Medicine for treating knee osteoarthritis as well as preparation method and application thereof

Abstract

The invention relates to a medicine for treating knee osteoarthritis as well as a preparation method and application thereof. The medicine is prepared from traditional Chinese medicine extract, NP700, dihydroxyaluminium aminoacetate, glycerin, tartaric acid, superfine silica powder, CMC-Na, azone and microemulsion, wherein the traditional Chinese medicine extract is prepared by mixing and extracting traditional Chinese medicines such as hedyotis diffusa, salvia miltiorrhiza, frankincense and myrrh; nP700 is used as a framework material, dihydroxyaluminum aminoacetate is used as a cross-linking agent, glycerin is used as a humectant, superfine silica powder is used as a filling agent, CMC-Na is used as a tackifier, and tartaric acid is used as a cross-linking regulator, so that a novel transdermal drug delivery preparation is prepared. The composition can be used for treating diseases such as knee osteoarthritis; the simple formula reduces interference of complex components, reduces sensitization, has no obvious skin damage, can act for a long time, has a stable curative effect, and can achieve a sustained and controlled release effect. The gel patch is tightly attached to the skin, does not affect the movement of limbs, and does not easily fall off like a traditional plaster. The problems that in the prior art, drugs are difficult to diffuse into dermis, the drug release speed is unstable, the drug stability is poor, and the adhesion is insufficient are solved. Compared with a traditional application agent, irritation is small, the drug loading capacity is larger, and the bioavailability of the drug is improved.

Description

Technical Field

[0001] The present invention relates to the technical field of traditional Chinese medicines, and in particular to a medicine for treating knee osteoarthritis, and a preparation method and application thereof. Background Art

[0002] Knee osteoarthritis (KOA) is a bone and joint disease characterized by gradual and progressive degeneration of the joints, also known as degenerative joint disease and proliferative osteoarthritis. Knee pain, limited movement, dysfunction, abnormal joint morphology, and even disability are common clinical symptoms of KOA. Knee pain seriously affects the quality of life and mental health of patients, and becomes the main motivation for patients to seek medical treatment. According to the epidemiological survey results of the Department of Orthopedics and Joints of Peking University People's Hospital, the overall incidence of KOA in people over 65 years old in my country is 8.1%. The extension of life expectancy will lead to a continuous increase in the number of KOA patients in the future. The years of life lost due to disability (Years Lived with Disability, YLD) caused by KOA per 100,000 people in my country has increased from 92.5% in 1990 to 98.8% in 2017.

[0003] At present, both traditional Chinese medicine and Western medicine provide a variety of treatment methods. In terms of Western medicine treatment, analgesics for KOA patients mainly include non-steroidal anti-inflammatory drugs and opioids, including patches containing non-steroidal anti-inflammatory drugs such as flurbiprofen gel patch, loxoprofen sodium gel patch, ketoprofen patch, indomethacin bab patch, etc.; patches containing opioids such as buprenorphine transdermal patch, transdermal patch, etc. However, long-term use of non-steroidal anti-inflammatory drugs can easily lead to gastrointestinal complications and induce drug tolerance. In addition, it is inconvenient to use, easy to fall off, and the release rate is unstable, which leads to poor efficacy. In contrast, traditional Chinese medicine treatment is mainly based on oral and external treatment of traditional Chinese medicine. For example, in clinical practice, maltose and powder have been used for on-site preparation of drugs. The drug loading capacity is limited and there is a certain irritation to the skin. It is not convenient to store and carry, which limits the bioavailability of the drug. However, the therapeutic effects of these two methods are not satisfactory. For the treatment of knee osteoarthritis, there are existing patent applications such as: Patent application number CN202210103203.8, which proposes a pharmaceutical composition and acupoint ointment for chronic pain diseases. Currently used for pain treatment, it is symptomatic and has the characteristics of one prescription for one person, but it is difficult to expand production. Another example: Patent application number CN202210603052.2, which discloses a Chinese medicine composition patch for the treatment of knee osteoarthritis and its preparation method and application, which can relieve patients' pain symptoms and improve joint function, but the administration time is short, easy to fall off, and cannot act on the affected area for a long time. The above Chinese medicine plasters or gel ointments all have problems such as the difficulty of drugs to diffuse into the dermis, unstable drug release rate, poor drug stability and insufficient adhesion. The drug efficacy is uneven due to environmental factors, and the drug is easily affected by light, heat and oxygen, and the lack of adhesion may cause shedding or displacement, thereby affecting the efficacy. Therefore, it is urgent to design a transdermal preparation for knee osteoarthritis with high efficacy and high safety.

[0004] Fireweed is the dried whole herb of Leontopodium franchetii Beauv., a plant of the Asteraceae family. It is harvested in summer and autumn, removed of mud and sand, and dried. This product is cold in nature and slightly bitter in taste. Because the ancients used fireweed to ignite and strike stones to make fire, it was named "fireweed". After processing, it can be made into fireweed fluff. Fireweed is used for direct or indirect moxibustion of acupoints, using its warm power to regulate temperature and plasma osmotic pressure, accelerate blood circulation, and affect the body's tissue metabolism and nerve function. According to the characteristics of acupoints, reasonable medication is given, and through the conduction of meridians, the effects of dispelling cold and dampness, warming the meridians and unblocking the collaterals, promoting qi and relieving pain, and activating blood circulation and dispersing nodules are achieved. Data mining and attribute relationship analysis of fireweed showed that it has a high correlation with the liver pathway and shows good efficacy in treating cold and dampness diseases, which is consistent with the understanding of traditional Chinese medicine on the pathogenesis of knee osteoarthritis. In the ancient Yi medical books "The Book of Good Medicines for Treating Diseases" and "The Theory of Cosmic Humanities" and the modern document "Yi Medicine", there are also records of fireweed being used as medicine. "Selected Chinese Herbal Medicines in Simao, Yunnan" records that fireweed can "repel wind, warm the stomach, eliminate epidemic toxins. Treat knife wounds, abdominal pain, abdominal cramps, and asthma", and the whole plant is "neutral and light in taste". Taking fireweed internally can benefit the kidneys and promote diuresis. For external use, it can be ground into powder and applied topically. It can also be processed into fireweed velvet, which is used as the main raw material to make moxibustion sticks and then ignite to treat diseases, which is fireweed moxibustion.

[0005] Our team's previous research found that fireweed contains chemical components such as flavonoids, organic acids, alkaloids, cardiac glycosides, saponins, anthraquinones, phenols, tannins, coumarins and lactones. Fireweed preparations made from it can be used for external application to treat knee osteoarthritis. It has the effects of dredging meridians, dispersing cold evil, removing dampness, promoting qi movement, relieving pain, and supporting yang qi, but there is still a lack of standardized and scientific clinical research. The main drug in the compound is fireweed, which can dissipate blood stasis and relieve pain, promote dampness and reduce swelling, and clear away heat and detoxify; the secondary drug is salvia miltiorrhiza, which can promote blood circulation and remove blood stasis, and strengthen the main drug's function of removing blood stasis and promoting blood circulation; frankincense can promote qi and promote blood circulation, and myrrh can promote blood circulation, dissipate blood stasis and relieve pain. Salvia miltiorrhiza, frankincense, and myrrh assist the main drug in strengthening the effect of promoting blood circulation and relieving pain. The whole prescription has the functions of clearing heat and detoxifying, promoting blood circulation and relieving pain.

