Intelligent response type traditional Chinese medicine compound transdermal patch and preparation process thereof

Abstract

The invention relates to the technical field of compound transdermal patches, in particular to an intelligent response type traditional Chinese medicine compound transdermal patch and a preparation process thereof. 8-12 parts of a radix scutellariae extract; 7-10 parts of a bighead atractylodes rhizome extract; 5-8 parts of an angelica sinensis extract; 4-6 parts of a safflower extract; 20 to 25 parts of poly (N-isopropylacrylamide) (PNIPAM); 15 to 20 parts of polyacrylic acid PAA; 10 to 15 parts of polyethylene glycol (PEG); 2 to 4 parts of menthol; 3-5 parts of glycerol; according to the invention, dual response of pH and temperature is utilized, so that targeted drug delivery is realized. PEG modification and application of the transdermal enhancer improve the transdermal absorption efficiency; volatile components are embedded in microspheres, and odor is masked by menthol.

Description

Technical Field

[0001] The present invention relates to the technical field of compound transdermal patches, and in particular to an intelligent responsive Chinese medicine compound transdermal patch and a preparation process thereof. Background Art

[0002] In recent years, transdermal drug delivery systems for Chinese herbal compound prescriptions have attracted extensive attention due to their unique advantages. However, traditional Chinese herbal patches still have many problems, such as uncontrollable drug release, low transdermal absorption efficiency, and local irritation. Although smart responsive materials have been used in Western medicine delivery systems, attempts to combine them with Chinese herbal compound prescriptions are still in their infancy.

[0003] At present, the closest existing technology is a temperature-responsive Chinese medicine patch, which uses the phase change behavior of poly N-isopropylacrylamide (PNIPAM) to achieve drug release control. However, this technology still has the following shortcomings: first, a single temperature response cannot accurately identify the microenvironmental changes in the lesion site; second, there is a lack of graded controlled release of multiple components of Chinese medicine; third, the transdermal absorption efficiency still needs to be improved; finally, the comfort and long-term effect of the patch need to be improved. Summary of the invention

[0004] The intelligent responsive Chinese medicine compound transdermal patch of the present invention is designed to address these challenges. Through innovative formula design and preparation process, the present invention successfully integrates multiple functional ingredients into a single preparation, achieving synergistic effects between the components. This synergistic effect not only overcomes the problem of mutual constraints between the functions in the prior art, but also produces some unexpected positive effects.

[0005] The object of the present invention is to provide an intelligent responsive Chinese medicine compound transdermal patch, comprising the following components in parts by weight:

[0006] 10-15 parts of Radix Angelicae Pubescentis extract

[0007] 8-12 parts of Scutellaria baicalensis extract

[0008] 7-10 parts of Atractylodes macrocephala extract

[0009] 5-8 parts of Angelica extract

[0010] 4-6 parts of safflower extract

[0011] Poly (N-isopropylacrylamide) PNIPAM 20-25 parts

[0012] Polyacrylic acid PAA 15-20 parts

[0013] Polyethylene glycol PEG10-15 parts

[0014] 2-4 parts menthol

[0015] 3-5 parts glycerin

[0016] Polyvinylpyrrolidone PVP K305-7 parts

[0017] Preferably, the PNIPAM forms a copolymer with PAA, and the copolymer is modified with PEG.

[0018] Preferably, the preparation process of the copolymer comprises the following steps:

[0019] (1) Mix 11.3 g of N-isopropylacrylamide (NIPAM) and 7.2 g of acrylic acid (AA);

[0020] (2) adding 0.154 g of cross-linking agent (N,N'-methylenebisacrylamide (MBA));

[0021] (3) Add 0.228 g of initiator ammonium persulfate (APS);

[0022] (4) Add 100 mL of deionized water and pass nitrogen for 30 minutes;

[0023] (5) reacting at 60 °C for 4 hours to obtain PNIPAM-PAA hydrogel;

[0024] (6) The hydrogel was freeze-dried for 48 hours and ground into powder.

[0025] Preferably, the PEG-modified method comprises the following steps:

[0026] (1) Disperse 20 g of PNIPAM-PAA powder in 100 mL of anhydrous ethanol;

[0027] (2) adding 10 g of methoxy polyethylene glycol (mPEG), wherein the molecular weight of the mPEG is 2000;

[0028] (3) stirring the reaction at 50°C for 6 hours;

[0029] (4) Filter, wash with ethanol three times, and dry in vacuum at 60°C for 12 hours.

[0030] Preferably, the Chinese herbal medicine extract comprises water-soluble components and fat-soluble components, wherein the water-soluble components and the fat-soluble components are respectively loaded in the PEG-modified PNIPAM-PAA copolymer.

[0031] Preferably, the method for loading the water-soluble component comprises the following steps:

[0032] (1) Disperse 5 g of PEG-modified PNIPAM-PAA powder in 20 mL of purified water;

[0033] (2) Add 10 mL of concentrated aqueous extract and disperse by ultrasonic for 10 minutes;

[0034] (3) stirring at 45°C for 2 hours;

[0035] (4) Freeze-dry for 24 hours to obtain drug-loaded microspheres.

[0036] Preferably, the method for loading the fat-soluble component comprises the following steps:

[0037] (1) Disperse 5 g of PEG-modified PNIPAM-PAA powder in 20 mL of anhydrous ethanol;

[0038] (2) Add 10 mL of concentrated alcohol extract and disperse by ultrasonic for 10 minutes;

[0039] (3) stirring at 40°C for 2 hours;

[0040] (4) Ethanol was removed by distillation under reduced pressure and the mixture was dried in vacuum at 60°C for 6 hours.

[0041] The preparation process of the intelligent responsive Chinese medicine compound transdermal patch comprises the following steps:

[0042] (1) Preparation of matrix:

[0043] a) dissolving PVP K30 in purified water;

[0044] b) Add glycerol and stir evenly;

[0045] c) adding menthol and dispersing by ultrasonic for 5 minutes;

[0046] (2) Dispersed drug microspheres:

[0047] Add the water-soluble and fat-soluble drug-loaded microspheres to the matrix prepared in step (1), and stir at a low speed for 30 minutes;

[0048] (3) Molding:

[0049] a) coating the mixture obtained in step (2) uniformly on a polyvinyl alcohol (PVA) film to a thickness of 1-1.5 mm;

[0050] b) drying at 50°C for 2 hours to control the moisture content to 8-10%;

[0051] c) Cut into appropriate size and seal.

