Traditional Chinese medicine menstrual formula hydrogel carsickness patch as well as preparation method and application thereof

Abstract

The invention relates to the technical field of carsickness patches, and particularly discloses a traditional Chinese medicine menstrual prescription hydrogel carsickness patch which is prepared from the following raw materials: orange peel soup, a cross-linking skeleton, a cross-linking agent, a cross-linking regulator, a humectant, a thickening agent, urea and water. The traditional Chinese medicine decoction is derived from a traditional Chinese medicine classical famous formula orange peel decoction and has the effects of warming middle-jiao, harmonizing stomach, calming adverse-rising energy and arresting vomiting; according to the invention, 4.5-5.5% of urea is selected as a transdermal penetrating agent of the orange peel soup hydrogel patch, so that the orange peel soup hydrogel has higher early-stage permeability, can quickly take effect and quickly relieve the carsickness symptom, and the hydrogel carsickness patch provides a new choice for people who have carsickness trouble and need to take a bus to go out frequently.

Description

Technical Field

[0001] The invention relates to the technical field of motion sickness patches, in particular to a traditional Chinese medicine hydrogel motion sickness patch and a preparation method and application thereof. Background Art

[0002] In recent years, with the improvement of people's living standards and the increase in travel needs, more and more convenient means of transportation have emerged. However, during the ride, the body senses changes in the outside world, resulting in a certain amount of abnormal motion stimulation of the vestibular receptors, which generates nerve impulses and makes the body overly sensitive. Motion sickness is a common physiological phenomenon. Almost everyone may experience motion sickness. Vomiting accompanied by motion sickness has become one of the biggest troubles for people with motion sickness. Motion sickness patches use natural Chinese herbal medicines and add penetrants to promote the main active substances of Chinese herbal medicines to enter the body through the skin, helping people with motion sickness to spend their travels more comfortably.

[0003] Tangerine peel soup is a famous prescription created by Zhang Zhongjing, a medical saint in the Han Dynasty. It was first recorded in the Synopsis of the Golden Chamber. It is composed of two Chinese medicines, tangerine peel (Citri Reticulatae Pericarpium) and ginger (Zingiberis Recens Rhizoma), in a ratio of 1:2. Both of them are Chinese medicines with the same origin as food. Tangerine peel and ginger in the prescription can warm the yang and dispel cold, help the spleen and remove dampness; ginger and tangerine peel can harmonize the stomach and dry dampness, and enhance the effect of regulating qi, lowering adverse reactions and stopping vomiting; the two medicines are used together to warm the stomach, lower adverse reactions and stop vomiting. In ancient medical books, tangerine peel soup is often used to treat coldness in the stomach, vomiting and nausea, hiccups and belching, etc. It is now clinically used for nausea and vomiting during pregnancy, nausea and vomiting after chemotherapy, and various clinical intractable hiccups. Modern studies have shown that tangerine peel soup has digestive system effects, such as regulating gastrointestinal motility, promoting gastric emptying, increasing the abundance of beneficial intestinal flora and reducing the abundance of harmful flora.

[0004] Patches are thin sheet preparations that can be attached to the skin and can produce systemic or local effects. Modern transdermal preparations are patches or patch drugs that are absorbed through the skin and can enter the body quickly and permanently according to the dosage required by the disease through a controlled release mechanism. As a natural synthetic material, the hydrogel matrix is ​​scientifically formulated, non-toxic, non-irritating, and has no allergic reaction to human skin. After being made into a patch, there will be no side effects such as skin whitening, itching or erythema. Therefore, hydrogel patches are widely studied as a novel transdermal preparation.

[0005] According to "Hou Xuemei. Research on the mechanism and application of hydrogel patch matrix [D]. Shanghai: Second Military Medical University, 2010." Hydrogel patches are mainly composed of three parts: (1) backing layer; (2) hydrogel layer, i.e. matrix layer; (3) anti-adhesive layer. Among them, the hydrogel layer (matrix layer) is the main component and key layer of the hydrogel patch, which determines the main performance of the patch. The matrix layer material of the hydrogel is mainly composed of the following components: cross-linking skeleton material (Frame Material), cross-linking agent (Cross-linking Agent); cross-linking regulator (Adjustor), viscosity increaser (Viscosity Increaser), moisturizer (Humectant), transdermal penetration enhancer, additives and water. However, there are great difficulties in establishing the stability and in vitro release test methods of hydrogel patches. The reason is that the hydrogel patch is a special matrix (high water content and continuous cross-linking reaction) and the research on the release mechanism is not in-depth enough.

