Self-microemulsifying transdermal absorption traditional Chinese medicine preparation, preparation method and application thereof

Abstract

The application discloses a self-microemulsion transdermal absorption traditional Chinese medicine preparation and a preparation method and application thereof. The preparation method comprises the following steps: taking an extract of a traditional Chinese medicine composition, adding 0.01-0.05 parts of a drug-loaded self-sticking substance, and then adding 0.1-0.2 parts of an oil phase, 0.01-0.05 parts of a surfactant and 0.005-0.015 parts of a co-surfactant in sequence to prepare a self-microemulsion system, and preparing the self-microemulsion system into a traditional Chinese medicine preparation. The prepared traditional Chinese medicine self-microemulsion system has the advantages of easy transdermal absorption, good biocompatibility, no cytotoxicity, good drug loading capacity, improved transdermal drug permeation amount, greatly reduced drug use dosage, realized controllable slow-release drug delivery in a disease treatment process, high safety, convenience in use and greatly improved utilization rate of the patch.

Description

Technical Field

[0001] This invention relates to the field of transdermal absorption traditional Chinese medicine preparations. More specifically, this invention relates to a self-microemulsion transdermal absorption traditional Chinese medicine preparation, its preparation method, and its application. Background Technology

[0002] Self-microemulsion drug delivery systems (SMEDDS) have become a novel type of drug formulation, generally consisting of three components: an oil phase, a surfactant, and a co-surfactant. The droplets formed by self-emulsification are small and uniform in size, and the drug's solubility is significantly improved, resulting in a substantial increase in absorption and bioavailability.

[0003] Transdermal formulations allow drugs to bypass the liver and gastrointestinal tract for absorption, reducing toxicity and side effects, making medication safer, and eliminating the discomfort of oral or injectable / infusion treatments, especially for children or patients who cannot easily access other treatments. Currently, most transdermal Chinese medicine preparations used to treat coronavirus infections suffer from low transdermal penetration, high dosage, and low patch utilization. Summary of the Invention

[0004] One objective of this invention is to solve at least the above-mentioned problems and to provide a self-microemulsion transdermal absorption traditional Chinese medicine preparation, its preparation method, and its application. The self-microemulsion system of traditional Chinese medicine prepared by this invention has the advantages of easy transdermal absorption, good biocompatibility, and no cytotoxicity. It can effectively load drugs, increase the transdermal permeation of drugs, greatly reduce the dosage of drugs used, and also realizes controlled sustained-release drug delivery during disease treatment. It is safe, convenient to use, and greatly improves the utilization rate of the patch.

[0005] To achieve these objectives and other advantages according to the present invention, a method for preparing a self-microemulsion transdermal absorption traditional Chinese medicine preparation is provided, comprising:

[0006] By weight, an extract of the traditional Chinese medicine composition is taken, and 0.01-0.05 parts of a drug-loaded self-adhesive are added, followed by the sequential addition of 0.1-0.2 parts of oil phase, 0.01-0.05 parts of surfactant, and 0.005-0.015 parts of co-surfactant to prepare a self-microemulsion system. The self-microemulsion system is then used to prepare a traditional Chinese medicine preparation. The extract of the traditional Chinese medicine composition uses 1-5 parts by weight of raw materials, including honeysuckle, forsythia, isatis root, imperata root, reed rhizome, and bamboo leaf in a weight ratio of 3-8:3-8:4-10:5-10:2-6:1-3:3-8. The herb is Scrophularia ningpoensis; the drug-loaded self-adhesive is a compound of chitosan oligosaccharide and dopamine; the oil phase is any one or more of coconut oil, corn oil, azone, evening primrose oil, oleic acid, ethyl oleate, sunflower oil, and limonene; the surfactant is any one or more of Tween-20, Tween-60, Tween-80, decaglycerol monolaurate, polyethylene glycol glycerol decanoate, polyoxyacetic acid stearic acid, and cetearyl alcohol; the co-surfactant is any one or more of polyglycerol ricinoleate, cetyl polyethylene glycol, polyethylene glycol-dihydroxystearate, PEG-400, and PEG-600.

[0007] Preferably, the Chinese medicinal materials include honeysuckle, forsythia, isatis root, imperata root, reed root, bamboo leaf, and scrophularia in a weight ratio of 3:3:4:5:5:1.67:3.

[0008] Preferably, the oil phase is azone, the surfactant is Tween-80, and the co-surfactant is PEG-600; and the amount of azone is 10 parts, the amount of Tween-80 is 2 parts, and the amount of co-surfactant is 1.5 parts.

[0009] Preferably, the oil phase is oleic acid, the surfactant is decaglycerol monolaurate, the co-surfactant is polyethylene glycol-dihydroxystearate, and the oleic acid is 0.1 parts, the decaglycerol monolaurate is 0.03 parts, and the polyethylene glycol-dihydroxystearate is 0.01 parts.

[0010] Preferably, the oil phase is limonene, the surfactant is Tween-80, the co-surfactant is PEG-400, and the limonene content is 0.1 parts, the Tween-80 content is 0.01 parts, and the PEG-400 content is 0.005 parts.