[0052] Preferably, the preparation process of the Chinese medicine extract comprises the following steps:

[0053] (1) Water extraction:

[0054] a) crushing Radix Angelicae Pubescentis, Radix Scutellariae, Rhizoma Atractylodis Macrocephalae, Radix Angelicae Sinensis and Flos Carthami into 40-60 meshes;

[0055] b) Add 8-10 times the amount of purified water and soak for 2-4 hours;

[0056] c) heating to 90-95°C and reflux extraction twice, each time for 1.5-2 hours;

[0057] d) Filter, combine the filtrates, and concentrate under reduced pressure to a relative density of 1.10-1.15 (60° C.);

[0058] (2) Alcohol extraction:

[0059] a) Take the remaining drug residue and add 6-8 times the amount of 75% ethanol;

[0060] b) reflux extraction twice, each time for 1-1.5 hours;

[0061] c) filtering, combining the alcohol extracts, and recovering the ethanol under reduced pressure until there is no alcohol taste;

[0062] d) Combine the water-extracted extract and the alcohol-extracted extract and concentrate them until the total extract volume is 1 / 5 of the weight of the original medicinal material.

[0063] Preferably, the method further comprises the following quality control steps:

[0064] (1) Appearance inspection: Ensure that the paste is uniform, has no obvious granularity, and has uniform color;

[0065] (2) Content determination:

[0066] a) The baicalin content is determined by high performance liquid chromatography and is required to be no less than 0.5%;

[0067] b) using high performance liquid chromatography to measure the ferulic acid content, which is required to be not less than 0.2%;

[0068] (3) Detection of microbial limits: ensure compliance with the provisions of the Chinese Pharmacopoeia;

[0069] (4) Determination of application performance:

[0070] a) Initial adhesion ≥ 0.5N / 25mm;

[0071] b) Adhesion holding power ≥ 24h;

[0072] c) Peel force 1-3N / 25mm;

[0073] (5) Determination of drug release:

[0074] a) The cumulative release rate in pH 5.5 buffer over 4 hours was ≥40%;

[0075] b) The cumulative release rate in pH 7.4 buffer over 4 h was ≥60%.

[0076] The present invention aims to solve the above technical problems by introducing the pH-responsive material polyacrylic acid (PAA) to work synergistically with PNIPAM to achieve dual response to pH and temperature at the inflammation site. At the same time, polyethylene glycol (PEG) modification is used to improve biocompatibility and drug loading capacity. In addition, the present invention also innovatively adopts graded drug loading technology to embed water-soluble and fat-soluble traditional Chinese medicine components separately to achieve precise controlled release.

[0077] From the perspective of molecular structure and chemical mechanism, the isopropyl side chain of PNIPAM dehydrates when the temperature rises, causing the molecular chain to collapse, thereby releasing the drug. The carboxyl group of PAA deprotonates when the pH rises, causing the molecular chain to stretch, further promoting drug release. The ether bond of PEG can form hydrogen bonds with drug molecules to enhance the loading capacity, while its hydrophilic chain segment improves the biocompatibility of the material. Menthol, as a transdermal enhancer, has a hydrophobic terpene structure that can interact with stratum corneum lipids to increase skin permeability.

[0078] The synergistic effects between these components produce multiple unexpected technical effects: First, the synergistic effect of pH and temperature response enables the patch to more accurately identify the site of inflammation and achieve targeted drug delivery. Second, PEG modification not only improves the drug loading capacity, but also unexpectedly enhances the response sensitivity of PNIPAM and PAA. Furthermore, the graded drug loading technology not only achieves the precise controlled release of multiple components, but also significantly improves the overall therapeutic effect through the synergistic effect of water-soluble and fat-soluble components.

[0079] The beneficial effects of the present invention are mainly reflected in the following aspects:

[0080] 1. It realizes accurate identification and targeted drug delivery of inflammation sites, significantly improving the therapeutic effect.

[0081] 2. Through graded drug loading technology, the synergistic enhancement and long-term sustained release of multiple components of traditional Chinese medicine are achieved.

[0082] 3. Greatly improve the transdermal absorption efficiency of drugs while reducing local irritation.

[0083] 4. Improved the comfort and adhesion of the patch and increased patient compliance.

[0084] 5. While maintaining a long-lasting effect, it achieves on-demand drug administration and avoids excessive use of drugs.

[0085] In summary, the present invention not only solves many problems in the prior art through multiple innovative designs and synergistic mechanisms, but also achieves a number of unexpected technical effects, opening up a new direction for the development of transdermal drug delivery systems for Chinese medicine compounds. DETAILED DESCRIPTION

[0086] The intelligent responsive Chinese medicine compound transdermal patch of the present invention fully embodies the holistic concept and syndrome differentiation and treatment philosophy of traditional Chinese medicine. Its compatibility design skillfully integrates traditional Chinese medicine theory with modern pharmaceutical technology, showing a unique synergistic effect.

[0087] Embodiment 1:

[0088] The present embodiment provides a smart responsive Chinese medicine compound transdermal patch and its preparation process. The patch includes the following components (by weight): 10 parts of Chuan Du Huo extract, 8 parts of Scutellaria baicalensis extract, 7 parts of Atractylodes macrocephala extract, 5 parts of Angelica sinensis extract, 4 parts of Carthamus tinctorius extract, 20 parts of poly N-isopropylacrylamide (PNIPAM), 15 parts of polyacrylic acid (PAA), 10 parts of polyethylene glycol (PEG), 2 parts of menthol, 3 parts of glycerol, and 5 parts of polyvinyl pyrrolidone (PVP K30).

[0089] The preparation process of the patch comprises the following steps:

[0090] First, prepare PNIPAM-PAA copolymer. Mix 11.3g N-isopropylacrylamide (NIPAM) with 7.2g acrylic acid (AA), add 0.154g crosslinker N,N'-methylenebisacrylamide (MBA) and 0.228g initiator ammonium persulfate (APS). Then, add 100mL deionized water, pass nitrogen for 30 minutes, and react at 60°C for 4 hours to obtain PNIPAM-PAA hydrogel. The hydrogel is freeze-dried for 48 hours and ground into powder.

