Traditional Chinese medicine transdermal patch capable of relieving abdominal distension and promoting appetite and preparation method

Abstract

The invention belongs to the technical field of traditional Chinese medicine preparations, and particularly relates to a traditional Chinese medicine transdermal patch capable of relieving abdominal distension and promoting appetite and a preparation method. The traditional Chinese medicine transdermal patch is prepared from acrylate pressure-sensitive adhesive, traditional Chinese medicine extracts, a transdermal enhancer and glycerol, wherein the traditional Chinese medicine extracts are prepared from 16 traditional Chinese medicines such as oriental wormwood, semen cassiae, rheum officinale and rhizoma alismatis; an external dosage form is researched and developed on the basis of a stagnation eliminating and liver nourishing prescription, the burden of an oral preparation on gastrointestinal tracts is avoided, and the traditional Chinese medicine composition is suitable for fatty liver patients accompanied by abdominal distension and anorexia. Through the synergistic effect of the transdermal enhancer, the transdermal absorption efficiency and skin retention volume of the traditional Chinese medicine active ingredients can be enhanced, the effects of treating fatty liver, relieving abdominal distension and promoting appetite are achieved, and an external treatment choice with good compliance is provided for clinic.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine preparation technology, specifically relating to a transdermal patch of traditional Chinese medicine that can relieve abdominal distension and promote appetite, and its preparation method. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Fatty liver disease refers to a pathological condition characterized by excessive fat deposition in the liver. It is generally classified into alcoholic fatty liver disease and non-alcoholic fatty liver disease. Non-alcoholic fatty liver disease refers to fat deposition unrelated to excessive alcohol consumption and has become one of the most common liver diseases worldwide in recent years, especially prevalent in obese patients, those with diabetes, and those with metabolic syndrome.

[0004] Chinese Patent Publication No. CN1191082A discloses a traditional Chinese medicine composition for treating fatty liver and its preparation method. This composition consists of Artemisia capillaris, Cassia tora, Rheum palmatum, Polyporus umbellatus, Crataegus pinnatifida, Alisma plantago-aquatica, Trichosanthes kirilowii, Ligustrum lucidum, Eclipta prostrata, Lycium barbarum, Atractylodes lancea, Atractylodes macrocephala, Citrus reticulata, Cirsium japonicum, Bupleurum chinense, and Glycyrrhiza uralensis, and is used to treat fatty liver. Chinese Patent Publication No. CN109331097A studies the properties of the raw materials in Huazhi Rougan granules, employing different extraction processes for different raw materials to improve yield and ensure the activity and content of each active ingredient. Simultaneously, it screens excipients and their dosage ratios in the formulation. The resulting Huazhi Rougan granules meet the requirements of the current Chinese Pharmacopoeia for various performance indicators such as water content, disintegration time, and dissolution rate.

[0005] In existing technologies, prescriptions for relieving liver stagnation and softening the liver are mostly formulated into oral preparations, such as granules. Although these meet pharmacopoeia standards, they have certain limitations: for patients with abdominal distension and loss of appetite, oral administration may increase the burden on the gastrointestinal tract and reduce treatment compliance. Topical preparations are less used in the treatment of fatty liver. Current technologies lack topical dosage forms that can balance efficacy and patient compliance, especially topical preparations that can relieve abdominal distension and promote appetite, making it difficult to meet diverse clinical needs.

[0006] Therefore, developing a topical preparation based on the "resolving stagnation and softening the liver" prescription to overcome the limitations of oral preparations has become an important direction in the current treatment of fatty liver. Summary of the Invention

[0007] To overcome the problems of existing oral formulations of traditional Chinese medicine for relieving abdominal distension and promoting appetite, such as heavy gastrointestinal burden and low patient compliance, and the lack of topical formulations that balance efficacy and compliance in the treatment of fatty liver, this invention provides a transdermal patch of traditional Chinese medicine that can relieve abdominal distension and promote appetite, and its preparation method. The specific technical solution is as follows:

[0008] I. Composition of Traditional Chinese Medicine Transdermal Patches

[0009] This invention relates to a transdermal patch containing traditional Chinese medicine, comprising acrylate pressure-sensitive adhesive, herbal extracts, transdermal penetration enhancers, and glycerin. The herbal extracts are derived from Artemisia capillaris, Cassia tora (stir-fried), Rheum palmatum (stewed in wine), Alisma plantago-aquatica, Polyporus umbellatus, Crataegus pinnatifida, Atractylodes lancea (stir-fried with wheat bran), Atractylodes macrocephala (stir-fried with wheat bran), Citrus reticulata peel, Trichosanthes kirilowii, Ligustrum lucidum (steamed in wine), Eclipta prostrata, Lycium barbarum, Cirsium japonicum, Bupleurum chinense (vinegar-processed), and Glycyrrhiza uralensis through a specific process. Each herb is cleaned, processed, and combined in proportion, then extracted stepwise (water extraction, alcohol extraction, and volatile oil extraction). The product is prepared by purification and drying, which can fully retain active ingredients such as emodin, hesperidin, wolfberry polysaccharide, chlorogenic acid, and atractylone. The transdermal absorption enhancer is composed of azone, tragacanth gum, and ergosterol in a weight ratio of 5:3:2. The synergistic effect of the three can significantly improve the transdermal absorption efficiency and skin retention of the active ingredients of traditional Chinese medicine. The weight ratio of each component is as follows: 100 parts by weight of acrylate pressure-sensitive adhesive, 35-50 parts by weight of traditional Chinese medicine extract, 3-8 parts by weight of transdermal absorption enhancer, and 4-7 parts by weight of glycerin.

[0010] II. Preparation methods of traditional Chinese medicine extracts

[0011] 1. Pre-processing of medicinal materials: All medicinal materials are cleaned and processed (such as stewing with rhubarb wine, stir-frying with cassia seeds, etc.). Atractylodes lancea, Atractylodes macrocephala, tangerine peel, and licorice are pulverized and passed through an 80-mesh sieve to obtain fine powder, while the remaining medicinal materials are pulverized and passed through a 20-mesh sieve to obtain coarse powder.