[0006] The fireweed used in the present invention is processed fireweed fluff. In the summer of August to September every year, fresh fireweed is collected on the high mountains of Liangshan Yi Autonomous Prefecture, Sichuan. After drying, it is repeatedly kneaded into small pieces by hand, and the impurities and grass stems therein are removed, leaving the fireweed fluff of light gray and uniform size. Fireweed, as an important raw material in the fire moxibustion treatment of Yi medicine, has the effects of dispelling cold and dampness, promoting qi and relieving pain, preventing diseases and health care, and is widely used in the treatment of cold and dampness diseases, surgical diseases and gynecological diseases. Clinically, it has significant therapeutic effects on diseases such as spleen and stomach deficiency and cold, gastric colic, cold cold, neuralgic headache, acute appendicitis, epistaxis, chronic rhinitis, hydatid disease of the liver, cold diarrhea, bronchial asthma, rheumatic diseases, periarthritis of the shoulder, bone hyperplasia, ovarian cysts, and severe neurological mental illness. Although fireweed has significant therapeutic effects in the treatment of knee osteoarthritis, its clinical use has major defects and poor patient compliance. Currently, the clinical application of fireweed is rather confusing and lacks relevant quality control research, resulting in variable efficacy, so it is crucial to develop a preparation.

[0007] In the early stage, our team proved through animal experiments that fireweed can effectively improve the symptoms of rats with knee osteoarthritis model, so this therapy has good anti-inflammatory and pain relief effects. On the basis of clarifying the pharmacology and efficacy, this project team combined the Triz theory to find innovative solutions, improved the existing knee osteoarthritis patches on the market, and developed a new fireweed transdermal drug delivery preparation that can act for a long time, has stable efficacy, and can achieve a sustained and controlled release effect. The new preparation for transdermal drug delivery of fireweed comprises a backing layer, a paste layer and an anti-adhesive film; the paste layer is a gel layer formed by a Chinese medicine composition and a matrix for loading the Chinese medicine composition, wherein the Chinese medicine composition is composed of Chinese medicine raw materials of fireweed, salvia miltiorrhiza, frankincense and myrrh; the backing layer is the carrier part of the gel patch, which mainly plays a supporting role of the paste, and uses a needle-punched elastic non-woven fabric; the anti-adhesive film is a surface covering part, which is used to protect the matrix layer and prevent drug leakage during storage, and a PET release film is selected; the matrix of the paste layer includes ethyl oleate, polyoxyethylene hydrogenated castor oil EL40, and PEG400 in the microemulsion, and NP700, aluminum glycolate, glycerol, micro-powder silica gel, CMC-Na, tartaric acid, and a penetration enhancer in the gel matrix as a preferred embodiment; in the paste layer, the Chinese medicine composition, its water extract, alcohol extract, volatile oil, and Chinese medicine extract, and the drug loading amount is 15wt.% calculated by the addition amount of the Chinese medicine extract. Among the excipients used in this prescription, NP700 is used as a skeleton material, aluminum glycolate is used as a crosslinking agent, glycerol is used as a moisturizer, micro-powdered silica gel is used as a filler, CMC-Na is used as a thickener, and tartaric acid is used as a crosslinking regulator. The skeleton material can make the paste sticky, and it is also a key substance to produce sufficient cohesion and elasticity. The crosslinking agent can adjust the degree of crosslinking of the polymer compound. Its type and amount have a decisive effect on the properties, hardness, and crosslinking speed of the plaster. The matrix prepared with glycerol as a moisturizer has better ductility and is non-irritating. The crosslinking regulator mainly adjusts the speed of the crosslinking reaction. Choosing tartaric acid as a crosslinking regulator is not only easy to apply, but also has good plaster molding performance and is economical and cheap. The filler affects the excipient and plasticity of the traditional Chinese medicine gel plaster.

[0008] When the plaster adheres to the skin surface, the drug is released, penetrates the epidermal stratum corneum and enters the active epidermis. The drug diffuses to the dermis and is absorbed by the capillaries to enter the systemic circulation. At the same time, it stimulates the nerve endings, dilates the blood vessels through reflection, promotes local blood circulation, improves the nutrition of surrounding tissues, and achieves the purpose of reducing swelling, inflammation and analgesia. At the same time, the drug penetrates through the skin in the affected area to reach the subcutaneous tissue, and produces a relative advantage in drug concentration locally, thereby exerting a strong pharmacological effect locally. The transdermal preparation has higher safety, better efficacy, lower irritation, and has the characteristics of controllable drug release rate and higher bioavailability, so as to solve the problems of high efficacy and high stability that cannot be achieved by existing knee osteoarthritis preparations. While protecting and inheriting the unique cultural heritage of Yi medicine, it makes positive contributions to the cause of human health. Summary of the invention

[0009] In order to overcome the shortcomings of the prior art, one of the purposes of this application is to provide a drug for treating knee osteoarthritis, the second purpose is to provide a method for preparing the drug for treating knee osteoarthritis, and the third purpose is to provide the use of the drug for treating knee osteoarthritis in the preparation of a pharmaceutical preparation for treating knee osteoarthritis, so as to give full play to the anti-inflammatory and analgesic effects of the combination of traditional Chinese medicine and the in vitro transdermal penetration promotion of the gel, so as to facilitate clinical promotion and use.

[0010] In order to achieve the above object, the present invention adopts the following technical scheme:

[0011] The medicine for treating knee osteoarthritis of the present invention is prepared from the following ingredients in parts by weight: 2-8 parts of traditional Chinese medicine extract, 0.5-1.75 parts of NP700, 0.02-0.12 parts of aluminum glycolate, 4-16 parts of glycerol, 0.02-0.12 parts of tartaric acid, 0.25-1.5 parts of micro powder silica gel, 0.1-0.35 parts of CMC-Na, 0.2-0.8 parts of azone, and 6-14 parts of microemulsion.

[0012] Preferably, the drug for treating knee osteoarthritis of the present invention is prepared from the following ingredients in parts by weight: 3-5 parts of traditional Chinese medicine extract, 1-1.5 parts of NP700, 0.04-0.08 parts of aluminum glycolate, 6-10 parts of glycerol, 0.06-0.08 parts of tartaric acid, 0.5-1.25 parts of micropowder silica gel, 0.2-0.25 parts of CMC-Na, 0.4-0.6 parts of azone, and 8.5-12.5 parts of microemulsion.