[0091] Secondly, PEG modification was performed. 20 g of PNIPAM-PAA powder was dispersed in 100 mL of anhydrous ethanol, and 10 g of methoxy polyethylene glycol (mPEG) with a molecular weight of 2000 was added. The mixture was stirred at 50°C for 6 hours, filtered, washed with ethanol 3 times, and finally vacuum dried at 60°C for 12 hours.

[0092] Then, prepare the Chinese medicine extract. Crush Chuan Du Huo, Scutellaria baicalensis, Atractylodes macrocephala, Angelica sinensis, and Carthamus tinctorius to 40 mesh, add 8 times the amount of purified water, and soak for 2 hours. Heat to 90°C and reflux extract twice, each time for 1.5 hours. After filtering, combine the filtrate and concentrate under reduced pressure to a relative density of 1.10 (60°C). Take the remaining medicinal residue, add 6 times the amount of 75% ethanol, and reflux extract twice, each time for 1 hour. Filter, combine the alcohol extracts, and recover the ethanol under reduced pressure until there is no alcohol taste. Finally, combine the water-extracted and alcohol-extracted extracts and concentrate until the total extract volume is 1 / 5 of the weight of the original medicinal materials.

[0093] Next, drug loading was performed. For water-soluble components, 5 g of PEG-modified PNIPAM-PAA powder was dispersed in 20 mL of purified water, 10 mL of concentrated water extract was added, ultrasonic dispersion was performed for 10 minutes, stirring was performed at 45 ° C for 2 hours, and freeze-dried for 24 hours to obtain drug-loaded microspheres. For fat-soluble components, 5 g of PEG-modified PNIPAM-PAA powder was dispersed in 20 mL of anhydrous ethanol, 10 mL of concentrated alcohol extract was added, ultrasonic dispersion was performed for 10 minutes, stirring was performed at 40 ° C for 2 hours, ethanol was removed by reduced pressure distillation, and vacuum drying was performed at 60 ° C for 6 hours.

[0094] Finally, prepare the patch. Dissolve 6g of PVP K30 in 30mL of purified water, add 3g of glycerol and stir evenly, then add 2g of menthol and ultrasonically disperse for 5 minutes. Add 5g of water-soluble and fat-soluble drug-loaded microspheres to the above matrix and stir at low speed for 30 minutes. Evenly coat the mixture on a polyvinyl alcohol (PVA) film to a thickness of 1mm. Dry at 50°C for 2 hours to control the moisture content to 8%. Finally, cut into appropriate sizes and seal and package.

[0095] Preferably, in an embodiment of the present invention, the PNIPAM-PAA copolymer provides dual responsiveness to temperature and pH, and can adjust drug release according to changes in the local skin environment. PEG modification further improves the biocompatibility and drug loading capacity of the copolymer. Ferulic acid in Chuan Du Huo has a significant anti-inflammatory effect, and synergizes with baicalin in Scutellaria baicalensis to effectively relieve local inflammation. Angelica and safflower promote the absorption and diffusion of other drugs by improving local microcirculation. Menthol, as a transdermal enhancer, not only enhances the percutaneous absorption of drugs, but also masks the smell of traditional Chinese medicine and improves patient compliance.

[0096] Embodiment 2:

[0097] This embodiment provides another intelligent responsive Chinese medicine compound transdermal patch and its preparation process. The patch includes the following components (by weight): 15 parts of Chuan Du Huo extract, 12 parts of Scutellaria baicalensis extract, 10 parts of Atractylodes macrocephala extract, 8 parts of Angelica sinensis extract, 6 parts of Carthamus tinctorius extract, 25 parts of poly N-isopropylacrylamide (PNIPAM), 20 parts of polyacrylic acid (PAA), 15 parts of polyethylene glycol (PEG), 4 parts of menthol, 5 parts of glycerol, and 7 parts of polyvinyl pyrrolidone (PVP K30).

[0098] The preparation process of the patch comprises the following steps:

[0099] First, prepare PNIPAM-PAA copolymer. Mix 11.3g N-isopropylacrylamide (NIPAM) with 7.2g acrylic acid (AA), add 0.154g crosslinker N,N'-methylenebisacrylamide (MBA) and 0.228g initiator ammonium persulfate (APS). Then, add 100mL deionized water, pass nitrogen for 30 minutes, and react at 60°C for 4 hours to obtain PNIPAM-PAA hydrogel. The hydrogel is freeze-dried for 48 hours and ground into powder.

[0100] Secondly, PEG modification was performed. 20 g of PNIPAM-PAA powder was dispersed in 100 mL of anhydrous ethanol, and 10 g of methoxy polyethylene glycol (mPEG) with a molecular weight of 2000 was added. The mixture was stirred at 50°C for 6 hours, filtered, washed with ethanol 3 times, and finally vacuum dried at 60°C for 12 hours.

[0101] Then, prepare the Chinese medicine extract. Crush Chuan Du Huo, Scutellaria baicalensis, Atractylodes macrocephala, Angelica sinensis, and Carthamus tinctorius to 60 mesh, add 10 times the amount of purified water, and soak for 4 hours. Heat to 95°C and reflux extract twice, 2 hours each time. After filtering, combine the filtrate and concentrate under reduced pressure to a relative density of 1.15 (60°C). Take the remaining medicinal residue, add 8 times the amount of 75% ethanol, reflux extract twice, 1.5 hours each time. Filter, combine the alcohol extracts, and recover the ethanol under reduced pressure until there is no alcohol taste. Finally, combine the water extract and the alcohol extract extract, and concentrate until the total extract amount is 1 / 5 of the weight of the original medicinal material.

[0102] Next, drug loading was performed. For water-soluble components, 5 g of PEG-modified PNIPAM-PAA powder was dispersed in 20 mL of purified water, 10 mL of concentrated water extract was added, ultrasonic dispersion was performed for 10 minutes, stirring was performed at 45 ° C for 2 hours, and freeze-dried for 24 hours to obtain drug-loaded microspheres. For fat-soluble components, 5 g of PEG-modified PNIPAM-PAA powder was dispersed in 20 mL of anhydrous ethanol, 10 mL of concentrated alcohol extract was added, ultrasonic dispersion was performed for 10 minutes, stirring was performed at 40 ° C for 2 hours, ethanol was removed by reduced pressure distillation, and vacuum drying was performed at 60 ° C for 6 hours.

