Gel emplastrum for treating rheumatoid arthritis and preparation method thereof

Abstract

The invention discloses a gel emplastrum for treating rheumatoid arthritis and a preparation method of the gel emplastrum. The gel emplastrum comprises a backing layer, an emplastrum body layer and an anti-sticking layer, the paste layer is prepared from the following components in parts by weight: 1 to 5 parts of sodium polyacrylate, 0.05 to 0.25 part of dihydroxyaluminium aminoacetate, 0.1 to 2 parts of DL-tartaric acid, 0.025 to 0.2 part of kaolin, 10 to 30 parts of glycerol, 1 to 10 parts of Tibetan medicine composition extract, 1 to 10 parts of aromatic water, 0.5 to 5 parts of wine-processed benzoin and 0.5 to 1.5 parts of penetration enhancer. The Tibetan medicine concept is adopted for treating rheumatoid arthritis, and the gel emplastrum has an excellent penetration promoting effect, can play a curative effect to the maximum extent, remarkably improves patient compliance and is safe to use.

Description

Technical Field

[0001] The invention belongs to the technical field of traditional Chinese medicine, and specifically relates to a gel patch for treating rheumatoid arthritis and a preparation method thereof. Background Art

[0002] Rheumatoid arthritis (RA) is a chronic progressive autoimmune disease characterized by chronic inflammation, synovial hyperplasia, and abnormal vascular proliferation. Currently, the clinical treatment of rheumatoid arthritis mainly uses chemical drugs, such as glucocorticoids, nonsteroidal anti-inflammatory drugs, and small molecule targeted drugs, but these chemical drugs are expensive and long-term use will produce drug resistance and obvious adverse reactions, and their use will cause significant damage to liver and kidney function.

[0003] External therapy is an important method for treating rheumatoid arthritis. It mainly includes application, smearing, fumigation, acupuncture, massage, etc. External therapy can be directly applied to the affected area. Its active ingredients can enter the blood after entering the skin through the stratum corneum to produce local or systemic therapeutic effects. It can avoid the first-pass effect of the liver, reduce the loss of active ingredients, maintain a stable blood drug concentration, reduce adverse drug reactions, and have a higher safety. It is easy to use and the drug administration can be interrupted at any time.

[0004] Tibetan medicine has known rheumatoid arthritis for a long time, which is inseparable from the special geographical environment of Tibetan areas. Tibetan medicine classifies rheumatoid arthritis as "true brucellosis", which is caused by the disorder of the three factors of long, triba and bacon in the body, and the excessive yellow water gathering in the joints. Tibetan medicine has a unique understanding of the treatment of rheumatoid arthritis. Therefore, the present invention adopts the Tibetan medicine concept to treat rheumatoid arthritis with unique therapeutic advantages. Summary of the invention

[0005] The present invention explores a new combination of traditional Tibetan medicine for treating rheumatoid arthritis, and provides a gel patch for treating rheumatoid arthritis. The present invention adopts the concept of Tibetan medicine to treat rheumatoid arthritis. The gel patch has an excellent penetration-promoting effect, can maximize the therapeutic effect, significantly increase patient compliance, and is safe to use.

[0006] Another object of the present invention is to provide a method for preparing the gel patch.

[0007] The object of the present invention is achieved in the following ways:

[0008] A gel patch for treating rheumatoid arthritis, the gel patch comprising a backing layer, a paste layer and an anti-adhesive layer, wherein the paste layer is made of the following components in parts by weight:

[0009] 1-5 parts of sodium polyacrylate, 0.05-0.25 parts of aluminum glycolate, 0.1-2 parts of DL-tartaric acid, 0.025-0.2 parts of kaolin, 10-30 parts of glycerol, 1-10 parts of Tibetan medicine composition extract, 1-10 parts of aromatic water, 0.5-5 parts of wine-made benzoin, and 0.5-1.5 parts of penetration enhancer.

[0010] Preferably, the paste layer is made of the following components in parts by weight:

[0011] 3-5 parts of sodium polyacrylate, 0.1-0.2 parts of aluminum glycolate, 0.5-1.5 parts of DL-tartaric acid, 0.1-0.2 parts of kaolin, 20-30 parts of glycerol, 1-5 parts of Tibetan medicine composition extract, 1-5 parts of aromatic water, 1-2 parts of wine-made benzoin, and 0.5-1 part of penetration enhancer.

[0012] Most preferably, the paste layer is made of the following components in parts by weight:

[0013] 3 parts of sodium polyacrylate, 0.12 parts of aluminum glycolate, 0.75 parts of DL-tartaric acid, 0.15 parts of kaolin, 25 parts of glycerin, 5 parts of Tibetan medicine composition extract, 5 parts of aromatic water, 2 parts of wine-made benzoin, and 0.8 parts of a penetration enhancer.

[0014] In the Chinese medicine gel patch of the present invention, the backing layer is the carrier part of the gel patch, which mainly plays a supporting role of the paste, and uses the needle-punched elastic non-woven fabric commonly used in the art. The anti-adhesive layer is the surface covering part, which is used to protect the matrix layer and prevent drug leakage during storage, and non-adhesive isolation paper is selected.

[0015] The paste layer of the invention is a gel layer formed by the Tibetan medicine composition extract, aromatic water, wine-made benzoin and an auxiliary material matrix for loading the medicine. The matrix includes sodium polyacrylate, aluminum glycolate, glycerol, kaolin, DL-tartaric acid and a penetration enhancer.

[0016] Preferably, the penetration enhancer is a mixture of borneol and azone, with a weight ratio of 1:0.5 to 2, preferably 1:2.

[0017] Preferably, the wine-made benzoin is prepared by the following method: taking benzoin fine powder (without sieving) in a mortar, adding 3-6 times the weight of rice wine and grinding it to a thick paste, pouring it into a centrifuge tube and sealing it for storage, wherein each gram of wine-made benzoin contains 0.1-0.5g of benzoin.