[0012] 2. Step-by-step extraction:

[0013] (1) Water extraction: Take the coarse powder of Artemisia capillaris, Polyporus umbellatus, Alisma plantago-aquatica, Crataegus pinnatifida, Trichosanthes kirilowii, Ligustrum lucidum, Eclipta prostrata, Lycium barbarum, Cirsium japonicum and Glycyrrhiza uralensis, add purified water and decoct twice, combine the filtrates and concentrate to obtain clear extract.

[0014] (2) Alcohol extraction: Take the crude powder of cassia seed, rhubarb and bupleurum, reflux extract twice with 70% ethanol, recover the ethanol and obtain the alcohol extract concentrate, combine with the water extract and concentrate.

[0015] (3) Extraction of volatile oil: Take fine powder of Atractylodes lancea, Atractylodes macrocephala and Citrus reticulata peel, and extract the volatile oil by steam distillation. Mix the extracted aqueous solution with the above combined thick paste.

[0016] 3. Purification and drying:

[0017] The combined products were centrifuged and purified. The supernatant was concentrated, vacuum dried, and then pulverized through a 100-mesh sieve to obtain the traditional Chinese medicine extract.

[0018] III. Preparation Methods of Transdermal Patches of Traditional Chinese Medicine

[0019] (1) Preparation of transdermal penetration enhancer solution: Add purified water to tragacanth gum, stir and swell at 40-50℃ to form a colloid, then add azone and ergosterol, and stir until homogeneous;

[0020] (2) Matrix mixing and molding: Take acrylic pressure-sensitive adhesive, add Chinese herbal extract, transdermal penetration promoter solution and glycerin, emulsify at high speed and degas under vacuum, coat it on the backing material, dry it and cover it with an anti-stick layer, and cut it to get the product.

[0021] The transdermal patch of traditional Chinese medicine of this invention can be used to prepare medicines for treating fatty liver (especially non-alcoholic fatty liver), while also relieving abdominal distension and promoting appetite, and is suitable for fatty liver patients with gastrointestinal discomfort.

[0022] Compared with the prior art, the technical advantages of the present invention are as follows:

[0023] (1) Dosage form advantage: This invention uses transdermal patch for external administration, avoiding the stimulation of the gastrointestinal tract by oral preparations, improving patient compliance, and is especially suitable for fatty liver patients with abdominal distension and loss of appetite.

[0024] (2) Optimization of extraction process: This invention combines step-by-step extraction (water extraction, alcohol extraction, volatile oil extraction) with low temperature vacuum concentration and centrifugal purification, which can better retain active ingredients and improve efficacy than traditional methods.

[0025] (3) Synergistic effect of transdermal penetration enhancer: This invention uses azone, tragacanth gum and ergosterol in a specific ratio as a transdermal penetration enhancer, which can significantly enhance the efficiency of drug transdermal absorption and the amount retained in the skin. The penetration enhancement effect is better than that of single component or conventional transdermal penetration enhancer.

[0026] (4) Clear therapeutic effect: The transdermal patch of traditional Chinese medicine in this invention has the dual effects of treating fatty liver (improving lipid metabolism and reducing liver damage) and relieving abdominal distension and promoting appetite (regulating gastrointestinal hormones and reducing intestinal inflammation), providing a topical treatment option with good compliance for clinical use. Attached Figure Description

[0027] Figure 1 24-hour cumulative transdermal dose. Detailed Implementation

[0028] To make the objectives and technical solutions of this invention clearer, the following embodiments are provided for further explanation. However, the scope of protection of this invention is not limited to these embodiments; the embodiments are merely for illustrative purposes. Those skilled in the art should understand that any changes or equivalent substitutions that do not depart from the concept of this invention are included within the scope of protection of this invention.

[0029] Example 1: Preparation process of traditional Chinese medicine extract

[0030] I. Pre-processing of medicinal materials

[0031] 1. Verification of Cleaning and Processing

[0032] All medicinal materials were cleaned and selected according to the provisions of Part I of the Chinese Pharmacopoeia, removing impurities, non-medicinal parts, and moldy materials. Specifically: Rhubarb stewed in wine needed to reach a dark brown surface, brownish-red cross-section, and a wine aroma; Cassia seeds stir-fried until slightly puffed up and fragrant; Atractylodes lancea stir-fried with wheat bran and Atractylodes macrocephala stir-fried with wheat bran needed to reach a yellowish-brown surface and a burnt aroma; Ligustrum lucidum steamed in wine needed to reach a dark brown color and a slightly sweet and bitter taste; and Bupleurum chinense processed with vinegar needed to reach a light brownish-yellow surface and a vinegar aroma. All processed medicinal materials were verified to meet the standards before use.

[0033] 2. Crushing and sieving

[0034] Atractylodes lancea (stir-fried with wheat bran), Atractylodes macrocephala (stir-fried with wheat bran), Citrus reticulata peel, and Glycyrrhiza uralensis were separately pulverized in a pulverizer, passed through an 80-mesh pharmacopoeia sieve, and made into fine powder. After sieving, they were set aside. Artemisia capillaris, Cassia tora (stir-fried), Rheum palmatum (stewed with wine), Alisma plantago-aquatica, Polyporus umbellatus, Crataegus pinnatifida, Trichosanthes kirilowii, Ligustrum lucidum (steamed with wine), Eclipta prostrata, Lycium barbarum, Cirsium japonicum, and Bupleurum chinense (processed with vinegar) were separately pulverized in a hammer mill into coarse powder of 20 mesh. After sieving,

[0035] II. Extraction Process

[0036] 1. Water extraction: Take the coarse powder of Artemisia capillaris, Polyporus umbellatus, Alisma plantago-aquatica, Crataegus pinnatifida, Trichosanthes kirilowii, Ligustrum lucidum (steamed with wine), Eclipta prostrata, Lycium barbarum, Cirsium japonicum, and Glycyrrhiza uralensis, add 8 times the amount of purified water, soak for 1 hour, place in a multi-functional extraction tank, heat to boiling, maintain a gentle boil and decoct for 1.5 hours, filter through a 300-mesh filter cloth, and collect the first filtrate; add 6 times the amount of purified water to the residue, decoct again for 1 hour, filter in the same way, combine the two filtrates, let stand for 24 hours, take the supernatant, place it in a rotary evaporator, and concentrate under reduced pressure at a vacuum of 0.06-0.08 MPa and a temperature of 60-70℃ to obtain a clear extract with a relative density of 1.10-1.15 (measured at 60℃), for later use.