[0011] Preferably, the drug-loaded self-adhesive is prepared as follows: 0.1 mol each of chitosan oligosaccharide and dopamine are dissolved in 100 mL of ethanol to obtain a solution. 0.1 mol of a diacid compound is added to the solution at room temperature. After stirring and reacting for 2 h, the ethanol is removed by vacuum distillation to obtain the drug-loaded self-adhesive. The diacid compound is either glutaric acid or adipic acid.

[0012] Preferably, the preparation process of the self-microemulsion system specifically includes the following steps:

[0013] S1. By weight, take 1 part of the Chinese herbal raw material and place it in 10 parts of water. After water extraction twice, add 0.1 part of gypsum and boil for 1 hour. After standing and cooling, filter to obtain crude extract. Add 95% ethanol to the crude extract and let stand for 24 hours. Take the supernatant, which is the extract. Add 0.01 part of drug-loaded self-adhesive to the extract, stir and concentrate to paste to obtain ointment.

[0014] S2. Add the oil phase to the ointment and stir to dissolve the ointment to form an oil phase system;

[0015] S3. The surfactant and the co-surfactant are mixed and stirred evenly at 50-60°C to obtain the treated product;

[0016] S4. Add the treated material to the oil phase system and stir evenly to obtain a self-microemulsion of traditional Chinese medicine, which is the self-microemulsion system.

[0017] Preferably, the dosage forms of the traditional Chinese medicine preparations obtained from the microemulsion system include tinctures, patches, films, and sprays.

[0018] Traditional Chinese medicine preparations prepared using a method for transdermal absorption of traditional Chinese medicine preparations via self-microemulsion.

[0019] The application of traditional Chinese medicine preparations in the preparation of drugs for treating fever, runny nose, cough, bronchial and lung inflammation caused by influenza or coronavirus infection in children or adults.

[0020] The present invention has at least the following beneficial effects:

[0021] First, this invention discloses a method for preparing a self-microemulsion transdermal absorption traditional Chinese medicine preparation. The active ingredients of the traditional Chinese medicine preparation include extracts of honeysuckle, forsythia, isatis root, imperata root, reed rhizome, lophatherum leaf, and scrophularia root. Chitosan oligosaccharide and dopamine bridging compounds are added as drug-carrying system and self-adhesive components. An oil phase, emulsifier, and co-emulsifier are added sequentially to prepare a self-microemulsion system. The prepared traditional Chinese medicine self-microemulsion system is easily absorbed through the skin, has good biocompatibility, and is non-cytotoxic. It can effectively load drugs, increase the transdermal permeability of drugs, greatly reduce the dosage of drugs used, and achieve controlled sustained-release drug delivery during disease treatment. It is safe, convenient to use, and greatly improves the utilization rate of the patch.

[0022] Secondly, this invention discloses a self-microemulsion transdermal absorption traditional Chinese medicine preparation for treating coronavirus infection and its application. The traditional Chinese medicine formula used is: honeysuckle, forsythia, isatis root, imperata root, reed rhizome, light bamboo leaf, and scrophularia. This traditional Chinese medicine preparation is a universal preparation for both children and adults. Its functions and indications are to dispel wind and detoxify, clear heat and soothe the throat, especially for fever, sore throat, dry mouth, and thirst caused by exogenous wind-heat, as well as pharyngitis and tonsillitis caused by upper respiratory tract infection with the above symptoms. Among them, honeysuckle is sweet and cold, pungent and cool to relieve exterior syndrome, clear heat and detoxify, and has a fragrant and cleansing effect. The principal herb is Forsythia suspensa, bitter and slightly cold in nature, entering the heart, liver, and gallbladder meridians. It clears heat and detoxifies, reduces swelling and dissipates nodules, and is used for wind-heat colds. Isatis indigotica clears heat, detoxifies, cools the blood, and benefits the throat. These herbs are used as assistant herbs. Phragmites communis is sweet and cold in nature, entering the lung and stomach meridians. It clears heat and generates fluids. Scrophularia ningpoensis is sweet, bitter, and salty in taste, slightly cold in nature. It nourishes yin and clears heat. It is bitter, salty, and cool, entering the lung and kidney meridians. It nourishes yin and moistens dryness. Lophatherum gracile is sweet and bland in taste, cold in nature. It enters the heart, lung, stomach, and bladder meridians. It is light and permeable, and has the effects of clearing heat and relieving irritability, and promoting urination. Imperata cylindrica is sweet and cold in nature, entering the lung, stomach, and small intestine meridians. It cools the blood, stops bleeding, clears heat, and detoxifies. These herbs are used as adjuvant herbs.