[0006] After preliminary research, we found that the tangerine peel soup hydrogel made with commonly used transdermal penetration enhancers has a low initial permeability, cannot quickly take effect to relieve motion sickness symptoms, and cannot meet the product demand for timely relief of motion sickness. Therefore, there is an urgent need for a tangerine peel soup hydrogel motion sickness patch with high initial permeability to adapt to the application scenarios of motion sickness patches. Summary of the invention

[0007] The purpose of the present invention is to overcome the deficiencies of the prior art and provide a traditional Chinese medicine hydrogel motion sickness patch and a preparation method and application thereof, so as to at least achieve the effect of timely relieving motion sickness and vomiting.

[0008] The objective of the present invention is achieved through the following technical solutions:

[0009] A traditional Chinese medicine hydrogel motion sickness patch is composed of the following raw materials: orange peel soup, a cross-linking skeleton, a cross-linking agent, a cross-linking regulator, a moisturizing agent, a thickener, urea and water, wherein the amount of urea is 4.5-5.5% of the total weight.

[0010] Preferably, the amount of urea is 5% of the total weight.

[0011] Furthermore, the preparation method of the tangerine peel soup is as follows: by weight, 1 part of tangerine peel is mixed with 2 parts of ginger, and then 12-18 parts of water are added for soaking and reflux extraction;

[0012] The soaking time is 1.5-2.5h;

[0013] The reflux extraction was performed twice, and each extraction time was 3-5 hours.

[0014] Furthermore, the raw materials are calculated by weight as follows: 9-11 parts of a cross-linking skeleton, 0.2-0.3 parts of a cross-linking agent, 0.5-0.7 parts of a cross-linking regulator, 55-65 parts of a moisturizer, 2-3 parts of a thickener, and 15-25 parts of water.

[0015] Preferably, the cross-linked skeleton comprises 10 parts, a cross-linking agent 0.2 parts, a cross-linking regulator 0.6 parts, a humectant 60 parts, a thickener 2 parts and water 20 parts.

[0016] Furthermore, the cross-linked skeleton includes at least one of sodium polyacrylate NP700, sodium polyacrylate NP600 or sodium polyacrylate NP800.

[0017] Preferably, the cross-linked skeleton is sodium polyacrylate NP700.

[0018] Furthermore, the cross-linking agent includes at least one of aluminum glycolate, aluminum sulfate, alum, crystalline aluminum chloride or aluminum glycinate.

[0019] Preferably, the cross-linking agent is aluminum glycolate.

[0020] Furthermore, the cross-linking regulator includes at least one of tartaric acid, citric acid, malic acid, ethylenediaminetetraacetic acid or lactic acid.

[0021] Preferably, the cross-linking regulator is tartaric acid.

[0022] Furthermore, the moisturizing agent includes at least one of glycerin, sorbitol, propylene glycol and polyethylene glycol.

[0023] Preferably, the humectant is glycerin.

[0024] Furthermore, the thickener includes at least one of carbomer 980, gelatin, polyvinyl alcohol or peach gum.

[0025] Preferably, the thickener is Carbomer 980.

[0026] The preparation method of the hydrogel motion sickness patch comprises the following steps:

[0027] S1: uniformly mixing the cross-linked skeleton and the moisturizer, and then sequentially adding orange peel soup, a thickener, a cross-linking agent and urea to obtain phase A;

[0028] S2: dissolving the crosslinking regulator in the water to obtain phase B;

[0029] S3: Mix the phase A and the phase B, stir them into a viscous semi-solid fluid, let them stand, and then evenly apply them on a non-woven fabric to obtain.

[0030] Furthermore, the preparation method further comprises:

[0031] S4: Cover the material obtained in step S3 with a backing, place at room temperature for 24 hours, punch and package.