[0013] Furthermore, the medicine for treating knee osteoarthritis of the present invention is prepared from the following ingredients in parts by weight: 4 parts of Chinese medicine extract, 1.35 parts of NP700, 0.04 parts of aluminum glycolate, 7 parts of glycerol, 0.06 parts of tartaric acid, 1.25 parts of micropowder silica gel, 0.2 parts of CMC-Na, 0.6 parts of azone, and 12.5 parts of microemulsion.

[0014] Furthermore, the Chinese medicine extract of the present invention is prepared from the following Chinese medicine raw materials in parts by weight: 18 parts of fireweed, 5 parts of salvia miltiorrhiza, 5 parts of frankincense, and 5 parts of myrrh.

[0015] Furthermore, the microemulsion of the present invention is prepared from the following ingredients in percentage by weight: 14.8% EL-40, 14.8% PEG 400, 2.6% ethyl oleate, 1.1% volatile oil, and 66.7% water.

[0016] The method for preparing the medicine for treating knee osteoarthritis of the present invention comprises the following steps:

[0017] S1, weighing fireweed, salvia miltiorrhiza, frankincense, and myrrh according to the prescribed amount, adding 4-10 times the amount of water of the medicinal materials to soak for 0.5-1h, using steam distillation to continuously extract for 6-10h, collecting volatile oils for later use;

[0018] S2, filtering the water extract in step S1, concentrating the filtrate to obtain a water extract for later use;

[0019] S3, adding 6-12 times the amount of 70-85% ethanol to the drug residue filtered in step S2, extracting for 2-4 times, each time for 0.5-1.5 hours, combining the extracts, filtering the alcohol extract, collecting the filtrate, recovering the ethanol under reduced pressure, obtaining an alcohol extract, and setting aside;

[0020] S4, combining the water extract and the alcohol extract, concentrating to a Chinese medicine extract having a relative density of 1.15-1.25 at 50-60° C., and setting aside;

[0021] S5, taking NP-700, aluminum glycolate, micro-powder silica gel, azone, and glycerol according to the prescription ratio, adding NP-700, aluminum glycolate, micro-powder silica gel, and azone to glycerol, stirring and mixing evenly, as phase A;

[0022] S6, taking CMC-Na and tartaric acid according to the prescription ratio, fully swelling the CMC-Na with the microemulsion, and adding tartaric acid to dissolve as phase B;

[0023] The microemulsion preparation method is as follows: 14.8% EL-40, 14.8% PEG400, 2.6% ethyl oleate, 1.1% volatile oil prepared in step S1, and 66.7% water are taken by weight percentage, and magnetic stirring is performed at room temperature for 30 minutes to mix evenly to obtain the microemulsion;

[0024] S7, adding the Chinese medicine extract prepared in step S4 to phase A, stirring evenly, then adding phase B, stirring sufficiently, coating the prepared gel patch evenly on the backing, and drying at 40° C. to obtain.

[0025] Furthermore, step S1 of the present invention is specifically as follows: weigh fireweed, salvia miltiorrhiza, frankincense, and myrrh according to the prescription ratio, add 6 times the amount of water of the medicinal materials and soak for 0.5h, use steam distillation to continuously extract for 8h, collect volatile oil, and set aside.

[0026] Furthermore, step S3 of the present invention is specifically as follows: adding 10 times the amount of 80% ethanol to the filtered medicinal residues for extraction 3 times, each time for 1 hour, combining the extracts, filtering the alcohol extract, collecting the filtrate, recovering ethanol under reduced pressure, obtaining an alcohol extract, and setting it aside.

[0027] Application of the medicine of the present invention or the medicine prepared by the preparation method in preparing a pharmaceutical preparation for treating knee osteoarthritis.

[0028] The pharmaceutical preparations of the present invention include but are not limited to: gel ointments (gel patches).

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] 1. The present invention develops a new product of anti-inflammatory and analgesic fireweed transdermal Chinese medicine gel patch, which has the effects of promoting blood circulation and removing blood stasis, relieving pain and removing numbness, and can be used to treat diseases such as knee osteoarthritis; due to the simplified formula, the interference of complex ingredients is reduced, the sensitization is reduced, and there is no obvious skin damage.

[0031] 2. The present invention obtains a novel transdermal drug delivery preparation which is convenient to use, has controllable dosage, good adhesion and sustained effect by rationally matching the matrix with the Chinese medicine ingredients. (1) Through the investigation of microemulsion, the microemulsion formula is EL-4014.8%, PEG-400 14.8%, ethyl oleate 2.6%, volatile oil 1.1%, water 66.7%, the particle size and PDI of the prepared microemulsion meet the standards, and the process is stable. (2) Through the investigation of the performance of the Chinese medicine gel patch, the results show that the optimal formula composition is: NP700, aluminum glycolate, glycerol, micropowder silica gel, CMC-Na, tartaric acid, penetration enhancer azone, microemulsion, extract = 1.35g: 0.04g: 7g: 1.25g: 0.2g: 0.06g: 0.6g: 12.5g: 4g. The sensory score, initial adhesion, lasting adhesion and comprehensive score of the product prepared under the optimal formula are good.

[0032] 3. Compared with the traditional stasis-eliminating plaster, the product of the present invention uses a sustained-release skeleton, which has better drug controlled-release effect, better tolerance, stronger affinity with drugs, no irritation and sensitization, and more moderate and controllable viscosity. The gel patch fits tightly to the skin, does not affect limb movement, and does not fall off as easily as traditional plasters. It solves the problems of drugs being difficult to diffuse into the dermis, unstable drug release rate, poor drug stability, and insufficient adhesion in the prior art.

[0033] 4. Compared with traditional patches, the gel patch screened out by the present invention has less irritation, a larger drug loading capacity, and the drug can easily enter the dermis, thereby improving the bioavailability of the drug. DETAILED DESCRIPTION

[0034] The following examples are used to illustrate the present invention but are not intended to limit the scope of the present invention.

[0035] Example 1 Preparation of Chinese medicine extract

[0036] Prescription: 18 parts of fireweed, 5 parts of salvia miltiorrhiza, 5 parts of frankincense, and 5 parts of myrrh.

[0037] The preparation method is as follows:

[0038] S1, weigh fireweed, salvia miltiorrhiza, frankincense, and myrrh according to the prescription amount, add 6 times the amount of water of the medicinal materials and soak for 0.5h, use steam distillation to continuously extract for 8h, collect volatile oil and set aside;

[0039] S2, filtering the water extract in step S1, concentrating the filtrate to obtain a water extract for later use;

[0040] S3, adding 10 times the amount of 80% ethanol to the drug residue filtered in step S2 for extraction three times, each time for 1 hour, combining the extracts, filtering the alcohol extract, collecting the filtrate, and recovering the ethanol under reduced pressure to obtain an alcohol extract for later use;

[0041] S4, combining the water extract and the alcohol extract, and concentrating them to a Chinese medicine extract having a relative density of 1.15-1.25 at 50-60°C.

[0042] Example 2 Preparation of Chinese medicine extract

[0043] Prescription: 18 parts of fireweed, 5 parts of salvia miltiorrhiza, 5 parts of frankincense, and 5 parts of myrrh.

