CN117338892A - Gel emplastrum for treating arthralgia and preparation method thereof - Google Patents

Abstract

The invention discloses a gel emplastrum for treating arthralgia, which is prepared from radix aconiti, asarum, rhizoma atractylodis, radix angelicae pubescentis, radix achyranthis bidentatae, whole angelica sinensis, rhizoma dioscoreae nipponicae, obscured homalomena rhizome, cortex schizophragmatis integrifolii radicis, radix clematidis, lignum pini nodi, red graminei, herba taxilli, rhizoma cibotii, cortex acanthopanacis, caulis spatholobi, rhizoma sparganii and rhizoma curcumae. The invention has better viscosity and formability, has the functions of dispelling wind and removing dampness, strengthening tendons and bones, removing blood stasis and relieving pain, and is suitable for people suffering from rheumatalgia.

Description

Gel plaster for treating arthralgia and preparation method thereof

Field of the invention:

The invention relates to a gel plaster for treating arthralgia and a preparation method thereof, belonging to the technical field of medicines.

Background Art

Arthralgia is a common disease, mainly manifested as gout. Arthralgia is caused by excessive hobbies, declining kidney qi, disordered drainage and overnutrition. From the perspective of traditional Chinese medicine, arthralgia is related to the tendons and blood of the human body. If the yang qi is deficient, the tendons cannot be nourished, which leads to fibromyalgia and other diseases. In Suwen Bilun, it is mentioned that "the three qi are mixed and combined to form arthralgia", "if the qi is against, it will be arthralgia, if it is followed, it will be cured. If it does not combine with wind, cold and dampness, it will not be arthralgia", which shows that the occurrence of arthralgia is related to the strength of the positive qi and the defensive qi. If the human body's yang qi is deficient, the defensive yang will be insufficient, and the function of resisting external evil will be weakened, and the wind, cold and dampness will take advantage of the opportunity to enter; in addition, if the positive qi is insufficient, the ability to expel evil will decrease, and the wind, cold and dampness will be retained in the muscles, tendons and bones, and the meridians and qi and blood will be blocked, forming arthralgia. Irregular diet and excessive fatigue are all causes of the disease. Due to individual differences, there is no best treatment for arthralgia, but it can be treated through traditional Chinese medicine physiotherapy, external medications, and oral medications.

Gel patches first appeared in Germany. After being developed by Japanese scholars, they were called stereotyped plasters. The water-soluble matrix of plasters has good moisturizing properties, little skin irritation, high bioavailability, and large drug loading capacity. They are more suitable for use in traditional Chinese medicines with many components and large dosages. Gel patches have many advantages. First, because it is a transdermal preparation, the administration method can avoid the first-pass effect of the liver and reduce irritation to the gastrointestinal tract. Second, it can avoid fluctuations in blood drug concentration caused by oral administration. Third, it can extend the administration time and reduce the number of administrations. Fourth, the plaster can carry more drugs, is easy to fit the skin, and is less irritating and easy to use. However, there are certain shortcomings in the plaster, such as unstable product quality, large dosage, easy to remove the plaster and leak the plaster, etc.

The invention uses an orthogonal test method to perform an extraction process and find a matrix formula, which is convenient and reliable. The plaster has good viscosity and formability under the optimal matrix formula. The matrix content is detected by high performance liquid chromatography, and the quality standard is stable. The preparation process of the compound bitong plaster is feasible, and the bitong formula has good effects of dispelling wind and dampness, strengthening tendons and bones, and removing blood stasis and relieving pain, thereby achieving the expected purpose of the subject design.

Summary of the invention

The technical problem to be solved by the present invention is to provide a gel plaster for treating arthralgia and a preparation method thereof. The gel plaster of the present invention has the effects of dispelling wind and dampness, strengthening tendons and bones, and removing blood stasis and relieving pain, and is used for treating rheumatic arthralgia and is suitable for people with rheumatic arthralgia. The preparation operation is easy, and the prepared plaster has good viscosity and formability, and the product quality is good.

In order to solve the above technical problems, the present invention adopts the following technical solutions:

A gel plaster for treating arthralgia. The medicinal active ingredients thereof are calculated by weight as follows: 90-150 parts of processed Chuanwu, 40-80 parts of northern asarum, 60-120 parts of atractylodes, 60-120 parts of angelica, 60-120 parts of angelica sinensis, 200-400 parts of rhizoma dicophora, 200-400 parts of rhizoma scutellariae, 200-400 parts of rhizoma scutellariae, 130-230 parts of clematis, 100-200 parts of pine knot, 100-200 parts of red hemp, 90-150 parts of parasitic plant, 90-150 parts of cibotium bark, 90-150 parts of cortex acanthopanacis, 100-200 parts of millettia reticulata, 90-150 parts of trillium and 90-150 parts of zedoaria.

The above-mentioned gel patch for treating arthralgia, its medicinal active ingredients are calculated by weight: 100-140 parts of processed Chuanwu, 50-70 parts of northern asarum, 70-110 parts of atractylodes, 70-110 parts of Duhuo, 70-110 parts of Achyranthes bidentata, 100-140 parts of whole angelica, 250-350 parts of Rhizoma Dioscoreae, 250-350 parts of Rhizoma Dioscoreae, 250-350 parts of Radix Clematis, 120-180 parts of pine knot, 80-120 parts of red hemp, 100-140 parts of mistletoe, 100-140 parts of Cibotium bark, 100-140 parts of Acanthopanax, 120-180 parts of Millettia reticulata, 100-140 parts of Trillium, and 100-140 parts of Curcuma.

Specifically, the aforementioned gel patch for treating arthralgia, its medicinal active ingredients are calculated by weight: 120 parts of processed Chuanwu, 60 parts of northern asarum, 90 parts of atractylodes, 90 parts of Duhuo, 90 parts of Achyranthes, 120 parts of whole angelica, 300 parts of Rhizoma Cynoglossi, 300 parts of Rhizoma Cynoglossi, 300 parts of Rhizoma Cynoglossi, 180 parts of Clematidis, 150 parts of pine knot, 100 parts of red hemp, 120 parts of mistletoe, 120 parts of Cibotium bark, 120 parts of Acanthopanax, 150 parts of Millettia reticulata, 120 parts of Trillium, and 120 parts of Curcuma.

The preparation method of the aforementioned gel patch for treating arthralgia is carried out according to the following steps:

(1) Weighing the medicinal materials according to the prescription ratio, crushing them into coarse powder, accurately weighing the total mass of the medicinal materials to 15-20 g using an electronic analytical balance, soaking them in 12-18 times ethanol for 18-30 hours, refluxing and extracting them for 2-4 hours, filtering, and drying the filtrate at 60-80° C. to obtain a Chinese medicine ointment for later use;

(2) Accurately weigh 0.55-0.75 g of sodium polyacrylate, 0.45-0.65 g of kaolin, and 6.5-7.5 g of glycerol, mix well as phase A, and set aside;

(3) Accurately weigh 0.03-0.05 g aluminum glycinate, 10-14 g tartaric acid, and 0.2-0.4 g menthol, mix well as phase B, and set aside;

(4) Heat phase A in a water bath at 60-80° C. and stir rapidly for 6-8 minutes. Then add phase B to phase A and continue stirring rapidly for 6-8 minutes to obtain a gel matrix for later use.

(5) Add the Chinese medicine ointment to the gel matrix and stir for 20-30 minutes. Spread the obtained paste on a non-woven fabric of 8 cm*12 cm and place it in a cool place until it cools and solidifies to obtain a gel patch.

In the above step (1), the medicinal materials are weighed according to the prescription ratio, crushed into coarse pieces, and the total mass of the medicinal materials is accurately weighed with an electronic analytical balance to be 17.1 g. The medicinal materials are soaked in 15 times ethanol for 24 hours, refluxed for extraction for 3 hours, filtered, and the filtrate is dried at 70° C. to obtain a Chinese medicine ointment for later use.