[0037] 2. Alcohol Extraction: Take coarse powders of cassia seed (stir-fried), rhubarb (stewed in wine), and bupleurum (processed with vinegar), add 6 times the amount of 70% ethanol, soak for 0.5 hours, place in a reflux extractor, heat and reflux for 1.5 hours, filter through a 300-mesh filter cloth, and collect the first filtrate; add 4 times the amount of 70% ethanol to the residue, reflux for 1 hour, filter in the same way, combine the two filtrates, place in a rotary evaporator, and reduce the pressure to recover ethanol until there is no alcohol odor under vacuum conditions of 0.06-0.08 MPa and 50-60℃ to obtain the concentrated alcohol extract, combine with the above water extract, and continue to concentrate to a thick paste with a relative density of 1.20-1.25 (measured at 60℃), for later use.

[0038] 3. Volatile oil extraction: Take fine powders of Atractylodes lancea (stir-fried with wheat bran), Atractylodes macrocephala (stir-fried with wheat bran), and Citrus reticulata peel, add 8 times the amount of purified water, put them into a volatile oil extractor, and extract for 6 hours according to Method A of the volatile oil determination method in the Chinese Pharmacopoeia. Collect the volatile oil, add 0.1% vitamin E as an antioxidant, seal in a brown bottle, and refrigerate at 4°C for later use. Filter the extracted aqueous solution through a 300-mesh filter cloth and mix it with the above-combined thick paste.

[0039] III. Purification and Drying

[0040] 1. Centrifugal purification: Add 3 times the amount of purified water to the combined viscous paste for dilution, stir well, and then inject the solution into a high-speed centrifuge. Set the speed to 10000 r / min and the centrifugation time to 35 minutes. After centrifugation, take the supernatant and discard the bottom precipitate.

[0041] 2. Drying and powdering: The supernatant after centrifugation is placed in a rotary evaporator and concentrated under reduced pressure to an extract with a relative density of 1.30-1.35 (measured at 60℃). Then, it is transferred to a vacuum drying oven and dried at 60℃ and 0.08MPa for 8-10 hours. After drying, it is put into an ultra-micro pulverizer and pulverized into fine powder. The powder is then passed through a 100-mesh pharmacopoeia sieve to obtain the Chinese herbal extract.

[0042] Example 2: Herbal Extracts

[0043] The dosage of each Chinese herbal ingredient is as follows: Artemisia capillaris 260g, Cassia tora (stir-fried) 260g, Rheum palmatum (stewed in wine) 172g, Alisma plantago-aquatica 280g, Polyporus umbellatus 260g, Crataegus pinnatifida 260g, Atractylodes lancea (stir-fried with wheat bran) 206g, Atractylodes macrocephala (stir-fried with wheat bran) 206g, Citrus reticulata 172g, Trichosanthes kirilowii 280g, Ligustrum lucidum (steamed in wine) 280g, Eclipta prostrata 280g, Lycium barbarum 250g, Cirsium japonicum 170g, Bupleurum chinense (processed with vinegar) 150g, Glycyrrhiza uralensis 58g.

[0044] Preparation method: Prepared according to the preparation process in Example 1.

[0045] Example 3: Herbal Extracts

[0046] The dosage of each Chinese herbal ingredient is as follows: Artemisia capillaris 220g, Cassia tora (stir-fried) 220g, Rheum palmatum (stewed in wine) 140g, Alisma plantago-aquatica 240g, Polyporus umbellatus 220g, Crataegus pinnatifida 220g, Atractylodes lancea (stir-fried with wheat bran) 170g, Atractylodes macrocephala (stir-fried with wheat bran) 170g, Citrus reticulata 140g, Trichosanthes kirilowii 240g, Ligustrum lucidum (steamed in wine) 240g, Eclipta prostrata 240g, Lycium barbarum 210g, Cirsium japonicum 140g, Bupleurum chinense (processed with vinegar) 120g, Glycyrrhiza uralensis 45g.

[0047] Preparation method: Prepared according to the preparation process in Example 1.

[0048] Example 4: Herbal Extracts

[0049] The dosage of each Chinese herbal ingredient is as follows: Artemisia capillaris 300g, Cassia tora (stir-fried) 300g, Rheum palmatum (stewed in wine) 200g, Alisma plantago-aquatica 320g, Polyporus umbellatus 300g, Crataegus pinnatifida 300g, Atractylodes lancea (stir-fried with wheat bran) 240g, Atractylodes macrocephala (stir-fried with wheat bran) 240g, Citrus reticulata 200g, Trichosanthes kirilowii 320g, Ligustrum lucidum (steamed in wine) 320g, Eclipta prostrata 320g, Lycium barbarum 290g, Cirsium japonicum 200g, Bupleurum chinense (processed with vinegar) 180g, Glycyrrhiza uralensis 70g.

[0050] Preparation method: Prepared according to the preparation process in Example 1.

[0051] Comparative Example 1: Traditional Chinese Medicine Extracts

[0052] The dosage of each Chinese herbal ingredient is as follows: Artemisia capillaris 260g, Cassia tora (stir-fried) 260g, Rheum palmatum (stewed in wine) 172g, Alisma plantago-aquatica 280g, Polyporus umbellatus 260g, Crataegus pinnatifida 260g, Atractylodes lancea (stir-fried with wheat bran) 206g, Atractylodes macrocephala (stir-fried with wheat bran) 206g, Citrus reticulata 172g, Trichosanthes kirilowii 280g, Ligustrum lucidum (steamed in wine) 280g, Eclipta prostrata 280g, Lycium barbarum 250g, Cirsium japonicum 170g, Bupleurum chinense (processed with vinegar) 150g, Glycyrrhiza uralensis 58g.