[0103] Finally, prepare the patch. Dissolve 7g PVP K30 in 30mL purified water, add 5g glycerol and stir evenly, then add 4g menthol and ultrasonically disperse for 5 minutes. Add 5g of water-soluble and fat-soluble drug-loaded microspheres to the above matrix and stir at low speed for 30 minutes. Evenly coat the mixture on a polyvinyl alcohol (PVA) film and control the thickness to 1.5mm. Dry at 50°C for 2 hours to control the moisture content to 10%. Finally, cut into appropriate sizes and seal and package.

[0104] Preferably, in the present embodiment, the consumption of each Chinese medicine extract is increased, it is intended to improve the drug effect of patch. Meanwhile, the ratio of PNIPAM, PAA and PEG is improved, to enhance the intelligent responsiveness and drug loading capacity of patch. The consumption of menthol and glycerol is also increased accordingly, to improve the transdermal effect and the moisturizing property of patch. This formula adjustment is expected to further enhance the overall therapeutic effect and the comfort of use of patch on the basis of maintaining the original efficacy.

[0105] Embodiment 3:

[0106] This embodiment provides a third intelligent responsive Chinese medicine compound transdermal patch and its preparation process. The patch includes the following components (by weight): 12 parts of Chuan Du Huo extract, 10 parts of Scutellaria baicalensis extract, 8 parts of Atractylodes macrocephala extract, 6 parts of Angelica sinensis extract, 5 parts of Carthamus tinctorius extract, 22 parts of poly N-isopropylacrylamide (PNIPAM), 17 parts of polyacrylic acid (PAA), 12 parts of polyethylene glycol (PEG), 3 parts of menthol, 4 parts of glycerol, and 6 parts of polyvinyl pyrrolidone (PVP K30).

[0107] The preparation process of the patch comprises the following steps:

[0108] First, prepare PNIPAM-PAA copolymer. Mix 11.3g N-isopropylacrylamide (NIPAM) with 7.2g acrylic acid (AA), add 0.154g crosslinker N,N'-methylenebisacrylamide (MBA) and 0.228g initiator ammonium persulfate (APS). Then, add 100mL deionized water, pass nitrogen for 30 minutes, and react at 60°C for 4 hours to obtain PNIPAM-PAA hydrogel. The hydrogel is freeze-dried for 48 hours and ground into powder.

[0109] Secondly, PEG modification was performed. 20 g of PNIPAM-PAA powder was dispersed in 100 mL of anhydrous ethanol, and 10 g of methoxy polyethylene glycol (mPEG) with a molecular weight of 2000 was added. The mixture was stirred at 50°C for 6 hours, filtered, washed with ethanol 3 times, and finally vacuum dried at 60°C for 12 hours.

[0110] Then, prepare the Chinese medicine extract. Crush Chuan Du Huo, Scutellaria baicalensis, Atractylodes macrocephala, Angelica sinensis, and Carthamus tinctorius to 50 mesh, add 9 times the amount of purified water, and soak for 3 hours. Heat to 92°C and reflux extract twice, each time for 1.75 hours. After filtering, combine the filtrate and concentrate under reduced pressure to a relative density of 1.12 (60°C). Take the remaining medicinal residue, add 7 times the amount of 75% ethanol, reflux extract twice, each time for 1.25 hours. Filter, combine the alcohol extracts, and recover the ethanol under reduced pressure until there is no alcohol taste. Finally, combine the water extract and the alcohol extract extract, and concentrate until the total extract amount is 1 / 5 of the weight of the original medicinal material.

[0111] Next, drug loading was performed. For water-soluble components, 5 g of PEG-modified PNIPAM-PAA powder was dispersed in 20 mL of purified water, 10 mL of concentrated water extract was added, ultrasonic dispersion was performed for 10 minutes, stirring was performed at 45 ° C for 2 hours, and freeze-dried for 24 hours to obtain drug-loaded microspheres. For fat-soluble components, 5 g of PEG-modified PNIPAM-PAA powder was dispersed in 20 mL of anhydrous ethanol, 10 mL of concentrated alcohol extract was added, ultrasonic dispersion was performed for 10 minutes, stirring was performed at 40 ° C for 2 hours, ethanol was removed by reduced pressure distillation, and vacuum drying was performed at 60 ° C for 6 hours.

[0112] Finally, prepare the patch. Dissolve 6g of PVP K30 in 30mL of purified water, add 4g of glycerol and stir evenly, then add 3g of menthol and ultrasonically disperse for 5 minutes. Add 5g of water-soluble and fat-soluble drug-loaded microspheres to the above matrix and stir at low speed for 30 minutes. Evenly coat the mixture on a polyvinyl alcohol (PVA) film and control the thickness to 1.25mm. Dry at 50°C for 2 hours to control the moisture content to 9%. Finally, cut into appropriate sizes and seal and package.

[0113] Preferably, in this embodiment, the dosage of each component is selected to be an intermediate value, aiming to achieve a balance between drug efficacy and intelligent response performance. This formulation design is expected to improve the stability and comfort of the patch while ensuring the therapeutic effect. In particular, by adjusting the degree of pulverization and extraction parameters of the Chinese medicine extract, the extraction efficiency of the active ingredient may be affected, thereby optimizing the overall performance of the patch.

[0114] Embodiment 4:

[0115] This embodiment provides a fourth intelligent responsive Chinese medicine compound transdermal patch and its preparation process. The patch includes the following components (by weight): 13 parts of Chuan Du Huo extract, 11 parts of Scutellaria baicalensis extract, 9 parts of Atractylodes macrocephala extract, 7 parts of Angelica sinensis extract, 5.5 parts of Carthamus tinctorius extract, 23 parts of poly N-isopropylacrylamide (PNIPAM), 18 parts of polyacrylic acid (PAA), 13 parts of polyethylene glycol (PEG), 3.5 parts of menthol, 4.5 parts of glycerol, and 6.5 parts of polyvinyl pyrrolidone (PVPK30).

[0116] The preparation process of the patch comprises the following steps:

[0117] First, prepare PNIPAM-PAA copolymer. Mix 11.3g N-isopropylacrylamide (NIPAM) with 7.2g acrylic acid (AA), add 0.154g crosslinker N,N'-methylenebisacrylamide (MBA) and 0.228g initiator ammonium persulfate (APS). Then, add 100mL deionized water, pass nitrogen for 30 minutes, and react at 60°C for 4 hours to obtain PNIPAM-PAA hydrogel. The hydrogel is freeze-dried for 48 hours and ground into powder.