In the above step (2), 0.63 g of sodium polyacrylate, 0.55 g of kaolin and 7 g of glycerol were accurately weighed as phase A for later use.

In the above step (3), accurately weigh 0.04 g of aluminum glycinate, 12 g of tartaric acid and 0.3 g of menthol as phase B for later use.

In the above step (4), phase A is placed in a water bath at 70° C. and heated, and rapidly stirred for 7 minutes. Phase B is then added to phase A, and rapidly stirred for 7 minutes to obtain a gel matrix for later use;

In the above step (5), the Chinese medicine ointment is added to the gel matrix and stirred for 25 minutes. The obtained paste is spread on a non-woven fabric of 8 cm*12 cm and placed in a cool place to cool and solidify, thereby obtaining a gel patch.

Compared with the prior art, the present invention has the following beneficial effects:

The gel plaster for treating arthralgia of the present invention is prepared from processed Chuanwu, Asarum, Atractylodes, Angelicae Pubescentis, Achyranthes bidentata, Angelica sinensis, Rhizoma Dioscoreae, Rhizoma Cibotii, Rhizoma Cibotii, Rhizoma Cibotii, Rhizoma Acanthopanacis, Caulis Spatholobi, Rhizoma Tripterygii, and Rhizoma Curcumae. Chuanwu is the dried mother root of Aconitumcarmichaelii Debx. of the Ranunculaceae family; it is excavated from late June to early August, the sub-roots, fibrous roots and mud and sand are removed, and it is dried in the sun; it is pungent and bitter in taste, hot in nature, highly toxic, and enters the heart, liver, kidney and spleen meridians; it has the effects of dispelling wind and dampness, warming the meridians and relieving pain; it is used for wind-cold-damp arthralgia, joint pain, cold pain in the heart and abdomen, pain caused by cold hernia and anesthesia and analgesia; processed Chuanwu is a processed product of Chuanwu. Asarum is the dried root and rhizome of Asarumheterotropoides Fr. Schmidt var. mandshuricum (Maxim.) Kitag., a plant of the Aquilegiaceae family. It is dug up in summer when the fruit is ripe or in early autumn, and the above-ground parts and mud and sand are removed, and then dried in the shade. It tastes spicy and is warm in nature. It enters the heart, lung, and kidney meridians. It has the effects of dispelling cold, dispelling wind and relieving pain, opening the orifices, warming the lungs and transforming fluid. It is used for colds caused by wind and cold, headaches, toothaches, nasal congestion and runny nose, allergic rhinitis, sinusitis, rheumatic pain, and coughs with phlegm and fluid. Atractylodes lancea is the dried rhizome of Atractylodes lancea (Thunb.) DC. or Atractylodes chinensis (DC.) Koidz. of the Asteraceae family. It is dug up in spring and autumn, the sand is removed, it is dried in the sun, and the fibrous roots are removed. It tastes pungent and bitter and is warm in nature. It enters the spleen, stomach, and liver meridians. It has the effects of drying dampness and spleen, dispelling wind and cold, and improving eyesight. It is used for dampness blocking the middle jiao, abdominal distension, diarrhea, edema, beriberi, rheumatism, colds, night blindness, and blurred vision. Duhuo is the dried root of Angelica pubescens Maxim.f.biserrata Shan et Yuan, a plant of the Apiaceae family. It is dug when the seedlings just sprout in early spring or when the stems and leaves wither in late autumn, and the fibrous roots and mud are removed, and it is dried to half dry, piled for 2 to 3 days, and then dried to completely dry after it softens. It tastes pungent and bitter, and is slightly warm in nature. It enters the kidney and bladder meridians. It has the effects of dispelling wind and dampness, relieving numbness and relieving pain. It is used for wind-cold-dampness arthritis, pain in the waist and knees, headache caused by the hidden wind of Shaoyin, and headache caused by wind-cold and dampness. Achyranthes bidentata is the dried root of Achyranthes bidentata Bl., a plant of the Amaranthaceae family. It tastes bitter, sweet, and sour, and is neutral in nature. It enters the liver and kidney meridians. It has the effects of removing blood stasis and relieving menstruation, nourishing the liver and kidney, strengthening the tendons and bones, promoting diuresis and relieving stranguria, and guiding blood downward. It is used for amenorrhea, dysmenorrhea, soreness of the waist and knees, weakness of the tendons and bones, stranguria, edema, headache, dizziness, toothache, mouth sores, vomiting blood, and epistaxis. Angelica sinensis is the dried root of Angelica sinensis (Oliv.) Diels of the Umbelliferae family. It is dug up in late autumn, and the fibrous roots and mud are removed. After the water evaporates slightly, it is tied into small bundles, hung on a shed, and slowly smoked dry with fireworks. The whole angelica includes the head, middle, and tail of the angelica. It tastes sweet and spicy and is warm in nature. It enters the liver, heart, and spleen meridians. It has the effects of nourishing blood and activating blood circulation, regulating menstruation and relieving pain, and moistening the intestines and relieving constipation. It is used for blood deficiency and sallow complexion, dizziness and palpitations, irregular menstruation, amenorrhea and dysmenorrhea, abdominal pain due to deficiency and cold, rheumatism, injuries due to falls, carbuncles, and ulcers, and dry intestines and constipation. Wine-boiled angelica can activate blood circulation and regulate menstruation; it is used for amenorrhea and dysmenorrhea, rheumatism, and injuries due to falls. Dioscorea nipponica Makino is a dried rhizome of Dioscorea nipponica Makino, a plant of the Dioscoreaceae family. It is dug in spring and autumn, washed, the fibrous roots and skin are removed, and dried in the sun. It tastes sweet and bitter, and is warm in nature. It enters the liver, kidney, and lung meridians. It has the effects of dispelling wind and dampness, relaxing muscles and tendons, activating blood circulation and relieving pain, and resolving phlegm and relieving cough. It is used for rheumatism, joint swelling, pain and numbness, injuries from falls, sprains, and coughs and asthma. Homalomena occulta (Lour.) Schott is a dried rhizome of Homalomena occulta (Lour.) Schott, a plant of the Araceae family. It tastes bitter and pungent, and is warm in nature. It enters the liver and kidney meridians. It has the effects of dispelling rheumatism and strengthening tendons and bones. It is used for wind-cold and dampness, cold pain in the waist and knees, cramps and numbness, and weakness of tendons and bones. Difeng, also known as Difengpi, is the dried bark of Illiciumdifengpi K.I.B.et K.I.M., a plant of the Magnoliaceae family. It tastes slightly pungent and astringent, and is warm in nature. It is slightly toxic. It enters the bladder and kidney meridians. It has the effects of dispelling wind and dampness, promoting qi and relieving pain. It is used for rheumatic pain and back pain caused by overwork. Clematis chinensis is the dried root and rhizome of Clematischinensis Osbeck, Clematis hexapetala Pall. or Clematis manshurica Rupr., a plant of the Ranunculaceae family. It tastes pungent and salty, and is warm in nature. It enters the bladder meridian. It has the effects of dispelling wind and rheumatism and unblocking meridians. It is used for rheumatic pain, numbness of limbs, cramps of tendons and veins, and difficulty in flexion and extension. Pine knots are the branches and trunks of the Yunnan pine (Pinusyunnanensis Franch) of the Pinaceae family. They are bitter and warm in nature. They have the effects of dispelling wind and dampness, relaxing muscles and tendons, activating blood circulation and stopping bleeding. They are used to treat joint pain, stiffness of tendons and bones, numbness and weakness of feet, and pain caused by falls. Red hemp is the root of Laportea bulbifera (Sieb.etZace) Wedd. of the Urticaceae family. They are pungent and warm in nature. They have the effects of dispelling wind and dampness, activating blood circulation and removing blood stasis. They are mainly used to treat rheumatic pain, numbness of limbs, injuries caused by falls, pain caused by fractures, and irregular menstruation. Mulberry is the dried stems and branches with leaves of Taxillus chinensis (DC.) Danser, a plant of the family Loranaceae; harvested from winter to the next spring, the thick stems removed, cut into sections, dried, or steamed and dried; bitter and sweet in taste, neutral in nature; enters the liver and kidney meridians; has the effects of removing rheumatism, nourishing the liver and kidney, strengthening the tendons and bones, and calming the fetus; used for rheumatic pain, soreness of the waist and knees, weakness of the tendons and bones, metrorrhagia, bleeding during pregnancy, restless fetal movement, and dizziness. Cibotium barometz is the dried rhizome of Cibotium barometz (L.) J. Sm., a plant of the family Pteridaceae; bitter and sweet in taste, warm in nature; enters the liver and kidney meridians; has the effects of removing rheumatism, nourishing the liver and kidney, and strengthening the waist and knees; used for rheumatic pain, soreness of the waist and knees, and weakness of the lower limbs. Acanthopanax bark is the dried root bark of Acanthopanax gracilistylus W.W.Smith, a plant of the Araliaceae family; it is pungent and bitter in taste, warm in nature; it enters the liver and kidney meridians; it has the effects of dispelling wind and dampness, nourishing the liver and kidney, strengthening tendons and bones, promoting diuresis and reducing swelling; it is used for rheumatic arthralgia, weak tendons and bones, delayed walking in children, physical weakness, edema, and beriberi. Millettia reticulata is the dried vine stem of Spatholobus suberectus Dunn, a plant of the Leguminosae family; it is bitter and sweet in taste, warm in nature; it enters the liver and kidney meridians; it has the effects of promoting blood circulation and replenishing blood, regulating menstruation and relieving pain, and relaxing tendons and activating collaterals; it is used for irregular menstruation, dysmenorrhea, amenorrhea, rheumatic arthralgia, numbness and paralysis, and anemia and chlorosis. Sparganium is the dried tuber of Sparganiumstoloniferum Buch.-Ham. of the family Sparganium; it is pungent and bitter, and neutral in nature; it enters the liver and spleen meridians; it has the effects of breaking blood and promoting qi, eliminating accumulation and relieving pain; it is used for lumps and masses, dysmenorrhea, amenorrhea due to blood stasis, chest pain, and distension and pain caused by food accumulation. Curcuma is the dried rhizome of Curcuma phaeocaulis VaL., Curcuma kuangsiensis S.G.LeeetC.F.Liang or Curcuma wenyujin Y.H.ChenetC.Ling of the family Zingiberaceae; it is pungent and bitter, and warm in nature; it enters the liver and spleen meridians; it has the effects of promoting qi and breaking blood, eliminating accumulation and relieving pain; it is used for lumps and masses, amenorrhea due to blood stasis, chest pain, and distension and pain caused by food accumulation.

