactant, polylactic acid, epoxidized soybean oil, carboxymethyl cellulose, water, and glycerol, mix them, stir evenly, and mix them well with the functional coating solution to obtain a low-density network scaffold structure; the mass ratio of polylactic acid to epoxidized soybean oil is 1-3:4-5; the structure and properties of the material, such as dispersibility, stability, and pore structure, are affected by polylactic acid and epoxidized soybean oil, so as to achieve the purpose of regulating the internal structure of the composite membrane.

[0017] Step 5: Encapsulate the pressure control tank

[0018] Place the low-density network scaffold structure between the gel-state pressure transmission control layer and the microchannel transfer layer, and then attach it to the substrate.

[0019] Preferably, the microchannel transfer layer includes polyethylene or polypropylene or polylactic acid or chitosan or silicon-containing polyacrylic acid or silica gel; the swellable hydrogel in Step 2 includes carbomer or polymethacrylic acid hydrogel or polyacrylic acid hydrogel or a mixture thereof.

[0020] Preferably, the low-density network scaffold structure is placed between the gel-state pressure transmission control layer and the microchannel transfer layer by a coating method.

[0021] Preferably, the preparation method of the functional coating solution includes: dissolving 25-35 g of gum arabic in distilled water, heating it to 50-55 °C, pouring in 5-7 g of menthol, 5-10 g of valerian root extract, 1-3 g of sorbitan ester, 10-25 g of gelatin, and 1-5 mL of extracellular vesicles, and stirring until dissolved to form a functional coating solution.

[0022] Preferably, the preparation method of the valerian root extract includes: stirring and extracting dry valerian root and acetone at a mass ratio of 1:6-10 at 60-70 °C for at least 1 h, cooling, filtering, and removing the solvent.

[0023] Preferably, the preparation method of the valerian root extract includes: stirring and extracting dry valerian root and acetone at a mass ratio of 1:10 at 60-70 °C for at least 1 h, cooling, filtering, concentrating the filtrate, and drying and removing the solvent under reduced pressure at 50 °C.

[0024] Preferably, step four is as follows:

[0025] Dissolve 25 - 35 g of gum arabic in 100 ml of distilled water, heat to 50 - 55 °C, pour in 5 - 7 g of menthol, 5 - 10 g of valerian root extract, 1 - 3 g of sorbitan ester, 10 - 25 g of gelatin, and 1 - 5 mL of extracellular vesicles, and stir until dissolved to form a functional coating solution.

[0026] Take 10 - 15 g of polyvinyl alcohol, 1 - 3 g of BRIJ35 neutral surfactant, 1 - 3 g of polylactic acid, 4 - 5 g of epoxidized soybean oil, 5 - 9 g of carboxymethyl cellulose, 50 ml of water, and 4 - 8 g of glycerol, mix them, stir evenly, and mix well with 50 - 60 mL of the functional coating solution to obtain a low - density mesh scaffold structure.

[0027] Preferably, step four is as follows:

[0028] Dissolve 25 g of gum arabic in 100 ml of distilled water, heat to 50 - 55 °C, pour in 5 g of menthol, 5 g of valerian root extract, 3 g of sorbitan ester, 25 g of gelatin, and 1 mL of extracellular vesicles, and stir until dissolved to form a functional coating solution.

[0029] Take 10 g of polyvinyl alcohol, 1 g of BRIJ35 neutral surfactant, 1 g of polylactic acid, 4 g of epoxidized soybean oil, 5 g of carboxymethyl cellulose, 50 ml of water, and 4 g of glycerol, mix them, stir evenly, and mix well with 50 mL of the functional coating solution to obtain a low - density mesh scaffold structure.

[0030] Preferably, the extracellular vesicles are mesenchymal stem cell - derived extracellular vesicles.

[0031] Preferably, the preparation method of the extracellular vesicles includes: inoculating adipose - derived mesenchymal stem cells in a culture medium, culturing for 14 days, collecting the supernatant, and filtering to obtain extracellular vesicles.

[0032] The culture medium is based on DMEM / F12, and 0.5 - 2 mg / L of the small peptide KQQAWQVDES, 5 - 20 mg / L of annexin V, 10 - 50 mg / L of vitamin C, and 2.5 - 5 mg / L of glutathione are added to the basic culture medium.

[0033] We found that the small peptide KQQAWQVDES can replace the conventionally used glutathione in the culture medium, and the extracellular vesicles obtained after adding this small peptide have better effects and can more effectively promote wound healing. Experiments show that if KQQAWQVDES is replaced with glutathione and the method of test example 2 is used for testing, the 7 - day wound healing rate drops from 99% to 86%.

[0034] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0035] Through the unique multi-layer structure design and precise preparation process of the present invention, the long-acting and stable release of drugs can be achieved, which helps to reduce the frequency of drug administration and improve patient compliance.