[0044] The preparation method is as follows:

[0045] S1, weigh fireweed, salvia miltiorrhiza, frankincense, and myrrh according to the prescription amount, add 4 times the amount of water of the medicinal materials and soak for 0.5h, use steam distillation to continuously extract for 6h, collect volatile oil and set aside;

[0046] S2, filtering the water extract in step S1, concentrating the filtrate to obtain a water extract for later use;

[0047] S3, adding 6 times the amount of 70% ethanol to the drug residue filtered in step S2 and extracting twice, each time for 0.5 h, combining the extracts, filtering the alcohol extract, collecting the filtrate, and recovering the ethanol under reduced pressure to obtain an alcohol extract for later use;

[0048] S4, combining the water extract and the alcohol extract, and concentrating them to a Chinese medicine extract with a relative density of 1.15 at 50°C.

[0049] Example 3 Preparation of Chinese medicine extract

[0050] Prescription: 18 parts of fireweed, 5 parts of salvia miltiorrhiza, 5 parts of frankincense, and 5 parts of myrrh.

[0051] The preparation method is as follows:

[0052] S1, weigh fireweed, salvia miltiorrhiza, frankincense, and myrrh according to the prescription amount, add 10 times the amount of water of the medicinal materials to soak for 1 hour, use steam distillation to continuously extract for 10 hours, collect volatile oil, and set aside;

[0053] S2, filtering the water extract in step S1, concentrating the filtrate to obtain a water extract for later use;

[0054] S3, adding 12 times the amount of 85% ethanol to the drug residue filtered in step S2 for extraction 4 times, each time for 1.5 hours, combining the extracts, filtering the alcohol extract, collecting the filtrate, and recovering the ethanol under reduced pressure to obtain an alcohol extract;

[0055] S4, combining the water extract and the alcohol extract, and concentrating them to a Chinese medicine extract with a relative density of 1.25 at 60°C.

[0056] Example 4 Preparation of microemulsion

[0057] prescription:

[0058] 14.8% EL-40, 14.8% PEG 400, 2.6% ethyl oleate, 1.1% volatile oil, 66.7% water.

[0059] The preparation method is as follows:

[0060] Take 14.8% EL-40, 14.8% PEG400, 2.6% ethyl oleate, 1.1% volatile oil and 66.7% water by weight, stir magnetically for 30 minutes at room temperature and mix evenly to obtain the product.

[0061] The volatile oil described in the prescription is the volatile oil collected in Example 1.

[0062] Example 5 A drug for treating knee osteoarthritis

[0063] Prescription: 4g Chinese medicine extract, 1.35g NP700, 0.04g aluminum glycolate, 7g glycerol, 0.06g tartaric acid, 1.25g micropowder silica gel, 0.2g CMC-Na, 0.6g azone, 12.5g microemulsion.

[0064] Example 6 A drug for treating knee osteoarthritis

[0065] Prescription: 4g Chinese medicine extract, 0.5g NP700, 0.06g aluminum glycolate, 6g glycerol, 0.04g tartaric acid, 0.5g micropowder silica gel, 0.2g CMC-Na, 0.6g azone, 8.5g microemulsion.

[0066] Example 7 A drug for treating knee osteoarthritis

[0067] Prescription: 2g Chinese medicine extract, 0.5g NP700, 0.02g aluminum glycolate, 4g glycerol, 0.02g tartaric acid, 0.25g micropowder silica gel, 0.1g CMC-Na, 0.2g azone, 8.5g microemulsion.

[0068] Example 8 A drug for treating knee osteoarthritis

[0069] Prescription: 8g Chinese medicine extract, 1.75g ​​NP700, 0.12g aluminum glycolate, 16g glycerol, 0.12g tartaric acid, 1.5g micropowder silica gel, 0.15g CMC-Na, 0.8g azone, 14g microemulsion.

[0070] Example 9 A drug for treating knee osteoarthritis

[0071] Prescription: 4g Chinese medicine extract, 1.0g NP700, 0.08g aluminum glycolate, 8g glycerol, 0.06g tartaric acid, 1.25g micropowder silica gel, 0.2g CMC-Na, 0.6g azone, 12.5g microemulsion.

[0072] Example 10 A drug for treating knee osteoarthritis

[0073] Prescription: 4g Chinese medicine extract, 1.5g NP700, 0.04g aluminum glycolate, 10g glycerol, 0.08g tartaric acid, 0.75g micropowder silica gel, 0.25g CMC-Na, 0.6g azone, 8.5g microemulsion.

[0074] Example 11 A drug for treating knee osteoarthritis

[0075] Prescription: 4g Chinese medicine extract, 0.5g NP700, 0.06g aluminum glycolate, 6g glycerol, 0.04g tartaric acid, 0.75g micropowder silica gel, 0.25g CMC-Na, 0.6g azone, 8.5g microemulsion.

[0076] Example 12 A drug for treating knee osteoarthritis

[0077] Prescription: 4g Chinese medicine extract, 0.5g NP700, 0.06g aluminum glycolate, 6g glycerol, 0.04g tartaric acid, 1.0g micropowder silica gel, 0.2g CMC-Na, 0.6g azone, 8.5g microemulsion.

[0078] Example 13 A drug for treating knee osteoarthritis

[0079] Prescription: 4g Chinese medicine extract, 1.35g NP700, 0.04g aluminum glycolate, 7g glycerol, 0.06g tartaric acid, 0.5g micropowder silica gel, 0.2g CMC-Na, 0.6g azone, 12.5g microemulsion.

[0080] Example 14 A drug for treating knee osteoarthritis

[0081] Prescription: 4g Chinese medicine extract, 1.0g NP700, 0.04g aluminum glycolate, 6.89g glycerol, 0.06g tartaric acid, 1.25g micropowder silica gel, 0.2g CMC-Na, 0.6g azone, 12.5g microemulsion.

[0082] Example 15 A drug for treating knee osteoarthritis

[0083] Prescription: 4g Chinese medicine extract, 1.5g NP700, 0.04g aluminum glycolate, 10g glycerol, 0.06g tartaric acid, 0.88g micropowder silica gel, 0.2g CMC-Na, 0.6g azone, 12.5g microemulsion.

[0084] The Chinese medicine extracts prepared in Examples 1-3, the microemulsions prepared in Example 4, and the drug prescriptions in Examples 5-15 were used in the preparation of the following Chinese medicine gel plaster for treating knee osteoarthritis:

[0085] Example 16 Preparation of a Chinese medicine gel patch for treating knee osteoarthritis

[0086] (1) Take NP-700, aluminum glycolate, micro-powder silica gel, azone, and glycerol according to the prescription ratio, add NP-700, aluminum glycolate, micro-powder silica gel, and azone to glycerol, stir and mix evenly, and use the mixture as phase A;

[0087] (2) CMC-Na and tartaric acid are taken according to the prescription ratio, CMC-Na is fully swollen with microemulsion, and tartaric acid is added to dissolve as phase B;

[0088] (3) Add the Chinese medicine extract to phase A and stir evenly, then add phase B and stir thoroughly, and evenly apply the prepared gel patch on the backing of the elastic non-woven fabric and dry at 40°C to obtain the product.