Solution:

The main pathogenesis of arthralgia is that wind, cold and dampness block the meridians, resulting in poor circulation of qi and blood. In the prescription, Zhui Di Feng, Chuan Shan Long and Qian Nian Jian can dispel wind and dampness, strengthen tendons and bones, and promote blood circulation and relieve pain. They are the main drugs; Wei Ling Xian, Millettia reticulata and Hong He Ma can dispel wind and dampness and dredge the meridians; arthralgia consumes qi and blood over a long period of time and affects the liver and kidneys, so mistletoe, dog spine, and Acanthopanax can dispel rheumatism, nourish the liver and kidneys, and strengthen tendons and bones; Chuan Wu can dispel wind and dampness, dispel cold and relieve pain. The above are assistant drugs that help the main drugs dispel wind and dampness, strengthen tendons and bones, and promote blood circulation and relieve pain. Bone, blood circulation and pain relief; Asarum can search for wind, cold and dampness in tendons and bones, unblock meridians and relieve pain; Pine knot and Atractylodes can invigorate the spleen and dry dampness; Duhuo can dispel wind and cold, overcome dampness and relieve pain; Rheumatism and arthralgia can enter the meridians for a long time, and blood stasis and phlegm can block the meridians, which cannot be resolved without blood-breaking products. Therefore, whole Angelica, Trigonosciadium japonicum, Curcuma zedoaria, etc. are used to break blood and dissolve blood stasis, promote qi and relieve pain, and also imply the meaning of "treating wind first treat blood, and blood circulation will eliminate wind by itself". The above are adjuvant drugs; Achyranthes bidentata can nourish the liver and kidney, strengthen tendons and bones, and guide the drugs downward to unblock meridians, which is an adjuvant drug. All the drugs are used together to play the role of dispelling wind and dampness, strengthening tendons and bones, removing blood stasis and relieving pain.

Compared with the prior art, the beneficial effects are as follows:

1. The orthogonal test method is convenient and reliable for extraction process and finding matrix formula. The plaster has good viscosity and formability under the optimal matrix formula. The oleanolic acid content detected by HPLC can reach a maximum of 0.05%. The quality standard is stable. The preparation process of Compound Bitong Plaster is feasible, achieving the expected purpose of the project design.

The low-dose and high-dose groups of Bitong Fang and the prednisone acetate group all have a significant inhibitory effect on the ear swelling of mice caused by xylene, and can reduce the ear swelling of mice, indicating that Bitong Fang has a good anti-inflammatory effect. Each drug-administered group was compared with the blank control group, and there was statistical significance (p < 0.05). Among them, the swelling degree of the high-dose group of Bitong Fang was significantly less than that of the low-dose group, indicating that the high-dose group had a better anti-inflammatory effect than the low-dose group. Therefore, the present invention has a good analgesic and anti-inflammatory effect, can significantly reduce the number of twistings caused by acetic acid to the abdominal cavity of mice and inhibit the ear swelling of mice caused by xylene.

The gel patch prepared by the optimal formula in the experiment has good coating properties, smooth and uniform texture, soft and smooth surface, no obvious large particles, few bubbles, good viscosity and no residue. This Bitong gel patch adheres to the unique advantages of traditional Chinese medicine, uses modern preparation equipment and modern Chinese medicine cataplasm transdermal drug delivery technology, and innovates and transforms traditional Chinese medicine patch preparations. This is an innovative development of traditional Chinese medicine patches, and has practical and far-reaching significance for the innovative development of traditional Chinese medicine.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: Diagram of the medicinal material soaking process in Example 1;

Figure 2: Chinese medicine ointment of Example 1;

Figure 3: Gel patch of Example 1

Figure 4: Spectrum of oleanolic acid content detection reference substance;

Figure 5: Spectrum of test sample No. 1 for oleanolic acid content detection;

Figure 6: Spectrum of test sample No. 2 for oleanolic acid content detection;

Figure 7: Standard curve of oleanolic acid content measured by HPLC;

Figure 8: Diagram of the process of mouse writhing experiment;

Figure 9: Diagram of the xylene-induced ear swelling experiment process.

DETAILED DESCRIPTION

The present invention will be further described below in conjunction with the embodiments, but they are not intended to limit the present invention.

Example 1.

Prescription: processed Chuanwu 12g, northern Asarum 6g, Atractylodes 9g, Duhuo 9g, Achyranthes bidentata 9g, whole Angelica 12g, Rhizoma Cynoglossi 30g, Rhizoma Cibotii 30g, Radix Achyranthis Bidentatae 30g, Clematidis 18g, Turpentine 15g, Hemp 10g, Viscum album 12g, Cibotium bark 12g, Acanthopanax cortex 12g, Millettia reticulata 15g, Trillium 12g, Curcuma 12g.

Process: (1) Weigh the medicinal materials according to the prescription ratio, crush them into coarse pieces, accurately weigh the total mass of the medicinal materials to be 17.1 g using an electronic analytical balance, soak them in 15 times ethanol for 24 hours, reflux extract for 3 hours, filter, and dry the filtrate at 70° C. to obtain a Chinese medicine ointment for later use;

(2) Accurately weigh 0.63 g of sodium polyacrylate, 0.55 g of kaolin, and 7 g of glycerol as phase A and set aside;

(3) Accurately weigh 0.04 g aluminum glycinate, 12 g tartaric acid, and 0.3 g menthol as phase B and set aside;

(4) Heat phase A in a water bath at 70°C and stir rapidly for 7 minutes, then add phase B to phase A and continue stirring rapidly for 7 minutes to obtain a gel matrix for later use;

(5) Add the Chinese medicine ointment to the gel matrix and stir for 25 minutes. Spread the obtained paste on a non-woven fabric of 8 cm*12 cm and place it in a cool place until it cools and solidifies to obtain a gel patch.