[0053] Preparation method:

[0054] (1) Grind licorice and thistle into fine powder under vacuum;

[0055] (2) Pulverize Alisma plantago-aquatica, Ligustrum lucidum, Rheum palmatum, and Cassia tora, add 75% ethanol and reflux twice, combine the filtrates and set aside;

[0056] (3) Prepare powdered Bupleurum, Atractylodes lancea, Atractylodes macrocephala, Lycium barbarum, Citrus reticulata peel, and Polyporus umbellatus. Add Artemisia capillaris and decoct to extract volatile oil inclusion complex. Refine the volatile oil inclusion complex with β-cyclodextrin. Set aside the residue and aqueous solution.

[0057] (4) The Chinese medicine residue and aqueous solution in step (3) are boiled twice with Trichosanthes kirilowii, hawthorn and Eclipta prostrata, and the decoction is mixed.

[0058] (5) Combine the filtrate from step (2) and the decoction obtained in (4), filter, concentrate to a clear paste with a relative density of 1.03, add ethanol to make the alcohol content 65%, let stand for 15 hours, filter, recover ethanol under reduced pressure and concentrate to a relative density of 1.23 to obtain a thick paste, vacuum degree -0.09Mpa, drying temperature 90℃, pulverize under vacuum through an 80-mesh sieve to obtain fine powder;

[0059] (6) Mix the fine powder obtained in steps (5) and (1) with the product obtained in step (3) to obtain the fine powder of the liver-regulating and liver-soothing extract.

[0060] Active ingredient content

[0061] The contents (mg / g extract) of emodin, hesperidin, wolfberry polysaccharide, chlorogenic acid, and atractylone in the herbal extracts of Examples 2-4 and Comparative Example 1 were determined by high performance liquid chromatography according to the Chinese Pharmacopoeia.

[0062] Emodin, derived from rhubarb, has its main active ingredient, emodin (an anthraquinone compound), which becomes more stable after being processed by stewing with wine. Emodin promotes gastrointestinal motility, improves intestinal microcirculation, and can relieve abdominal distension. It also regulates liver and gallbladder function, helping to alleviate discomfort in the liver area, and is one of the core components of the prescription for "regulating qi and relieving constipation." Hesperidin, derived from dried tangerine peel, is a flavonoid compound with significant gastrointestinal motility regulation. It promotes digestive juice secretion and enhances gastrointestinal smooth muscle contraction, thereby improving loss of appetite. It also has anti-inflammatory and gastrointestinal mucosal protective effects, directly related to the efficacy of "regulating qi and strengthening the spleen." Lycium barbarum polysaccharides, derived from Lycium barbarum, are key to its liver and kidney tonifying effects. They regulate immune function, protect liver cells, and help alleviate discomfort in the liver area. They can also indirectly promote appetite by regulating the neuroendocrine system, making them particularly suitable for weakened digestive function caused by physical weakness. Chlorogenic acid, derived from Artemisia capillaris, is the main active ingredient in Artemisia capillaris. It possesses hepatoprotective, choleretic, anti-inflammatory, and antioxidant properties, promoting bile secretion and excretion, and helping to alleviate abdominal distension and decreased appetite caused by damp-heat in the liver and gallbladder. Its anti-inflammatory properties can also reduce gastrointestinal mucosal inflammation and assist in improving digestive function. Atractylodes ketone, derived from Atractylodes lancea, is more easily extracted after being stir-fried with wheat bran. It has the effects of strengthening the spleen and drying dampness, promoting gastrointestinal motility, and relieving abdominal distension and poor appetite caused by dampness obstructing the middle jiao (middle burner). It can also regulate the balance of intestinal flora and enhance digestive and absorptive functions.

[0063] Table 1 Content of active ingredients in the herbal extracts of Examples 2-4 and Comparative Example 1

[0064]

[0065] Table 1 shows the contents of five key active ingredients (emodin, hesperidin, wolfberry polysaccharide, chlorogenic acid, and atractylone) in the herbal extracts of Examples 2-4 and Comparative Example 1. The following conclusions can be drawn: The extraction process of the present invention is more conducive to the preservation of active ingredients. The extraction process used in Examples 2-4 (stepwise water extraction, alcohol extraction, volatile oil extraction, combined with low temperature vacuum concentration, centrifugal purification, etc.) can preserve active ingredients more efficiently than the process of Comparative Example 1 (such as high temperature drying, alcohol precipitation, volatile oil inclusion, etc.).

[0066] Example 5: Transdermal Chinese Medicine Patch

[0067] Formula: 100g acrylic pressure-sensitive adhesive, 40g Chinese herbal extract from Example 2, 5g transdermal penetration enhancer, and 5g glycerin.

[0068] Preparation method:

[0069] (1) Preparation of transdermal penetration enhancer solution

[0070] Take tragali gum (30% of the total weight of transdermal penetration enhancer), add 5 times the amount of purified water, heat to 40-50℃, and stir at 300 r / min at this temperature until it is completely swollen to form a colloidal solution. Then add azone (50% of the total weight of transdermal penetration enhancer) and ergosterol (20% of the total weight of transdermal penetration enhancer) in sequence, and continue stirring for 10 minutes to obtain a homogeneous transdermal penetration enhancer solution.