[0036] The promoting effect of the composite film of the present invention on wound healing is significantly enhanced. A variety of functional components added, such as menthol, valerian root extract, etc., jointly create a microenvironment conducive to cell proliferation and migration, accelerating the tissue repair and regeneration process. It can shorten the wound healing time, reduce the probability of infection, and improve the treatment effect.

[0037] The preparation method of the present invention is relatively simple and has low cost, which is conducive to large-scale production and clinical application, and has broad market prospects and social value. Description of the Drawings

[0038] Figure 1 : Statistical chart of the experimental results of Experimental Example 1. Detailed Embodiments

[0039] To better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0040] Unless otherwise specified, the experimental methods used in the embodiments of the present invention are all conventional methods.

[0041] Unless otherwise specified, the materials, reagents, etc. used in the embodiments of the present invention can all be obtained from commercial channels.

[0042] Preparation method of valerian root extract: According to the mass ratio of 1:6 - 10, dry valerian root and acetone are stirred and extracted at 60 - 70 °C for at least 1 h. Cool, filter, concentrate the filtrate, and dry under reduced pressure at 50 °C to remove the solvent. The preparation method of the extract used in the following examples is: According to the mass ratio of 1:10, dry valerian root and acetone are stirred and extracted at 60 - 70 °C for 1 h. Cool, filter, concentrate the filtrate, and dry under reduced pressure at 50 °C to remove the solvent.

[0043] The weight-average molecular weight of the polylactic acid is 70,000 g / mol.

[0044] The extracellular vesicles described are adipose mesenchymal stem cell extracellular vesicles.

[0045] Adipose mesenchymal stem cells are inoculated into the culture medium at an inoculation density of 1×10 5 / cm 2 , placed in an incubator with 5% CO 2 , 37 °C, and a saturated humidity of 95% for 14 days, then the supernatant is collected and filtered through a 0.22 μm filter membrane to obtain extracellular vesicles.

[0046] The cell culture medium is based on DMEM / F12, and 0.5 - 2 mg / L of the small peptide KQQAWQVDES, 5 - 20 mg / L of annexin V, 10 - 50 mg / L of vitamin C, and 2.5 - 5 mg / L of glutathione are added to the basic medium.

[0047] Specifically, the culture medium used in the examples is: based on DMEM / F12, and 0.5 - 2 mg / L of the small peptide KQQAWQVDES, 5 - 20 mg / L of annexin V, 10 - 50 mg / L of vitamin C, and 2.5 mg / L of glutathione are added to the basic medium. More specifically: based on DMEM / F12, and 2 mg / L of the small peptide KQQAWQVDES, 5 mg / L of annexin V, 10 mg / L of vitamin C, and 2.5 mg / L of glutathione are added to the basic medium.

[0048] Structure of the long - acting controlled - release medical composite membrane: It includes a composite membrane main body 1 and a micro - channel transfer layer 2 provided at the bottom of the composite membrane main body 1. The composite membrane main body 1 is sequentially divided into a low - density through - mesh support structure layer 3, a gel - state pressure transmission control layer 4, and a restricted - membrane pressure transmission control layer 5 from the inside to the outside. An auxiliary skin fixation layer 6 is provided at the bottom of the micro - channel transfer layer 2. Pressure - controllable micro - gels 7 are evenly distributed inside the gel - state pressure transmission control layer 4. Transfer micro - channels 8 are evenly distributed on the micro - channel transfer layer 2. Function bodies 9 are evenly distributed inside the low - density through - mesh support structure layer 3, and the function bodies 9 are extracellular vesicles. Its structure can refer to the utility model patent CN 210301777U.

[0049] Preparation method of the long - acting controlled - release medical composite membrane:

[0050] Step 1: Surface modification of the restricted membrane:

[0051] The polyurethane restricted membrane (thickness 0.1 - 0.3 mm) is blown with hydrochloric acid gas; the blowing treatment is carried out at a flow rate of 0.5 - 1 L / min for 5 - 10 minutes;

[0052] Step 2: Preparation of the aqueous dispersion of micro - gels:

[0053] A swellable hydrogel (30 - 50 g of carbomer or polymethacrylic acid hydrogel or polyacrylic acid hydrogel or a mixture thereof) is added to water, and slow stirring is carried out at 35 - 45 °C for more than 6 hours to form an aqueous dispersion of micro - gels;

[0054] Step 3: Viscosity increase and structure strengthening of the aqueous dispersion of micro - gels:

[0055] The aqueous dispersion of micro - gels is uniformly dispersed and fixed on the surface of the modified restricted membrane, and continuous UV irradiation (wavelength 254 nm) is carried out for 15 - 30 minutes to form a gel - state pressure transmission control layer;

[0056] Step 4: Prepare a low-density mesh support structure:

[0057] Dissolve 25 - 35 g of gum arabic in 100 ml of distilled water, heat to 50 - 55 °C, pour in 5 - 7 g of menthol, 5 - 10 g of valerian root extract, 1 - 3 g of sorbitan ester, 10 - 25 g of gelatin, and 1 - 5 mL of extracellular vesicles, and stir until dissolved to form a functional coating solution;

[0058] Take 10 - 15 g of polyvinyl alcohol, 1 - 3 g of BRIJ35 neutral surfactant, 1 - 3 g of polylactic acid, 4 - 5 g of epoxidized soybean oil, 5 - 9 g of carboxymethyl cellulose, 50 ml of water, and 4 - 8 g of glycerol, mix and stir evenly, and mix well with 50 - 60 mL of the functional coating solution to obtain a low-density mesh support structure;

[0059] Step 5: Encapsulation of the pressure control tank

[0060] By coating, place the low-density mesh support structure between the gel-state pressure transmission control layer and the microchannel transfer layer to form a pressure control tank; attach the pressure control tank to a substrate (such as release paper), and after attachment, it can be wound up and cut to obtain a long-acting controlled-release medical composite film.

[0061] Example 1: Preparation method of a medical composite film

[0062] Step 1: Surface modification of the restrictive film

[0063] Blow hydrochloric acid gas on the polyurethane restrictive film (thickness 0.1 - 0.3 mm); blow at a flow rate of 1 L / min for 5 minutes;

[0064] Step 2: Prepare an aqueous dispersion of microgel particles

[0065] Add a swellable hydrogel (30 g of carbomer 940) to water, and slowly stir at 35 - 45 °C for more than 6 hours to form an aqueous dispersion of microgel particles;

[0066] Step 3: Viscosity increase and structure strengthening of the aqueous dispersion of microgel particles

[0067] Uniformly disperse and fix the aqueous dispersion of microgel particles on the surface of the modified restrictive film, and continuously perform UV irradiation (wavelength 254 nm) for 15 minutes to form a gel-state pressure transmission control layer;

[0068] Step 4: Prepare a low-density mesh support structure:

[0069] Dissolve 25 g of gum arabic in 100 ml of distilled water, heat to 50 - 55 °C, pour in 5 g of menthol, 5 g of valerian root extract, 3 g of sorbitan ester, 25 g of gelatin, and 1 mL of extracellular vesicles, and stir until dissolved to form a functional coating solution;

[0070] Take 10 g of polyvinyl alcohol, 1 g of BRIJ35 neutral surfactant, 1 g of polylactic acid, 4 g of epoxidized soybean oil, 5 g of carboxymethyl cellulose, 50 ml of water, and 4 g of glycerol, mix them, stir evenly, and mix well with 50 mL of the functional coating solution to obtain a low-density network scaffold structure;

[0071] Step Five: Pressure control groove encapsulation

[0072] By coating, set the low-density network scaffold structure between the gel-state pressure transmission control layer and the microchannel transfer layer to form a pressure control groove; attach the pressure control groove to a substrate (such as release paper), and after attachment, it can be wound and cut to obtain a long-acting controlled-release medical composite film.

[0073] Example 2: Preparation method of medical composite film

[0074] The composite film structure is the same as that in Example 1. Some parameters in the preparation method are slightly different.

[0075] Step One: Surface modification of the restriction membrane

[0076] Perform hydrochloric acid gas blowing treatment on the polyurethane restriction membrane (thickness 0.1 - 0.3 mm); blow at a flow rate of 1 L / min for 5 minutes;

[0077] Step Two: Preparation of microgel aqueous dispersion

[0078] Add swellable hydrogel (30 g of carbomer 940) to water, and slowly stir at 35 - 45 °C for more than 6 hours to form a microgel aqueous dispersion;

[0079] Step Three: Viscosity increase and structure strengthening of the microgel aqueous dispersion

[0080] Uniformly disperse and fix the microgel aqueous dispersion on the surface of the modified restriction membrane, and continuously perform UV irradiation (wavelength 254 nm) for 30 minutes to form a gel-state pressure transmission control layer;

[0081] Step Four: Preparation of low-density network scaffold structure

[0082] Dissolve 35 g of gum arabic in 100 ml of distilled water, heat to 50 - 55 °C, pour in 7 g of menthol, 5 g of valerian root extract, 3 g of sorbitan ester, 10 g of gelatin, and 5 mL of extracellular vesicles, and stir until dissolved to form a functional coating solution;

[0083] Take 15 g of polyvinyl alcohol, 3 g of BRIJ35 neutral surfactant, 3 g of polylactic acid, 4 g of epoxidized soybean oil, 9 g of carboxymethyl cellulose, 50 ml of water, and 8 g of glycerol, mix them, stir evenly, and mix well with 50 mL of functional coating liquid to obtain a low-density mesh support structure;

[0084] Step Five: Encapsulation of Pressure Control Tank

[0085] Through coating, the low-density mesh support structure is disposed between the gel-state pressure transmission control layer and the microchannel transfer layer to form a pressure control tank; the pressure control tank is attached to a substrate (such as release paper), and after attachment, it can be wound up and cut to obtain a long-acting controlled-release medical composite film.