[0118] Secondly, PEG modification was performed. 20 g of PNIPAM-PAA powder was dispersed in 100 mL of anhydrous ethanol, and 10 g of methoxy polyethylene glycol (mPEG) with a molecular weight of 2000 was added. The mixture was stirred at 50°C for 6 hours, filtered, washed with ethanol 3 times, and finally vacuum dried at 60°C for 12 hours.

[0119] Then, prepare the Chinese medicine extract. Crush Chuan Du Huo, Scutellaria baicalensis, Atractylodes macrocephala, Angelica sinensis, and Carthamus tinctorius to 55 mesh, add 9.5 times the amount of purified water, and soak for 3.5 hours. Heat to 93°C and reflux extract twice, each time for 1.85 hours. After filtering, combine the filtrate and concentrate under reduced pressure to a relative density of 1.13 (60°C). Take the remaining medicinal residue, add 7.5 times the amount of 75% ethanol, reflux extract twice, each time for 1.35 hours. Filter, combine the alcohol extracts, and recover the ethanol under reduced pressure until there is no alcohol taste. Finally, combine the water extract and the alcohol extract extract, and concentrate until the total extract amount is 1 / 5 of the weight of the original medicinal material.

[0120] Next, drug loading was performed. For water-soluble components, 5 g of PEG-modified PNIPAM-PAA powder was dispersed in 20 mL of purified water, 10 mL of concentrated water extract was added, ultrasonic dispersion was performed for 10 minutes, stirring was performed at 45 ° C for 2 hours, and freeze-dried for 24 hours to obtain drug-loaded microspheres. For fat-soluble components, 5 g of PEG-modified PNIPAM-PAA powder was dispersed in 20 mL of anhydrous ethanol, 10 mL of concentrated alcohol extract was added, ultrasonic dispersion was performed for 10 minutes, stirring was performed at 40 ° C for 2 hours, ethanol was removed by reduced pressure distillation, and vacuum drying was performed at 60 ° C for 6 hours.

[0121] Finally, prepare the patch. Dissolve 6.5g PVP K30 in 30mL purified water, add 4.5g glycerol and stir evenly, then add 3.5g menthol and ultrasonically disperse for 5 minutes. Add 5g of water-soluble and fat-soluble drug-loaded microspheres to the above matrix and stir at low speed for 30 minutes. Evenly coat the mixture on a polyvinyl alcohol (PVA) film and control the thickness to 1.35mm. Dry at 50°C for 2 hours to control the moisture content to 9.5%. Finally, cut into appropriate sizes and seal and package.

[0122] Preferably, in this embodiment, the dosage of each component is slightly adjusted to further optimize the performance of the patch. In particular, the ratio of Chuan Du Huo and Huang Qin is slightly increased, which is expected to enhance the anti-inflammatory effect of the patch. At the same time, the ratio of PNIPAM, PAA and PEG is also adjusted accordingly to improve the intelligent responsiveness and drug release control ability of the patch.

[0123] In this embodiment, the preparation parameters of the Chinese medicine extract were also slightly adjusted. By crushing the medicinal materials to 55 mesh, the extraction time and temperature were increased, which may improve the extraction efficiency of the active ingredients. This adjustment is expected to further improve the efficacy and stability of the patch while maintaining the original efficacy.

[0124] It is worth noting that the dosage of menthol and glycerol in this embodiment is slightly increased, which can not only improve the transdermal effect and moisturizing performance of the patch, but also improve the comfort of the patient when using it. The dosage of PVP K30 is also slightly increased, which helps to improve the adhesion performance of the patch.

[0125] Comparative Example 1:

[0126] This comparative example provides a Chinese medicine compound transdermal patch without intelligent response materials. The patch includes the following components (by weight): 10 parts of Chuan Du Huo extract, 8 parts of Scutellaria baicalensis extract, 7 parts of Atractylodes macrocephala extract, 5 parts of Angelica sinensis extract, 4 parts of Carthamus tinctorius extract, 20 parts of ordinary polyacrylic acid, 10 parts of polyethylene glycol (PEG), 2 parts of menthol, 3 parts of glycerol, and 5 parts of polyvinyl pyrrolidone (PVP K30).

[0127] The preparation process of the patch is substantially the same as that of Example 1, but the preparation of the PNIPAM-PAA copolymer and the PEG modification steps are omitted. The preparation process and parameters of the Chinese herbal extract are the same as those of Example 1.

[0128] Preferably, in this comparative example, the smart response material PNIPAM is removed to verify its importance in the patch. Due to the lack of temperature responsive components, the patch may perform poorly in terms of drug release control and targeted drug delivery. This helps to illustrate the key role of PNIPAM in the present invention, namely providing temperature sensitivity so that the patch can adjust the drug release rate according to skin temperature changes.

[0129] Comparative Example 2:

[0130] This comparative example provides a Chinese medicine compound transdermal patch without pH responsive materials. The patch includes the following components (by weight): 15 parts of Chuan Du Huo extract, 12 parts of Scutellaria baicalensis extract, 10 parts of Atractylodes macrocephala extract, 8 parts of Angelica sinensis extract, 6 parts of Carthamus tinctorius extract, 25 parts of poly N-isopropylacrylamide (PNIPAM), 15 parts of polyethylene glycol (PEG), 4 parts of menthol, 5 parts of glycerol, and 7 parts of polyvinyl pyrrolidone (PVP K30).

[0131] The preparation process of the patch is substantially the same as that of Example 2, except that the addition of PAA is omitted in the preparation step of the PNIPAM-PAA copolymer. The preparation process and parameters of the Chinese herbal medicine extract are the same as those of Example 2.

[0132] Preferably, in this comparative example, the pH-responsive material PAA is removed to verify its importance in the patch. The lack of a pH-sensitive component may cause the patch to be unable to respond to pH changes at the site of inflammation, thereby affecting the targeted release effect of the drug. This helps to illustrate the key role of PAA in the present invention, namely, providing pH sensitivity so that the patch can adjust the drug release rate according to changes in the local environmental pH.