Dosage and Administration: Use one gel patch every 12 hours, 10 days as a course of treatment.

Example 2.

Prescription: processed Chuanwu 9g, northern Asarum 4g, Atractylodes 6g, Duhuo 6g, Achyranthes bidentata 6g, whole Angelica 9g, Rhizoma Cynoglossi 20g, Rhizoma Cibotii 20g, Radix Clematis 13g, pine knot 10g, red hemp 10, mistletoe 9, Cibotium bark 9, Acanthopanax cortex 9, Millettia reticulata 10, Trillium 9, Curcuma 9.

Process: (1) Weigh the medicinal materials according to the prescription ratio, crush them into coarse powder, accurately weigh the total mass of the medicinal materials to 15 g using an electronic analytical balance, soak them in 12 times ethanol for 18 hours, reflux extract for 2 hours, filter, and dry the filtrate at 60° C. to obtain a Chinese medicine ointment for later use;

(2) Accurately weigh 0.55 g of sodium polyacrylate, 0.45 g of kaolin, and 6.5 g of glycerol, mix well as phase A, and set aside;

(3) Accurately weigh 0.03 g aluminum glycinate, 10 g tartaric acid, and 0.2 g menthol, mix well as phase B, and set aside;

(4) Heat phase A in a water bath at 60°C and stir rapidly for 6 min. Then add phase B to phase A and continue stirring rapidly for 6 min to obtain a gel matrix for later use.

(5) Add the Chinese medicine ointment to the gel matrix and stir for 20 minutes. Spread the resulting paste on a non-woven fabric of 8 cm*12 cm and place it in a cool place until it cools and solidifies to obtain a gel patch.

Dosage and Administration: Use one gel patch every 12 hours, 10 days as a course of treatment.

Example 3.

Prescription: processed Chuanwu 15g, northern Asarum 8g, Atractylodes 12g, Duhuo 12g, Achyranthes bidentata 12g, whole Angelica 15g, Rhizoma Cynoglossi 40g, Rhizoma Cibotii 40g, Radix Achyranthis Bidentatae 40g, Clematidis 23g, Turpentine 20g, Hemp 20g, Viscum album 15g, Cibotium bark 15g, Acanthopanax cortex 15g, Millettia reticulata 20g, Trillium 15g, Curcuma 15g.

Process: (1) Weigh the medicinal materials according to the prescription ratio, crush them into coarse powder, accurately weigh the total mass of the medicinal materials to 20 g using an electronic analytical balance, soak them in 18 times ethanol for 30 hours, reflux extract for 4 hours, filter, and dry the filtrate at 80° C. to obtain a Chinese medicine ointment for later use;

(2) Accurately weigh 0.75 g of sodium polyacrylate, 0.65 g of kaolin, and 7.5 g of glycerol, mix well as phase A, and set aside;

(3) Accurately weigh 0.05 g aluminum glycinate, 14 g tartaric acid, and 0.4 g menthol, mix well as phase B, and set aside;

(4) Heat phase A in a water bath at 80°C and stir rapidly for 8 minutes, then add phase B into phase A and continue stirring rapidly for 8 minutes to obtain a gel matrix for later use;

(5) Add the Chinese medicine ointment to the gel matrix and stir for 30 minutes. Spread the resulting paste on a non-woven fabric of 8 cm*12 cm and place it in a cool place until it cools and solidifies to obtain a gel patch.

Dosage and Administration: Use one gel patch every 12 hours, 10 days as a course of treatment.

Example 4.

Prescription: processed Chuanwu 11g, northern asarum 8g, Atractylodes 8g, Duhuo 10g, Achyranthes bidentata 12g, whole Angelica 9g, Rhizoma Cynoglossi 25g, Rhizoma Cibotii 30g, Rhizoma Dioscoreae 40g, Clematidis 22g, Turpentine 10g, Hemp 12g, Viscum album 15g, Cibotium bark 14g, Acanthopanax acanthopanax 12g, Millettia reticulata 20g, Trillium 10g, Curcuma 15g.

Process: (1) Weigh the medicinal materials according to the prescription ratio, crush them into coarse powder, accurately weigh the total mass of the medicinal materials to be 18 g using an electronic analytical balance, soak them in 14 times ethanol for 28 hours, reflux extract for 2 hours, filter, and dry the filtrate at 65° C. to obtain a Chinese medicine ointment for later use;

(2) Accurately weigh 0.65 g of sodium polyacrylate, 0.50 g of kaolin, and 7.5 g of glycerol, mix well as phase A, and set aside;

(3) Accurately weigh 0.035 g aluminum glycinate, 11 g tartaric acid, and 0.35 g menthol, mix well as phase B, and set aside;

(4) Heat phase A in a water bath at 65°C and stir rapidly for 8 minutes, then add phase B into phase A and continue stirring rapidly for 8 minutes to obtain a gel matrix for later use;

(5) Add the Chinese medicine ointment to the gel matrix and stir for 25 minutes. Spread the resulting paste on a non-woven fabric of 8 cm*12 cm and place it in a cool place until it cools and solidifies to obtain a gel patch.

Dosage and Administration: Use one gel patch every 12 hours, 10 days as a course of treatment.

Example 5.

Prescription: processed Chuanwu 9g, northern Asarum 4g, Atractylodes 10g, Duhuo 12g, Achyranthes bidentata 7g, whole Angelica 12g, Rhizoma Cynoglossi 40g, Rhizoma Cibotii 30g, Rhizoma Dioscoreae 35g, Clematidis 15g, Turpentine 10g, Hemp 10g, Viscum album 15g, Cibotium bark 11g, Acanthopanax cortex 9g, Millettia reticulata 18g, Trillium 13g, Curcuma 13g.

Process: (1) Weigh the medicinal materials according to the prescription ratio, crush them into coarse powder, accurately weigh the total mass of the medicinal materials to be 16 g using an electronic analytical balance, soak them in 14 times ethanol for 20 hours, reflux extract for 4 hours, filter, and dry the filtrate at 70° C. to obtain a Chinese medicine ointment for later use;

(2) Accurately weigh 0.70 g of sodium polyacrylate, 0.60 g of kaolin, and 6.5 g of glycerol, mix well as phase A, and set aside;

(3) Accurately weigh 0.04 g aluminum glycinate, 11 g tartaric acid, and 0.35 g menthol, mix well as phase B, and set aside;

(4) Heat phase A in a water bath at 70°C and stir rapidly for 6 min. Then add phase B to phase A and continue stirring rapidly for 6 min to obtain a gel matrix for later use.

(5) Add the Chinese medicine ointment to the gel matrix and stir for 30 minutes. Spread the resulting paste on a non-woven fabric of 8 cm*12 cm and place it in a cool place until it cools and solidifies to obtain a gel patch.

Dosage and Administration: Use one gel patch every 12 hours, 10 days as a course of treatment.