[0086] Example 3: Preparation Method of Medical Composite Film

[0087] The composite film structure is the same as that in Example 1. Some parameters in the preparation method are slightly different.

[0088] Step One: Surface Modification of Restriction Film

[0089] Perform hydrochloric acid gas blowing treatment on the polyurethane restriction film (thickness 0.1 - 0.3 mm); blow at a flow rate of 1 L / min for 5 minutes;

[0090] Step Two: Preparation of Aqueous Microgel Dispersion

[0091] Add swellable hydrogel (30 g of carbomer 940) to water, and slowly stir at 35 - 45 °C for more than 6 hours to form an aqueous microgel dispersion;

[0092] Step Three: Viscosity Enhancement and Structure Strengthening of Aqueous Microgel Dispersion

[0093] Uniformly disperse and fix the aqueous microgel dispersion on the surface of the modified restriction film, and continuously perform UV irradiation (wavelength 254 nm) for 30 minutes to form a gel-state pressure transmission control layer;

[0094] Step Four: Preparation of Low-Density Mesh Support Structure

[0095] Dissolve 35 g of gum arabic in 100 ml of distilled water, heat to 50 - 55 °C, pour in 5 g of menthol, 10 g of valerian root extract, 1 g of sorbitan ester, 10 g of gelatin, and 2 mL of extracellular vesicles, and stir until dissolved to form a functional coating liquid;

[0096] Take 10 g of polyvinyl alcohol, 1 g of BRIJ35 neutral surfactant, 1 g of polylactic acid, 5 g of epoxidized soybean oil, 5 g of carboxymethyl cellulose, 50 ml of water, and 5 g of glycerol, mix them, stir evenly, and mix well with 60 mL of functional coating liquid to obtain a low-density mesh support structure;

[0097] Step Five: Encapsulation of the Pressure Control Groove

[0098] Through coating, a low-density mesh support structure is disposed between the gel-state pressure transmission control layer and the microchannel transfer layer to form a pressure control groove; the pressure control groove is attached to a substrate (such as release paper), and after attachment, it can be wound up and cut to obtain a long-acting controlled-release medical composite film.

[0099] Example 4: Preparation Method of a Medical Composite Film

[0100] The structure of the composite film is the same as that in Example 1. There are slight differences in some parameters in the preparation method.

[0101] Step One: Surface Modification of the Restriction Film

[0102] The polyurethane restriction film (thickness 0.1 - 0.3 mm) is blown with hydrochloric acid gas; the blowing treatment is carried out at a flow rate of 0.5 L / min for 10 minutes.

[0103] Step Two: Preparation of the Microgel Aqueous Dispersion

[0104] A swellable hydrogel (50 g of Carbopol 940) is added to water, and slow stirring is carried out at 35 - 45 °C for more than 6 hours to form a microgel aqueous dispersion.

[0105] Step Three: Viscosity Increase and Structure Strengthening of the Microgel Aqueous Dispersion

[0106] The microgel aqueous dispersion is uniformly dispersed and fixed on the surface of the modified restriction film, and continuous UV irradiation (wavelength 254 nm) is carried out for 30 minutes to form a gel-state pressure transmission control layer.

[0107] Step Four: Preparation of the Low-Density Mesh Support Structure

[0108] 25 g of gum arabic is dissolved in 100 ml of distilled water, heated to 50 - 55 °C, and 7 g of menthol, 10 g of valerian root extract, 3 g of sorbitan ester, 25 g of gelatin, and 1 mL of extracellular vesicles are poured in and stirred until dissolved to form a functional coating solution.

[0109] 15 g of polyvinyl alcohol, 3 g of BRIJ35 neutral surfactant, 1 g of polylactic acid, 5 g of epoxidized soybean oil, 6 g of carboxymethyl cellulose, 50 ml of water, and 8 g of glycerol are taken, mixed and stirred evenly, and then fully mixed with 60 mL of the functional coating solution to obtain a low-density mesh support structure.

[0110] Step Five: Encapsulation of the Pressure Control Groove

[0111] By coating, a low-density mesh support structure is disposed between the gel-state pressure transmission control layer and the microchannel transfer layer to form a pressure control groove; the pressure control groove is adhered to a substrate (such as release paper), and after adhesion, it can be wound and cut to obtain a long-acting controlled-release medical composite film.

[0112] Example 5: Preparation method of medical composite film

[0113] The composite film structure is the same as that in Example 1. Some parameters in the preparation method are slightly different.

