Anti-inflammatory and analgesic external traditional Chinese medicine preparation for arthritis and preparation method thereof

Abstract

The invention relates to the technical field of traditional Chinese medicine, in particular to an externally-applied traditional Chinese medicine preparation for resisting inflammation and easing pain of arthritis and a preparation method of the externally-applied traditional Chinese medicine preparation for resisting inflammation and easing pain of arthritis. The traditional Chinese medicine composition is convenient to use, controllable in administration dosage, good in adhesiveness, capable of taking effect continuously, good in skin followability and small in irritation; the drug loading capacity is high; the cuticle can be improved, and the bioavailability of the medicine is improved; the adhesive is suitable for cleaning and can be repeatedly adhered; and the medicine can be stored and transported for a long time and is convenient for clinical popularization and use.

Description

Technical Field

[0001] The invention relates to the technical field of traditional Chinese medicine, and in particular to an external Chinese medicine preparation for anti-inflammatory and analgesic arthritis and a preparation method thereof. Background Art

[0002] Knee osteoarthritis is a common clinical disease, often with joint pain, stiffness, swelling and limited mobility. Inflammation is usually associated with pain and is caused by tissue damage or autoimmune processes. Inflammatory pain not only affects the patient's quality of life, but also causes psychological trauma to the patient. The number of patients has increased year by year, and it has increasingly become a disease that affects human health worldwide.

[0003] In 2023, the Expert Consensus on the Diagnosis and Treatment of Knee Osteoarthritis with Integrated Traditional Chinese and Western Medicine recommended "Huli Powder" as a Chinese patent medicine for treatment. It is composed of four herbs: Radix Aconitum, Panax Notoginseng, Glehnia littoralis, and Glehnia littoralis. It is often taken orally or applied externally to treat rheumatism, numbness, swelling, pain, and cramps, with significant efficacy. Currently, there are three oral dosage forms: powder, tablet, and capsule. Clinical external use is mostly temporary application. There is a lack of a dose-controlled transdermal drug delivery system, which makes patients' medication compliance poor and it is difficult to achieve the expected therapeutic effect. Therefore, the development of a dose-controlled transdermal drug delivery preparation has important theoretical and practical significance and can fill the clinical demand. Summary of the invention

[0004] In order to overcome the above technical defects, the present invention aims at the shortcomings of the existing dosage forms of Hulisan in clinical use and provides a safe and reliable preparation method of a traditional Chinese medicine gel plaster for anti-inflammatory and analgesic treatment of osteoarthritis.

[0005] One of the purposes of the present invention is to provide an external Chinese medicine preparation for anti-inflammatory and analgesic arthritis, comprising a Chinese medicine composition and pharmaceutical excipients acceptable in the art, wherein the Chinese medicine composition comprises 65 to 85 parts by weight of processed Aconitum carmichaelii, 5 to 15 parts of Panax notoginseng, 10 to 30 parts of Panax notoginseng, and 1 to 10 parts of Panax notoginseng.

[0006] The present invention is based on the Yunnan Yi medicine "Hulisan" as an effective prescription for treating rheumatism, numbness, swelling, pain and cramps. After long-term practice, the curative effect is definite. Processed Radix Aconitum dispels wind and dampness, dispels cold and relieves pain, and is the main drug. Panax notoginseng promotes blood circulation and removes blood stasis, relieves swelling and relieves pain, and is the assistant drug. Ginseng schizonepeta can strengthen the waist and kidney, strengthen tendons and bones; white ginseng invigorates qi and promotes blood circulation, assists the main drug in dispelling wind and dampness, dispelling cold and relieving pain, and is a total of adjuvant drugs.

[0007] In some embodiments, the amount of the traditional Chinese medicine composition added is 10 to 30% of the total mass.

[0008] In some embodiments, the Chinese medicine composition comprises:

[0009] 70-85 parts by weight, or 68-85 parts by weight, or 70-80 parts by weight, or 73-80 parts by weight, or 73-78 parts by weight, such as 75 parts by weight of processed Aconitum kusnezoffii; and

[0010] 5-12 parts, or 5-10 parts by weight, or 7-10 parts by weight, or 8-15 parts by weight, or 8-12 parts by weight, or 10-12 parts by weight, such as 10 parts by weight, of Panax notoginseng; and

[0011] 10-25 parts, or 10-22 parts by weight, or 10-20 parts by weight, or 10-18 parts by weight, or 12-28 parts by weight, or 15-25 parts by weight, or 15-20 parts by weight, such as 15 parts by weight of Baiyun ginseng; and

[0012] The amount of broken ginseng is 3-10 parts, or 3-7 parts by weight, or 3-5 parts by weight, or 5-10 parts by weight, or 1-5 parts by weight, such as 5 parts by weight.