[0018] Preferably, the aromatic water is prepared by the following method: taking Oxytropis falciformis, Cynanchum wilfordii, Terminalia chebula, Terminalia chebula, Phyllanthus emblica, Trichosanthes kirilowii and Rheum officinale, collecting a mixture of volatile oil and distilled water by steam distillation to obtain the aromatic water.

[0019] Preferably, the Tibetan medicine composition extract is prepared by taking Oxytropis falcatus, Cynanchum wilfordii, Terminalia chebula, Terminalia chebula, Emblica emblica, Trichosanthes kirilowii and Rheum officinale, collecting a mixture of volatile oil and distilled water by steam distillation to obtain aromatic water, then heating the residue with water for extraction, filtering, and concentrating the extract to obtain an extract with a relative density of 1.2-1.5 at 25°C, and finally adding artificial musk and mixing evenly to obtain the Tibetan medicine composition extract.

[0020] The raw material proportions in the Tibetan medicine composition extract are as follows: 40-60 parts of falcate oxytropis, 40-60 parts of scutellaria baicalensis, 30-40 parts of terminalia chebula, 30-40 parts of hairy terminalia chebula, 30-40 parts of emblica fructus, 20-30 parts of scutellaria baicalensis, 10-20 parts of subrheum and 0.1-1 parts of artificial musk; preferably 45-55 parts of falcate oxytropis, 45-55 parts of scutellaria baicalensis, 30-35 parts of terminalia chebula, 30-35 parts of hairy terminalia chebula, 30-35 parts of emblica fructus, 20-25 parts of scutellaria baicalensis, 15-20 parts of subrheum and 0.1-0.5 parts of artificial musk.

[0021] Preferably, the heating extraction is performed 2-5 times, the amount of water added each time is 10-15 times the total weight of the medicinal materials, and the extraction time each time is 1-3 hours.

[0022] The preparation method of the Tibetan medicine composition gel plaster comprises the following steps:

[0023] (1) Weigh DL-tartaric acid according to proportion and dissolve it in aromatic water, add aluminum glycolate and mix well to form phase A;

[0024] (2) Weigh the penetration enhancer, wine-made benzoin, Tibetan medicine composition extract, kaolin, and sodium polyacrylate according to the proportion, add them to glycerol and mix evenly to form phase B;

[0025] (3) Slowly add phase A to phase B and stir thoroughly to obtain a paste. Evenly apply the prepared paste on the backing layer of the gel patch and place it in a sealed place for 0.5-1 hour to complete crosslinking, and then cover with an anti-sticking layer.

[0026] The Tibetan medicine composition gel plaster has significant therapeutic effect when used in preparing medicine for treating rheumatoid arthritis.

[0027] The components used in the present invention are as follows:

[0028] Oxytropis falcata Bunge is the dried whole herb of the plant Oxytropis D.C. of the Leguminosae family. Its Tibetan name is "Edaxia, Daxia, Daxia". It complies with the provisions of the "Ministry of Health Drug Standards" under Oxytropis on page 101 of the first volume of Tibetan medicine. It has the effects of anti-inflammatory and analgesic, clearing away heat and detoxifying, stopping bleeding and promoting tissue regeneration, and can be used to treat burns, knife wounds, etc.

[0029] Tinospora sinensis is the dried stem of Tinospora sinensis (Lour.) Merr., a plant of the Menispermaceae family. It complies with the provisions of Tinospora sinensis on page 87 of the first volume of Tibetan medicine in the "Medical Standards of the Ministry of Health". It has the effects of relaxing muscles and tendons, dispelling wind and relieving pain, and is used to treat rheumatism, arthralgia, traumatic injuries, etc.

[0030] Benzoin is a brown dried resin from Styraxtonkinensis (Pierre) Craibex Hart., a plant of the family Styracaceae. The Chinese Pharmacopoeia states that benzoin has the effects of awakening the mind, promoting qi and blood circulation, and is used to treat stroke, phlegm syncope, heart and stomach pain, etc.

[0031] Terminalia chebula Retz. or Terminalia chebula Retz. var. tomentella Kurt. of the Combretaceae family is a dried mature fruit (without core). The Chinese Pharmacopoeia records that Terminalia chebula has the effects of astringing the intestines and stopping diarrhea, astringing the lungs and stopping coughing, and is used to treat chronic diarrhea, dysentery, blood in the stool and prolapse of the anus.

[0032] Terminalia bellirica (Gaertn.) Roxb., a plant of the family Combretaceae, is a dried mature fruit (without core). The Chinese Pharmacopoeia records that Terminalia bellirica has the effects of clearing away heat and detoxifying, astringing and nourishing blood, and is used to treat various heat syndromes, diarrhea, jaundice, etc.

[0033] Phyllanthus emblica L. is the dried mature fruit (without core) of the Euphorbiaceae plant Phyllanthus emblica L. The Chinese Pharmacopoeia records that Phyllanthus emblica L. has the effects of clearing heat and cooling blood, promoting digestion and strengthening the stomach, and is used to treat blood heat, blood stasis, indigestion, etc.

[0034] Rheum pumilum Maxim is the dried root and rhizome of Rheum pumilum Maxim. It complies with the provisions of Rheum pumilum Maxim in the Botanical Medicine Specification of Qinghai Tibetan Medicine Specification. It has the effects of antibacterial and anti-inflammatory, clearing away heat and detoxifying, and is used to treat stagnation, red and swollen eyes, etc.

[0035] Hand-Mazz is the dried root of Aconitum pendulum Busch and Aconitum flavum Hand-Mazz. It complies with the provisions of the "Health Ministry Drug Standards" Tibetan Medicine Volume 1, Page 79, Hand-Mazz. It has the effects of dispelling wind and relieving pain, dispersing blood stasis and stopping bleeding, and is used for rheumatic joint pain, traumatic injuries, etc.