[0089] Dosage and Administration: For external use, tear off the backing layer and apply directly to the affected area. It can be applied continuously for 1-2 weeks.

[0090] In order to further verify the effectiveness of the present invention, the inventors conducted a series of verification experiments, as follows:

[0091] 1. Extraction of Chinese herbal medicine extract

[0092] (1) Weigh the following components in the following weight ratio: 18 parts of fireweed, 5 parts of salvia miltiorrhiza, 5 parts of frankincense, and 5 parts of myrrh. Soak each component in 6 times the amount of water for 0.5 hours, extract continuously for 8 hours by steam distillation, collect the volatile oil, and set aside;

[0093] (2) Filter the aqueous extract in step (1), and concentrate the filtrate to obtain an aqueous extract for later use.

[0094] (3) taking the drug residue filtered in step (2), adding 10 times the amount of 80% ethanol and extracting for 3 times, each time for 1 hour, combining the extracts, filtering the alcohol extract, collecting the filtrate, and recovering the ethanol under reduced pressure to obtain an alcohol extract;

[0095] (4) The water extract of step (2) and the alcohol extract of step (3) are combined and concentrated to a Chinese medicine extract having a relative density of 1.15 to 1.25 (50 to 60° C.) for later use.

[0096] 2. Preparation of Microemulsion

[0097] Microemulsions were prepared by water addition titration. The oil phase and mixed emulsifier were mixed evenly in a mass ratio of 9:1, 8:2, 7:3, 6:4, 5:5, 4:6, 3:7, 2:8, and 1:9, and weighed. Ultrapure water was added dropwise under magnetic stirring. When the solution changed from clear to turbid and then from turbid to clear, it was weighed again to calculate the mass of the water phase added at the critical point. The mixed emulsifier, oil phase, and water phase were taken as three vertices, and the area of ​​the microemulsion region was used as an indicator to draw the pseudo-ternary phase using Origin 2019 software.

[0098] (1) Oil phase screening

[0099] Km=1:1 was fixed, Tween-80 was used as the surfactant, anhydrous ethanol was used as the co-surfactant, and the volatile oil was mixed with each oil phase auxiliary material in a ratio of 1:9.

[0100] The results showed that when ethyl oleate was used as the oil phase auxiliary material, the microemulsion area was the largest, so ethyl oleate and volatile oil were selected as the oil phase.

[0101] (2) Screening of surfactants

[0102] The Km was fixed at 1:1, the oil phase was volatile oil:ethyl oleate=1:9, and anhydrous ethanol was used as a co-surfactant. The microemulsion area formed when Tween-80, Tween-60, and EL-40 were used as surfactants was examined. Among them, Tween-60 could not form microemulsion.

[0103] Results: When EL-40 was used as surfactant, the microemulsion area was larger, so EL-40 was selected as surfactant.

[0104] (3) Screening of co-surfactants

[0105] Km was fixed at 1:1, the oil phase was volatile oil:ethyl oleate=1:9, EL-40 was used as surfactant, and the microemulsion area formed when anhydrous ethanol, glycerol, 1,2-propylene glycol, and PEG-400 were used as co-surfactants was investigated.

[0106] Results: When PEG-400 was used as surfactant, the microemulsion area was larger, so PEG-400 was selected as co-surfactant.

[0107] (4) Screening of the ratio of surfactant to co-surfactant Km

[0108] Based on the screened oil phase, surfactant and co-surfactant, the Km values ​​were set to 1:1, 1:2, 2:1, 3:1, and 4:1, respectively, to draw a pseudo-ternary phase.

[0109] Results: When Km=1:1, the microemulsion area is larger, so the ratio of emulsifier to co-emulsifier Km=1:1 is selected.

[0110] (5) Determination of the optimal prescription

[0111] In the pseudo-ternary phase with Km=1:1, points in the center and vicinity of the microemulsion region (oil phase: mixed surfactant ratio were 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, respectively) were selected to prepare microemulsions, and their particle size and PDI were evaluated.

[0112] The results are shown in Table 1. When the oil phase-mixed surfactant ratio is 1:8, the particle size and PDI are the smallest, so this ratio is selected as the optimal ratio of oil phase and mixed emulsifier in the microemulsion formulation.

[0113] Table 1 Prescription investigation results

[0114]

[0115] (6) Oil loading screening

[0116] The quality of the microemulsion was evaluated by increasing the ratio of volatile oil to ethyl oleate, based on its state, particle size and PDI. The results are shown in Table 2.

[0117] Table 2 Screening of drug loading

[0118]

[0119]

[0120] The results in Table 2 show that when the ratio of volatile oil to ethyl oleate is 3:7, microemulsion can be formed, and the state is good, the particle size and PDI are small, which meets the requirements of microemulsion, so the ratio of volatile oil to ethyl oleate is determined to be 3:7. Through the above experimental investigation, the microemulsion formula is determined to be EL-40 14.8%, PEG-400 14.8%, ethyl oleate 2.6%, volatile oil 1.1%, and water 66.7%.

[0121] (7) Best prescription verification test

[0122] According to the above prescription, three microemulsions were prepared in parallel, and their particle size and PDI were tested to investigate the process stability. The results are shown in Table 3. The results show that the particle size of the three microemulsions is less than 30nm, which meets the standard, and the process is stable.

[0123] Table 3 Optimal prescription verification

[0124]

[0125] 3. Screening experiment of components of Chinese medicine gel patch

[0126] This Chinese medicine gel patch uses needle-punched elastic non-woven fabric as the backing layer and PET release film as the anti-adhesive film to protect the matrix layer and prevent drug leakage during storage; the matrix of the paste layer includes ethyl oleate, polyoxyethylene hydrogenated castor oil EL40, and PEG400 in the microemulsion; NP700 is selected as the skeleton material, aluminum glycolate as the cross-linking agent, glycerin as the moisturizer, micro-powder silica gel as the filler, CMC-Na as the viscosity enhancer, and tartaric acid as the cross-linking regulator.

[0127] 3.1 Single factor study of gel patch matrix

[0128] (1) Investigation of the dosage of NP700

[0129] Aluminum glycolate 0.06g, glycerol 6g, tartaric acid 0.04g, CMC-Na 0.2g, micro powder silica gel 0.5g, penetration enhancer azone 0.6g, microemulsion 8.5g, extract 4g, the amount of NP700 was controlled to be 0.5g, 0.75g, 1g, 1.25g, 1.5g, 1.75g ​​respectively. According to the preparation method of traditional Chinese medicine gel plaster, sensory score was used as the evaluation index to select the optimal amount of NP700. The results are shown in Table 4, and the optimal amount range is 1 to 1.5g.