[0071] (2) Matrix mixing and molding

[0072] Take acrylic pressure-sensitive adhesive, add the traditional Chinese medicine extract, the above-mentioned transdermal penetration enhancer solution, and glycerin, place it in a high-speed homogenizer, and emulsify for 5 minutes at a speed of 3000-5000 r / min; transfer the emulsified mixture to a vacuum degassing machine, and degas for 20 minutes under a vacuum of 0.09 MPa to remove air bubbles; uniformly coat the degassed matrix onto the non-woven fabric backing material, with the coating thickness controlled at 0.2-0.3 mm, place it in a forced-air drying oven, and dry at 60℃ for 5 minutes to allow the solvent to evaporate; after cooling, cover with a silicone paper anti-stick layer, cut into patches of 10cm×12cm using an automatic cutting machine, and seal in an aluminum-plastic composite bag to obtain the traditional Chinese medicine transdermal patch.

[0073] Example 6: Transdermal Chinese Medicine Patch

[0074] Formula: 100g acrylic pressure-sensitive adhesive, 35g of herbal extract from Example 3, 3g of transdermal penetration enhancer, and 4g of glycerin.

[0075] Preparation method:

[0076] (1) Preparation of transdermal penetration enhancer solution

[0077] Take tragali gum (30% of the total weight of transdermal penetration enhancer), add 5 times the amount of purified water, heat to 40-50℃, and stir at 300 r / min at this temperature until it is completely swollen to form a colloidal solution. Then add azone (50% of the total weight of transdermal penetration enhancer) and ergosterol (20% of the total weight of transdermal penetration enhancer) in sequence, and continue stirring for 10 minutes to obtain a homogeneous transdermal penetration enhancer solution.

[0078] (2) Matrix mixing and molding

[0079] Take acrylic pressure-sensitive adhesive, add the traditional Chinese medicine extract, the above-mentioned transdermal penetration enhancer solution, and glycerin, place it in a high-speed homogenizer, and emulsify for 5 minutes at a speed of 3000-5000 r / min; transfer the emulsified mixture to a vacuum degassing machine, and degas for 20 minutes under a vacuum of 0.09 MPa to remove air bubbles; uniformly coat the degassed matrix onto the non-woven fabric backing material, with the coating thickness controlled at 0.2-0.3 mm, place it in a forced-air drying oven, and dry at 60℃ for 5 minutes to allow the solvent to evaporate; after cooling, cover with a silicone paper anti-stick layer, cut into patches of 10cm×12cm using an automatic cutting machine, and seal in an aluminum-plastic composite bag to obtain the traditional Chinese medicine transdermal patch.

[0080] Example 7: Transdermal Chinese Medicine Patch

[0081] Formula: 100g acrylic pressure-sensitive adhesive, 50g of herbal extract from Example 4, 8g transdermal penetration enhancer, and 7g glycerin.

[0082] Preparation method:

[0083] (1) Preparation of transdermal penetration enhancer solution

[0084] Take tragali gum (30% of the total weight of transdermal penetration enhancer), add 5 times the amount of purified water, heat to 40-50℃, and stir at 300 r / min at this temperature until it is completely swollen to form a colloidal solution. Then add azone (50% of the total weight of transdermal penetration enhancer) and ergosterol (20% of the total weight of transdermal penetration enhancer) in sequence, and continue stirring for 10 minutes to obtain a homogeneous transdermal penetration enhancer solution.

[0085] (2) Matrix mixing and molding

[0086] Take acrylic pressure-sensitive adhesive, add the traditional Chinese medicine extract, the above-mentioned transdermal penetration enhancer solution, and glycerin, place it in a high-speed homogenizer, and emulsify for 5 minutes at a speed of 3000-5000 r / min; transfer the emulsified mixture to a vacuum degassing machine, and degas for 20 minutes under a vacuum of 0.09 MPa to remove air bubbles; uniformly coat the degassed matrix onto the non-woven fabric backing material, with the coating thickness controlled at 0.2-0.3 mm, place it in a forced-air drying oven, and dry at 60℃ for 5 minutes to allow the solvent to evaporate; after cooling, cover with a silicone paper anti-stick layer, cut into patches of 10cm×12cm using an automatic cutting machine, and seal in an aluminum-plastic composite bag to obtain the traditional Chinese medicine transdermal patch.

[0087] Transdermal absorption of the traditional Chinese medicine transdermal patch of this invention

[0088] To verify the irreplaceability of this formulation, a single-factor experiment was designed based on Example 5. By comparing the effects of different transdermal absorption enhancers (or formulations) on the transdermal absorption efficiency of the active ingredients in the patch, the superiority of the transdermal absorption enhancer of the present invention was clarified.

[0089] Experimental group: 100g acrylate pressure-sensitive adhesive, 40g Chinese herbal extract from Example 2, 5g glycerin, and the total amount of transdermal penetration enhancer was fixed at 5g (consistent with Example 5).

[0090] Variable factors: The composition and ratio of transdermal penetration enhancers, with the following 6 groups (only the transdermal penetration enhancers are different, and the rest of the preparation process is the same as in Example 5).

[0091] Table 2 Single-factor experimental design of transdermal penetration enhancers

[0092]

[0093]

[0094] Transdermal absorption efficiency determination

[0095] The Franz diffusion cell method was used, with rat abdominal skin (hairless and defatted) as the transdermal barrier. The receiving solution was phosphate buffer (pH 7.4) containing 20% ​​ethanol. The temperature was 32 ± 0.5℃, and the stirring speed was 500 r / min. Samples were taken periodically, and the cumulative transdermal amount (Qn, μg / cm³) of emodin, hesperidin, and atractylone (three representative active ingredients, representing anthraquinones, flavonoids, and volatile oils, respectively) in the receiving solution was determined by HPLC. 2 ).

[0096] Table 4. Transdermal absorption efficiency of each group (μg / cm³) 2 )

[0097]

[0098] Skin retention measurement

[0099] After the experiment, the skin was peeled off, cut into pieces, and extracted with methanol using ultrasound. The retention of the three active ingredients in the skin was then measured (reflecting the effective accumulation of the drug in the skin).