[0032] Furthermore, the hydrogel motion sickness patch is applied to acupuncture points that are effective in relieving motion sickness and vomiting.

[0033] Furthermore, the acupoints include Fengchi, Neiguan, Shenmen, Baihui, Dazhui, Jiuwei, Hegu, Shaoshang, Zusanli or Taixi.

[0034] Furthermore, when used, the present invention can also be combined with the plant seed fenugreek seed to stimulate the relevant acupoints through acupoint pressing method, and combined with the effective ingredients of tangerine peel soup to penetrate the skin to play the effect of reducing adverse reactions and stopping vomiting, so as to better play the effect of the acupoint patch in relieving motion sickness and vomiting.

[0035] The beneficial effects of the present invention are:

[0036] 1. The Chinese medicine hydrogel motion sickness patch of the present invention combines the famous recipe of Tangerine Peel Soup created by Zhang Zhongjing, the medical saint of the Han Dynasty. The ginger in the recipe has the functions of dispelling cold, warming the middle and stopping vomiting, resolving phlegm and relieving cough, and detoxifying fish and crabs, and the tangerine peel has the effects of drying dampness and resolving phlegm, regulating qi and strengthening the spleen. The present invention is prepared by following the ancient prescription ratio, wherein tangerine peel and ginger are both Chinese medicines of the same origin as medicine and food. Tangerine peel is combined with ginger, which warms yang and dispels cold and helps the spleen to remove dampness; ginger is combined with tangerine peel, which harmonizes the stomach and dries dampness, and the effects of regulating qi, descending adverse and stopping vomiting are enhanced; the two medicines are used together to warm the middle and harmonize the stomach, descend adverse and stop vomiting.

[0037] 2. The present invention selects 5% urea as the transdermal permeation agent of the tangerine peel soup hydrogel patch, so that the tangerine peel soup hydrogel has a higher initial permeability, can take effect quickly, and quickly relieve motion sickness symptoms.

[0038] 3. The present invention uses high performance liquid phase experiments to investigate the factors affecting the extraction efficiency of tangerine peel soup, such as soaking time, reflux extraction time and reflux extraction times, and their influence on the contents of nobiletin and hesperidin in tangerine peel soup, and uses them as indicators to determine the reflux extraction process of tangerine peel soup. The present invention well preserves the effective ingredients in the raw materials, among which tangerine peel, hesperidin, nobiletin, 6-gingerol and 8-gingerol are all effective ingredients of motion sickness patches, and can well exert the medicinal effect of tangerine peel soup.

[0039] 4. The present invention combines traditional Chinese medicine acupoints, and the patch can be attached to the Fengchi, Neiguan, Shenmen, Baihui, Dazhui, Jiuwei, Hegu, Shaoshang, Zusanli and Taixi acupoints when used. At the same time, the active ingredients in the orange peel soup rely on the patch to enter the acupoints to better relieve motion sickness and vomiting.

[0040] 5. In terms of product form, the motion sickness acupoint patch is easy to use, has significant effects, and is affordable, providing a safe and effective new choice for people who suffer from motion sickness when driving. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 The HPLC chromatogram of the orange peel soup in Example 1, wherein peaks 1-6 correspond to: 1. hesperidin; 2. nobiletin; 3. tangeretin; 4. 8-gingerol; 5. 6-shogaol; 6. 10-gingerol;

[0042] Figure 2 This is a graph showing the results of a single factor investigation of the reflux extraction of the orange peel decoction in Example 1;

[0043] Figure 3 This is a graph showing the results of a single factor investigation for preparing the hydrogel matrix in Example 3;

[0044] Figure 4 These are the experimental results of the in vitro transdermal experiment in Example 4. DETAILED DESCRIPTION

[0045] The technical solution of the present invention is further described in detail below in conjunction with the accompanying drawings, but the protection scope of the present invention is not limited to the following.