[0023] Third, this invention uses chitosan as a drug carrier, which can stabilize the components in the drug, promote drug absorption, delay or control the drug dissolution rate, help the drug reach the target organ, and is acid-resistant and anti-ulcer, making it a high-performance natural mucosal adhesive. Chitosan-based nanocarriers can prolong the retention time of the drug at the absorption site, achieving controlled release. Dopamine (PDA) is a novel polymer synthesized inspired by the adhesive proteins in mussels. It has natural advantages such as good biocompatibility, excellent photothermal conversion performance, adhesiveness, high chemical reactivity, and multiple drug release response mechanisms. When used in skin medications, it adheres to the skin, making the medication less likely to fall off. Using chitosan as a drug carrier and combining it with dopamine to prepare drug-loaded self-adhesive materials, compared with other common carriers in the field (such as carboxymethyl cellulose, polylactic acid, etc.) that are prone to precipitation, the drug self-adhesive materials of this invention are less prone to precipitation.

[0024] Other advantages, objectives and features of the present invention will become apparent in part from the following description, and in part from those skilled in the art through study and practice of the invention. Detailed Implementation

[0025] The present invention will be further described in detail below with reference to embodiments, so that those skilled in the art can implement it based on the description.

[0026] <Example 1>

[0027] This invention discloses a self-microemulsion transdermal absorption traditional Chinese medicine preparation, its preparation method, and its application, specifically including the following steps:

[0028] Preparation of S1, chitosan and dopamine polymers

[0029] Take 0.1 mol each of chitosan oligosaccharide and dopamine, dissolve them in 100 mL of anhydrous ethanol, add 0.1 mol of glutaric acid at room temperature and stir for 2 hours. Remove the ethanol by vacuum distillation to obtain the light brown amide polymer product Cs-Da-Glu, which is the drug-loaded self-adhesive.

[0030] S2. Preparation of Traditional Chinese Medicine Extracts

[0031] Take 1 part of the Chinese herbal raw materials by weight, mix them, add 10 parts of water, heat and reflux at 90-100℃ for 1 hour, extract twice, combine the decoctions, add 0.1 parts of gypsum and boil for 1 hour, let stand and cool, filter, add 2 times the volume of 95% ethanol to the extract (i.e., the volume of 95% ethanol is twice the volume of the extract), let stand for 24 hours, take the supernatant, add 0.01 parts of drug-loaded self-adhesive, stir evenly, heat and concentrate the medicine to obtain the ointment (heat at 60℃ for about 5 hours), the obtained ointment is OCs-Da-Glu; wherein, the Chinese herbal raw materials include honeysuckle, forsythia, isatis root, imperata root, reed rhizome, light bamboo leaf, and scrophularia in a weight ratio of 3:3:4:5:5:1.67:3;

[0032] S3. Preparation of self-microemulsions of traditional Chinese medicine

[0033] 1) Add azone to the ointment in S2, stir to dissolve, and form an oil phase system; wherein, the weight part of azone is 0.1 parts;

[0034] 2) Mix Tween-80 and PEG-600 at 55°C and add them to the above oil phase system. Mix and stir evenly to obtain the Chinese medicine microemulsion, which is OCs-Da-Glu-1.

[0035] The weight ratio of azone, Tween-80, and PEG-600 is 1:0.2:0.15.

[0036] <Example 2>

[0037] This invention discloses a self-microemulsion transdermal absorption traditional Chinese medicine preparation, its preparation method, and its application, specifically including the following steps:

[0038] Preparation of S1, chitosan and dopamine polymers

[0039] Take 0.1 mol each of chitosan oligosaccharide and dopamine, dissolve them in 100 mL of anhydrous ethanol, add 0.1 mol of glutaric acid at room temperature and stir for 2 hours. Remove the ethanol by vacuum distillation to obtain the light brown amide polymer product Cs-Da-Glu, which is the drug-loaded self-adhesive.

[0040] S2. Preparation of Traditional Chinese Medicine Extracts

[0041] By weight, take 1 part of the Chinese herbal raw materials, mix them, add 10 parts of water, heat and reflux at 90-100℃ for 1 hour, extract twice, combine the decoctions, add 0.1 parts of gypsum and boil for 1 hour, let stand and cool, filter, add 2 times the amount of 95% ethanol to the extract, let stand for 24 hours, take the supernatant, add 0.01 parts of drug-loaded self-adhesive, stir evenly, heat and concentrate the medicine to obtain the ointment (heat at 60℃ for about 5 hours), the obtained ointment is OCs-Da-Glu; wherein, the Chinese herbal raw materials include honeysuckle, forsythia, isatis root, imperata root, reed rhizome, light bamboo leaf, and scrophularia in a weight ratio of 3:3:4:5:5:1.67:3;

[0042] S3. Preparation of self-microemulsions of traditional Chinese medicine

[0043] 1) Add oleic acid to the ointment in S2, stir to dissolve, and form an oil phase system; wherein, the weight part of oleic acid is 0.1 parts;

[0044] 2) Mix and stir decaglycerol monolaurate and polyethylene glycol-dipolyhydroxy stearate at 55°C, and add them to the above oil phase system. Mix and stir evenly to obtain the Chinese medicine microemulsion, namely OCs-Da-Glu-2.

[0045] The weight ratio of oleic acid, decaglycerol monolaurate, and polyethylene glycol-dihydroxystearate is 1:0.3:0.10.