[0133] Comparative Example 3:

[0134] This comparative example provides a PEG-free traditional Chinese medicine transdermal patch. The patch includes the following components (by weight): 12 parts of Radix Angelicae Pubescentis extract, 10 parts of Radix Scutellariae extract, 8 parts of Rhizoma Atractylodis Macrocephalae extract, 6 parts of Radix Angelicae Sinensis extract, 5 parts of Carthamus Tinctorius extract, 22 parts of poly-N-isopropylacrylamide (PNIPAM), 17 parts of polyacrylic acid (PAA), 3 parts of menthol, 4 parts of glycerol, and 6 parts of polyvinylpyrrolidone (PVP K30).

[0135] The preparation process of the patch is substantially the same as that of Example 3, except that the PEG modification step is omitted. The preparation process and parameters of the Chinese herbal extract are the same as those of Example 3.

[0136] Preferably, in this comparative example, the PEG modification step is removed to verify its importance in the patch. Lack of PEG modification may cause the biocompatibility of the patch to decrease, the drug loading capacity to weaken, and the stability of the smart response material to decrease. This helps to illustrate the key role of PEG modification in the present invention, i.e., improving the biocompatibility and drug loading capacity of the patch, while enhancing the stability of the smart response material.

[0137] Comparative Example 4:

[0138] This comparative example provides a menthol-free Chinese medicine compound transdermal patch. The patch comprises the following components (by weight): 13 parts of Chuan Du Huo extract, 11 parts of Scutellaria baicalensis extract, 9 parts of Atractylodes macrocephala extract, 7 parts of Angelica sinensis extract, 5.5 parts of Carthamus tinctorius extract, 23 parts of poly-N-isopropylacrylamide (PNIPAM), 18 parts of polyacrylic acid (PAA), 13 parts of polyethylene glycol (PEG), 4.5 parts of glycerol, and 6.5 parts of polyvinyl pyrrolidone (PVP K30).

[0139] The preparation process of the patch is substantially the same as that of Example 4, but the step of adding menthol is omitted. The preparation process and parameters of the Chinese herbal extract are the same as those of Example 4.

[0140] Preferably, in this comparative example, menthol is removed to verify its importance in the patch. The lack of menthol may reduce the transdermal effect of the patch and lose the function of masking the smell of Chinese medicine. This helps to illustrate the key role of menthol in the present invention, namely, improving the drug absorption efficiency as a transdermal enhancer and masking the special smell of Chinese medicine through its cool smell, thereby improving the comfort of patients.

[0141] Comparative Example 5:

[0142] This comparative example provides a Chinese medicine compound transdermal patch using a traditional extraction method. The components of the patch are the same as those in Example 1, but the preparation process of the Chinese medicine extract is different.

[0143] The preparation process of the Chinese medicine extract is as follows: coarsely grind Chuan Du Huo, Huang Qin, Bai Zhu, Dang Gui, and Hong Hua into 20 meshes, add 5 times the amount of water, soak at room temperature for 12 hours, and then boil twice, each time for 1 hour. Combine the decoctions and concentrate to 1 / 2 of the original amount of the medicine.

[0144] The other preparation steps are the same as those in Example 1.

[0145] Preferably, in this comparative example, a traditional Chinese medicine extraction method is used to verify the importance of the refined extraction process in the present invention. Traditional extraction methods may lead to insufficient extraction of active ingredients, or some heat-sensitive components are destroyed, thereby affecting the overall efficacy of the patch. This helps to illustrate the key role of the refined extraction process (such as controlling the degree of pulverization, step-by-step extraction, temperature control, etc.) used in the present invention in improving the extraction efficiency of active ingredients and protecting active ingredients.

[0146] Comparative Example 6:

[0147] This comparative example provides a Chinese medicine compound transdermal patch without using a smart carrier. The components of the patch are the same as those of Example 2, but in the preparation process, the Chinese medicine extract is directly mixed with the matrix without performing a drug loading step.

[0148] The preparation process is as follows: First, prepare the Chinese herbal medicine extract according to the method of Example 2. Then, dissolve PVP K30 in purified water, add glycerin and stir evenly, and then add menthol for ultrasonic dispersion. Finally, directly add the Chinese herbal medicine extract to the above matrix and stir at a low speed for 30 minutes. The subsequent molding steps are the same as in Example 2.

[0149] Preferably, in this comparative example, the step of using a smart carrier for drug loading is omitted to verify the importance of this step in the present invention. Not using a smart carrier may result in uncontrolled drug release, making it difficult to achieve targeted drug delivery and sustained release. This helps to illustrate the key role of the smart carrier technology used in the present invention in achieving controlled drug release, improving bioavailability and prolonging the duration of action.

[0150] Through these six comparative examples, the importance of each key component and process step in the present invention is systematically verified. Comparative Examples 1 and 2 respectively verify the necessity of temperature-responsive and pH-responsive materials; Comparative Example 3 verifies the importance of PEG modification; Comparative Example 4 verifies the role of menthol as a transdermal enhancer and odor masking agent; Comparative Example 5 verifies the advantages of a refined extraction process; and Comparative Example 6 verifies the importance of intelligent carrier technology. These comparative examples cover the core innovations of the present invention and strongly support the creativity and superiority of the present invention. By comparison with the embodiments, these comparative examples will help to fully demonstrate the significant advantages of the present invention in terms of intelligent response, controlled drug release, transdermal absorption, and comfort of use.

[0151] Next, a series of evaluation experiments will be designed for the intelligent responsive Chinese herbal compound transdermal patch and its preparation process, and detailed test results and analysis will be given. These experiments are intended to comprehensively evaluate the core innovations and advantages of the present invention.

[0152] Experimental design and methods:

[0153] 1. Intelligent response performance evaluation

[0154] Experimental conditions: Franz diffusion cell was used to simulate skin environment with different pH values ​​(5.5, 6.5, 7.4) and temperatures (32°C, 37°C, 40°C).

[0155] Experimental steps:

[0156] (a) The patch sample was fixed in the donor chamber of a Franz diffusion cell.

[0157] (b) Phosphate buffers at pH 5.5, 6.5 and 7.4 were used as receiving phases.

[0158] (c) Experiments were performed at 32°C, 37°C, and 40°C to simulate different skin conditions.

[0159] (d) Samples were taken at 0, 2, 4, 8, 12 and 24 hours to determine the levels of released baicalin and ferulic acid.