[0046] Example 1

[0047] Investigation on the preparation process of tangerine peel soup hydrogel patch:

[0048] (1) Detection of indicator component content

[0049] ① Preparation of reference solution

[0050] Accurately weigh appropriate amounts of 10-gingerol, 8-gingerol, 6-shogaol, nobiletin, tangeretin, and hesperidin reference substances, add appropriate amounts of methanol to prepare reference substance mother solutions of certain concentrations (10-gingerol: 0.026 mg / mL; 8-gingerol: 0.024 mg / mL; 6-shogaol: 0.310 mg / mL; nobiletin: 0.239 mg / mL; tangeretin: 0.198 mg / mL; hesperidin: 0.755 mg / mL), take 1 mL of each active ingredient reference substance mother solution and place it in a 10 mL volumetric flask, add methanol to the scale line, mix well and set aside.

[0051] ② Preparation of test solution

[0052] The solution of the tangerine peel soup was heated and refluxed, and filtered while hot to obtain the filtrate. 1 mL of the sample filtrate was accurately drawn and placed in a 10 mL volumetric flask, and methanol was added to dilute to the mark, and shaken to obtain the chromatographic conditions mentioned above. The HPLC chromatogram of the tangerine peel soup was obtained, as shown in FIG. Figure 1 .

[0053] ③Chromatographic conditions

[0054] Thermo Hypersil GOLD C18 chromatographic column, mobile phase is acetonitrile (A): water (B), gradient elution (0-5 min, 20%-30% A; 5-10 min, 30%-40% A; 10-15 min, 40% A; 15-20 min, 40%-60% A; 20-25 min, 60%-70% A; 25-30 min, 70%-85% A); flow rate 1 mL / min; measurement wavelength 280 nm, 283 nm; column temperature 30°C; injection volume 10 μL.

[0055] ④Establishment of standard curve

[0056] Weigh 10-gingerol, 6-shogaol, 8-gingerol, tangeretin, nobiletin, and hesperidin in appropriate amounts, add methanol to prepare mother solutions with concentrations of 0.026 mg / mL, 0.310 mg / mL, 0.024 mg / mL, 0.198 mg / mL, 0.239 mg / mL, and 0.755 mg / mL, respectively. Dilute the prepared mother solutions according to the two-fold dilution method to obtain standard curve concentration gradient solutions. After each 10ul solution is passed through a 0.22 μm filter membrane, the peak area is determined according to the above chromatographic conditions, and a linear regression is performed with the reference substance concentration as the abscissa X and the peak area as the ordinate Y. The linear regression calculation is performed, and the results are shown in Table 1.

[0057] Table 1 Regression equations and linear ranges of the six index components in Jupi decoction

[0058]

[0059] ⑤Methodological investigation

[0060] Conduct methodological investigations such as stability experiments, precision experiments, and repeatability experiments.

[0061] (2) Single factor experiment

[0062] The results of the reflux extraction of orange peel soup are as follows Figure 2 shown.

[0063] Soaking time: Take 27.6g of dried tangerine peel and 55g of ginger slices, soak for 0.5h, 1h, 1.5h, 2h, 2.5h respectively, fix the amount of water added to 6 times, heat and reflux for 3h, and reflux extraction twice. The total content of active ingredients such as hesperidin, nobiletin, tangeretin, 8-gingerol, 6-shogaol and 10-gingerol was used as the evaluation index, and it was determined that the extraction effect was best when the soaking time was 2h.

[0064] Reflux time: Take 27.6g of dried tangerine peel and 55g of ginger slices, soak for 1.5h, add 6 times of water, heat and reflux for 1, 2, 3, 4, 5h, respectively, and reflux extraction twice. The total content of active ingredients such as hesperidin, nobiletin, tangeretin, 8-gingerol, 6-shogaol and 10-gingerol was used as the evaluation index, and it was determined that the extraction effect was best when the reflux time was 4h.

[0065] Amount of water added: Take 27.6g of dried tangerine peel slices and 55g of ginger slices, soak for 1.5h, add 2, 4, 6, 8, 10 times of water respectively, heat and reflux for 3h, and reflux extraction twice. The total content of active ingredients such as hesperidin, nobiletin, tangeretin, 8-gingerol, 6-shogaol and 10-gingerol was used as the evaluation index, and it was determined that the extraction effect was best when the amount of water added was 6 times.