[0036] Artificial musk is artificially synthesized musk.

[0037] Tibetan medicine has experienced thousands of years of development and has formed a unique, scientific and complete Tibetan medicine system, which guides people to identify and prevent diseases in practice. The Tibetan medicine composition used in the present invention is an empirical prescription combined by the inventor based on the theoretical knowledge of Tibetan medicine combined with many years of clinical practice. In the prescription, Oxytropis falcatus clears heat, reduces swelling and relieves pain, and is the main medicine; Caulis oxytropis and Rheum officinale dispel wind, promote dampness and relieve swelling, and are the ministerial medicines; Tripterygium wilfordii, wine-made benzoin, and artificial musk relieve pain and relieve swelling, and are the adjuvants; Terminalia chebula, Terminalia chebula hairy and Emblica officinalis nourish blood and promote blood circulation, and reconcile all the medicines, and are the guiding medicines. All the medicines are used together to play the effects of promoting blood circulation, removing blood stasis, unblocking collaterals, detoxifying, reducing swelling and relieving pain, clearing heat, removing wind and dampness, and promoting qi and blood circulation. In particular, the use of Tripterygium wilfordii in combination with Terminalia chebula can reduce the overall toxicity. The Tibetan medicine composition has reasonable compatibility and has the effects of promoting blood circulation, removing blood stasis, reducing swelling and relieving pain. The present invention adds the Tibetan medicine composition to the matrix, optimizes the matrix prescription ratio on this basis, and prepares a gel patch with comprehensive sensory and best transdermal promotion effect. Modern pharmacological research shows that the gel patch can maximize the therapeutic effect, and the therapeutic effect is comparable to the clinically commonly used non-steroidal anti-inflammatory chemical drug flurbiprofen gel patch.

[0038] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0039] 1. The Tibetan medicine composition used in the paste layer of the present invention has a reasonable compatibility. It is an empirical prescription combined by the inventor based on the theoretical knowledge of Tibetan medicine combined with many years of clinical practice. The compatibility of monarch, minister, assistant and envoy is reasonable, which is reported for the first time.

[0040] 2. In order to better exert the therapeutic effect of the Tibetan medicine composition, the present invention uses falcate oxtera, strychnos nux vomica, terminalia chebula, terminalia chebula, emblica emblica, trichosanthes kirilowii and rheum officinale in the form of water extracts, collects the aromatic oil and distilled water in the water extraction process of the composition to obtain aromatic water, which replaces the water phase in the traditional gel patch preparation. The essence of the ancient method is integrated with modern science, and the essence of the efficacy of Tibetan medicine is retained to the maximum extent.

[0041] 3. In the present invention, benzoin is not extracted with water, but is added directly to the plaster excipients together with the extract in the form of wine, which greatly increases the absorption efficiency of the active ingredients and improves the therapeutic effect.

[0042] 4. Combined with modern medical theory, the effective ingredients of the Tibetan medicine composition of the present invention, the main drug falcate oxytropis, include flavonoids, polysaccharides and alkaloids. Among them, the flavonoid component 2',4'-dihydroxychalcone has good anti-inflammatory and antioxidant activities, and is also the exclusive component of the main drug falcate oxytropis. In addition to flavonoids, falcate oxytropis polysaccharide is also another main component of the Tibetan medicine composition for antioxidant and anti-inflammatory properties. Since 2',4'-dihydroxychalcone is a hydrophobic component and falcate oxytropis polysaccharide is a hydrophilic component, in order to increase the transdermal absorption rate of two effective ingredients with opposite solubility properties in the same system, the present invention has been optimized through a large number of plaster preparations, and it is found that a specific combination and ratio of penetration enhancers can increase the transdermal absorption rate of two effective ingredients with opposite solubility properties in the same system, with the best penetration-promoting effect and the best efficacy. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 Effects of different processing methods of benzoin and different addition methods of aromatic water on the efficacy of the plaster. #p<0.05, vs blank group; *p<0.05, vs model group; **p<0.01, vs model group.

[0044] Figure 2 Chromatograms of Oxytropis falcifolia polysaccharide and 2',4'-dihydroxychalcone in transdermal test. (a) Chromatogram of blank sample (b) Chromatogram of transdermal test sample

[0045] Figure 3 This is a graph showing the trend of rat body weight changes.

[0046] Figure 4 Figure 1 shows the degree and score of rat foot swelling. A shows the thickness of the right foot of the rat on day 21; B shows the thickness of the left foot on day 21; C shows the curve of the swelling scores of the other three feet. #p<0.05, vs control; *p<0.05, vs model; **p<0.01, vsmodel.

[0047] Figure 5 The figure shows the volume change trend of the right foot of rats and the two-foot figure of rats in each group. A: blank group; B: model group; C: positive drug group; D: comparative example 7 ointment group; E: low-dose group of gel patch of Example 6; F: high-dose group of gel patch of the present invention of Example 6. #p<0.05, vs control; *p<0.05, vs model; **p<0.01, vs model.

[0048] Figure 6 HE staining of rat knee joint sections. A: blank group; B: model group; C: positive drug group; D: comparative example 7 ointment group; E: Example 6 gel patch low-dose group; F: Example 6 gel patch high-dose group. Specific implementation methods

[0049] The present invention is further illustrated below in conjunction with specific examples. The following examples are only used to explain the present invention in detail and are not used to limit the scope of the present invention. In addition, it should be understood that after reading the contents of the present invention, various equivalent forms of modifications to the present invention made by those skilled in the art all fall within the scope defined by the claims attached to this application.