[0114] Step 1: Surface modification of the restrictive film

[0115] The polyurethane restrictive film (thickness 0.1 - 0.3 mm) is treated by blowing hydrochloric acid gas; the blowing treatment is carried out at a flow rate of 1 L / min for 10 minutes.

[0116] Step 2: Preparation of the aqueous dispersion of microgel

[0117] A swellable hydrogel (30 g of polymethacrylic acid hydrogel) is added to water, and slow stirring is carried out at 35 - 45 °C for more than 6 hours to form an aqueous dispersion of microgel.

[0118] Step 3: Viscosity increase and structure strengthening of the aqueous dispersion of microgel

[0119] The aqueous dispersion of microgel is uniformly dispersed and fixed on the surface of the modified restrictive film, and continuous UV irradiation (wavelength 254 nm) is carried out for 30 minutes to form a gel-state pressure transmission control layer.

[0120] Step 4: Preparation of the low-density mesh support structure

[0121] 35 g of gum arabic is dissolved in 100 ml of distilled water, heated to 50 - 55 °C, and 7 g of menthol, 5 g of valerian root extract, 3 g of sorbitan ester, 20 g of gelatin, and 5 mL of extracellular vesicles are poured in and stirred until dissolved to form a functional coating solution.

[0122] 15 g of polyvinyl alcohol, 3 g of BRIJ35 neutral surfactant, 2 g of polylactic acid, 5 g of epoxidized soybean oil, 9 g of carboxymethyl cellulose, 50 ml of water, and 8 g of glycerol are taken, mixed and stirred evenly, and fully mixed with 50 mL of the functional coating solution to obtain a low-density mesh support structure.

[0123] Step 5: Encapsulation of the pressure control groove

[0124] By coating, a low-density mesh support structure is disposed between the gel-state pressure transmission control layer and the microchannel transfer layer to form a pressure control groove; the pressure control groove is adhered to a substrate (such as release paper), and after adhesion, it can be wound and cut to obtain a long-acting controlled-release medical composite film.

[0125] Example 6: Preparation Method of Medical Composite Film

[0126] The composite film structure is the same as that of Example 1. The preparation method is slightly different.

[0127] Step 1: Surface modification of the restrictive membrane

[0128] The polyurethane restrictive membrane (thickness 0.1 - 0.3 mm) is blown with hydrochloric acid gas; the blowing treatment is carried out at a flow rate of 1 L / min for 10 minutes;

[0129] Step 2: Preparation of microgel aqueous dispersion

[0130] Swelling water gel (50 g polyacrylic acid hydrogel) is added to water, and slowly stirred at 35 - 45 °C for more than 6 hours to form a microgel aqueous dispersion;

[0131] Step 3: Viscosity increase and structure strengthening of the microgel aqueous dispersion

[0132] The microgel aqueous dispersion is uniformly dispersed and fixed on the surface of the modified restrictive membrane, and continuously irradiated with UV (wavelength 254 nm) for 15 minutes to form a gel-state pressure transmission control layer;

[0133] Step 4: Preparation of low-density network scaffold structure

[0134] 25 g of gum arabic is dissolved in 100 ml of distilled water, heated to 50 - 55 °C, and 7 g of menthol, 5 g of valerian root extract, 1 g of sorbitan ester, 25 g of gelatin, and 1 mL of extracellular vesicles are poured in and stirred until dissolved to form a functional coating solution;

[0135] 15 g of polyvinyl alcohol, 3 g of BRIJ35 neutral surfactant, 3 g of polylactic acid, 4 g of epoxidized soybean oil, 9 g of carboxymethyl cellulose, 50 ml of water, and 8 g of glycerol are taken, mixed and stirred evenly, and fully mixed with 60 mL of the functional coating solution to obtain a low-density network scaffold structure;

[0136] Step 5: Encapsulation of the pressure control tank

[0137] The low-density network scaffold structure is set between the gel-state pressure transmission control layer and the microchannel transfer layer by coating to form a pressure control tank; the pressure control tank is attached to a substrate (such as release paper), and after attachment, it can be wound and cut to obtain a long-acting controlled-release medical composite film.

[0138] Comparative Example 1: Preparation Method of Medical Composite Film

[0139] The composite film structure is the same as that of Example 1. The preparation method is different, and the extract in Step 4 is replaced with wintergreen oil.