The present invention has carried out a lot of experimental studies, and the following are the results of the experimental studies of the present invention:

1. Process Research

1.1 Extraction process optimization

1.1.1 Extraction process optimization

According to the prescription ratio (prescription of embodiment 1), the medicinal material is weighed and crushed to form coarse particles, accurately weighed with an electronic analytical balance (the total mass of the medicinal material is 17.1g), the medicinal material is placed in a 1000mL beaker, soaked with ethanol, and loaded into a 2000mL round-bottomed flask after soaking. Then it is loaded into a corresponding electronic temperature-adjusting electric heating sleeve, a spherical reflux condenser is assembled at the mouth of the flask, and the electric heating sleeve is energized for heating, and the state of keeping the solvent boiling is obtained, and it is taken out after a certain time, and the filtrate is filtered while hot by a circulating water multi-purpose vacuum pump, a suction filtration bottle, filter paper and a Buchner funnel, and the filtrate obtained is loaded into a 500mL round-bottomed flask, and it cannot exceed one-third thereof, and is put into a rotary evaporator for rotary evaporation, and ethanol and most of the water are removed to obtain the final liquid, and the liquid is loaded into a beaker, and placed in an electric heating blast drying oven, and maintained at 70°C, and the medicine is dried to obtain an ointment, and the ointment is weighed, and the ointment rate is calculated. In this experimental design process, the orthogonal test method was used for record and guidance. Nine groups of experiments were prepared, and a three-level orthogonal test was conducted with four factors: ethanol concentration, solvent dosage, reflux time, and soaking time. The designed extraction factors are shown in Table 1:

Table 1 Orthogonal factors and levels

Orthogonal test L ₉ (3 ⁴ ) was used for extraction, and the design is shown in Table 2:

Table 2 Orthogonal test of Chinese herbal medicine extraction

1.1.2 Extraction process results

After 9 experiments, the results are shown in Table 3:

Table 3 Orthogonal test results

According to the size of the range R, it can be seen from intuitive analysis that the order of influence of these four factors on the extraction effect is: ethanol concentration (A) > solvent dosage (B) > reflux time (C) > soaking time (D). The optimal extraction process combination is preliminarily determined to be A ₁ B ₃ C ₃ D ₂ , that is, in the reflux extraction, the ethanol concentration is 60%, the solvent dosage is 15 times that of the medicinal material, the reflux time is 3 hours, and the medicinal material is soaked for 24 hours.

1.1.3 Discussion

In this experimental condition, the experimental design involves 3 levels and 4 factors. From the above experimental results, we can see that the concentration of ethanol is the smallest in the three-level experiment, and the range shows that the concentration of ethanol is the biggest factor affecting the extraction rate of medicinal materials. Different Chinese medicinal materials have different extraction rates at different ethanol concentrations, but more Chinese medicinal materials prefer low-concentration ethanol solutions. From the analysis of the experimental results, the lower the ethanol concentration of the Chinese medicinal materials in this prescription, the higher the extraction rate, and the active ingredients in the medicine are more easily soluble in water; from the range R, we know that the amount of solvent is the second largest factor affecting the extraction rate of the drug. From the analysis of the experimental results K of the use of solvents, As the amount of solvent used increases, the extraction rate of the drug increases, so it can be concluded that the greater the amount of solvent used, the better; from the above table, we can see that the length of the reflux time is the third most important factor affecting the drug extraction rate. In the performance of its K value, the extraction rate becomes higher as the reflux time increases; among the four factors, although the R of the soaking time is relatively small, it also has an important influence on the drug extraction rate. According to the experimental results, the best soaking time for medicinal materials is 24 hours, but from the results of the K value, the gap between K1 and K2 and K3 is more obvious, while the values of K2 and K3 are not much different. Based on this result, it can be seen that the soaking time is more than 24 hours. Studies have shown that temperature, extraction time, degree of grinding and solvent all have an impact on the extraction rate. The penetration, dissolution and diffusion capabilities of the effective ingredients of medicinal materials increase with increasing temperature, and the viscosity of the solution decreases with increasing temperature. Therefore, heating during extraction can enhance molecular movement, soften tissues, and increase solubility, thereby increasing the extraction rate. The extraction rate of Chinese herbal medicine ingredients increases with the extension of extraction time until equilibrium is reached. The finer the medicinal materials are ground, the larger the surface area, the more contact area with the solvent, and the higher the probability of the substance coming out, so the extraction rate is higher. In addition, stirring, the amount of extraction solvent used, etc. also have a certain relationship with the extraction rate.

1.2 Formulation process optimization

1.2.1 Preparation of Compound Bitong Gel Patch

The gel patch is composed of three parts, namely the backing layer, the anti-adhesive layer and the paste. The backing layer is made of non-woven fabric, which is cheap and easy to buy; the anti-adhesive layer is the protective layer of the paste, and cellophane is better; the paste is the part where the active ingredients of the medicinal materials exist, which is the key to determining the quality of the entire patch. The paste is composed of the active ingredients of the medicinal materials and the patch matrix, and the matrix is composed of adhesives, regulators, fillers, moisturizers and transdermal enhancers. The matrix is selected to use aluminum glycinate, sodium polyacrylate, glycerol, tartaric acid, kaolin and menthol. Except for menthol, the other five materials have a great influence on the quality of the patch molding. Therefore, 11g glycerol, 0.63g sodium polyacrylate, 0.04g aluminum glycinate, 0.12g tartaric acid and 0.65g kaolin are selected as the standard line, and the use of these materials is taken above and below, and multiple level experiments are designed, and menthol is taken as 0.30g. Using the commonly used orthogonal test table, a 5-factor 4-level orthogonal test is designed to find the best matrix ratio.

The factor level design is shown in Table 4:

Table 4 Orthogonal test factors and levels of plaster matrix

Commonly used orthogonal table L ₁₆ (4 ⁵ ) design experiments are shown in Table 5:

Table 5 Orthogonal test of plaster matrix

According to the experimental design, sodium polyacrylate, kaolin and glycerol were accurately weighed and placed in a 100 mL beaker as phase A; aluminum glycinate, tartaric acid and menthol were accurately weighed and placed on weighing paper as phase B. Phase A was heated in a 70°C water bath and stirred rapidly for 7 minutes, then phase B was added to phase A and continued to stir rapidly for 7 minutes. The resulting paste was spread on a 8cm*12cm non-woven fabric and placed in a cool place until it cooled and solidified. This step was repeated to complete 16 experiments.

After the 16 experiments were completed, they were spread out in a cool place and left to stand for 48 hours. The 16 formed patches were scored based on subjective evaluation, mainly based on the appearance, film residue, skin follow-up and penetration of the patches. The evaluation details are shown in Table 6:

Table 6 Evaluation criteria for plaster matrix

After obtaining the optimal matrix dosage ratio from the experimental results, the ointment extracted by the optimal extraction process was added, and the stirring time was used as a factor to test the effect of different stirring times on the plaster. The stirring time was designed to be 15min, 20min and 25min, corresponding to experimental groups 1, 2 and 3, respectively. The plaster was heated and stirred in a 70°C water bath, and after the paste was obtained, it was spread on a 8cm*12cm non-woven fabric while hot, and the finished product was obtained after it was cooled. The heat resistance, initial adhesion and lasting adhesion of the plasters of the three groups of experiments were tested and evaluated.

1.2.2 Evaluation indicators of Fufang Bitong Gel Patch

(1) Appearance: Place the obtained molded patches on a test bench and arrange them in order. Subjectively evaluate their appearance. The evaluation criteria shall be in accordance with the above standards.

(2) Heat resistance: Take three pieces of gel patches to be tested and heat them in a 60°C oven for 2 hours. After they cool down, observe the degree of seepage on the back of the patches. According to the above evaluation criteria, make a subjective evaluation and observe the glossiness of the patch surface. It should still be sticky when touched lightly with a finger.

(3) Determination of initial adhesion: The initial adhesion is determined by the ramp rolling coin stopping method. The backing of the gel patch sample is fixed to the floor with double-sided tape. The ramp slide is attached to the edge of the patch backing, with the sticky side of the gel patch facing up. The slope is at an angle of 13° to the ground. The slide is 40 cm long. The coin is stationary and rolls at a position 9 cm above the ground. The rolling coin is composed of three 1-yuan coins bonded together by glue and has a mass of 18 g. After the coin rolls down, use a ruler to measure the sliding distance of the coin on the surface of the patch to determine the quality of the initial adhesion of the patch.

(4) Determination of holding force: Lay the sample with the sticky surface facing upward on the test bench, place a hard board underneath, and tape the backing layer to the hard board. Use a 95g, 4cm wide roll of cling film as the test tool. After laying the patch flat, gently place the cling film on the sticky surface of the patch and let it stand for 1 min. Then turn the patch 180° so that the cling film is placed underneath and hung on the patch. Record the time it takes to fall to determine the holding force of the patch.