[0013] In some embodiments, the external Chinese medicine preparation comprises, from bottom to top, a backing layer, a paste layer and an anti-sticking layer, and the paste layer comprises the Chinese medicine composition and the pharmaceutical excipients.

[0014] The second object of the present invention is to provide a method for preparing a Chinese medicine preparation for external use, wherein the Chinese medicine preparation for external use is prepared into a gel and / or a patch according to a conventional method in the art.

[0015] The present invention prepares a gel patch with optimal performance by screening the composition and ratio of the matrix, and on this basis, optimizing the ratio of the matrix to the drug, combining the matrix molding and preparation molding processes.

[0016] In some embodiments, the gel is prepared by the following method: mixing the traditional Chinese medicine composition with the pharmaceutical excipients, and the amount of the external Chinese medicine composition added is 10 to 30% of the total mass of the gel; the traditional Chinese medicine composition is an ethanol extract of Aconitum kusnezoffii, Panax notoginseng, Panax baiyunensis, and Panax ginseng, and the pharmaceutical excipients include NP700, aluminum glycolate, kaolin, glycerin, tartaric acid, PVP K90, water, a penetration enhancer, and a preservative.

[0017] In a further specific embodiment, the Chinese medicine composition and the pharmaceutical excipients are mixed by the following method: tartaric acid and PVPK90 are dissolved in water and swelled overnight to form phase A; aluminum glycolate, NP700, kaolin, a penetration enhancer, and a preservative are added to glycerol and stirred evenly to form phase B; the extract is added to phase B and stirred evenly to obtain phase C; phase A is added to phase C and stirred evenly.

[0018] In some embodiments, the patch is prepared by the following method: the traditional Chinese medicine composition and the pharmaceutical excipients are mixed evenly, coated on a backing material to form a paste layer, and finally covered with a protective film; the amount of the external traditional Chinese medicine composition added is 10 to 30% of the total mass of the gel; the traditional Chinese medicine composition is an ethanol extract of Aconitum kusnezoffii, Panax notoginseng, Panax baiyunensis, and Panax ginseng, and the pharmaceutical excipients include NP700, aluminum glycolate, kaolin, glycerin, tartaric acid, PVP K90, water, a penetration enhancer, and a preservative.

[0019] In some embodiments, the mass ratio of NP700, aluminum glycolate, kaolin, glycerol, tartaric acid, PVP K90, water, penetration enhancer and preservative is (7-11): (0.6-0.8): (1.0-2.0): (30-40): (0.8-1.2): (4.0-8.0): (20-30): (1-5): (2-4).

[0020] In some embodiments, the penetration enhancer is any one of propylene glycol, azone and menthol; preferably, propylene glycol.

[0021] In some embodiments, the support body is composed of a raw material including a fiber sheet, and the fiber sheet is composed of a woven or non-woven fabric of natural fibers and / or synthetic fibers.

[0022] Compared with the prior art, the present invention has the following technical effects:

[0023] (1) The external Chinese medicine preparation of the present invention has a reasonable ratio of the matrix and the Chinese medicine components, and the obtained gel patch is easy to use, has a controllable dosage, good adhesion and sustained effect, and good skin followability. It solves the problems of traditional Chinese medicine anti-inflammatory and analgesic large compound preparations without extraction, rough administration method, easy contamination of clothes, inaccurate dosage, poor adhesion, poor drug permeability, and unstable efficacy. It can provide a reference for the reform of similar external preparation dosage forms and facilitate clinical promotion and use;

[0024] (2) Through the transdermal drug delivery system, no obvious liver and kidney toxicity was detected. Compared with oral or injection therapy, it is less likely to cause gastrointestinal adverse reactions and cardiovascular diseases. In clinical practice, Hulisan is often used for external application to treat KOA pain and joint swelling, with significant efficacy and wide praise from patients. In the clinical use of "Hulisan", the drug has always been administered by powder application, which has a limited drug loading capacity, is not convenient for storage and carrying, and limits the bioavailability of the drug.

[0025] (3) The present invention optimizes the dosage form, and the gel patch selected has better skin compatibility and less irritation than the original patch; has a larger drug loading capacity; can improve the stratum corneum and increase the bioavailability of the drug; is suitable for cleaning and can be repeatedly pasted; and can be mass-produced industrially and can be stored and transported for a long time, which is convenient for clinical promotion and use. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 This is the histopathological section of mice according to the present invention. DETAILED DESCRIPTION

[0027] In order to make those skilled in the art better understand the technical solution of the present invention, the present invention is described in detail below in conjunction with specific embodiments. The experimental methods in the following examples that do not specify specific conditions are usually based on conventional conditions or conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight. Unless otherwise defined, all professional and scientific terms used in the text have the same meanings as those familiar to those skilled in the art. In addition, any method and material similar or equivalent to the recorded content can be applied to the present invention. The preferred implementation methods and materials described in the text are for demonstration purposes only.