[0140] Step 1: Modification of the surface of the restrictive membrane:

[0141] Blow hydrochloric acid gas onto the polyurethane restrictive membrane (with a thickness of 0.1 - 0.3 mm); blow at a flow rate of 1 L / min for 5 minutes;

[0142] Step 2: Preparation of the aqueous dispersion of microgel particles:

[0143] Add swellable hydrogel (30 g of Carbomer 940) to water, and slowly stir at 35 - 45 °C for more than 6 hours to form an aqueous dispersion of microgel particles;

[0144] Step 3: Viscosity increase and structure strengthening of the aqueous dispersion of microgel particles:

[0145] Uniformly disperse and fix the aqueous dispersion of microgel particles on the surface of the modified restrictive membrane, and continuously perform UV irradiation (wavelength 254 nm) for 15 minutes to form a gel - state pressure transmission control layer;

[0146] Step 4: Preparation of a low - density network scaffold structure:

[0147] Dissolve 25 g of gum arabic in 100 ml of distilled water, heat to 50 - 55 °C, pour in 5 g of menthol, 5 g of wintergreen oil, 3 g of sorbitan ester, 25 g of gelatin, and 1 mL of extracellular vesicles, and stir until dissolved to form a functional coating solution;

[0148] Take 10 g of polyvinyl alcohol, 1 g of BRIJ35 neutral surfactant, 1 g of polylactic acid, 4 g of epoxidized soybean oil, 5 g of carboxymethyl cellulose, 50 ml of water, 4 g of glycerol, mix and stir evenly, and fully mix with 50 mL of the functional coating solution to obtain a low - density network scaffold structure;

[0149] Step 5: Encapsulation of the pressure control tank

[0150] By coating, set the low - density network scaffold structure between the gel - state pressure transmission control layer and the micro - channel transfer layer to form a pressure control tank; attach the pressure control tank to a substrate (such as release paper), and after attachment, it can be wound and cut to obtain a long - acting controlled - release medical composite film.

[0151] Comparative Example 2: Preparation method of the medical composite film

[0152] The composite film structure is the same as that in Example 1. The preparation method is similar to that in Example 1, with the difference that other valerian root extracts are used.

[0153] Preparation method of the valerian root extract: According to a mass ratio of 1:10, stir - extract dried valerian root and ethanol at 60 - 70 °C for 1 h. Cool, filter, concentrate the filtrate, and remove the solvent by drying under reduced pressure at 50 °C.

[0154] Comparative Example 3: Preparation Method of Medical Composite Film

[0155] The composite film structure is the same as that of Example 1. The preparation method is different, and polylactic acid and epoxidized soybean oil are replaced with phospholipids.

[0156] Step 1: Restricted Membrane Surface Modification

[0157] Blow hydrochloric acid gas on the polyurethane restricted membrane (thickness 0.1 - 0.3 mm); blow at a flow rate of 1 L / min for 5 minutes;

[0158] Step 2: Preparation of Microgel Aqueous Dispersion

[0159] Add swellable hydrogel (30 g carbomer 940) to water, and slowly stir at 35 - 45 °C for more than 6 hours to form a microgel aqueous dispersion;

[0160] Step 3: Viscosity Enhancement and Structure Strengthening of Microgel Aqueous Dispersion

[0161] Uniformly disperse and fix the microgel aqueous dispersion on the surface of the modified restricted membrane, and continuously perform UV irradiation (wavelength 254 nm) for 15 minutes to form a gel - state pressure transmission control layer;

[0162] Step 4: Preparation of Low - Density Network Scaffold Structure

[0163] Dissolve 25 g of gum arabic in 100 ml of distilled water, heat to 50 - 55 °C, pour in 5 g of menthol, 5 g of valerian root extract, 3 g of sorbitan ester, 25 g of gelatin, and 1 mL of extracellular vesicles, and stir until dissolved to form a functional coating solution;

[0164] Take 10 g of polyvinyl alcohol, 1 g of BRIJ35 neutral surfactant, 5 g of phospholipids, 5 g of carboxymethyl cellulose, 50 ml of water, 4 g of glycerol, mix and stir evenly, and fully mix with 50 mL of the functional coating solution to obtain a low - density network scaffold structure;

[0165] Step 5: Pressure Control Groove Encapsulation

[0166] Through coating, set the low - density network scaffold structure between the gel - state pressure transmission control layer and the micro - channel transfer layer to form a pressure control groove; stick the pressure control groove on a substrate (such as release paper), and after sticking, it can be wound and cut to obtain a long - acting controlled - release medical composite film.

[0167] Comparative Example 4: Preparation Method of Medical Composite Film

[0168] The composite film structure is the same as that of Example 1. The preparation method is different. Polylactic acid and epoxidized soybean oil are used in other ratios.