[0100] Table 5. Skin retention volume for each group (μg / cm³) 2 )

[0101]

[0102]

[0103] Tables 4 and 5 show that the experimental group exhibited significantly better permeation-enhancing effects on the three representative active ingredients than the control groups. Whether anthraquinones, flavonoids, or volatile oils, the transdermal transport efficiency of the experimental group was significantly superior. This is closely related to the synergistic effect of the three components in the transdermal penetration enhancer. Azone's stratum corneum penetration enhancement, tragacanth gum's moisturizing and solubilizing effects, and ergosterol's regulation of lipid channels form a highly efficient transdermal system. Regarding skin retention, the accumulation of the three components in the skin of the experimental group was higher than that of the control group, indicating that it not only promotes transdermal drug absorption but also forms an effective reservoir in the local skin, facilitating the sustained efficacy of the drug. The transdermal penetration enhancer composed of azone, tragacanth gum, and ergosterol in a specific ratio in this invention, through the synergistic effect of multiple components, improves drug transdermal efficiency while ensuring effective local accumulation in the skin. Its effect is significantly superior to single-component, other ratios, and conventional transdermal penetration enhancers, fully demonstrating the irreplaceable nature of the composition and ratio of this transdermal penetration enhancer. The transdermal absorption efficiency and skin retention of the transdermal patches in Examples 6 and 7 were similar to those in the experimental group. In Example 6, the cumulative transdermal absorption rates of emodin, hesperidin, and atractylodesone over 24 hours were 37.85 ± 2.27 μg / cm³. 2 51.74±3.14μg / cm 2 27.09±1.97μg / cm 2 The skin retention amount was 12.73±1.06 μg / cm³. 2 18.25±1.18μg / cm 2 9.10±0.93μg / cm 2 In Example 7, the cumulative transdermal absorption rates of emodin, hesperidin, and atractylodesone in the transdermal patch over 24 hours were 38.07 ± 1.98 μg / cm³. 2 52.10±3.42μg / cm 2 27.31±1.65μg / cm 2 The skin retention amount was 12.84±1.10 μg / cm³. 2 17.87±1.26μg / cm 2, 9.36 ± 1.02 μg / cm 2 .

[0104] Pharmacodynamic effect of the traditional Chinese medicine transdermal patch for treating non-alcoholic fatty liver in the present invention

[0105] Experimental animals:

[0106] SPF-grade SD rats, weighing 180 - 220 g, experimental animal license number: SYXK(Shandong)20180008, provided by Lunan Pharmaceutical Group Co., Ltd. Adaptively fed for 1 week before the experiment. Feeding environment: temperature 22 - 25°C, humidity 50 - 60%, 12h light-dark cycle, free access to food and water, single-cage feeding to accurately record food intake.

[0107] Experimental drugs:

[0108] Traditional Chinese medicine transdermal patch of Example 5 of the present invention: Specification 10 cm × 12 cm.

[0109] Traditional Chinese medicine transdermal patch of Example 6 of the present invention: Specification 10 cm × 12 cm.

[0110] Traditional Chinese medicine transdermal patch of Example 7 of the present invention: Specification 10 cm × 12 cm.

[0111] Positive control drug: Huazhi Rougan Granules (Shandong Xinsdai Pharmaceutical Co., Ltd., national drug approval number Z20090077), usage: oral administration, dissolved with purified water before use.

[0112] Modeling feed: High-fat feed (basic feed + 20% lard + 10% egg yolk powder + 2% cholesterol).

[0113] [[ID=三十二]]Main reagents:

[0114] Serum biochemical indexes: Detection kits for total cholesterol (TC), triglyceride (TG), alanine aminotransferase (ALT), and aspartate aminotransferase (AST).

[0115] Inflammatory factors: ELISA kits for tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6).

[0116] Gastrointestinal hormones: ELISA kits for ghrelin (Ghrelin) and cholecystokinin (CCK).

[0117] Main instruments:

[0118] Biochemical detection: Automatic biochemical analyzer.

[0119] Behavioral recording: Animal behavior video analysis system.

[0120] Food intake monitoring: Intelligent feed weighing system (equipped for each cage, accuracy 0.1 g).

[0121] Experimental methods

[0122] Modeling and grouping: After one week of adaptive feeding, the rats were randomly divided into 6 groups of 10 rats each.

[0123] Normal control group: fed with basal feed + blank back patch, once a day for 8 consecutive weeks.

[0124] Model control group: fed a high-fat diet + applied blank back patch once a day for 8 consecutive weeks.

[0125] Example 5 group: high-fat diet feeding + back application of Example 5 patch, once a day (12 hours / time), for 8 consecutive weeks.

[0126] Example 6 group: High-fat diet feeding + application of Example 6 patch to the back, usage is the same as Example 5 group.

[0127] Example 7 group: High-fat diet feeding + application of Example 7 patch to the back, usage is the same as Example 5 group.

[0128] Positive control group: fed with high-fat diet and administered Huazhi Rougan granules by gavage once a day for 8 consecutive weeks.

[0129] Sample collection and testing:

[0130] Behavioral observation (recorded twice a week, 30 minutes each time):

[0131] Abdominal pain-related behaviors: The number of times rats curled up their abdomens, the frequency of their stretching behavior, and the duration of their reduced activity were recorded using a video analysis system.

[0132] Appetite-related indicators: The intelligent feed system records daily feed intake and feeding frequency (interval between feedings).

[0133] Serum and tissue collection: After fasting for 12 hours at the end of the experiment, blood was collected under anesthesia (abdominal aorta), and serum was separated by centrifugation (3000 r / min × 15 min) and stored at -80℃; liver, gastric antrum and jejunum tissues were collected, some of which were fixed in 4% paraformaldehyde (liver and intestine), and some were frozen at -80℃ (gastric antrum and liver).

[0134] Testing indicators:

[0135] Treatment efficacy for fatty liver: same as before (weight, liver index, serum TC / TG / ALT / AST, liver tissue NAS score).

[0136] Mechanism of abdominal pain:

[0137] Serum inflammatory factors: TNF-α and IL-6 levels were detected by ELISA (reflecting the degree of visceral inflammation).