1.2.3 Results

The subjective scoring results of the 16 experiments on matrix prescriptions are shown in Table 7:

Table 7 Evaluation results of plaster matrix

After completing 16 groups of orthogonal tests, we learned through subjective scoring that the appearance and shape of the experiments in groups 3, 4, 11, 14 and 15 were the best, and the film residue in group 9 was the best. The skin followability of the experiment was very good, the viscosity was acceptable, and the penetration degree of the experiments in groups 3 and 4 was the lowest, and the experimental effect was the best. Substituting the sensory score values into the corresponding experimental orthogonal table, we get the following, and calculate its K value and R value, as shown in Table 8.

Table 8 Results of orthogonal test of plaster matrix

From the comparison of the range R, it can be seen intuitively that the influence of these five factors on the matrix from large to small is: tartaric acid, glycerol, sodium polyacrylate, aluminum glycinate, and kaolin. It can be seen that kaolin has little effect on the plaster matrix, and the main factors that affect the quality of the matrix are glycerol and tartaric acid. From the K value of the experimental results, it can be analyzed that the optimal process for preparing the plaster matrix is A ₁ B ₃ C ₃ D ₃ E ₂ , that is, the amount of glycerol is 7g, sodium polyacrylate is 0.63g, aluminum glycinate is 0.04g, tartaric acid is 0.12g and kaolin is 0.55g; in addition, it is better to reduce the amount of glycerol used.

The experimental results obtained by using the dosage ratio of the matrix and adding the ointment are shown in Table 9:

Table 9 Evaluation results of molded patches

The experimental results show that the appearance of the patch becomes more uniform with increasing heating and stirring time, and reduces bubbles and particles; the heat resistance is evaluated based on the penetration of the fabric, and the experimental results show that the heat resistance has nothing to do with the stirring time of the patch; in the initial adhesion test, as the stirring time increases, the sliding distance of the coin decreases; in the sustained adhesion test, the time the test tool falls becomes longer as the stirring time increases.

1.2.4 Discussion

In the patch, the formula, proportion and selection of matrix materials are the key to the quality of the gel patch dosage form, and multiple experiments are needed to explore. It can be clearly seen in the experiment that with the increase in the amount of glycerol, the skin followability of the paste will weaken, and the degree of penetration will increase. Glycerol is mostly used as a moisturizer. The K value obtained in 16 groups of experiments shows that as the amount of glycerol decreases, the score will increase. The optimal amount in this experiment is 7g, but there is also the possibility that the smaller the amount of glycerol, the better. With the increase in the amount of sodium polyacrylate, the total score first increases and then decreases, resulting in a peak. According to this ratio, the amount of sodium polyacrylate is best at about 0.63g. Aluminum glycinate, tartaric acid and kaolin, like sodium polyacrylate, all have peaks, and the amount is easier to determine. However, the dosage of tartaric acid has a greater effect on the formation of the patch. Some literature points out that when the ratio of the cross-linking regulator and the Ph regulator is similar, the paste has a better viscosity and a moderate cross-linking speed. For example, the ratio of aluminum glycolate and tartaric acid is the same. Therefore, adjusting the test and indenting the ratio can ensure the best preparation process of the experiment.

On the basis of single factor investigation, uniform experimental design was used, with skin followability, adhesion, excipient and film residue as evaluation indexes of breast gel ointment, the matrix prescription dosage was improved, and the optimized matrix prescription mass ratio was 0.6475:0.1712:0.1446:0.0163:0.0068 for glycerol:pure water:sodium polyacrylate:Al(OH) ₃ :tartaric acid. In this experiment, the usage ratio of glycerol was small.

The heating and stirring time also has a great impact on the patch. The experimental results show that the longer the heating and stirring time, the better the appearance, more uniform, with fewer bubbles and particles, and the initial adhesion and lasting adhesion also increase. The final results of the experiment show that the longer the heating and stirring time, the better.

Existing evaluation indicators for gel patches include sensory evaluation indicators, including appearance, film residue, skin follow-up, and penetration. Although they have certain guiding value, the large differences in subjective evaluations and many factors make the analysis of the experimental results less rigorous and reliable. Therefore, this experiment added an objective evaluation of initial adhesion and lasting adhesion to make the experiment more reliable and easier to derive objective laws of the experiment. In addition, since the effects of glycerol dosage and stirring time on the experiment did not reach a peak, there is still room for exploration, which needs to be noted and paid attention to in future research.

1.3 Content determination

1.3.1 Preparation of test solution

Take 3.12 g of the extracted ointment and 0.94 g of the molded patch, put them in 100 mL beakers, add 15 mL and 10 mL of methanol respectively, put them in an ultrasonic cleaner for ultrasonic cleaning, and fully dissolve them.

1.1 Preparation of standard solution

Take 5 clean 10mL volumetric bottles, put 5mg oleanolic acid standard in the first volumetric bottle, add 5mL methanol, shake and dissolve, and then add methanol to the scale line; take 5mL of solution from the first volumetric bottle and add it to the second volumetric bottle, make up to the scale line, and mix evenly; take 5mL of solution from the second volumetric bottle and add it to the third volumetric bottle, add methanol to make up to the scale line, and mix thoroughly; continue the subsequent operations in this way, and there are solutions of certain concentrations in the 5 volumetric bottles. The solution concentrations of volumetric bottles 1 to 5 are 0.5mg/mL, 0.25mg/mL, 0.125mg/mL, 0.0625mg/mL and 0.03125mg/mL, respectively, to obtain 5 reference solutions of different concentrations.

1.3.2 High performance liquid chromatography assay

(1) Preparation of injection solution

Use a 5mL syringe to take the above test sample and standard solution, pass it through a microporous filter membrane, filter it and place it in a high-liquid vial, about 1 to 1.5mL.

(2) Chromatographic conditions

Chromatographic column: GH0525046C18A (4.6 mm × 250 mm, 5 μm); mobile phase: acetonitrile: water = 90:10; injection volume: 10 μL; column temperature: 30 ° C; wavelength: 205 nm; flow rate: 1.0 mL/min.

1.3.3 Results

(1) Spectra of reference and test samples

The spectrum of the reference substance is shown in FIG4 , in which oleanolic acid is the largest peak, with a retention time of 10.395 min, a peak area of 3899.65186 mAU*s, and a concentration of oleanolic acid of 0.5 mg/mL.

As shown in Figure 5, compared with the corresponding retention time in the reference substance, in test sample No. 1, the retention time of oleanolic acid was 10.396 min, and the peak area was 838.33606 mAU*s.

As shown in Figure 6, compared with the corresponding retention time in the reference substance, in test sample No. 2, the retention time of oleanolic acid was 10.541 min, and the peak area was 103.32717 mAU*s.

(2) Data processing

The peak areas of 5 different concentrations of the reference substance measured by HPLC are shown in Table 10, with the designed solution concentration as the abscissa and the peak area as the ordinate. The results are shown in Figure 7, and the standard curve of oleanolic acid content is obtained.

Table 10 HPLC determination results of oleanolic acid standard

As a result, R ² =0.9999, so the reliability of the standard curve is high. Substitute the peak area of the sample corresponding to the retention time into the standard curve Y=7764.9X+19.658 obtained above to calculate the concentration and content of oleanolic acid in the sample. The results are shown in Table 11:

Table 11 Oleanolic acid content in the test samples

From the results, it can be seen that the oleanolic acid content in the unformed ointment is 0.05%, and the oleanolic acid content in the ointment after being formed is 0.03%. It can be seen that there is a certain loss in the process of forming the ointment into a dosage form, but from the perspective of the amount of loss, the fluctuation is not large and the impact is small. The ointment formed into a dosage form may be not uniform enough or not completely dissolved in methanol. The content of oleanolic acid is lower than that of the directly extracted ointment. Therefore, it is more accurate to take the average value and use the oleanolic acid content in the formed patch as 0.04% of the ointment as the evaluation standard.