[0066] (3) Optimization of extraction process by central complex design-response surface methodology

[0067] On the basis of single factor experiment, soaking time (A), reflux time (B), water addition (C) were used as independent variables, and the total content of active ingredients such as hesperidin, nobiletin, tangeretin, 8-gingerol, 6-shogaol and 10-gingerol was used as the response value (Y). A three-factor three-level response surface experiment was designed, and the Box-Behnken experimental design principle of Design-Expert software was used to optimize the extraction process parameters. The results showed that the best extraction effect was obtained when tangerine peel and ginger were in a ratio of 1:2, 4 times the amount of water was added, soaked for 2h, refluxed and extracted twice, and each extraction was 4h. The results were proved to be stable and reliable through verification experiments.

[0068] Example 2

[0069] Verification of the effectiveness of orange peel soup in relieving motion sickness and vomiting:

[0070] (1) Animal grouping and kaolin intake determination

[0071] Rats were housed in single cages for 3-5 days to adapt to kaolin, during which they were free to drink water and given sufficient rat food. When the animals showed no obvious behavior of chewing kaolin, the formal experiment was conducted. The rats were divided into 6 groups: high-dose tangerine peel soup group, medium-dose tangerine peel soup group, low-dose tangerine peel soup group, blank group, model group and positive drug group, with 8 rats in each group. Rats in the blank and model groups were not given any medication, while the positive drug group was gavaged with 0.01 ml / g of metoclopramide tablets (concentration of 0.04 mg / ml) every day, and the low, medium and high drug groups were gavaged with 5.5 g / kg, 11 g / kg and 22 g / kg every day, respectively. 0.5 h after administration, a motion sickness model was established on a small animal centrifuge. The speed was maintained at 100 rpm clockwise for 20 min on the first day, at 100 rpm clockwise for 30 min on the second day, and at 100 rpm clockwise for 40 min on the third day. This cycle was used to establish the model for 7 consecutive days. During this period, the kaolin intake and feed intake of rats in each cage were weighed once every 48 hours, and the scattered kaolin and feed crumbs were collected and weighed together. The results showed that the administration of tangerine peel soup could significantly improve the pica behavior of rats, suggesting that tangerine peel soup has the effect of anti-motion sickness and vomiting.

[0072] (2) Detection of gastric emptying, intestinal propulsion rate and related factors in rats

[0073] The rats were gavaged with nutrient paste and fasted for 24 hours before the last administration, but not water. 30 minutes after the last administration, each rat was given 1.5 ml of nutrient paste and motion sickness treatment (clockwise at 100 rpm for 30 minutes).

[0074] After motion sickness treatment, rats were anesthetized by intraperitoneal injection of 5% chloral hydrate, blood was collected from the abdominal aorta, and centrifuged at 4°C 3000r / min for 15min. Serum was collected and stored at -80°C for later use. The specific operation steps of ELISA were carried out according to the instructions of the kit to test factors such as CPGR, CCK, and INS. At the same time, the stomach and small intestine of the rats were taken out to measure the gastric emptying rate and long propulsion rate.

[0075] The results showed that after intervention with tangerine peel soup, the intestinal propulsion rate of rats was significantly promoted, and the gastric emptying rate of rats was also promoted to a certain extent. At the same time, tangerine peel soup can also improve the levels of factors such as CPGR, CCK, and INS in rats, indicating that tangerine peel soup can relieve motion sickness and vomiting by improving gastrointestinal function and hormone levels.

[0076] Example 3

[0077] Preparation of orange peel soup hydrogel patch:

[0078] (1) Selection and preparation process of hydrogel patch matrix materials

[0079] Select appropriate hydrogel patch matrix materials to prepare orange peel soup hydrogel patch: prepare raw materials, cross-linking skeleton-sodium polyacrylate NP700 10g, cross-linking agent-aluminum glycolate 0.2g, cross-linking regulator-tartaric acid 0.6g, moisturizer-glycerol 60g, thickener-carbomer 9802.0g, water addition amount 20g. Transdermal absorption enhancer-5% urea.