[0138] Appetite regulation:

[0139] Serum gastrointestinal hormones: ELISA was used to detect the levels of Ghrelin (which promotes appetite) and CCK (which inhibits appetite).

[0140] Statistical analysis: SPSS 22.0 software was used for statistical analysis of the obtained data. Quantitative data were analyzed using... This indicates that one-way ANOVA was used for comparisons among multiple groups, and independent samples t-tests were used for comparisons between two groups. A p-value < 0.05 was considered statistically significant.

[0141] Experimental Results and Analysis

[0142] Indicators related to the treatment efficacy of fatty liver

[0143] Weight: Reflects the overall degree of obesity. Fatty liver is often associated with obesity, and changes in weight can indirectly reflect the regulatory effect of drugs on lipid metabolism. Liver index (liver weight / body weight × 100%): Reflects the degree of liver enlargement. In fatty liver, fat accumulation in hepatocytes leads to an increase in liver volume and a rise in the liver index. This indicator can directly reflect the improvement in liver fat accumulation.

[0144] Table 6. Rat body weight and liver index

[0145]

[0146]

[0147] Fatty liver disease is often accompanied by lipid metabolism disorders. Elevated serum TC (total cholesterol) and TG (triglycerides) levels are typical characteristics of fatty liver, and their decrease suggests improved lipid metabolism. Serum ALT (alanine aminotransferase) and AST (aspartate aminotransferase) are sensitive indicators of hepatocellular damage. Under normal circumstances, they are mainly found within hepatocellular cells. When fatty liver causes hepatocellular damage, they are released into the blood. A decrease in their levels indicates reduced hepatocellular damage. The NAS score (non-alcoholic fatty liver disease activity score) assesses the degree of steatosis, inflammation, and ballooning degeneration of hepatocellular cells through pathological examination. A higher score indicates more severe liver tissue lesions, and a lower score suggests improved liver pathological damage.

[0148] Table 7. Serum TC / TG / ALT / AST and liver tissue NAS score in rats

[0149]

[0150] Table 7 shows that, compared with the normal control group, the serum TC, TG, ALT, AST levels and liver tissue NAS score of the model control group were significantly increased (P<0.01), indicating that the non-alcoholic fatty liver model was successfully established and that the rats exhibited obvious lipid metabolism disorders and hepatocyte damage. Compared with the model control group, the above indicators in the Example 5 group, Example 6 group, Example 7 group and the positive control group were significantly reduced (P<0.01), indicating that the transdermal patch of traditional Chinese medicine of the present invention can effectively improve lipid metabolism, reduce hepatocyte damage, and alleviate pathological damage to liver tissue in fatty liver rats.

[0151] Behavioral indicators related to abdominal pain

[0152] The number of daily abdominal contractions reflects the frequency of the rat's somatic contraction response when experiencing abdominal pain; a higher frequency indicates more severe abdominal pain. The frequency of stretching behavior reflects the number of stretching movements performed by the rat in a comfortable abdominal state; a lower frequency may indicate more severe abdominal pain. The duration of decreased activity refers to the duration for which the rat reduces its activity due to abdominal pain; a longer duration indicates a greater impact of abdominal pain on activity.

[0153] Table 8 Behavioral indicators related to abdominal pain in rats

[0154]

[0155] Table 8 shows that the normal control group rats exhibited fewer abdominal curl-up frequency, higher stretching frequency, and shorter duration of reduced activity. The model control group, however, showed the opposite trend, with a significantly increased number of abdominal curl-up frequency, a significantly decreased stretching frequency, and a significantly prolonged duration of reduced activity (P<0.01), indicating significant abdominal pain-related behaviors in the model rats. Compared with the model control group, the abdominal pain-related behaviors in groups 5, 6, and 7, as well as the positive control group, were significantly improved (P<0.01), manifested as a decrease in the number of abdominal curl-up frequency, an increase in the stretching frequency, and a shortened duration of reduced activity. This demonstrates that the transdermal patch of traditional Chinese medicine of this invention can effectively alleviate abdominal pain symptoms in fatty liver rats.

[0156] Inflammatory markers

[0157] Serum TNF-α and IL-6 are two important inflammatory factors; elevated levels indicate enhanced inflammatory response in the body and are correlated with the occurrence and severity of abdominal pain. The jejunal tissue inflammation score assesses the degree of intestinal inflammation through pathological examination of jejunal tissue; a higher score indicates more severe intestinal inflammation and may exacerbate abdominal pain.

[0158] Table 9 Inflammatory markers related to abdominal pain in rats

[0159]

[0160]

[0161] Table 9 shows that the serum TNF-α and IL-6 levels and jejunal tissue inflammation scores of the model control group rats were significantly higher than those of the normal control group (P<0.01), indicating that the model rats had a significant inflammatory response, and that intestinal inflammation was involved in the occurrence of abdominal pain. Compared with the model control group, the serum TNF-α and IL-6 levels and jejunal tissue inflammation scores of the Example 5 group, Example 6 group, Example 7 group and positive control group were significantly reduced (P<0.01), indicating that the transdermal patch of traditional Chinese medicine of the present invention can relieve abdominal pain by reducing the level of inflammatory factors and alleviating intestinal inflammation.

[0162] Indicators related to appetite-stimulating effect

[0163] Table 10. Indicators related to appetite-stimulating effects

[0164]

[0165] Table 10 shows that the average daily food intake, feeding frequency, and serum ghrelin level of the model control group rats were significantly lower than those of the normal control group, while the serum CCK level was significantly higher than that of the normal control group (P<0.01), indicating that the model rats had significant loss of appetite. Compared with the model control group, the average daily food intake, feeding frequency, and serum ghrelin level of the Example 5 group, Example 6 group, Example 7 group, and positive control group were significantly increased, while the serum CCK level was significantly decreased (P<0.05 or P<0.01), indicating that the transdermal patch of traditional Chinese medicine of the present invention can effectively promote the appetite of fatty liver rats.