2. Pharmacodynamics studies

2.1 Experimental Materials

2.1.1 Experimental drugs

Bitong prescription: weigh 12g of processed Chuanwu, 6g of northern asarum, 9g of Atractylodes, 9g of Angelica dahurica, 9g of Angelica sinensis, 30g of Rhizoma Cynoglossi, 30g of Rhizoma Cibotii, 30g of Rhizoma Cynoglossi, 18g of Clematidis, 15g of Pine knotweed, 10g of Hemp, 12g of Viscum album, 12g of Cibotium bark, 12g of Cortex Acanthopanacis, 15g of Millettia reticulata, 12g of Tripterygium wilfordii, and 12g of Curcuma zedoaria, grind them into coarse powder, then soak them in 15 times the amount of 60% ethanol for 24h, reflux extraction for 3h, then filter them while hot to obtain a filtrate, use a rotary evaporator to remove ethanol and other solvents in the filtrate, and finally dry them in an oven at 70℃ to obtain the extract used in the experiment.

Enteric-coated aspirin tablets, Yunnan Baiyao Group Co., Ltd., batch number: ZJA2202. Specification: 25 mg/tablet, national medicine standard: H53021845. Usage and dosage: Oral, 2 to 4 tablets at a time, once a day.

Prednisone acetate tablets, Zhejiang Xianju Pharmaceutical Co., Ltd., batch number: LA22503. Specification: 5 mg/tablet, national medicine standard: H33021207. Usage and dosage: Oral, 1 tablet at a time, twice a day.

Glacial acetic acid (analytical grade), Chengdu Jinshan Chemical Reagent Co., Ltd., batch number: 20221006, specification: 500 mL/bottle.

Xylene (analytical grade), Chongqing Wansheng Chuandong Chemical Co., Ltd., specification: 500mL/bottle.

2.1.2 Experimental animals and feed

SPF mice, weighing 19-23 g, were provided by SPF (Beijing) Biotechnology Co., Ltd., license number: SCXK (Beijing) 2019-0010. Adaptive feeding: All mice were used after 3 days of adaptive feeding at the Experimental Animal Center of the School of Pharmacy of Guizhou University.

Feed and bedding: Complete pellet feed and corn cob bedding were provided by Chongqing Watson Biotechnology Co., Ltd.

Rearing environment: SPF animal room 501, 503, School of Pharmacy, Guizhou University. The indoor environment is clean and quiet, equipped with aluminum frame sheet coarse air filter and indoor ventilation system provided by Suzhou Huatai Air Filter Co., Ltd., humidity 30-40%, temperature 22-25℃. Laboratory Animal Use License No.: SYXK (Guizhou) 2022-0004. Mice were housed in separate cages, fed with complete feed, and free to drink Nongfu Spring natural mineral water.

2.1.3 Dose selection

According to the dose of the test drug (raw drug) used clinically in adults, two dose groups of Bitong Prescription were set: high (4 times the equivalent dose) and low (equivalent dose). Aspirin group and prednisone acetate group were set up as the positive control group. The equivalent dose was calculated using the kilogram body weight dose conversion coefficient method, and the body weight of an adult was calculated as 50 kg.

2.2 Experimental methods

2.2.1 Analgesic effect - twisting method

Forty-eight SPF mice weighing 18-22g were randomly divided into an acetic acid blank group, an aspirin group (0.72g·kg ^-1 ·d ^-1 ), a low-dose Bitong Fang group (1.75g·kg ^-1 ·d ^-1 ), and a high-dose Bitong Fang group (7g·kg ^-1 ·d ^-1 ), with 12 mice in each group. The blank group was given an equal amount of distilled water, and the experimental groups were given aspirin and different doses of Bitong Fang solution. The administration was once a day for 7 consecutive days. 1.5h after the last administration, each mouse was intraperitoneally injected with 0.6% acetic acid, 0.2mL/mouse. The number of writhing reactions (abdominal contraction and concavity, extension of hind limbs, buttocks lifting, crawling) 15min after the injection of acetic acid solution was observed. The t-test method was used to compare whether there was a significant difference in the number of writhing reactions of mice in each treatment group and the model group that did not receive treatment, so as to determine whether the experimental results were statistically significant.

2.2.2 Anti-inflammatory effect - xylene-induced mouse ear swelling method

Forty-eight SPF mice weighing 18-22g were randomly divided into a xylene blank group, a prednisone acetate group (0.09g·kg ^-1 ·d ^-1 ), a low-dose Bitong Fang group (1.75g·kg ^-1 ·d ^-1 ), and a high-dose Bitong Fang group (7g·kg ^-1 ·d ^-1 ), with 12 mice in each group. The blank group was given an equal amount of distilled water, and the experimental groups were gavaged with prednisone acetate and Bitong Fang solutions of different concentrations. Once a day, the medication was continued for 7 days. 1.5h after the last administration, xylene (0.02mL/mouse) was evenly applied to the front and back of the left ear of the mouse to cause inflammation. Then, the mouse was killed suddenly 25 minutes later, and a 6mm punch was used to punch a round ear piece at the same part of both ears of the mouse and weigh it. The weight difference between the left and right ears was calculated. The t-test method was used to compare whether there was a significant difference in the degree of ear swelling between each treatment group and the model group that did not receive treatment, in order to determine whether the experimental results were statistically significant.

2.3 Statistical analysis

The calculation method of pain inhibition rate in acetic acid writhing test is as follows: pain inhibition rate = (number of writhing reactions in blank group - number of writhing reactions in drug-treated group) / number of writhing reactions in blank group × 100%. The weight of the right ear piece of each mouse minus the weight of the left ear piece is the swelling degree. The experimental results are expressed as mean ± standard deviation, and the experimental data are statistically analyzed using SPSS27.0. The one-way ANOVA test is used for inter-group comparison, and the F test is used for variance analysis.

2.4 Results and Discussion

2.4.1 Experimental Results

Effect of Bitong Fang on the number of abdominal writhings caused by acetic acid in mice: The number of writhings in the aspirin group and the high-dose Bitong Fang group was significantly reduced, which was statistically significant compared with the blank control group (p < 0.05). This shows that the high-dose Bitong Fang group can effectively relieve the pain caused by acetic acid in the abdominal cavity of mice, indicating that Bitong Fang has a good analgesic effect. Among them, the analgesic effect of the high-dose Bitong Fang group was significantly better than that of the low-dose group. The results are shown in Table 12.

Table 12 Effect of Bitong Recipe on the number of writhing times of mice with acetic acid-induced peritonitis (n=12, x±s)

Note: Compared with the blank control group, a p＜0.05

Effect of Bitong Recipe on the degree of ear swelling of mice caused by xylene: The experimental results show that the low-dose and high-dose groups of Bitong Recipe and the prednisone acetate group have a significant inhibitory effect on the ear swelling of mice caused by xylene, and can reduce the ear swelling of mice, indicating that Bitong Recipe has a good anti-inflammatory effect. The comparison between each medication group and the blank control group was statistically significant (p < 0.05). Among them, the swelling degree of the high-dose group of Bitong Recipe was significantly less than that of the low-dose group, indicating that the high-dose group had a better anti-inflammatory effect than the low-dose group. The results are shown in Table 13.

Table 13 Effect of Bitong Recipe on xylene-induced ear swelling in mice (n=12, x±s)

Group Dose (g·kg ^-1 ) Swelling Blank control group - 3.8±1.5 Aspirin group 0.09 1.7± ^0.6a Bitongfang low dose group 1.75 2.2± ^0.7a Bitongfang high dose group 7.00 1.7±1.1 ^a

Note: Compared with the blank control group, ^a p＜0.05

2.4.2 Discussion

Frankincense contains terpene compounds such as β-glutene, α-pinene, β-pinene, etc., which have a fresh, aromatic and sweet smell; myrrh contains phenolic compounds such as bisabolol and myrrhol, which give it a woody and sweet smell. These two Chinese medicines as spices in the compound can not only improve the taste and smell of the compound, but also have the effects of promoting blood circulation, relaxing muscles and relieving pain.