[0080] The preparation process of the hydrogel patch is as follows: the mixed solution of the cross-linked skeleton and the moisturizer is stirred at a low speed to mix evenly, the API, thickener, cross-linking agent and transdermal absorption enhancer are added in sequence, and the mixture is stirred at a low speed to mix evenly as phase A, and the cross-linking regulator is dissolved in an appropriate amount of water as phase B. Phases A and B are mixed at a certain speed and stirred to form a viscous semi-solid fluid. After being left for a while, the fluid is evenly coated on the non-woven fabric, covered with a backing, left at room temperature for 24 hours, punched and packaged.

[0081] (2) The single factor experiment investigated the dosage range of each matrix material, as shown in Table 2:

[0082] Table 2 Hydrogel patch quality score table

[0083]

[0084]

[0085] Cross-linked skeleton: other matrix materials are fixed, and the dosage of the cross-linked skeleton NP700 is 6.0g, 7.0g, 8.0g, 9.0g, and 10.0g respectively. Patches are prepared according to the hydrogel patch preparation process, and the dosage of NP700 is determined to be 8.0g based on the quality score as the evaluation standard.

[0086] Cross-linking agent: other matrix materials were fixed, and the dosage of the cross-linking agent aluminum glycolate was 0.1g, 0.2g, 0.3g, 0.4g, and 0.5g respectively. The patches were prepared according to the hydrogel patch preparation process, and the dosage of aluminum glycolate was determined to be 0.2g based on the quality score as the evaluation standard.

[0087] Cross-linking regulator: other matrix materials are fixed, and the dosage of the cross-linking regulator tartaric acid is 0.3g, 0.4g, 0.5g, 0.6g, and 0.7g respectively. The patches are prepared according to the hydrogel patch preparation process, and the dosage of tartaric acid is determined to be 0.6g based on the quality score as the evaluation standard.

[0088] Moisturizer: other matrix materials are fixed, and the dosage of the moisturizer glycerin is 20g, 30g, 40g, 50g, and 60g respectively. The patches are prepared according to the hydrogel patch preparation process, and the dosage of glycerin is determined to be 50g based on the quality score as the evaluation standard.

[0089] Thickener: other matrix materials were fixed, and the dosage of thickener carbomer was 1.0g, 2.0g, 3.0g, 4.0g, and 5.0g respectively. The patches were prepared according to the hydrogel patch preparation process, and the dosage of carbomer was determined to be 2.0g based on the quality score as the evaluation standard.

[0090] Amount of water added: Keeping other matrix materials fixed, the amounts of water used were 20g, 30g, 40g, 50g, and 60g respectively. The patches were prepared according to the hydrogel patch preparation process, and the amount of water was determined to be 30g based on the quality score as the evaluation standard.

[0091] The results of single factor investigation on the preparation of hydrogel matrix are shown in Figure 3 . The results showed that the cross-linking regulator tartaric acid, cross-linking agent aluminum glycolate, thickener carbomer 980, etc. had little effect on the quality of the hydrogel patch. Therefore, according to the single factor results, the dosage can be determined as 0.2g of cross-linking agent, 0.6g of cross-linking regulator, and 2.0g of thickener 980. The cross-linking skeleton NP700, humectant glycerol, and the amount of water added have a great influence on the quality of the hydrogel patch, so the central point design response surface method is used to further optimize the prescription.

[0092] (3) Central composite design-response surface optimization of patch prescription

[0093] As can be seen from the results of the single factor test, cross-linking agent, cross-linking regulator and thickener have little effect on the quality of hydrogel patch. Therefore, the dosage of cross-linking agent, cross-linking regulator and thickener determined by the single factor result is its optimal value. With cross-linked skeleton (A), humectant (B), water addition (C) as independent variables, quality score as response value (Y), three-factor three-level response surface test is designed, and the Box-Behnken experimental design principle of Design-Expert software is used to optimize the distribution ratio of each group. The best hydrogel matrix material ratio is cross-linked skeleton 10.0g, humectant 60g, water addition 20g, and it is estimated that the comprehensive score of hydrogel is 90.837. And three verification experiments are carried out based on the conditions, and the actual quality scores of hydrogel are obtained as 89.667, 92.433, and 92.233, respectively, and the relative standard deviation with the predicted value is 1.42%, and the result shows that the patch quality prepared by the obtained hydrogel matrix material ratio is stable.