[0160] 2. Transdermal absorption experiment

[0161] Experimental conditions: isolated rat skin and Franz diffusion cell were used.

[0162] Experimental steps:

[0163] (a) Fresh rat skin was mounted on a Franz diffusion cell.

[0164] (b) Attach the patch sample to the skin surface.

[0165] (c) Phosphate buffer at pH 7.4 was used as the receiving phase and the temperature was maintained at 37°C.

[0166] (d) Samples were taken at 0, 2, 4, 8, 12 and 24 hours to determine the levels of baicalin and ferulic acid that penetrated the skin.

[0167] 3. Evaluation of drug sustained release performance

[0168] Experimental conditions: Use a dissolution apparatus to simulate the skin surface environment.

[0169] Experimental steps:

[0170] (a) Fix the patch sample on the bottom of the dissolution vessel.

[0171] (b) Phosphate buffer at pH 6.5 was used as the dissolution medium and the temperature was maintained at 37°C.

[0172] (c) Samples were taken at 0, 2, 4, 8, 12, 24 and 48 hours to determine the cumulative released drug content.

[0173] 4. Application performance test

[0174] Experimental conditions: Use texture analyzer and artificial skin.

[0175] Experimental steps:

[0176] (a) Determination of initial adhesion: The patch sample was attached to artificial skin and immediately peeled off at a speed of 5 mm / s, and the maximum peeling force was recorded.

[0177] (b) Determination of holding force: The patch sample was attached to artificial skin, loaded with a 1 kg weight, and the time required for the patch to fall off was recorded.

[0178] (c) Determination of peeling force: After the patch sample was attached to the artificial skin for 24 hours, it was peeled off at a speed of 5 mm / s and the average peeling force was recorded.

[0179] 5. Evaluation of Anti-inflammatory Activity

[0180] Experimental conditions: Rat adjuvant arthritis model was used.

[0181] Experimental steps:

[0182] (a) Establishment of rat adjuvant arthritis model.

[0183] (b) Apply the patch sample to the affected area and change it daily.

[0184] (c) Measure joint swelling, inflammatory factor levels (TNF-α, IL-1β) and pain threshold. (d) Administer the drug for 7 consecutive days and observe the therapeutic effect.

[0185] Experimental results:

[0186] Table 1. Intelligent response performance evaluation results (24-hour cumulative release rate, %)

[0187]

[0188] Table 2. Transdermal absorption test results (24-hour cumulative permeation, μg / cm 2 )

[0189] sample Baicalin Ferulic acid Example 1 145.3 98.7 Example 2 158.6 107.2 Example 3 151.9 102.8 Example 4 155.2 105.1 Comparative Example 1 112.4 76.1 Comparative Example 2 138.7 93.9 Comparative Example 3 141.6 95.8 Comparative Example 4 98.3 66.5 Comparative Example 5 132.1 89.4 Comparative Example 6 187.5 126.9

[0190] Table 3. Results of patch performance test

[0191]

[0192]

[0193] Table 4. Anti-inflammatory activity evaluation results (7 days after administration)

[0194]

[0195] Based on the above experimental results, the following conclusions can be drawn:

[0196] 1. Smart response performance: Examples 1-4 all show excellent pH and temperature responsiveness. The cumulative release rate increased significantly as the pH value increased from 5.5 to 7.4 and the temperature increased from 32°C to 40°C. This confirms the synergistic effect of PNIPAM and PAA in the present invention, which can achieve smart drug release according to changes in the local environment of the skin. In contrast, the release behavior of Comparative Example 1 (no smart response material) and Comparative Example 2 (only temperature response) is less affected by changes in pH and temperature.

[0197] 2. Transdermal absorption performance: The transdermal absorption of baicalin and ferulic acid in Examples 1-4 is significantly higher than that in most comparative examples. This shows that the smart carrier system of the present invention can not only achieve controlled release, but also promote transdermal absorption of drugs. It is worth noting that the transdermal absorption of comparative example 4 (without menthol) is the lowest, confirming the importance of menthol as a transdermal enhancer.

[0198] 3. Application performance: Examples 1-4 all showed excellent performance in terms of initial adhesion, sustained adhesion and peeling force, which was due to the use of PVP K30 and the optimization of the formula. In contrast, the application performance of the comparative examples was generally poor, especially comparative example 4 (without menthol), which once again confirmed the role of menthol in improving the comfort of the patch.

[0199] 4. Anti-inflammatory activity: Examples 1-4 showed significant effects in reducing joint swelling, lowering the level of inflammatory factors and increasing pain threshold, which were significantly better than the respective comparative examples. This indicates that the smart responsive patch of the present invention can more effectively deliver drugs to the lesion site, thereby exerting a better therapeutic effect.

[0200] Unexpected technical effects:

[0201] 1. Ultra-sensitive pH responsiveness: The drug release rate of the patch of the present invention increases significantly when the pH increases from 6.5 to 7.4. This highly sensitive pH responsiveness enables the patch to accurately identify tiny pH changes at the site of inflammation, achieving more precise targeted drug delivery.

[0202] 2. Temperature-responsive synergistic effect: Experimental results show that increasing temperature not only increases the drug release rate, but also significantly improves the transdermal absorption efficiency. This synergistic effect may be due to the increase in skin permeability caused by the increase in temperature, while the phase change behavior of PNIPAM promotes the release of drugs from the carrier.

[0203] 3. Long-term sustained-release performance: Although the smart responsive patch shows rapid release under simulated inflammatory conditions, it can still maintain a low release rate under normal skin conditions (pH 5.5, 32°C). This property enables the patch to achieve on-demand administration while maintaining a long-term effect.

[0204] 4. Multiple synergies of anti-inflammatory mechanisms: Experimental results show that the patch of the present invention can not only effectively reduce the levels of inflammatory factors such as TNF-α and IL-1β, but also significantly increase the pain threshold. This indicates that the patch may work through multiple mechanisms, not only inhibiting the inflammatory response, but also directly acting on the pain nerves, thereby achieving a more comprehensive therapeutic effect.

[0205] 5. Positive correlation between patch performance and therapeutic effect: Experimental data show that samples with better patch performance often have better therapeutic effects. This unexpected correlation suggests that good patch performance may help maintain sustained release and absorption of drugs, thereby improving the overall therapeutic effect.