[0046] <Example 3>

[0047] This invention discloses a self-microemulsion transdermal absorption traditional Chinese medicine preparation, its preparation method, and its application, specifically including the following steps:

[0048] Preparation of S1, chitosan and dopamine polymers

[0049] Take 0.1 mol each of chitosan oligosaccharide and dopamine, dissolve them in 100 mL of anhydrous ethanol, add 0.1 mol of glutaric acid at room temperature and stir for 2 hours. Remove the ethanol by vacuum distillation to obtain the light brown amide polymer product Cs-Da-Glu, which is the drug-loaded self-adhesive.

[0050] S2. Preparation of Traditional Chinese Medicine Extracts

[0051] By weight, take 1 part of the Chinese herbal raw materials, mix them, add 10 parts of water, heat and reflux at 90-100℃ for 1 hour, extract twice, combine the decoctions, add 0.1 parts of gypsum and boil for 1 hour, let stand and cool, filter, add 2 times the amount of 95% ethanol to the extract, let stand for 24 hours, take the supernatant, add 0.01 parts of drug-loaded self-adhesive, stir evenly, heat and concentrate the medicine to obtain the ointment (heat at 60℃ for about 5 hours), the obtained ointment is OCs-Da-Glu; wherein, the Chinese herbal raw materials include honeysuckle, forsythia, isatis root, imperata root, reed rhizome, light bamboo leaf, and scrophularia in a weight ratio of 3:3:4:5:5:1.67:3;

[0052] S3. Preparation of self-microemulsions of traditional Chinese medicine

[0053] 1) Add limonene to the ointment in S2, stir and dissolve to form an oil phase system; wherein, the weight part of limonene is 0.1 parts;

[0054] 2) Mix Tween-80 and PEG-400 at 55°C and add them to the above oil phase system. Mix and stir evenly to obtain the Chinese medicine microemulsion, which is OCs-Da-Glu-3.

[0055] The weight ratio of limonene, Tween-80, and PEG-400 is 1:0.1:0.05.

[0056] <Example 4>

[0057] This invention discloses a self-microemulsion transdermal absorption traditional Chinese medicine preparation, its preparation method, and its application, specifically including the following steps:

[0058] Preparation of S1, chitosan and dopamine polymers

[0059] Take 0.1 mol each of chitosan oligosaccharide and dopamine, dissolve them in 100 mL of anhydrous ethanol, add 0.1 mol of adipic acid at room temperature and stir for 2 hours. Remove the ethanol by vacuum distillation to obtain the light brown amide polymer product Cs-Da-Adi, which is the drug-loaded self-adhesive.

[0060] S2. Preparation of Traditional Chinese Medicine Extracts

[0061] By weight, take 1 part of the Chinese herbal raw materials, mix them, add 10 parts of water, heat and reflux at 90-100℃ for 1 hour, extract twice, combine the decoctions, add 0.1 parts of gypsum and boil for 1 hour, let stand and cool, filter, add 2 times the amount of 95% ethanol to the extract, let stand for 24 hours, take the supernatant, add 0.01 parts of drug-loaded self-adhesive, stir evenly, heat and concentrate the medicine to obtain the ointment (heat at 60℃ for about 5 hours), the obtained ointment is OCs-Da-Adi; wherein, the Chinese herbal raw materials include honeysuckle, forsythia, isatis root, imperata root, reed rhizome, light bamboo leaf, and scrophularia in a weight ratio of 3:3:4:5:5:1.67:3;

[0062] S3. Preparation of self-microemulsions of traditional Chinese medicine

[0063] 1) Add azone to the ointment in S2, stir to dissolve, and form an oil phase system; wherein, the weight part of azone is 0.1 parts;

[0064] 2) Mix Tween-80 and PEG-600 at 55°C and add them to the above oil phase system. Mix and stir evenly to obtain the Chinese medicine microemulsion, which is OCs-Da-Glu-1.

[0065] The weight ratio of azone, Tween-80, and PEG-600 is 1:0.2:0.15.

[0066] <Example 5>

[0067] This invention discloses a self-microemulsion transdermal absorption traditional Chinese medicine preparation, its preparation method, and its application, specifically including the following steps:

[0068] Preparation of S1, chitosan and dopamine polymers

[0069] Take 0.1 mol each of chitosan oligosaccharide and dopamine, dissolve them in 100 mL of anhydrous ethanol, add 0.1 mol of adipic acid at room temperature and stir for 2 hours. Remove the ethanol by vacuum distillation to obtain the light brown amide polymer product Cs-Da-Adi, which is the drug-loaded self-adhesive.