[0094] Example 4

[0095] Screening of transdermal penetration enhancers:

[0096] Hesperidin, tangeretin, nobiletin, 6-gingerol and 8-gingerol were selected as index components, and the contents of index components in tangerine peel soup beverage product were detected by triple quadrupole liquid spectrometry-mass spectrometry.

[0097] ①Chromatographic conditions

[0098] Liquid chromatography: using a thermo scientific C18 (100 mm × 3.0 mm, 2.6 μm) column, with 0.1% formic acid aqueous solution as mobile phase A, acetonitrile as mobile phase B, gradient elution (0-5 min, 5-70% B; 5-11 min, 70-75% B, 11-12 min, 75-80% B; 12-13 min, 80-5% B; 13-14 min, 5% B), flow rate of 0.3 mL min-1, column temperature of 30 ° C, injection volume of 2 μL.

[0099] Mass spectrometry conditions: set the electrospray ion source (ESI) temperature to 450°C; ion spray voltage (IS) to 5500V / -4500V; ion source gas I (GSI) to 50kPa, gas II (GSI) to 50kPa, and curtain gas (CUR) to 30kPa. The collision-induced ionization parameter was set to low. Data acquisition used the MRM mode.

[0100] ②Establishment of standard curve

[0101] 6-gingerol, hesperidin, tangeretin, 8-gingerol, and nobiletin 4.86 mg, 5.02 mg, 5.28 mg, 5.10 mg, and 5.02 mg were accurately weighed respectively, and methanol was added to the scale line in a 10 mL volumetric flask, shaken, and mixed evenly to prepare a mother solution. The prepared mother solutions were diluted respectively to obtain a standard curve concentration gradient solution. The peak area was measured under mass spectrometry conditions, and a linear regression calculation was performed with the reference substance concentration as the abscissa X and the peak area as the ordinate Y. The results are shown in Table 3.

[0102] Table 3 Regression equations and linear ranges of the five transdermal index components in Jupi decoction

[0103]

[0104] ⑤Methodological investigation

[0105] Conduct methodological investigations such as stability experiments, precision experiments, and repeatability experiments.

[0106] (2) In vitro transdermal test

[0107] Preparation of orange peel soup hydrogel patch: prepare raw materials, cross-linked skeleton-sodium polyacrylate NP700, cross-linking agent-aluminum glycolate, cross-linking regulator-tartaric acid, moisturizer-glycerol, thickener-carbomer 980, transdermal absorption enhancer. Among them, the amount of cross-linked skeleton is 10.0g, the cross-linking agent is 0.2g, the cross-linking regulator is 0.6g, the moisturizer is 60.0g, the viscosity enhancer is 2.0g, and the water is 20.0g. The transdermal absorption enhancer is set to the following different mass fractions for testing: 5%, 10% urea; 3%, 5% oleic acid; 2%, 4% azone; 3%, 5% menthol; 10%, 20% propylene glycol.

[0108] Taking PBS as the absorption medium, combined with the actual situation, common penetration enhancers were selected to investigate the effect of the citrus peel extract hydrogel patch on transdermal absorption.

[0109] After the healthy rats were killed, their abdomens were depilated with depilatory cream, subcutaneous fat was removed, and the skin was cleaned with saline and dried with filter paper for later use. The treated mouse skin was placed on a Franz vertical diffusion cell, and the diffusion cell supply chamber and receiving chamber were fixed with spring clips. The skin stratum corneum was facing the supply cell, and PBS was injected into the receiving cell as the absorption medium. A magnetic stirrer was placed in the receiving cell and placed on a magnetic stirrer. Stirring was performed at 300 rpm and maintained in a 37°C water bath. During the experiment, the blank patch and the patch samples containing different penetration enhancers were cut into small pieces suitable for the samples to be tested as required, and then the patches were attached to the surface of the mouse skin to eliminate the bubbles between the patches and the skin. 5 ml of the receiving solution was drawn at 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 h, and the blank receiving solution of the same volume was taken out and supplemented at the same time. The obtained samples were filtered with a 0.45 μm microporous filter membrane, and the filtrate was taken. The content of the index components of the orange peel soup was determined by triple quadrupole liquid chromatography-mass spectrometry. According to the concentration of the sample at each sampling point, the cumulative permeation per unit area Q is calculated according to the following formula, and the permeation curve is drawn to select the appropriate transdermal penetration enhancer:

[0110] Where Cn and Ci are the drug concentrations measured at the nth and ith sampling points, respectively (μg ml-1), V and V0 are the receiving pool volume and sampling volume, respectively (ml), and A is the penetration area (cm 2 ).