Claims

1. A transdermal patch for traditional Chinese medicine, characterized in that, The transdermal patch containing traditional Chinese medicine comprises acrylate pressure-sensitive adhesive, traditional Chinese medicine extract, transdermal penetration enhancer, and glycerin; the transdermal penetration enhancer is composed of azone, tragacanth gum, and ergosterol; the traditional Chinese medicine extract is derived from Artemisia capillaris, Cassia tora, Rheum palmatum, Alisma plantago-aquatica, Polyporus umbellatus, Crataegus pinnatifida, Atractylodes lancea, Atractylodes macrocephala, Citrus reticulata peel, Trichosanthes kirilowii, Ligustrum lucidum, Eclipta prostrata, Lycium barbarum, Cirsium japonicum, Bupleurum chinense, and Glycyrrhiza uralensis.

2. The transdermal patch of traditional Chinese medicine according to claim 1, characterized in that, The transdermal patch containing traditional Chinese medicine comprises: 100 parts by weight of acrylate pressure-sensitive adhesive, 35-50 parts by weight of traditional Chinese medicine extract, 3-8 parts by weight of transdermal penetration enhancer, and 4-7 parts by weight of glycerin.

3. The transdermal patch of traditional Chinese medicine according to claim 1, characterized in that, The transdermal penetration enhancer is composed of azone, tragacanth gum, and ergosterol in a ratio of 5:3:

2.

4. The transdermal patch of traditional Chinese medicine according to claim 1, characterized in that, The herbal extract is derived from the following ingredients: Artemisia capillaris (220-300 parts by weight), Cassia tora (stir-fried) (220-300 parts by weight), Rheum palmatum (stewed in wine) (140-200 parts by weight), Alisma plantago-aquatica (240-320 parts by weight), Polyporus umbellatus (220-300 parts by weight), Crataegus pinnatifida (220-300 parts by weight), Atractylodes lancea (stir-fried with wheat bran) (170-240 parts by weight), Atractylodes macrocephala (stir-fried with wheat bran) (170-240 parts by weight), Citrus reticulata (140-200 parts by weight), Trichosanthes kirilowii (240-320 parts by weight), Ligustrum lucidum (steamed in wine) (240-320 parts by weight), Eclipta prostrata (240-320 parts by weight), Lycium barbarum (210-290 parts by weight), Cirsium japonicum (140-200 parts by weight), Bupleurum chinense (processed with vinegar) (120-180 parts by weight), and Glycyrrhiza uralensis (45-70 parts by weight).

5. The transdermal patch of traditional Chinese medicine according to claim 1, characterized in that, The herbal extract is composed of 260 parts by weight of Artemisia capillaris, 260 parts by weight of Cassia tora (stir-fried), 172 parts by weight of rhubarb (stewed in wine), 280 parts by weight of Alisma plantago-aquatica, 260 parts by weight of Polyporus umbellatus, 260 parts by weight of hawthorn, 206 parts by weight of Atractylodes lancea (stir-fried with wheat bran), 206 parts by weight of Atractylodes macrocephala (stir-fried with wheat bran), 172 parts by weight of tangerine peel, 280 parts by weight of Trichosanthes kirilowii, 280 parts by weight of Ligustrum lucidum (steamed in wine), 280 parts by weight of Eclipta prostrata, 250 parts by weight of Lycium barbarum, 170 parts by weight of Cirsium japonicum, 150 parts by weight of Bupleurum chinense (processed with vinegar), and 58 parts by weight of Glycyrrhiza uralensis.

6. The transdermal patch of traditional Chinese medicine according to claim 1, characterized in that, The preparation method of the traditional Chinese medicine extract includes: (1) Pre-processing of medicinal materials: Clean selection, processing, crushing and sieving Atractylodes lancea, Atractylodes macrocephala, Citrus reticulata peel and Glycyrrhiza uralensis to obtain fine powder, crushing and sieving Artemisia capillaris, Cassia tora, Rheum palmatum, Alisma plantago-aquatica, Polyporus umbellatus, Crataegus pinnatifida, Trichosanthes kirilowii, Ligustrum lucidum, Eclipta prostrata, Lycium barbarum, Cirsium japonicum and Bupleurum chinense to obtain coarse powder; (2) Extraction process: Take the powders of Artemisia capillaris, Polyporus umbellatus, Alisma plantago-aquatica, Crataegus pinnatifida, Trichosanthes kirilowii, Ligustrum lucidum, Eclipta prostrata, Lycium barbarum, Cirsium japonicum, and Glycyrrhiza uralensis for water extraction, take the powders of Cassia tora, Rheum palmatum, and Bupleurum chinense for alcohol extraction, take the powders of Atractylodes lancea, Atractylodes macrocephala, and Citrus reticulata for volatile oil extraction, and combine the water extract, alcohol extract, and aqueous solution after volatile oil extraction. (3) Purification and drying: The combined products were centrifuged, dried and powdered to obtain the Chinese herbal extract.

7. A method for preparing the transdermal patch of traditional Chinese medicine as described in claim 1, characterized in that, The preparation method includes the following steps: adding tragali gum to an appropriate amount of purified water, heating to 40-50℃, stirring at this temperature until it completely swells to form a colloidal solution, then adding azone and ergosterol in sequence to obtain a transdermal penetration enhancer solution; taking acrylate pressure-sensitive adhesive, adding traditional Chinese medicine extract, transdermal penetration enhancer, and glycerin, placing it in a high-speed homogenizer for emulsification, defoaming, coating, drying, covering with an anti-adhesive layer, and cutting to obtain a traditional Chinese medicine transdermal patch.

8. The use of the transdermal patch of traditional Chinese medicine according to claim 1 in the preparation of a drug for treating fatty liver.

9. The use of the transdermal patch of traditional Chinese medicine according to claim 1 in the preparation of a drug for treating non-alcoholic fatty liver disease.

10. The use of the transdermal patch of traditional Chinese medicine according to claim 1 in the preparation of a medicine for relieving abdominal distension and promoting appetite.

Images