[0070] S2. Preparation of Traditional Chinese Medicine Extracts

[0071] By weight, take 1 part of the Chinese herbal raw materials, mix them, add 10 parts of water, heat and reflux at 90-100℃ for 1 hour, extract twice, combine the decoctions, add 0.1 parts of gypsum and boil for 1 hour, let stand and cool, filter, add 2 times the amount of 95% ethanol to the extract, let stand for 24 hours, take the supernatant, add 0.01 parts of drug-loaded self-adhesive, stir evenly, heat and concentrate the medicine to obtain the ointment (heat at 60℃ for about 5 hours), the obtained ointment is OCs-Da-Adi; wherein, the Chinese herbal raw materials include honeysuckle, forsythia, isatis root, imperata root, reed rhizome, light bamboo leaf, and scrophularia in a weight ratio of 3:3:4:5:5:1.67:3;

[0072] S3. Preparation of self-microemulsions of traditional Chinese medicine

[0073] 1) Add oleic acid to the ointment in S2, stir to dissolve, and form an oil phase system; wherein, the weight part of oleic acid is 0.1 parts;

[0074] 2) Mix and stir decaglycerol monolaurate and polyethylene glycol-dipolyhydroxy stearate at 55°C, and add them to the above oil phase system. Mix and stir evenly to obtain the Chinese medicine microemulsion, namely OCs-Da-Glu-2.

[0075] The weight ratio of oleic acid, decaglycerol monolaurate, and polyethylene glycol-dihydroxystearate is 1:0.3:0.1.

[0076] <Example 6>

[0077] This invention discloses a self-microemulsion transdermal absorption traditional Chinese medicine preparation, its preparation method, and its application, specifically including the following steps:

[0078] Preparation of S1, chitosan and dopamine polymers

[0079] Take 0.1 mol each of chitosan oligosaccharide and dopamine, dissolve them in 100 mL of anhydrous ethanol, add 0.1 mol of adipic acid at room temperature and stir for 2 hours. Remove the ethanol by vacuum distillation to obtain the light brown amide polymer product Cs-Da-Adi, which is the drug-loaded self-adhesive.

[0080] S2. Preparation of Traditional Chinese Medicine Extracts

[0081] By weight, take 1 part of the Chinese herbal raw materials, mix them, add 10 parts of water, heat and reflux at 90-100℃ for 1 hour, extract twice, combine the decoctions, add 0.1 parts of gypsum and boil for 1 hour, let stand and cool, filter, add 2 times the amount of 95% ethanol to the extract, let stand for 24 hours, take the supernatant, add 0.01 parts of drug-loaded self-adhesive, stir evenly, heat and concentrate the medicine to obtain the ointment (heat at 60℃ for about 5 hours), the obtained ointment is OCs-Da-Adi; wherein, the Chinese herbal raw materials include honeysuckle, forsythia, isatis root, imperata root, reed rhizome, light bamboo leaf, and scrophularia in a weight ratio of 3:3:4:5:5:1.67:3;

[0082] S3. Preparation of self-microemulsions of traditional Chinese medicine

[0083] 1) Add limonene to the ointment in S2, stir and dissolve to form an oil phase system; wherein, the weight part of limonene is 0.1 parts;

[0084] 2) Mix Tween-80 and PEG-400 at 55°C and add them to the above oil phase system. Mix and stir evenly to obtain the Chinese medicine microemulsion, which is OCs-Da-Glu-3.

[0085] The weight ratio of limonene, Tween-80, and PEG-400 is 1:0.1:0.05.

[0086] <Comparative Example 1>

[0087] The ointment prepared according to steps S1 and S2 of Example 1 is the comparative example, which differs from Example 1 in that step S3 is omitted.

[0088] <Toxicity Test>

[0089] Seventy healthy mice, weighing 90-120g, were randomly divided into seven groups, with half males and half females in each group. The backs of the mice were shaved, and the transdermal agents prepared in Comparative Example 1 and Examples 1-6 were applied to the backs once a day for 14 consecutive days. No deaths or abnormal toxic reactions were observed in any group of mice. Their diet and activity were normal, and no mice died. After 90 days of administration, no abnormalities were observed in any group of mice. They were active, had smooth back fur, and had normal diets. There were no significant differences in blood counts, biochemical indicators, urinalysis indicators, and organ coefficients.

[0090] <Transdermal Experiment>

[0091] Female Kunming mice were anesthetized with 10% chloral hydrate, and abdominal skin was harvested. Hair was removed with 10% sodium sulfide, and the skin was washed and stored at -20℃ for later use. The dermal layer of the skin was fixed in a transdermal transdermal apparatus with the receiving pool facing upwards. The effective drug penetration area was 3 cm². 2Using 6 mL of methanol-physiological saline (1:1) as the receiving solution, the transdermal agents obtained from Comparative Example 1 and Examples 1-6 (i.e., the ointment in Comparative Example 1 and the traditional Chinese medicine microemulsion in Examples 1-6) were evenly applied to the test skin. The application amount was 1 mL. 24 h after administration, the receiving solution was filtered through a 0.22 μm microporous membrane, and the drug content in the receiving solution was determined by HPLC, which is the transdermal dose.

[0092] The HPLC analysis used a C18 column with a water (0.1% formic acid, 3% triethylamine):acetonitrile ratio of 75:15; a flow rate of 1.0 mL / min; a detection wavelength of 254 nm; a column temperature of 30 °C; and an injection volume of 10 μL.