[0050] Example 1

[0051] formula:

[0052] 3 parts by weight of sodium polyacrylate, 0.12 parts by weight of aluminum glycolate, 0.75 parts by weight of DL-tartaric acid, 0.15 parts by weight of kaolin, 25 parts by weight of glycerol, 5 parts by weight of Tibetan medicine composition extract, 5 parts by weight of aromatic water, 2 parts by weight of wine-made benzoin and 0.8 parts by weight of penetration enhancer (the weight ratio of borneol to azone is 1:2). Among them, each gram of wine-made benzoin contains 0.175g of benzoin.

[0053] Preparation of wine-made benzoin: Take 1 benzoin fine powder in a mortar, add 5 times the weight of rice wine as the benzoin, grind until it becomes a thick paste, pour into a 50ml centrifuge tube and seal it for storage. The alcohol content of the rice wine is 15%.

[0054] Calculation of the amount of benzoin per gram of wine-made benzoin: Take 1.01320 g of wine-made benzoin, dry it in an oven at 105°C for 3 hours, then take it out and put it into a dryer to dry for 30 minutes, weigh it and get 0.1773 g, and calculate that the content of benzoin per gram of wine-made benzoin is 0.175 g.

[0055] Preparation of Tibetan medicine composition extract:

[0056] Ratio of medicinal materials: 40 parts by weight of falcate oxtera, 60 parts by weight of broad-ribbed sedge, 30 parts by weight of terminalia chebula, 40 parts by weight of terminalia chebula, 30 parts by weight of emblica fructus, 30 parts by weight of trichosanthes kirilowii, 10 parts by weight of sub-rheum, and 0.1 parts by weight of artificial musk.

[0057] Preparation of Tibetan medicine composition extract:

[0058] Take sickle-shaped oxtera, radix serratae, terminalia chebula, terminalia chebula, emblica emblica, ferox ferox and rhubarb according to proportion, steam distill for 6 hours to collect the mixture of volatile oil and distilled water to obtain aromatic water, then heat the residue with water for extraction, filter, concentrate the extract to obtain an extract with a relative density of 1.2 at 25°C, finally add artificial musk, mix evenly, and obtain a Tibetan medicine composition extract. The above heating extraction is performed twice, the amount of water added each time is 15 times the total weight of the medicinal materials, the extraction time each time is 2 hours, and the extract is collected twice.

[0059] Preparation steps of gel patch:

[0060] (1) Weigh DL-tartaric acid according to proportion and dissolve it in aromatic water, add aluminum glycolate and mix well to form phase A;

[0061] (2) weighing azone and borneol (the weight ratio of the two is 1:2), wine-made benzoin, Tibetan medicine composition extract, kaolin, and sodium polyacrylate according to the proportion, adding them to glycerol and mixing evenly to prepare phase B;

[0062] (3) Slowly add phase A to phase B and stir thoroughly to obtain a paste. Evenly apply the prepared paste on the backing layer and place it in a sealed place for 0.5-1 hour to complete crosslinking. Cover with an anti-sticking layer to obtain a gel patch.

[0063] Example 2

[0064] The remaining steps and dosages are the same as those in Example 1, except that the proportion of medicinal materials is: 60 parts by weight of Oxytropis falciformis, 40 parts by weight of Caulis Spatholobi, 40 parts by weight of Terminalia chebula, 40 parts by weight of Terminalia chebula, 40 parts by weight of Phyllanthus emblica, 20 parts by weight of Rheum officinale, 20 parts by weight of Rheum suber, and 1 part by weight of artificial musk. Among them, each gram of wine-made benzoin contains 0.18g of benzoin.

[0065] Example 3

[0066] The remaining steps and amounts are the same as those in Example 1, except that the proportion of medicinal materials is: 55 parts of falcate oxytropis, 50 parts of broad-ribbed sedge, 30 parts by weight of terminalia chebula, 30 parts by weight of terminalia chebula, 32 parts by weight of emblica, 24 parts by weight of scutellaria baicalensis, 15 parts by weight of sub-rheum, and 0.5 parts by weight of artificial musk; wherein each gram of wine-made benzoin contains 0.183 g of benzoin.

[0067] Example 4

[0068] The remaining steps and dosages are the same as those in Example 1, except that the weight ratio of sodium polyacrylate, aluminum glycolate, DL-tartaric acid, kaolin, glycerin, Tibetan medicine composition extract, aromatic water, wine-made benzoin and penetration enhancer is 1:0.05:0.1:0.2:30:1:10:0.5:1.5. The penetration enhancer is azone and borneol (the weight ratio of the two is 1:0.5)

[0069] Example 5

[0070] The remaining steps and dosages are the same as those in Example 1, except that the weight ratio of sodium polyacrylate, aluminum glycolate, DL-tartaric acid, kaolin, glycerin, Tibetan medicine composition extract, aromatic water, wine-made benzoin and penetration enhancer is 5:0.25:0.1:0.025:10:10:1:5:0.5. The penetration enhancer is azone and borneol (weight ratio 1:1)

[0071] Example 6

[0072] formula:

[0073] 3 parts by weight of sodium polyacrylate, 0.12 parts by weight of aluminum glycolate, 0.75 parts by weight of DL-tartaric acid, 0.15 parts by weight of kaolin, 25 parts by weight of glycerol, 5 parts by weight of Tibetan medicine composition extract, 5 parts by weight of aromatic water, 2 parts by weight of wine-made benzoin and 0.8 parts by weight of penetration enhancer (the weight ratio of borneol to azone is 1:2). Among them, each gram of wine-made benzoin contains 0.175g of benzoin.