[0130] Table 4 Results of the investigation on the dosage of NP700

[0131]

[0132]

[0133] (2) Investigation of the dosage of aluminum glycolate

[0134] NP700 1g, glycerol 6g, tartaric acid 0.04g, CMC-Na 0.2g, micro powder silica gel 0.5g, microemulsion 8.5g, extract 4g, the amount of aluminum glycolate was controlled to be 0.02g, 0.04g, 0.06g, 0.08g, 0.1g, 0.12g respectively. According to the preparation method of traditional Chinese medicine gel plaster, sensory score was used as the evaluation index to select the optimal amount of aluminum glycolate. The results are shown in Table 5. The optimal amount of aluminum glycolate ranges from 0.04 to 0.08g.

[0135] Table 5 Results of the investigation on the dosage of aluminum glycolate

[0136]

[0137] (3) Investigation of the amount of glycerol used

[0138] NP700 1g, aluminum glycolate 0.06g, tartaric acid 0.04g, CMC-Na 0.2g, microsilicon powder 0.5g, microemulsion 8.5g, extract 4g, the amount of glycerol was controlled to be 4g, 6g, 8g, 10g, 12g, 14g, 16g respectively. According to the preparation method of traditional Chinese medicine gel plaster, the sensory score was used as the evaluation index to select the optimal amount of glycerol. The results are shown in Table 6, and the optimal amount range is 6-10g.

[0139] Table 6 Results of the investigation on the dosage of glycerol

[0140]

[0141] (4) Investigation of the dosage of tartaric acid

[0142] NP700 1g, aluminum glycolate 0.06g, glycerol 6g, CMC-Na 0.2g, micropowder silica gel 0.5g, microemulsion 8.5g, extract 4g, the amount of tartaric acid was controlled to be 0.02g, 0.04g, 0.06g, 0.08g, 0.1g, 0.12g respectively. According to the preparation method of traditional Chinese medicine gel plaster, sensory score was used as the evaluation index to select the optimal amount of tartaric acid. The results are shown in Table 7, and the optimal amount is 0.06g.

[0143] Table 7 Results of the investigation on the dosage of tartaric acid

[0144]

[0145] (5) Investigation of the dosage of CMC-Na

[0146] NP700 1g, aluminum glycolate 0.06g, glycerol 6g, tartaric acid 0.04g, micropowder silica gel 0.5g, microemulsion 8.5g, extract 4g, the amount of CMC-Na was controlled to be 0.1g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g respectively. According to the preparation method of traditional Chinese medicine gel plaster, sensory score was used as the evaluation index to select the optimal amount of CMC-Na. The results are shown in Table 8, and the optimal amount is 0.2g.

[0147] Table 8 Results of the investigation on the dosage of CMC-Na

[0148]

[0149] (6) Investigation of the dosage of micro-powder silica gel

[0150] NP700 1g, aluminum glycolate 0.06g, glycerol 6g, tartaric acid 0.04g, CMC-Na 0.2g, microemulsion 8.5g, extract 4g, the amount of micro powder silica gel was controlled to be 0.25g, 0.5g, 0.75g, 1g, 1.25g, 1.5g respectively. According to the preparation method of traditional Chinese medicine gel plaster, sensory score was used as the evaluation index to select the optimal amount of micro powder silica gel. The results are shown in Table 9, and the optimal amount range is 0.5-1.25g.

[0151] Table 9 Results of the investigation on the dosage of micro powder silica gel

[0152]

[0153]

[0154] Note: Sensory score (full score 40 points) = spreadability (8 points) + uniformity (8 points) + permeability (8 points) + tracking (8 points) + residual (8 points). The specific scoring criteria are as follows. Spreadability: based on whether the paste is easy to spread, does not aggregate into lumps, does not break into strips, and does not overflow the backing; uniformity: based on whether the paste is uniform without lumps, smooth surface without particles, and no bubbles; permeability: based on whether the patch has no permeability; tracking: stick the gel patch on the back of the wrist, shake it vigorously 10 times, and see if the patch can stick to the wrist without falling off and without obvious gaps; residual: repeatedly stick the patch on the back of the hand, repeat 3 times, and according to the residual amount of the paste on the back of the hand, the above items are divided into 5 levels, 0, 2, 4, 6, 8 points.

[0155] 3.2 Box-Behnken response surface experiment to optimize prescription

[0156] On the basis of single factor experiment, NP700 (A), glycerin (B), micro powder silica gel (C) were used as independent variables, and the comprehensive score Y of sensory score (Y1), initial adhesion (Y2), and lasting adhesion (Y3) of gel patch was used as response value to conduct Box-Behnken response surface design, and the comprehensive score (full score 100 points) = sensory score (40 points) + initial adhesion (30 points) + lasting adhesion (30 points). Design-Expert 8.0.6 software was used to arrange the experiment. The factors and levels are shown in Table 10, the experimental design and results are shown in Table 11, and the variance analysis is shown in Table 12.

[0157] Table 10 Factor level table

[0158]

[0159] Table 11 Experimental design and results

[0160]

[0161]

[0162] Table 12 Variance analysis table

[0163]

[0164] Design-Expert 8.0.6 software was used to perform multiple linear regression and binomial fitting on the data in the table, and the regression equation was obtained: Y = 85.65 + 2.84A-5.62B + 4.30C + 1.85AB-0.29AC-0.32BC-1.88A 2 -4.67B 2 -1.29C 2 , the correlation coefficient of the equation is r = 0.9628, indicating that the model has a good fit and can analyze and predict the performance of the gel patch. The results of variance analysis are shown in Table 12. It can be seen that the model has significant differences (P < 0.05), and the lack of fit term P (= 0.8671) > 0.05, indicating that there is no significant difference in the lack of fit term, and the probability of the actual value and the predicted value not fitting is low, that is, the model is significant and the fitting equation has good predictive power for the experimental results. Each factor has a very significant effect on the performance of the gel patch, and the order of influence is B glycerol > C micro powder silica gel > ANP700. The optimal matrix prescription was selected with the maximum response value as the optimization target, and the optimal prescription conditions were A = 1.35g, B = 6.89g, C = 1.25g, that is, NP700 1.35g, glycerol 6.89g, micro powder silica gel 1.25g. For the convenience of operation, the present invention corrects it to 1.35 g of NP700, 7.00 g of glycerol, and 1.25 g of micropowder silica gel.

[0165] 3.3 Screening of microemulsion addition amount

[0166] According to the optimized prescription, the performance of the Chinese medicine gel patch was investigated in terms of sensory score, initial adhesion, and sustained adhesion with different microemulsion addition amounts. The results are shown in Table 13. Considering the comprehensive performance of the patch and to ensure the subsequent efficacy, the maximum microemulsion amount was selected to be 12.5 g.

[0167] Table 13 Effect of microemulsion addition on plaster performance

[0168]

[0169] Based on the above screening, the optimal prescription composition of the traditional Chinese medicine gel patch is: NP700, aluminum hydroxyglycolate, glycerin, micro-powder silica gel, CMC-Na, tartaric acid, penetration enhancer azone, microemulsion, extract = 1.35g: 0.04g: 7g: 1.25g: 0.2g: 0.06g: 0.6g: 12.5g: 4g.