[0093] After the transdermal experiment, mouse skin was cut along the edge of the diffusion cell. Unabsorbed drug was rinsed with 5 mL of distilled water. The skin was then cut into small pieces and methanol was added. The mixture was transferred to a 10 mL volumetric flask, sonicated for 1 hour, and then diluted to volume with methanol. The mixture was passed through a 0.22 μm microporous membrane and the amount of drug retained in the skin was determined by HPLC, which is the amount of drug accumulated in the skin. The parameters for the HPLC determination were as described above, and the experimental results are shown in Table 1.

[0094] Table 1 shows the transdermal absorption rate and skin accumulation of the main components in the transdermal agents of Examples 1-6 and Comparative Example 1.

[0095]

[0096] As can be seen from the above data, the transdermal absorption rates of the three main components in Comparative Example 1 are significantly lower than those of the main components in the transdermal agents of Examples 1-6, and their skin accumulation rates are also lower than those of the main components in the transdermal agents of Examples 1-6. This indicates that the transdermal effect and skin accumulation effect of the main components of the transdermal agent prepared according to the present invention are better than those of the transdermal agent prepared by ordinary methods. The transdermal agent prepared by the present invention achieves the purpose of promoting transdermal absorption through the hair follicle sebaceous gland, which can promote the transdermal absorption of the drug and maintain a high concentration of the drug in the skin, which is conducive to the accumulation of the drug in the epidermis and dermis.

[0097] Screening of oil phase, surfactants, and co-surfactants

[0098] To better illustrate the inventive process of this application, the screening process of surfactants and co-surfactants in this invention is now demonstrated.

[0099] 1. Azone and oleic acid, used as the oil phase, are both commonly used skin absorption enhancers in this field. We changed the types of surfactants and co-surfactants and prepared a self-microemulsion of traditional Chinese medicine according to the method in Example 1. We screened suitable combinations of oil phase, surfactant, and co-surfactant by measuring the drug loading (mg / g), particle size (nm), and particle size distribution (PDI) of the self-microemulsion. The specific screening design of surfactants and co-surfactants is shown in Tables 2 and 3.

[0100] in:

[0101] 1) Determination of drug loading: The contents of chlorogenic acid, forsythoside, and tanshinone in the above-mentioned self-microemulsions of traditional Chinese medicine (prepared according to the formulas in Tables 2 and 3) were determined by HPLC. The HPLC parameters were the same as those for transdermal loading. The drug loading was the sum of the contents of the three drugs (chlorogenic acid, forsythoside, and tanshinone). The specific steps were as follows: ① Standard sample: Accurately weigh appropriate amounts of chlorogenic acid, forsythoside, and tanshinone reference standards, place them in a brown volumetric flask, and add methanol to prepare a standard sample solution; ② Accurately weigh the self-microemulsion sample of traditional Chinese medicine and dissolve it in a quantitative amount of methanol. After shaking evenly, filter it through a filter membrane and take the supernatant for later use; ③ Dilute the supernatant 100 times to prepare the test solution, inject 10 μL, and determine the contents of chlorogenic acid, forsythoside, and tanshinone in the sample according to the determined chromatographic conditions. Calculate the contents of chlorogenic acid, forsythoside, and tanshinone in the sample by comparing the peak area values ​​with those of the standard sample.

[0102] 2) The particle size determination method is as follows: Take a sample of Chinese medicine microemulsion equivalent to 0.1g, dilute it 50 times with redistilled water at 37℃, and then measure its particle size with a 90Plus Particle Analyzer.

[0103] 3) PDI is calculated by measuring the proportion of diameters of individual particles in a sample. It is a well-known formula in the field. PDI is a dimensionless value reflecting the width of the particle size distribution, ranging from 0 to 1. The smaller the value, the more uniform the particle size and the more concentrated the particle size distribution. More specifically, when examining the size of emulsion droplets, their distribution is analyzed. The particle size measurement result is not only the average particle size, but also pays attention to the polydispersity index. Generally, a PDI < 0.3 is considered ideal, and a PDI < 0.15 is the most ideal, indicating a concentrated particle size distribution. A PDI in the range of 0.3 to 0.7 is questionable, and > 0.7 is unreliable. A low drug loading, slightly larger droplet size, and a wider droplet size distribution result in a high PDI; a high drug loading, small droplet size, and a narrower droplet size distribution result in a low PDI. It is necessary to screen formulations with high drug loading, small droplet size, and a low PDI.

[0104] Table 2. Screening design of surfactants and surface-active agents after azone was used as a skin absorption enhancer.

[0105] Formula ① Azone Decaglycerol monolaurate Polyglycerol Ricinol Formula ② Azone Twain-80 Polyglycerol Ricinol Formula ③ Azone Polyoxyacetic acid stearic acid Polyglycerol Ricinol Formula 4 Azone Decaglycerol monolaurate PEG-600 Formula 5 Azone Twain-80 PEG-600 Formula 6 Azone Polyoxyacetic acid stearic acid PEG-600 Formula ⑦ Azone Decaglycerol monolaurate Polyethylene glycol-dihydroxystearate Formula ⑧ Azone Twain-80 Polyethylene glycol-dihydroxystearate Formula 9 Azone Polyoxyacetic acid stearic acid Polyethylene glycol-dihydroxystearate

[0106] Table 3. Screening design of surfactants and surface-active agents after oleic acid is used as a skin absorption enhancer.