[0074] Preparation of Tibetan medicine composition extract:

[0075] Take 50 parts by weight of sickle-shaped oxtera, 50 parts by weight of broad-ribbed vine, 30 parts by weight of terminalia chebula, 30 parts by weight of terminalia chebula, 32 parts by weight of emblica, 24 parts by weight of iron club hammer and 20 parts by weight of sub-rheum, steam distill for 6 hours to collect the mixed solution of volatile oil and distilled water to obtain aromatic water, then use water heating reflux extraction for the residue, filter, concentrate the extract to obtain an extract with a relative density of 1.3 at 25°C, finally add 0.4 parts by weight of artificial musk, mix well, and obtain a Tibetan medicine composition extract. The above heating reflux extraction is performed twice, the amount of water added each time is 15 times the total weight of the medicinal materials, the extraction time each time is 2 hours, and the two extracts are combined.

[0076] Preparation steps of gel patch:

[0077] (1) Weigh DL-tartaric acid according to proportion and dissolve it in aromatic water, add aluminum glycolate and mix well to form phase A;

[0078] (2) Weigh the penetration enhancer, wine-made benzoin, Tibetan medicine composition extract, kaolin, and sodium polyacrylate according to the proportion, add them to glycerol, and mix them evenly to form phase B;

[0079] (3) Slowly add phase A to phase B and stir thoroughly to obtain a paste. Evenly apply the prepared paste on the backing layer and place it in a sealed place for 0.5-1 hour to complete crosslinking. Cover with an anti-sticking layer to obtain a gel patch.

[0080] Comparative Example 1 (Preparation of Tibetan medicine composition gel plaster by non-alcoholic internal addition method of benzoin)

[0081] Ratio of medicinal materials (by weight): 50 parts of falcate oxtera, 50 parts of broad-ribbed vine, 30 parts of terminalia chebula, 30 parts of hairy terminalia chebula, 32 parts of emblica, 24 parts of iron club hammer, 20 parts of sub-rheum, 0.4 parts of artificial musk, and 2 parts of benzoin.

[0082] Weigh sickle-shaped oxtera, smilax glabra, terminalia chebula, terminalia chebula, emblica emblica, scutellaria baicalensis, rhubarb, and benzoin according to proportion, steam distill for 6 hours to collect a mixture of volatile oil and distilled water to obtain aromatic water, heat the residues for 2 hours and reflux, extract 5 times, add 15 times of water of the total weight of the medicinal materials to the residues each time, filter the obtained extract, concentrate the filtrate to an extract with a relative density of 1.3 at 25° C., add artificial musk according to proportion, mix well, and obtain a Tibetan medicine composition extract;

[0083] Preparation of gel patch:

[0084] 3 parts by weight of sodium polyacrylate, 0.12 parts by weight of aluminum glycolate, 0.75 parts by weight of DL-tartaric acid, 0.15 parts by weight of kaolin, 25 parts by weight of glycerol, 5 parts by weight of Tibetan medicine composition extract, 5 parts by weight of aromatic water and 0.8 parts by weight of penetration enhancer.

[0085] (1) Weigh tartaric acid according to proportion and dissolve it in aromatic water, add aluminum glycolate according to proportion and mix well to form phase A;

[0086] (2) weighing azone, borneol (ratio 1:2), Tibetan medicine composition extract, kaolin, and sodium polyacrylate according to the proportion, adding them to glycerol, and mixing them evenly to prepare phase B;

[0087] (3) Slowly add phase A to phase B and stir thoroughly. Evenly apply the prepared gel patch on the backing, place in a sealed place until cross-linking is completed, cover with an anti-sticking layer, and cut to obtain the product.

[0088] Comparative Example 2 (Preparation of Tibetan Medicine Composition Gel Plaster Using Ordinary Water Phase)

[0089] The proportion of medicinal materials (by weight): 50 parts of falcate oxytropis, 50 parts of broad-ribbed sedge, 30 parts of terminalia chebula, 30 parts of terminalia chebula, 32 parts of emblica, 24 parts of cyperus rotundus, 20 parts of sub-rhubarb, 0.4 parts of artificial musk; 2 parts of wine-processed benzoin, wherein each gram of wine-processed benzoin contains 0.175g of benzoin.

[0090] Weigh sickle-shaped oxtera, smilax glabra, terminalia chebula, terminalia chebula, emblica emblica, cyperus rotundus, and rheum officinale in proportion, soak them in water for 2 hours, add water 15 times the total weight of the medicinal materials, heat and reflux for 2 hours, extract 5 times, filter the obtained extract, concentrate the filtrate to an extract with a relative density of 1.3, add artificial musk in proportion, mix well, and obtain a Tibetan medicine composition extract;

[0091] Preparation of gel patch:

[0092] 3 parts by weight of sodium polyacrylate, 0.12 parts by weight of aluminum glycolate, 0.75 parts by weight of DL-tartaric acid, 0.15 parts by weight of kaolin, 25 parts by weight of glycerol, 5 parts by weight of Tibetan medicine composition extract and 0.8 parts by weight of penetration enhancer.

[0093] (1) Weigh tartaric acid in proportion and dissolve it in water, add aluminum glycolate in proportion and mix well to obtain phase A;

[0094] (2) Weigh azone, borneol (ratio 1:2), wine-made benzoin, Tibetan medicine composition extract, kaolin, and sodium polyacrylate according to the proportion, add them to glycerol, and mix them evenly to prepare phase B;

[0095] (3) Slowly add phase A to phase B and stir thoroughly. Evenly apply the prepared gel patch on the backing, place in a sealed place until cross-linking is completed, cover with an anti-sticking layer, and cut to obtain the product.

[0096] Comparative Example 3 (Preparation of Tibetan medicine composition gel plaster without penetration enhancer)

[0097] Except that the penetration enhancers azone and borneol are not added, the rest are the same as in Example 6.

[0098] Comparative Example 4 (Tibetan medicine composition gel plaster with azone as penetration enhancer)

[0099] Except that penetration enhancer is changed to 0.8 part of azone, all the other are the same as Example 6.

[0100] Comparative Example 5 (Tibetan medicine composition gel plaster with borneol as penetration enhancer)

[0101] Except that the penetration enhancer was replaced by 0.8 parts of borneol, the rest was the same as Example 6.