[0169] Step 1: Modification of the surface of the limiting membrane:

[0170] Blow hydrochloric acid gas on the polyurethane limiting membrane (thickness 0.1 - 0.3 mm); blow at a flow rate of 1 L / min for 5 minutes;

[0171] Step 2: Preparation of the aqueous dispersion of microgel particles:

[0172] Add swellable hydrogel (30 g of Carbomer 940) to water, and slowly stir at 35 - 45 °C for more than 6 hours to form an aqueous dispersion of microgel particles;

[0173] Step 3: Viscosity increase and structure strengthening of the aqueous dispersion of microgel particles:

[0174] Uniformly disperse and fix the aqueous dispersion of microgel particles on the surface of the modified limiting membrane, and continuously perform UV irradiation (wavelength 254 nm) for 15 minutes to form a gel-state pressure transmission control layer;

[0175] Step 4: Preparation of a low-density network scaffold structure:

[0176] Dissolve 25 g of gum arabic in 100 ml of distilled water, heat to 50 - 55 °C, pour in 5 g of menthol, 5 g of valerian root extract, 3 g of sorbitan ester, 25 g of gelatin, and 1 mL of extracellular vesicles, and stir until dissolved to form a functional coating solution;

[0177] Take 10 g of polyvinyl alcohol, 1 g of BRIJ35 neutral surfactant, 4 g of polylactic acid, 1 g of epoxidized soybean oil, 5 g of carboxymethyl cellulose, 50 ml of water, 4 g of glycerol, mix and stir evenly, and mix well with 50 mL of the functional coating solution to obtain a low-density network scaffold structure;

[0178] Step 5: Encapsulation of the pressure control tank

[0179] By coating, place the low-density network scaffold structure between the gel-state pressure transmission control layer and the microchannel transfer layer to form a pressure control tank; attach the pressure control tank to a substrate (such as release paper), and after attachment, it can be wound up and cut to obtain a long-acting controlled-release medical composite film.

[0180] Experimental example 1:

[0181] Add ciprofloxacin to the composite film (add it to the functional coating solution in Step 4), and simulate the sustained-release effect of the composite film through the release rate of ciprofloxacin. Peel off the release paper, soak the composite film in a pH 7.4 phosphate buffer solution, and release it in a dissolution tester at 37 °C under the condition of 110 r / min. Collect the dissolution solution at different time points, filter the dissolution solution, measure its absorbance at 280 nm, calculate the release rate of ciprofloxacin at each time point, and draw an in vitro drug release curve.

[0182] The results showed that the composite film prepared in Example 1 (Group 1) could stably release ciprofloxacin. In Group 2 (Comparative Example 3) and Group 3 (Comparative Example 4), there was basically no further release after 30 min, and the highest release rate after 120 min was lower than that of the examples. This indicated that the composite film of the present invention had good long-acting controlled release ability.

[0183] The effects of other examples were equivalent to those of Example 1, with no significant differences, and the data were omitted.

[0184] Experimental Example 2:

[0185] The experimental animals were 6-week-old female mice (BALB / c) with a body weight of about 25 g. They were adaptively fed for one week before the experiment.

[0186] (1) Establish a wound model

[0187] Before the experiment, the back of the mice was depilated. After anesthetizing the mice, they were fixed on the operating table. The skin was disinfected with alcohol, and a circular full-thickness excision wound with an area of 1×1 cm was created using sterile surgical instruments. Then the mice were randomly grouped.

[0188] Blank control group: The skin wound surface was bandaged with a medical sterile gauze.

[0189] Positive control: Commercially available "chitosan antibacterial dressing".

[0190] Experimental group 1: The composite film of Example 1

[0191] Experimental group 2: The composite film of Comparative Example 1

[0192] Experimental group 3: The composite film of Comparative Example 2

[0193] Experimental group 4: The composite film of Comparative Example 3

[0194] Experimental group 5: The composite film of Comparative Example 4

[0195] The mice were housed separately in cages. On the 7th day, the mice were anesthetized, the wounds were photographed, and the wound healing rate was calculated according to the formula. Wound healing rate = (original wound area - current measured area) / original wound area × 100%.

[0196] Experimental data processing: SPSS software was used for data statistics. Three parallel experiments were carried out, and the results were expressed as mean ± standard deviation (x±s). P<0.05 indicated significant differences and statistical significance.

[0197] Table 1

[0198]

[0199] The results showed that: after 7 days of treatment, the healing rate of experimental group 1 was close to 100%, showing significant differences compared with other groups. There were scars on the skin surface and a bulging feeling on the skin surface in the blank group and the positive control group after healing. There were no obvious scars on the skin surface of the mice in Example 1 group after healing, and the skin color returned to normal. It shows that the composite film of the present invention has good wound healing promoting performance.