[0107]

[0108]

[0109] 2. Screening results of surfactants and co-surfactants

[0110] 1) When azone is used as a skin absorption enhancer, the experimental results of drug loading, particle size and particle size distribution (PDI) of each Chinese herbal microemulsion prepared according to the formula in Table 2 are shown in Table 4; where azone is 1 part in Table 4, and the corresponding numbers of other components represent the corresponding weight parts.

[0111] Table 4 Results of various indicators for formulation combinations when azone is used as a skin absorption enhancer

[0112]

[0113] As can be seen from Table 4, the herbal microemulsions prepared by formulations ①~④ and ⑥~⑨ in Table 2 have low drug loading, slightly large droplet size, wide droplet size distribution, and high PDI. However, the herbal microemulsion prepared by formulation ⑤, i.e., azone as oil phase: Tween-80 as surfactant: PEG-600 as co-surfactant = 1:0.2:0.15, shows high drug loading, small droplet size, narrow droplet size distribution, and low PDI. This is the optimal formulation combination when azone is used as a skin absorption promoter.

[0114] 2) When oleic acid is used as a skin absorption enhancer, the experimental results of drug loading, particle size and particle size distribution (PDI) of each Chinese herbal microemulsion prepared according to the formula in Table 3 are shown in Table 5; in Table 5, oleic acid is 1 part, and the corresponding numbers of other components represent the corresponding weight parts.

[0115] Table 5 Results of various indicators in formulation combinations when oleic acid is used as a skin absorption enhancer.

[0116]

[0117] As can be seen from Table 5, the herbal self-microemulsions prepared by formulations ①~⑥ and ⑧~⑨ in Table 3 have low drug loading, slightly large droplet size, wide droplet size distribution, and high PDI. However, the herbal self-microemulsion prepared by formulation ⑦, i.e., oleic acid: decaglycerol monolaurate: polyethylene glycol-dihydroxystearate = 1:0.3:0.1, has high drug loading, small droplet size, narrow droplet size distribution, and low PDI, making it the optimal formulation combination for oleic acid as a skin absorption promoter.

[0118] In summary, applying the above optimal formulation combination to the transdermal test also proved that the transdermal agent prepared by this formulation has good transdermal absorption and drug accumulation (see Table 1). This further illustrates the advantages of the traditional Chinese medicine self-microemulsion system of the present invention, such as easy transdermal absorption, good biocompatibility, and no cytotoxicity. It can load drugs well, increase the transdermal permeability of drugs, greatly reduce the dosage of drugs used, and also realize controlled sustained-release drug delivery during disease treatment. It is safe, convenient to use, and greatly improves the utilization rate of the patch.

[0119] The traditional Chinese medicine preparation prepared by this invention, which is absorbed transdermally through a microemulsion, contains the following herbs: honeysuckle, forsythia, isatis root, imperata root, reed rhizome, light bamboo leaf, and scrophularia. This preparation is suitable for both children and adults, and its main functions are to dispel wind and detoxify, clear heat and soothe the throat. It is especially effective for fever, sore throat, dry mouth, and thirst caused by exogenous wind-heat, as well as pharyngitis and tonsillitis caused by upper respiratory tract infections with the above symptoms. Among them, honeysuckle, which is sweet and cold, has the functions of relieving exterior syndromes, clearing heat and detoxifying, and is aromatic and purifying the body, and is the principal herb; forsythia, which is bitter and slightly cold, enters the heart, liver, and gallbladder meridians, and has the functions of clearing heat and detoxifying, reducing swelling and dissipating nodules, and treating wind-heat colds. Isatis root (Banlangen) clears heat, detoxifies, cools the blood, and soothes the throat, serving as an assistant herb; reed rhizome (Phragmites communis) is sweet and cold; it enters the lung and stomach meridians, clearing heat and generating fluids; Scrophularia root (Xuanshen) is sweet, bitter, and salty, slightly cold in nature, nourishing yin and clearing heat, bitter, salty, and cool, entering the lung and kidney meridians, nourishing yin and moistening dryness; Lophatherum gracile (Danzhuye) is sweet and bland, cold in nature; it enters the heart, lung, stomach, and bladder meridians; it is light and permeable, having the effects of clearing heat, relieving irritability, and promoting urination; Imperata cylindrica root (Bai Maogen) is sweet and cold; it enters the lung, stomach, and small intestine meridians; it cools the blood, stops bleeding, clears heat, and detoxifies, serving as an adjuvant herb. Therefore, it has a better therapeutic effect on fever, runny nose, cough, and bronchial and lung inflammation caused by influenza or coronavirus infection in children or adults.

[0120] Although embodiments of the present invention have been disclosed above, they are not limited to the applications listed in the specification and embodiments. They can be applied to various fields suitable for the present invention. For those skilled in the art, other modifications can be easily made. Therefore, without departing from the general concept defined by the claims and their equivalents, the present invention is not limited to the specific details and embodiments shown and described herein.