[0102] Comparative Example 6 (Tibetan medicine composition gel plaster with azone and menthol as penetration enhancers)

[0103] The same procedures as in Example 6 were followed except that the penetration enhancer was changed from azone and borneol (total weight 0.8 parts, ratio 1:2) to azone and menthol (total weight 0.8 parts, ratio 1:2).

[0104] Comparative Example 7 (Tibetan medicine composition ointment)

[0105] The proportion of medicinal materials: 50 parts of falcate oxtera, 50 parts of broad-ribbed vine, 30 parts of terminalia chebula, 30 parts of terminalia chebula, 32 parts of emblica, 24 parts of ferox, 20 parts of sub-rheum, 0.4 parts of artificial musk, 2 parts of wine-made benzoin. Among them, each gram of wine-made benzoin contains 0.175g of benzoin.

[0106] Take the above medicinal materials, grind them and mix them evenly, disperse them in vaseline of the same weight as the other auxiliary materials of the plaster of Example 6, mix them evenly, and you have it.

[0107] Experimental Example 1: Study on the effects of different processing methods of benzoin and different addition methods of aromatic water on the efficacy of the plaster

[0108] The present invention adopts rat adjuvant arthritis induced by complete Freund's adjuvant as a model to evaluate the anti-inflammatory and detumescent effects of Tibetan medicine composition gel plasters prepared by different processing methods.

[0109] 1. Experimental Methods

[0110] 1. Establishment of arthritis model and grouped drug administration

[0111] Thirty rats (male SD rats, 7-8 weeks old, weighing 180-200g) were selected and fed adaptively for 3 days, and 24 rats were injected intradermally with 0.1 mL of Freund's complete adjuvant into the right hind toe to prepare adjuvant arthritis rats. The remaining 6 rats were used as the blank group, and the same volume of 0.9% sodium chloride solution was injected into the same part of the blank group rats.

[0112] On the 12th day after modeling, 24 arthritic rats were randomly divided into 4 groups according to the swelling degree of the rats' soles, with 6 rats in each group, namely, the blank group, the model group, the Tibetan medicine composition gel patch group prepared in Example 6, the Tibetan medicine composition gel patch group prepared in Comparative Example 1, and the Tibetan medicine composition gel patch group prepared in Comparative Example 2. 24h before administration, the hair on the back of the rats was removed with a razor and a depilatory cream, and the rats were administered with drugs on the back starting from the 12th day after modeling, and each gel patch group was administered with 3cm*3cm, and the positive drug group was administered with 3cm*3cm of flurbiprofen gel patch. The drug was administered once every 1 day for 10 days.

[0113] 2. Efficacy evaluation method

[0114] The rat right foot volume measurement method was adopted. Two syringes (one 50mL and one 1mL) were used as communicating vessels, and the heads of the two syringes were connected with a rubber tube. A certain scale of water was added to the 50mL syringe, and the water scale in the 1mL syringe was adjusted to 0 by adjusting the height of the syringe before each measurement. The rat's right ankle joint was completely submerged in the water in the 50mL syringe, and the scale to which the water in the 1mL syringe rose was the rat's foot volume. The right foot volume of rats in each group was measured on the 10th day of administration.

[0115] 2. Experimental Results

[0116] The results of the right foot volume measurement of rats are shown in Figure 1 On the 10th day of administration, the volume of the right hind foot of the model group increased significantly compared with the blank group, indicating that the model was successfully established. Compared with the model group, the volume of the right hind foot of the Tibetan medicine gel patch group prepared in Example 6 decreased significantly, while the volume of the right hind foot of the Tibetan medicine gel patch group prepared in Comparative Example 1 and the Tibetan medicine gel patch group prepared in Comparative Example 2 decreased less, indicating that alcohol-made benzoin and aromatic water as the aqueous phase components of the gel patch have a good promoting effect on the efficacy of the Tibetan medicine composition gel patch.

[0117] Experimental Example 2: Study on the effect of different penetration enhancers on the transdermal efficiency of Tibetan medicine composition gel patch

[0118] 1. Experimental Methods

[0119] 1. Determination of drug transdermal efficiency by Franz diffusion cell method

[0120] The Franz diffusion cell method used in the present invention determines the transdermal efficiency of the drug. The effective diffusion area of ​​the Franz diffusion cell is 2.8 cm 2 , cut the Tibetan medicine composition gel plasters with different penetration enhancers in Example 6, Comparative Examples 3, 4, and 5 into discs of equal size, then place the mouse ex vivo skin between the receiving chamber and the supply chamber of the Franz diffusion cell, with the stratum corneum facing the supply chamber, and stick the cut plaster on the skin. The Franz diffusion cell was placed in a constant temperature water bath at 32±0.5°C, and the magnetic stirring speed was 200r / min. All the receiving solution was taken out after 12h, and the same volume of 50% ethanol saline preheated to 32°C was added at the same time. The taken out receiving solution was placed in an evaporating dish and evaporated to dryness, and then dissolved with 0.5mL chromatographic methanol, filtered through a 0.45μm microporous filter membrane, and the sample was analyzed by high performance liquid chromatography under the following chromatographic conditions, and the peak areas of 2',4'-dihydroxychalcone and falcate oxtera polysaccharide were recorded.

[0121] 2. Chromatographic conditions

[0122] The chromatographic column is Shimadzu VP-ODS C 18 (4.6×150mm, 5μm), acetonitrile (A)-0.1% formic acid water (B) (40:60); T: 35min, detection wavelength 345nm, column temperature 30℃, flow rate 1.0mL / min, injection volume 10μL.

[0123] 2. Experimental Results

[0124] 1. Chromatogram of compounds indicating transdermal efficiency

[0125] Results Figure 2 The retention time is 2.146min for polysaccharide, and the retention time is 27.223min for 2',4'-dihydroxychalcone. This chromatographic condition can simultaneously determine the content of two types of substances.