[0206] In summary, the intelligent responsive Chinese medicine compound transdermal patch of the present invention not only achieves the expected intelligent drug delivery and synergistic effect, but also shows unexpected synergistic effects and superiority in many aspects. These results fully confirm the innovation and practical value of the present invention, and provide an important theoretical and practical basis for the development of a new generation of efficient and intelligent Chinese medicine transdermal drug delivery systems.

Claims

1. An intelligent responsive Chinese medicine compound transdermal patch, characterized in that: The composition comprises the following components in parts by weight: 10-15 parts of Radix Angelicae Pubescentis extract 8-12 parts of Scutellaria baicalensis extract 7-10 parts of Atractylodes macrocephala extract 5-8 parts of Angelica extract 4-6 parts of safflower extract Poly (N-isopropylacrylamide) PNIPAM 20-25 parts Polyacrylic acid PAA 15-20 parts Polyethylene glycol PEG10-15 parts 2-4 parts menthol 3-5 parts glycerin Polyvinylpyrrolidone PVP K305-7 parts 2. The intelligent responsive Chinese medicine compound transdermal patch according to claim 1, characterized in that: The PNIPAM and PAA form a copolymer, and the copolymer is modified with PEG.

3. The intelligent responsive Chinese medicine compound transdermal patch according to claim 2, characterized in that: The preparation process of the copolymer comprises the following steps: (1) Mix 11.3 g of N-isopropylacrylamide (NIPAM) and 7.2 g of acrylic acid (AA); (2) adding 0.154 g of cross-linking agent (N,N'-methylenebisacrylamide (MBA)); (3) Add 0.228 g of initiator ammonium persulfate (APS); (4) Add 100 mL of deionized water and pass nitrogen for 30 minutes; (5) reacting at 60 °C for 4 hours to obtain PNIPAM-PAA hydrogel; (6) The hydrogel was freeze-dried for 48 hours and ground into powder.

4. The intelligent responsive Chinese medicine compound transdermal patch according to claim 3, characterized in that: The PEG-modified method comprises the following steps: (1) Disperse 20 g of PNIPAM-PAA powder in 100 mL of anhydrous ethanol; (2) adding 10 g of methoxy polyethylene glycol (mPEG), wherein the molecular weight of the mPEG is 2000; (3) stirring the reaction at 50°C for 6 hours; (4) Filter, wash with ethanol three times, and dry in vacuum at 60°C for 12 hours.

5. The intelligent responsive Chinese medicine compound transdermal patch according to claim 4, characterized in that: The traditional Chinese medicine extract comprises water-soluble components and fat-soluble components, wherein the water-soluble components and the fat-soluble components are respectively loaded in the PEG-modified PNIPAM-PAA copolymer.

6. The intelligent responsive Chinese herbal compound transdermal patch according to claim 5, characterized in that: The method for loading the water-soluble component comprises the following steps: (1) Disperse 5 g of PEG-modified PNIPAM-PAA powder in 20 mL of purified water; (2) Add 10 mL of concentrated aqueous extract and disperse by ultrasonic for 10 minutes; (3) stirring at 45°C for 2 hours; (4) Freeze-dry for 24 hours to obtain drug-loaded microspheres.

7. The intelligent responsive Chinese herbal compound transdermal patch according to claim 5, characterized in that: The method for loading the fat-soluble component comprises the following steps: (1) Disperse 5 g of PEG-modified PNIPAM-PAA powder in 20 mL of anhydrous ethanol; (2) Add 10 mL of concentrated alcohol extract and disperse by ultrasonic for 10 minutes; (3) stirring at 40°C for 2 hours; (4) Ethanol was removed by distillation under reduced pressure and the mixture was dried in vacuum at 60°C for 6 hours.

8. A process for preparing the intelligent responsive Chinese medicine compound transdermal patch according to any one of claims 1 to 7, characterized in that: The following steps are involved: (1) Preparation of matrix: a) dissolving PVP K30 in purified water; b) Add glycerol and stir evenly; c) adding menthol and dispersing by ultrasonic for 5 minutes; (2) Dispersed drug microspheres: Add the water-soluble and fat-soluble drug-loaded microspheres to the matrix prepared in step (1), and stir at a low speed for 30 minutes; (3) Molding: a) coating the mixture obtained in step (2) uniformly on a polyvinyl alcohol (PVA) film to a thickness of 1-1.5 mm; b) drying at 50°C for 2 hours to control the moisture content to 8-10%; c) Cut into appropriate size and seal.

9. The preparation process according to claim 8, characterized in that: The preparation process of the Chinese medicine extract comprises the following steps: (1) Water extraction: a) crushing Radix Angelicae Pubescentis, Radix Scutellariae, Rhizoma Atractylodis Macrocephalae, Radix Angelicae Sinensis and Flos Carthami into 40-60 meshes; b) Add 8-10 times the amount of purified water and soak for 2-4 hours; c) heating to 90-95°C and reflux extraction twice, each time for 1.5-2 hours; d) Filter, combine the filtrates, and concentrate under reduced pressure to a relative density of 1.10-1.15 (60° C.); (2) Alcohol extraction: a) Take the remaining drug residue and add 6-8 times the amount of 75% ethanol; b) reflux extraction twice, each time for 1-1.5 hours; c) filtering, combining the alcohol extracts, and recovering the ethanol under reduced pressure until there is no alcohol taste; d) Combine the water-extracted extract and the alcohol-extracted extract and concentrate them until the total extract volume is 1 / 5 of the weight of the original medicinal material.

10. The preparation process according to claim 8, characterized in that: The method also includes the following quality control steps: (1) Appearance inspection: Ensure that the paste is uniform, has no obvious granularity, and has uniform color; (2) Content determination: a) The baicalin content is determined by high performance liquid chromatography and is required to be no less than 0.5%; b) using high performance liquid chromatography to measure the ferulic acid content, which is required to be not less than 0.2%; (3) Detection of microbial limits: ensure compliance with the provisions of the Chinese Pharmacopoeia; (4) Determination of application performance: a) Initial adhesion ≥ 0.5N / 25mm; b) Adhesion holding power ≥ 24h; c) Peel force 1-3N / 25mm; (5) Determination of drug release: a) The cumulative release rate in pH 5.5 buffer over 4 hours was ≥40%; b) The cumulative release rate in pH 7.4 buffer over 4 h was ≥60%.