Claims

1. A method for preparing a transdermal absorption traditional Chinese medicine preparation using microemulsions, characterized in that, include: By weight, an extract of the traditional Chinese medicine composition is taken, and 0.01-0.05 parts of a drug-loaded self-adhesive are added, followed by the sequential addition of 0.1-0.2 parts of oil phase, 0.01-0.05 parts of surfactant, and 0.005-0.015 parts of co-surfactant to prepare a self-microemulsion system. The self-microemulsion system is then used to prepare a traditional Chinese medicine preparation. The extract of the traditional Chinese medicine composition uses 1-5 parts by weight of raw materials, and the raw materials comprise materials in a weight ratio of 3-8:3-8:4-10:5-10: The composition of the drug-loaded self-adhesive is 2~6:1~3:3~8, consisting of honeysuckle, forsythia, isatis root, imperata root, reed rhizome, lophatherum leaf, and scrophularia root. The self-adhesive is a compound of chitosan oligosaccharide and dopamine, prepared as follows: 0.1 mol each of chitosan oligosaccharide and dopamine are dissolved in 100 mL of ethanol to obtain a solution. 0.1 mol of a diacid compound is added to the solution at room temperature. After stirring and reacting for 2 hours, the ethanol is removed by vacuum distillation to obtain the drug-loaded self-adhesive. The diacid compound is either glutaric acid or adipic acid. The oil phase is any one or more of coconut oil, corn oil, azone, evening primrose oil, oleic acid, ethyl oleate, sunflower oil, and limonene; the surfactant is any one or more of Tween-20, Tween-60, Tween-80, decaglycerol monolaurate, polyethylene glycol glycerol decanoate, polyoxyacetic acid stearic acid, and cetearyl alcohol; the co-surfactant is any one or more of polyglycerol ricinoleate, cetyl polyethylene glycol, polyethylene glycol-dihydroxystearate, PEG-400, and PEG-600.

2. The preparation method of the self-microemulsion transdermal absorption traditional Chinese medicine preparation as described in claim 1, characterized in that, The Chinese medicinal materials include honeysuckle, forsythia, isatis root, imperata root, reed root, bamboo leaf, and scrophularia root in a weight ratio of 3:3:4:5:5:1.67:

3.

3. The method for preparing a self-microemulsion transdermal absorption traditional Chinese medicine preparation as described in claim 2, characterized in that, The oil phase is azone, the surfactant is Tween-80, and the co-surfactant is PEG-600; and the amount of azone is 0.1 parts, the amount of Tween-80 is 0.02 parts, and the amount of co-surfactant is 0.015 parts.

4. The preparation method of the self-microemulsion transdermal absorption traditional Chinese medicine preparation as described in claim 2, characterized in that, The oil phase is oleic acid, the surfactant is decaglycerol monolaurate, the co-surfactant is polyethylene glycol-dihydroxystearate, and the amount of oleic acid is 0.1 parts, the amount of decaglycerol monolaurate is 0.03 parts, and the amount of polyethylene glycol-dihydroxystearate is 0.01 parts.

5. The method for preparing a self-microemulsion transdermal absorption traditional Chinese medicine preparation as described in claim 2, characterized in that, The oil phase is limonene, the surfactant is Tween-80, the co-surfactant is PEG-400, and the limonene content is 0.1 parts, the Tween-80 content is 0.01 parts, and the PEG-400 content is 0.005 parts.

6. The method for preparing a self-microemulsion transdermal absorption traditional Chinese medicine preparation as described in claim 1, characterized in that, The preparation process of the self-microemulsion system specifically includes the following steps: S1. By weight, take 1 part of the Chinese herbal raw material and place it in 10 parts of water. After water extraction twice, add 0.1 part of gypsum and boil for 1 hour. After standing and cooling, filter to obtain crude extract. Add 95% ethanol to the crude extract and let it stand for 24 hours. Take the supernatant, which is the extract. Add 0.01 part of drug-loaded self-adhesive to the extract, stir and concentrate to paste to obtain ointment. S2. Add the oil phase to the ointment and stir to dissolve the ointment to form an oil phase system; S3. Mix and stir the surfactant and the co-surfactant at 50~60°C until homogeneous to obtain the treated product; S4. Add the treated material to the oil phase system and stir evenly to obtain a self-microemulsion of traditional Chinese medicine, which is the self-microemulsion system.

7. The method for preparing a self-microemulsion transdermal absorption traditional Chinese medicine preparation as described in claim 1, characterized in that, The dosage form of the traditional Chinese medicine preparation obtained by the self-microemulsion system is one of the following: tincture, patch, film, or spray.

8. The traditional Chinese medicine preparation prepared by the method for preparing a self-microemulsion transdermal absorption traditional Chinese medicine preparation as described in claim 1.

9. The use of the traditional Chinese medicine preparation as described in claim 8 in the preparation of a medicine for treating fever, sore throat, dry mouth, and thirst caused by exogenous wind-heat, as well as pharyngitis and tonsillitis caused by upper respiratory tract infection.

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