[0126] 2. Effects of different penetration enhancers on the transdermal efficiency of Tibetan medicine composite gel patch

[0127] The results are shown in Table 1. For the plasters with azone and borneol as penetration enhancers, the transdermal efficiency of 2',4'-dihydroxychalcone, polysaccharide and the total amount of the two are the highest. The transdermal efficiency of azone or borneol alone is poor. The transdermal effect of azone and menthol combination is slightly increased, but still not as good as the embodiment 6 group with azone and borneol as penetration enhancers. Therefore, using azone and borneol as penetration enhancers of the Tibetan medicine composition of the present invention can simultaneously increase the transdermal efficiency of two key drugs with completely different solubility properties, hydrophobicity and hydrophilicity.

[0128] Table 1 Effects of different penetration enhancers on the transdermal efficiency of Tibetan medicine composition gel patch

[0129]

[0130] Experimental Example 3 Pharmacodynamic Study of Tibetan Medicine Composition Gel Patch on Rheumatoid Arthritis Model in Rats

[0131] The present invention adopts rat adjuvant arthritis induced by complete Freund's adjuvant as a model to evaluate the anti-inflammatory and detumescent effects of the Tibetan medicine gel plaster of the present invention.

[0132] 1. Experimental Methods

[0133] 1. Establishment of arthritis (AA) model and grouping and drug administration

[0134] After 36 rats (male SD rats, 7-8 weeks old, weighing 180-200g) were adaptively fed for 3 days, 30 rats were selected and injected with 0.1mL of Freund's complete adjuvant intradermally in the right hind toe to prepare adjuvant arthritis rats. The remaining 6 rats were used as the blank group, and the same volume of 0.9% sodium chloride solution was injected into the same part of the blank group rats.

[0135] On the 12th day after modeling, 30 arthritic rats were randomly divided into 5 groups according to the swelling degree of rat paws, 6 rats in each group, namely, model group, positive drug flurbiprofen gel patch group, Tibetan medicine composition gel patch high-dose group, Tibetan medicine composition gel patch low-dose group, and comparative example 7 Tibetan medicine composition ointment group. 24h before administration, the hair on the back of the rats was removed with a razor and depilatory cream, and administration was started on the back of the rats from the 12th day after modeling. The high-dose group and low-dose group of Example 6 gel patch were administered 3cm*3cm and 1cm*3cm respectively, the comparative example 7 ointment was administered 3cm*3cm, and the positive drug group was administered flurbiprofen gel patch 3cm*3cm. The patch / drug application site was covered and fixed with breathable gauze. It was administered once every 1 day for 10 consecutive days.

[0136] 2. Efficacy evaluation method

[0137] (1) Changes in rat body weight

[0138] The body weight changes of rats in each group were measured before and after administration.

[0139] (2) Measurement of rat foot thickness and foot swelling score

[0140] Before modeling, the thickness of the right hind foot of each group of rats was measured with a vernier caliper as a normal indicator; starting from the third day after modeling, the thickness of the left and right hind foot of each group of rats was measured every three days, and the data were recorded.

[0141] Because rheumatoid arthritis is a systemic immune disease, the other three feet of the model rats will gradually swell, so it is also necessary to score the swelling of the other three feet of the rats. The two-person scoring is based on the degree of swelling from mild to severe, with a score of 0-6. The minimum sum of the scores of both parties is 0 and the maximum is 12.

[0142] (3) Measurement of rat right paw volume

[0143] Use two syringes (one 50mL and one 1mL) as communicating vessels, and connect the heads of the two syringes with a rubber tube. Add a certain scale of water to the 50mL syringe, and adjust the water scale in the 1mL syringe to 0 before each measurement by adjusting the height of the syringe. Submerge the entire area below the right ankle joint of the rat in the water in the 50mL syringe, and the scale to which the water in the 1mL syringe rises is the foot volume of the rat. The right foot volume of each group of rats was measured starting from the 12th day after modeling.

[0144] (4) Observation of pathological morphology of the ankle joint in rats

[0145] After the rats were killed, the ankle joints were separated, decalcified in EDTA decalcification solution, dehydrated with gradient ethanol, embedded in paraffin, and sliced ​​for hematoxylin-eosin staining. The pathological morphology of the rat ankle joints was observed under a microscope.

[0146] 2. Experimental Results

[0147] (1) Changes in rat body weight

[0148] Results Figure 3 Compared with day 0, the blank group had the largest weight gain on day 21, followed by the high-dose group of the gel patch in Example 6 and the positive drug group. These two groups gained more obvious weight after administration on day 12, and the model group had the least increase. This indicates that the high-dose group of the gel patch in Example 6 and the positive drug can alleviate the effects of autoimmune diseases in rats, such as reducing appetite and weight loss.

[0149] (2) Measurement of rat foot thickness and foot swelling score

[0150] Results Figure 4After administration on the 12th day, the thickness of the right hind foot of the positive drug group and the high-dose group of the gel patch of Example 6 began to show a decreasing trend, while the low-dose group of the gel patch of Example 6 and the ointment group of Comparative Example 7 showed no significant changes, while the thickness of the right hind foot of the model group showed a slow increasing trend. This result shows that the positive drug group and the high-dose group of the gel patch of Example 6 have an inhibitory effect on the swelling of the toes caused by rheumatoid arthritis in rats. After modeling, the remaining three feet of the rats were all affected and began to swell slowly. On the 15th day, i.e., the third day of administration, the swelling degree of the remaining three feet of the high-dose group of the gel patch of Example 6 began to decrease, while the low-dose group of the gel patch of Example 6, the ointment group of Comparative Example 7 and the positive drug group began to decrease after the 18th day, and the model group did not decrease. It shows that the high-dose group of the gel patch of Example 6 can significantly reduce the swelling degree of the remaining three feet of the modeling rats.