[0170] 4. Preparation method of Chinese medicine gel patch

[0171] Prescription composition: NP700, aluminum glycolate, glycerin, micro-powder silica gel, CMC-Na, tartaric acid, penetration enhancer azone, microemulsion, extract = 1.35g: 0.04g: 7g: 1.25g: 0.2g: 0.06g: 0.6g: 12.5g: 4g.

[0172] (1) Weigh NP-700, aluminum glycolate, micro-powder silica gel, and penetration enhancer azone according to the prescription ratio, add them to glycerol, and stir to mix evenly to obtain phase A;

[0173] (2) CMC-Na is taken according to the prescription ratio and fully swelled with microemulsion, and tartaric acid is added to dissolve as phase B;

[0174] The microemulsion preparation method is as follows: 14.8% EL-40, 14.8% PEG400, 2.6% ethyl oleate, 1.1% volatile oil prepared under the above "1. Preparation of Chinese medicine extract", and 66.7% water are taken by weight percentage, and magnetic stirring is performed at room temperature for 30 minutes to mix evenly to obtain the microemulsion.

[0175] (3) Add the Chinese herbal extract prepared under "I. Preparation of Chinese herbal extract" to phase A and stir evenly, then add phase B and stir thoroughly, evenly apply the prepared gel patch on the backing and dry at 40°C to obtain the product.

[0176] 5. Anti-inflammatory and analgesic experimental studies

[0177] In this study, a rat adjuvant arthritis model induced by complete Freund's adjuvant (CFA) was established to evaluate the anti-inflammatory and analgesic effects of the traditional Chinese medicine gel patch.

[0178] 5.1 Experimental animals

[0179] Male SD rats, SPF grade, weight (200 ± 20) g, were purchased from Shanghai Slake Experimental Animal Co., Ltd., animal quality certificate number: SCXK (Shanghai) 2022-0004. This experiment was approved by the Animal Ethics Committee of Guizhou University of Traditional Chinese Medicine (approval number: 202209A014).

[0180] 5.2 Drugs and reagents

[0181] Furbiprofen gel patch (Cat. No.: 208251, Beijing Taide Pharmaceutical Co., Ltd.); complete Freund's adjuvant (Cat. No.: F5881, Sigma, USA); isoflurane (Batch No. 22081301, purchased from Reward Life Science Technology Co., Ltd.); TG16W micro high-speed centrifuge (Changsha Xiangzhi Centrifuge Instrument Co., Ltd.); TGL16M desktop high-speed refrigerated centrifuge (Shanghai Lu Xiangyi Centrifuge Instrument Co., Ltd.); HT-111B constant temperature shaker (Shanghai Hetian Scientific Instrument Co., Ltd.); EasyWeLL series JY98-IIIN cell disruptor (Shanghai Rongyan Instrument Co., Ltd.); R500IP small animal anesthesia machine (Shenzhen Reward Life Science Technology Co., Ltd.); Nikon Eclipse E100 upright optical microscope, Nikon DS-U3 imaging system (Nikon, Japan).

[0182] 5.3 Experimental methods

[0183] Arthritis (AA) model establishment and grouping and drug administration

[0184] 60 male SD rats were adaptively fed for 1 week, randomly grouped and numbered according to body weight, and the thickness of the left hind foot plantar of the rats was measured with a vernier caliper before modeling. 50 rats were randomly selected and disinfected at the bottom of the left hind foot plantar, and CFA 0.1mL was intradermally injected to replicate the AA model. The remaining 10 rats were blank controls, and 0.1mL normal saline was injected according to the same method. The modeling cycle was 14 days. On the 14th day, 50 arthritis rats were randomly divided into 5 groups according to the swelling degree of the rat foot plantar, each group of 10, i.e., the model group, the positive drug group, and the high, medium and low dose groups of the Chinese medicine gel patch prepared by the present invention (each patch contains 6g, 4g, and 2g of extract, respectively). 24h before administration, the hair on the left hind leg of the rats was removed with a depilatory cream. The drug was administered to the left hind foot from the 15th day after modeling. The high, medium and low dose groups of the Chinese medicine gel patch were applied with different doses of patches, the positive drug group was applied with fulbiprofen gel patch, and the model group and the blank group were both applied with blank matrix patches. The administration area was 3cm×4cm, and the drug was administered once a day, each application was for 24h, and the drug was administered continuously for 14d.

[0185] 5.4 Efficacy evaluation method

[0186] (1) Swelling of the paw on the inflamed side

[0187] The thickness of the left hind paw of the rats was measured before modeling (0 day) and on the 1st, 14th, and 28th days after modeling, and the degree of swelling was calculated. Swelling degree (mm) = plantar thickness after modeling (mm) - plantar thickness before modeling (mm).

[0188] (2) Determination of TNF-α, 5-HT, IL-6, and IL-1β levels in rat serum

[0189] Blood was collected from the abdominal aorta of rats and allowed to stand for 2 h before being rotated at 4 °C and 3000 r / min. -1 Centrifuge for 10 min under the condition of 40 ° C, take the upper serum and store it at -80 ° C. Slowly thaw the serum at 4 ° C, and operate according to the instructions of the ELISA kit to detect the content of TNF-α, 5-HT, IL-6, and IL-1β in mouse serum.

[0190] (3) Determination of 5-HT and β-EP Contents in Rat Cerebral Cortex

[0191] After the rats were killed, the cerebral cortex was quickly peeled off on ice, temporarily stored in liquid nitrogen, and then transferred to -80°C for storage. The cerebral cortex was placed on ice, pre-cooled PBS was added, and two steel balls were placed in an automatic rapid grinder and ground six times at 60Hz, 30s each time. The cerebral cortex homogenate was then placed on ice for 30 minutes and then centrifuged (4°C, centrifugal radius 7cm, 3500r·min -1 , 15min), and the supernatant was aspirated for later use. The 5-HTβ and EP content in the mouse cerebral cortex was detected according to the instructions of the ELISA kit.

[0192] (4) Observation of pathological morphology of the ankle joint in rats

[0193] 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 (HE) staining. The pathological morphology of the rat ankle joints was observed under a microscope.

[0194] (5) Statistical analysis

[0195] GraphPad Prism 6.0 software was used for statistical analysis of the data, and the measured data were expressed as mean ± standard deviation. If the data were normally distributed and the variance was homogeneous, one-way analysis of variance or t-test was used for comparison between the two groups, otherwise non-parametric tests were used, and the difference was statistically significant when P < 0.05.

[0196] 5.5 Experimental Results

[0197] (1) Results of swelling on the inflamed side of the foot

[0198] The results are shown in Table 14. After modeling, the swelling degree of the paws of rats on the inflamed side increased significantly (P < 0.001), indicating that the modeling was successful. After administration, the swelling degree of the paws of rats in each group decreased to varying degrees, and the difference was significant (P < 0.05).