[0200] The above are only the preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, 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 long-acting controlled-release medical composite membrane, comprising a composite membrane body and a microchannel transmission layer arranged at the bottom of the composite membrane body, wherein the composite membrane body is divided into a low-density mesh support structure layer, a gel-state pressure transmission control layer and a limiting membrane pressure transmission control layer from the inside to the outside, characterized in that: The preparation method of the long-acting controlled-release medical composite membrane comprises the following steps: Step 1: Modification of limiting membrane surface The polyurethane restricting membrane is treated with hydrochloric acid gas blowing; Step 2: Preparation of microgel aqueous dispersion Adding swellable hydrogel into water to form a microgel aqueous phase dispersion; Step 3: Viscosity enhancement and structural strengthening of microgel aqueous dispersion The microgel aqueous dispersion is uniformly dispersed and fixed on the surface of the modified limiting membrane, and UV irradiation is continuously performed to form a gel-state pressure transmission control layer; Step 4: Preparation of low-density mesh support structure: Dissolve gum arabic in water, heat it, pour in menthol, valerian root extract, sorbitol ester, gelatin, and exosomes, stir until dissolved, and form a functional coating liquid; the valerian root extract is valerian root acetone extract; Take polyvinyl alcohol, surfactant, polylactic acid, epoxy soybean oil, carboxymethyl cellulose, water, and glycerin, mix and stir evenly, and fully mix with the functional coating liquid to obtain a low-density mesh support structure; the mass ratio of polylactic acid to epoxy soybean oil is 1-3:4-5; Step 5: Pressure control tank packaging The low-density mesh support structure is arranged between the gel pressure transmission control layer and the microchannel transmission layer, and then attached to the substrate.

2. The long-acting controlled-release medical composite membrane according to claim 1, characterized in that: The microchannel transfer layer includes polyethylene or polypropylene or polylactic acid or chitosan or silicon-containing polyacrylic acid or silica gel; the swellable hydrogel in step 2 includes carbomer or polymethacrylic acid hydrogel or polyacrylic acid hydrogel or a mixture thereof.

3. The long-acting controlled-release medical composite membrane according to claim 1, characterized in that: The low-density mesh support structure is arranged between the gel-state pressure transmission control layer and the microchannel transmission layer by a coating method.

4. The long-acting controlled-release medical composite membrane according to claim 1, characterized in that: The preparation method of the functional coating liquid includes: dissolving 25-35g of gum arabic in distilled water, heating to 50-55°C, pouring 5-7g of menthol, 5-10g of valerian root extract, 1-3g of sorbitol ester, 10-25g of gelatin, and 1-5mL of extracellular vesicles, stirring until dissolved to form a functional coating liquid.

5. The long-acting controlled-release medical composite membrane according to claim 1, characterized in that: The preparation method of valerian root extract comprises: extracting dried valerian root and acetone at a mass ratio of 1:6-10 at 60-70°C with stirring for at least 1 hour, cooling, filtering and removing the solvent.

6. The long-acting controlled-release medical composite membrane according to claim 1, characterized in that: The preparation method of valerian root extract comprises: extracting dried valerian root with acetone at a mass ratio of 1:10 at 60-70° C. with stirring for at least 1 hour, cooling, filtering, concentrating the filtrate, and drying under reduced pressure at 50° C. to remove the solvent.

7. The long-acting controlled-release medical composite membrane according to claim 1, characterized in that: Step 4 is: Dissolve 25-35 g of gum arabic in 100 ml of distilled water, heat to 50-55°C, pour in 5-7 g of menthol, 5-10 g of valerian root extract, 1-3 g of sorbitol ester, 10-25 g of gelatin, and 1-5 mL of exosomes, stir until dissolved to form a functional coating solution; Take 10-15g of polyvinyl alcohol, 1-3g of BRIJ35 neutral surfactant, 1-3g of polylactic acid, 4-5g of epoxy soybean oil, 5-9g of carboxymethyl cellulose, 50ml of water, and 4-8g of glycerol, mix and stir evenly, and mix thoroughly with 50-60mL of functional coating liquid to obtain a low-density mesh stent structure.

8. The long-acting controlled-release medical composite membrane according to claim 7, characterized in that: Step 4 is: Dissolve 25g of gum arabic in 100ml of distilled water, heat to 50-55°C, pour in 5g of menthol, 5g of valerian root extract, 3g of sorbitol ester, 25g of gelatin, and 1mL of cell exosomes, stir until dissolved to form a functional coating solution; Take 10g of polyvinyl alcohol, 1g of BRIJ35 neutral surfactant, 1g of polylactic acid, 4g of epoxy soybean oil, 5g of carboxymethyl cellulose, 50ml of water, and 4g of glycerol, mix and stir evenly, and mix thoroughly with 50mL of functional coating liquid to obtain a low-density mesh scaffold structure.

9. The long-acting controlled-release medical composite membrane according to claim 1, characterized in that: The cell exosomes are mesenchymal stem cell exosomes.

10. The long-acting controlled-release medical composite membrane according to claim 1, characterized in that: The method for preparing the cell exosomes comprises: inoculating adipose-derived mesenchymal stem cells in a culture medium and culturing them for 14 days, collecting the supernatant, filtering it, and obtaining the cell exosomes; The culture medium uses DMEM / F12 as a basic culture medium, and 0.5-2 mg / L of small peptide KQQAWQVDES, 5-20 mg / L of annexin V, 10-50 mg / L of vitamin C and 2.5-5 mg / L of glutathione are added to the basic culture medium.

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