Chuanwu has the function of "dispelling cold, dampness, wind and blood stasis." ("Zhenzhu Nang"), which contains a large number of aconite alkaloids. Studies have shown that aconite alkaloids can affect the release of dynorphin by spinal microglia, causing it to act on k-opioid receptors to produce analgesic effects. The coumarin components contained in Duhuo have a conjugated double bond structure and thus have obvious anti-inflammatory and analgesic activities. Dihydro-eugenol (dihydro-eugenol angelic acid ester) can block calcium channels and significantly inhibit the production of prolactin induced by thyrotropin-releasing hormone. The volatile oils in angelica can not only inhibit the edema and exudation of early inflammation, but also inhibit the proliferation of tissues and the formation of granulation tissue in the late stage of inflammation, and have obvious analgesic and anti-inflammatory activities. The A3 active part of Angelica sinensis (a neutral, non-phenolic part extracted from the total volatile oil of Angelica sinensis using the CO2 supercritical method) can significantly inhibit the ear swelling of mice caused by xylene and dose-dependently inhibit the expression of COX-2 mRNA and protein in the rat uterus induced by LPS (lipopolysaccharide), indicating that its analgesic effect may be related to its ability to inhibit the expression of COX-2 mRNA and protein. Angelica sinensis can also be often used as food in life. It is a Chinese medicine with both medicinal and edible properties. It can replenish blood, regulate menstruation and relieve pain. Therefore, its extract is also used as a raw material for products in the pharmaceutical and health care industries. β-eudesminol, one of the main components of Atractylodes lancea, can inhibit the expression of receptor interacting protein-2 and the activation of caspase-1 by blocking the activation of mast cell p38 mitogen-activated protein kinase and NF-kB, and produce an inflammatory response mediated by mast cells by antagonizing the expression of IL-6 by phorbol ester plus calcium ion carrier A23187 human mast cells. With the continuous development of modern science and technology, in-depth research and clinical verification of traditional Chinese medicine compound prescriptions will further improve the system of traditional Chinese medicine treatment of rheumatic diseases, and may achieve better curative effects, alleviate patients' pain, and improve their quality of life. At the same time, in terms of integration of traditional Chinese and Western medicine and personalized treatment, traditional Chinese medicine compound prescriptions are expected to become one of the important RA treatment methods.

Claims (9)

1. A gel emplastrum for treating arthralgia, which is characterized in that: the medicinal active ingredients of the composition are calculated according to the weight components: is prepared from radix aconiti preparata 90-150 parts, asarum sieboldii 40-80 parts, rhizoma atractylodis 60-120 parts, radix angelicae pubescentis 60-120 parts, achyranthes bidentata 60-120 parts, angelica sinensis 90-150 parts, rhizoma dioscoreae nipponicae 200-400 parts, rhizoma homalomenae 200-400 parts, cortex schizophragmatis integrifolii radicis 200-400 parts, radix clematidis 130-230 parts, pine node 100-200 parts, red graminea 100-200 parts, herba taxilli 90-150 parts, rhizoma cibotii 90-150 parts, cortex acanthopanacis 90-150 parts, caulis spatholobi 100-200 parts, rhizoma sparganii 90-150 parts and rhizoma curcumae 90-150 parts.

2. The gel patch for treating arthralgia according to claim 1, wherein: the medicinal active ingredients of the composition are calculated according to the weight components: is prepared from 100-140 parts of prepared common monkshood mother root, 50-70 parts of asarum, 70-110 parts of rhizoma atractylodis, 70-110 parts of radix angelicae pubescentis, 70-110 parts of achyranthes bidentata, 100-140 parts of whole angelica sinensis, 250-350 parts of Ningpo Yam rhizome, 250-350 parts of obscured homalomena rhizome, 250-350 parts of cortex schizophragmatis integrifolii radicis, 150-210 parts of radix clematidis, 120-180 parts of pine node, 80-120 parts of red graminea, 100-140 parts of mistletoe, 100-140 parts of rhizoma cibotii, 100-140 parts of cortex acanthopanacis, 120-180 parts of suberect spatholobus stem, 100-140 parts of rhizoma sparganii and 100-140 parts of rhizoma curcumae.

3. The gel patch for treating arthralgia as set forth in claim 2, wherein: the medicinal active ingredients of the composition are calculated according to the weight components: is prepared from prepared Sichuan aconite root 120 parts, asarum herb 60 parts, atractylodes rhizome 90 parts, pubescent angelica root 90 parts, achyranthes root 90 parts, chinese angelica root 120 parts, ningpo Yam rhizome 300 parts, homalomena rhizome 300 parts, dried rhizome of rehmannia 300 parts, clematis chinensis 180 parts, pine node 150 parts, red rice 100 parts, loranthus mulberry mistletoe 120 parts, cibotium barometz 120 parts, cortex acanthopanacis 120 parts, spatholobus stem 150 parts, burreed tuber 120 parts, zedoary 120 parts.

4. A method for preparing a gel patch for the treatment of pain according to any one of claims 1 to 3, wherein: the preparation method comprises the following steps:

(1) Weighing the medicinal materials according to the prescription proportion, crushing into coarse materials, accurately weighing 15-20g of the total mass of the medicinal materials by an electronic analytical balance, soaking for 18-30h by 12-18 times of ethanol, extracting for 2-4h by reflux, filtering, and drying the filtrate at 60-80 ℃ to obtain a traditional Chinese medicine ointment for later use;

(2) Accurately weighing 0.55-0.75g of sodium polyacrylate, 0.45-0.65g of kaolin and 6.5-7.5g of glycerin, and uniformly mixing to obtain a phase A for later use;

(3) Accurately weighing 0.03-0.05g of aluminum glycinate, 10-14g of tartaric acid and 0.2-0.4g of menthol, and uniformly mixing to obtain a phase B for later use;

(4) Heating the phase A on a water bath kettle at 60-80 ℃ for 6-8min, adding the phase B into the phase A, and continuously and rapidly stirring for 6-8min to obtain a gel matrix for later use;

(5) Adding the Chinese medicinal ointment into gel matrix, stirring for 20-30min, spreading the obtained ointment on 8cm x 12cm non-woven fabric, and cooling and solidifying in shade to obtain gel patch.

5. The method for preparing the gel patch for treating arthralgia as set forth in claim 4, wherein: in the step (1), the medicinal materials are weighed according to the prescription proportion, crushed into coarse materials, the total mass of the medicinal materials is accurately weighed to be 17.1g by an electronic analytical balance, the medicinal materials are soaked for 24 hours by 15 times of ethanol, the reflux extraction is carried out for 3 hours, the filtration is carried out, and the filtrate is dried at 70 ℃ to obtain the traditional Chinese medicine ointment for standby.

6. The method for preparing the gel patch for treating arthralgia as set forth in claim 4, wherein: in the step (2), 0.63g of sodium polyacrylate, 0.55g of kaolin and 7g of glycerin are accurately weighed as phase A for later use.

7. The method for preparing the gel patch for treating arthralgia as set forth in claim 4, wherein: in the step (3), 0.04g of aluminum glycinate, 12g of tartaric acid and 0.3g of menthol are accurately weighed as a B phase for standby.

8. The method for preparing the gel patch for treating arthralgia as set forth in claim 4, wherein: in the step (4), the phase A is heated on a water bath kettle at 70 ℃ and is rapidly stirred for 7min, the phase B is added into the phase A, and the rapid stirring is continued for 7min to obtain a gel matrix for later use.

9. The method for preparing the gel patch for treating arthralgia as set forth in claim 4, wherein: in the step (5), the traditional Chinese medicine ointment is added into the gel matrix, stirred for 25min, the obtained ointment is paved on non-woven fabrics with the length of 8cm and the length of 12cm, and the non-woven fabrics are placed in a shade place for cooling and solidifying to obtain the gel emplastrum.