[0199] Table 14 Results of swelling degree of the plantar fossa on the inflamed side

[0200]

[0201]

[0202] Note: Compared with the blank group, ###P<0.001; compared with the model group, *P<0.05, ***P<0.001

[0203] (2) Results of determination of TNF-α, 5-HT, IL-6, and IL-1β levels in rat serum

[0204] Compared with the blank group, the levels of TNF-α, 5-HT, IL-6, and IL-1β in the serum of rats in the model group were significantly increased (P < 0.001). Compared with the model group, the levels of these substances in each drug-treated group were significantly decreased to varying degrees (P < 0.05).

[0205] (3) Determination of 5-HT and β-EP Contents in Rat Cerebral Cortex

[0206] Compared with the blank group, the content of 5-HT and β-EP in the cerebral cortex of the model group was not much different; compared with the model group, the 5-HT and β-EP in each drug-treated group were significantly increased (P < 0.05), indicating that this experiment can increase the content of 5-HT and β-EP in the cerebral cortex of rats and achieve analgesic effect.

[0207] (4) Observation of pathological morphology of the ankle joint in rats

[0208] In the blank group, the joint tissue structure was clear and normal, the joint cavity was clean, the cartilage surface was smooth, the number of chondrocytes was abundant, oval and tightly arranged; there was no obvious hyperplasia of the synovium, and no obvious inflammatory cell infiltration. In the model group, there was detached tissue in the joint cavity, the cartilage surface was not smooth, the number of chondrocytes decreased, and the arrangement was irregular. Connective tissue hyperplasia was seen on one side of the synovium, accompanied by inflammatory cell infiltration, and the articular cartilage was severely damaged. Compared with the model group, the pathological conditions such as synovial cell hyperplasia and chondrocyte destruction in the positive drug group and each drug-treated group in this experiment were alleviated, the number of chondrocytes was abundant, and the infiltration of inflammatory cells was reduced.

[0209] Although the present invention has been described in detail above using general descriptions, specific implementation methods and experiments, it is obvious to those skilled in the art that some modifications or improvements can be made on the basis of the present invention. Therefore, these modifications or improvements made without departing from the spirit of the present invention are within the scope of protection claimed by the present invention.

Claims

1. A drug for treating knee osteoarthritis, characterized in that: The invention is prepared from the following ingredients in parts by weight: 2-8 parts of traditional Chinese medicine extract, 0.5-1.75 parts of NP700, 0.02-0.12 parts of aluminum glycolate, 4-16 parts of glycerol, 0.02-0.12 parts of tartaric acid, 0.25-1.5 parts of micro powder silica gel, 0.1-0.35 parts of CMC-Na, 0.2-0.8 parts of azone and 6-14 parts of microemulsion.

2. The drug for treating knee osteoarthritis according to claim 1, characterized in that: The invention is prepared from the following ingredients in parts by weight: 3-5 parts of Chinese medicine extract, 1-1.5 parts of NP700, 0.04-0.08 parts of aluminum glycolate, 6-10 parts of glycerol, 0.06-0.08 parts of tartaric acid, 0.5-1.25 parts of micro powder silica gel, 0.2-0.25 parts of CMC-Na, 0.4-0.6 parts of azone and 8.5-12.5 parts of microemulsion.

3. The drug for treating knee osteoarthritis according to claim 2, characterized in that: The invention is prepared from the following ingredients in parts by weight: 4 parts of Chinese medicine extract, 1.35 parts of NP700, 0.04 parts of aluminum glycolate, 7 parts of glycerol, 0.06 parts of tartaric acid, 1.25 parts of micro powder silica gel, 0.2 parts of CMC-Na, 0.6 parts of azone, and 12.5 parts of microemulsion.

4. The drug for treating knee osteoarthritis according to any one of claims 1, 2 or 3, characterized in that: The Chinese medicine extract is prepared from the following Chinese medicine raw materials in parts by weight: 18 parts of fireweed, 5 parts of salvia miltiorrhiza, 5 parts of frankincense, and 5 parts of myrrh.

5. The drug for treating knee osteoarthritis according to any one of claims 1, 2 or 3, characterized in that: The microemulsion is prepared from the following ingredients in percentage by weight: 14.8% EL-40, 14.8% PEG 400, 2.6% ethyl oleate, 1.1% volatile oil, 66.7% water.

6. A method for preparing a drug for treating knee osteoarthritis according to any one of claims 1, 2 or 3, characterized in that: The steps include: S1, weighing fireweed, salvia miltiorrhiza, frankincense, and myrrh according to the prescribed amount, adding 4-10 times the amount of water of the medicinal materials to soak for 0.5-1h, using steam distillation to continuously extract for 6-10h, collecting volatile oils for later use; S2, filtering the water extract in step S1, concentrating the filtrate to obtain a water extract for later use; S3, adding 6-12 times the amount of 70-85% ethanol to the drug residue filtered in step S2, extracting for 2-4 times, each time for 0.5-1.5 hours, combining the extracts, filtering the alcohol extract, collecting the filtrate, recovering the ethanol under reduced pressure, obtaining an alcohol extract, and setting aside; S4, combining the water extract and the alcohol extract, concentrating to a Chinese medicine extract having a relative density of 1.15-1.25 at 50-60° C., and setting aside; S5, taking NP-700, aluminum glycolate, micro-powder silica gel, azone, and glycerol according to the prescription ratio, adding NP-700, aluminum glycolate, micro-powder silica gel, and azone to glycerol, stirring and mixing evenly, as phase A; S6, taking CMC-Na and tartaric acid according to the prescription ratio, fully swelling the CMC-Na with the microemulsion, and adding tartaric acid to dissolve as phase B; The microemulsion preparation method is as follows: 14.8% EL-40, 14.8% PEG400, 2.6% ethyl oleate, 1.1% volatile oil prepared in step S1, and 66.7% water are taken by weight percentage, and magnetic stirring is performed at room temperature for 30 minutes to mix evenly to obtain the microemulsion; S7, adding the Chinese medicine extract prepared in step S4 to phase A, stirring evenly, then adding phase B, stirring sufficiently, coating the prepared gel patch evenly on the backing, and drying at 40° C. to obtain.

7. The preparation method according to claim 6, characterized in that: The step S1 specifically comprises: weighing fireweed, salvia miltiorrhiza, frankincense and myrrh according to the prescription ratio, adding 6 times amount of water of the medicinal materials to soak for 0.5h, extracting continuously for 8h by steam distillation, collecting volatile oil and setting aside.

8. The preparation method according to claim 6, characterized in that: The step S3 specifically comprises: adding 10 times the amount of 80% ethanol to the filtered medicinal residues for extraction three times, each time for 1 hour, combining the extracts, filtering the alcohol extracts, collecting the filtrate, and recovering the ethanol under reduced pressure to obtain an alcohol extract for later use.

9. Use of the drug according to any one of claims 1 to 3 or the drug prepared by the preparation method according to any one of claims 6 to 8 for preparing a pharmaceutical preparation for treating knee osteoarthritis.

10. The use according to claim 9, characterized in that: The pharmaceutical preparations include but are not limited to gel ointments.

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