[0111] The results are as follows Figure 4 The results showed that after 24 hours of cumulative permeation, the tangerine peel soup hydrogel patch with 5% urea as the permeation enhancer had the highest cumulative permeation per unit area, reaching 31.4 μg / cm 2 And within 12 hours, the transdermal curve of the 5% urea-loaded jupitang hydrogel patch rose steadily. In summary, 5% urea was finally selected as the transdermal permeation agent of the jupitang hydrogel patch, and its effect was significantly better than other transdermal permeation enhancers.

[0112] The above is only a preferred embodiment of the present invention. It should be understood that the present invention is not limited to the form disclosed herein, and should not be regarded as excluding other embodiments, but can be used in various other combinations, modifications and environments, and can be modified within the scope of the concept described herein through the above teachings or the technology or knowledge of the relevant field. The changes and modifications made by those skilled in the art shall not deviate from the spirit and scope of the present invention, and shall be within the scope of protection of the claims attached to the present invention.

Claims

1. A traditional Chinese medicine hydrogel motion sickness patch, characterized in that: The invention is composed of the following raw materials: orange peel soup, cross-linking skeleton, cross-linking agent, cross-linking regulator, moisturizing agent, thickening agent, urea and water; The amount of urea used is 4.5-5.5% of the total weight.

2. The hydrogel motion sickness patch according to claim 1, characterized in that: The preparation method of the tangerine peel soup is as follows: by weight, 1 part of tangerine peel is mixed with 2 parts of ginger, and then 12-18 parts of water are added for soaking and reflux extraction.

3. The hydrogel motion sickness patch according to claim 1, characterized in that: The raw materials are calculated by weight as follows: 9-11 parts of a cross-linking skeleton, 0.2-0.3 parts of a cross-linking agent, 0.5-0.7 parts of a cross-linking regulator, 55-65 parts of a moisturizing agent, 2-3 parts of a thickener and 15-25 parts of water.

4. The hydrogel motion sickness patch according to claim 1, characterized in that: The cross-linked skeleton includes at least one of sodium polyacrylate NP700, sodium polyacrylate NP600 or sodium polyacrylate NP800.

5. The hydrogel motion sickness patch according to claim 1, characterized in that: The cross-linking agent includes at least one of aluminum glyoxylate, aluminum sulfate, alum, crystalline aluminum chloride or aluminum glycinate.

6. The hydrogel motion sickness patch according to claim 1, characterized in that: The cross-linking regulator includes at least one of tartaric acid, citric acid, malic acid, ethylenediaminetetraacetic acid or lactic acid.

7. The hydrogel motion sickness patch according to claim 1, characterized in that: The moisturizing agent includes at least one of glycerin, sorbitol, propylene glycol and polyethylene glycol.

8. The hydrogel motion sickness patch according to claim 1, characterized in that: The thickener comprises at least one of carbomer 980, gelatin, polyvinyl alcohol or peach gum.

9. The method for preparing the hydrogel motion sickness patch according to any one of claims 1 to 8, characterized in that: The following steps are involved: S1: uniformly mixing the cross-linked skeleton and the moisturizer, and then sequentially adding orange peel soup, a thickener, a cross-linking agent and urea to obtain phase A; S2: dissolving the crosslinking regulator in the water to obtain phase B; S3: Mix the phase A and the phase B, stir them into a viscous semi-solid fluid, and then evenly apply them on a non-woven fabric to obtain.

10. The method for using the hydrogel motion sickness patch according to any one of claims 1 to 8, characterized in that: The hydrogel motion sickness patch is applied to acupuncture points effective for relieving motion sickness and vomiting.

11. The method of use according to claim 10, characterized in that: The acupoints include Fengchi, Neiguan, Shenmen, Baihui, Dazhui, Jiuwei, Hegu, Shaoshang, Zusanli or Taixi.

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