[0151] (3) Measurement of rat right paw volume

[0152] Results Figure 5 After administration on the 12th day, the volume of the right hind foot of the positive drug group and the high-dose group of the gel patch of Example 6 showed a downward trend, while there was no significant change in the ointment of Comparative Example 7 and the low-dose group of the gel patch of Example 6, and the model group showed an increasing trend. The results show that the positive drug group and the high-dose group of the gel patch of Example 6 can reduce the degree of swelling of the rat foot.

[0153] (4) Observation of pathological morphology of the ankle joint in rats

[0154] Results Figure 6 , the synovial structure of the ankle joint in the blank group was clear and complete, with no significant pathological changes. The synovial structure of the ankle joint in the blank group was clear and complete, with no significant pathological changes. More pannus was seen in the sections of the model group, which was composed of new microvessels, hyperplastic synovial cells, inflammatory cells and organized cellulose. There were fewer pannus in the low-dose group of the gel patch in Example 6 and the ointment group in Comparative Example 7. The synovial structure of the ankle joint in the high-dose group of the gel patch in Example 6 and the positive drug group was clear and complete, with fewer inflammatory cells, and the synovial pathology of the ankle joint of rats was significantly improved.

[0155] In summary, the gel patch prepared by the present invention has a good therapeutic effect on arthritis, and its efficacy is comparable to that of the clinically commonly used non-steroidal anti-inflammatory chemical drug flurbiprofen gel patch.

Claims

1. A gel patch for treating rheumatoid arthritis, comprising a backing layer, a paste layer and an anti-adhesive layer, characterized in that: The paste layer is made of the following components in parts by weight: 1-5 parts of sodium polyacrylate, 0.05-0.25 parts of aluminum glycolate, 0.1-2 parts of DL-tartaric acid, 0.025-0.2 parts of kaolin, 10-30 parts of glycerol, 1-10 parts of Tibetan medicine composition extract, 1-10 parts of aromatic water, 0.5-5 parts of wine-made benzoin, and 0.5-1.5 parts of penetration enhancer.

2. The gel patch according to claim 1, characterized in that The paste layer is made of the following components in parts by weight: 3-5 parts of sodium polyacrylate, 0.1-0.2 parts of aluminum glycolate, 0.5-1.5 parts of DL-tartaric acid, 0.1-0.2 parts of kaolin, 20-30 parts of glycerol, 1-5 parts of Tibetan medicine composition extract, 1-5 parts of aromatic water, 1-2 parts of wine-made benzoin, and 0.5-1 part of penetration enhancer.

3. The gel patch according to claim 1 or 2, characterized in that The penetration enhancer is a mixture of borneol and azone, with a weight ratio of 1:0.5-2.

4. The gel patch according to claim 1 or 2, characterized in that The wine-made benzoin is prepared by the following method: taking benzoin fine powder in a mortar, adding 3 to 6 times the weight of yellow wine and grinding it to a thick paste, pouring it into a centrifuge tube and sealing it for storage, wherein each gram of the wine-made benzoin contains 0.1 to 0.5 gram of benzoin.

5. The gel patch according to claim 1 or 2, characterized in that The aromatic water is prepared by the following method: taking Oxytropis falcatus, Cynanchum lappa, Terminalia chebula, Terminalia chebula, Phyllanthus emblica, Trichosanthes kirilowii and Rheum officinale, collecting a mixed liquid of volatile oil and distilled water through steam distillation to obtain the aromatic water.

6. The gel patch according to claim 1 or 2, characterized in that The Tibetan medicine composite extract is prepared by steam distilling volatile oil and distilled water to obtain aromatic water from falcate ostracum, strychnos nux vomica, terminalia chebula, terminalia chebula, emblica emblica, cyperus rotundus and rheum officinale, heating the residue with water for reflux extraction, filtering, concentrating the extract to obtain an extract with a relative density of 1.2-1.5 at 25 DEG C, and finally adding artificial musk and mixing evenly to obtain the Tibetan medicine composite extract.

7. The gel patch according to claim 6, characterized in that The raw material proportions in the Tibetan medicine composition extract are as follows: 40-60 parts of falcate oxytropis, 40-60 parts of scutellaria baicalensis, 30-40 parts of terminalia chebula, 30-40 parts of hairy terminalia chebula, 30-40 parts of emblica fructus, 20-30 parts of cyperus rotundus, 10-20 parts of subrheum and 0.1-1 part of artificial musk; preferably, 45-55 parts of falcate oxytropis, 45-55 parts of scutellaria baicalensis, 30-35 parts of terminalia chebula, 30-35 parts of hairy terminalia chebula, 30-35 parts of emblica fructus, 20-25 parts of cyperus rotundus, 15-20 parts of subrheum and 0.1-0.5 part of artificial musk.

8. The gel patch according to claim 6, characterized in that: The heating reflux extraction is performed 2 to 5 times, the amount of water added each time is 10 to 15 times the total weight of the medicinal materials, and the extraction time each time is 1 to 3 hours.

9. A method for preparing the gel patch according to claim 1 or 2, characterized in that The method comprises the following steps: (1) Weigh DL-tartaric acid according to proportion and dissolve it in aromatic water, add aluminum glycolate and mix well to form phase A; (2) Weigh the penetration enhancer, wine-made benzoin, Tibetan medicine composition extract, kaolin, and sodium polyacrylate according to the proportion, add them to glycerol and mix evenly to form phase B; (3) Slowly add phase A to phase B and stir thoroughly to obtain a paste. Evenly apply the prepared paste on the backing layer of the gel patch and place it in a sealed place for 0.5 to 1 hour to complete crosslinking, and then cover with an anti-sticking layer.

10. Use of the gel patch according to claim 1 or 2 in preparing a medicament for treating rheumatoid arthritis.

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