[0028] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0029] According to the present invention, on the one hand, a Chinese medicine preparation for external use for anti-inflammatory and analgesic purposes of arthritis is provided, comprising a Chinese medicine composition and pharmaceutical excipients acceptable in the art, wherein the Chinese medicine composition comprises 65-85 parts by weight of prepared Aconitum carmichaelii, 5-15 parts of Panax notoginseng, 10-30 parts of Panax baiyunensis, and 1-10 parts of Panax ginseng.

[0030] The present invention is based on the Yunnan Yi medicine "Hulisan" as an effective prescription for treating rheumatism, numbness, swelling, pain and cramps. After long-term practice, the curative effect is definite. Processed Radix Aconitum dispels wind and dampness, dispels cold and relieves pain, and is the main drug. Panax notoginseng promotes blood circulation and removes blood stasis, relieves swelling and relieves pain, and is the assistant drug. Ginseng schizonepeta can strengthen the waist and kidney, strengthen tendons and bones; white ginseng invigorates qi and promotes blood circulation, assists the main drug in dispelling wind and dampness, dispelling cold and relieving pain, and is a total of adjuvant drugs.

[0031] The pharmaceutical excipients of the present invention can be selected from one or more of the following: solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, adhesives, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integrities, penetration enhancers, pH regulators, buffers, plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculating agents, filter aids, and release retardants.

[0032] In some embodiments, the amount of the traditional Chinese medicine composition added is 10 to 30% of the total mass of the gel preparation.

[0033] In some embodiments, the Chinese medicine composition comprises:

[0034] 70-85 parts by weight, or 68-85 parts by weight, or 70-80 parts by weight, or 73-80 parts by weight, or 73-78 parts by weight, such as 75 parts by weight of processed Aconitum kusnezoffii; and

[0035] 5-12 parts, or 5-10 parts by weight, or 7-10 parts by weight, or 8-15 parts by weight, or 8-12 parts by weight, or 10-12 parts by weight, such as 10 parts by weight, of Panax notoginseng; and

[0036] 10-25 parts, or 10-22 parts by weight, or 10-20 parts by weight, or 10-18 parts by weight, or 12-28 parts by weight, or 15-25 parts by weight, or 15-20 parts by weight, such as 15 parts by weight of Baiyun ginseng; and

[0037] The amount of broken ginseng is 3-10 parts, or 3-7 parts by weight, or 3-5 parts by weight, or 5-10 parts by weight, or 1-5 parts by weight, such as 5 parts by weight.

[0038] In some embodiments, the external Chinese medicine preparation comprises, from bottom to top, a backing layer, a paste layer and an anti-sticking layer, and the paste layer comprises the Chinese medicine composition and the pharmaceutical excipients.

[0039] The second object of the present invention is to provide a method for preparing a Chinese medicine preparation for external use, wherein the Chinese medicine preparation for external use is prepared into a gel and / or a patch according to a conventional method in the art.

[0040] The present invention prepares a gel patch with optimal performance by screening the composition and ratio of the matrix, and on this basis, optimizing the ratio of the matrix to the drug, combining the matrix molding and preparation molding processes.

[0041] In some embodiments, the gel is prepared by the following method: mixing the traditional Chinese medicine composition with the pharmaceutical excipients, and the amount of the external Chinese medicine composition added is 10 to 30% of the total mass of the gel; the traditional Chinese medicine composition is an ethanol extract of Aconitum kusnezoffii, Panax notoginseng, Panax baiyunensis, and Panax ginseng, and the pharmaceutical excipients include NP700, aluminum glycolate, kaolin, glycerin, tartaric acid, PVP K90, water, a penetration enhancer, and a preservative.

[0042] According to the present invention, the ethanol extract of the traditional Chinese medicine composition is prepared by the following method: taking the drug raw materials according to the formula, crushing and mixing them, refluxing and extracting them with ethanol aqueous solution, taking the filter residue and extracting it with ethanol aqueous solution, combining the two extracts, filtering, and concentrating under reduced pressure to obtain the traditional Chinese medicine extract.

[0043] In a further specific embodiment, the gel is mixed by the following method: tartaric acid and PVPK90 are dissolved in water and swelled overnight as phase A; aluminum glycolate, NP700, kaolin, a penetration enhancer, and a preservative are added to glycerol and stirred evenly as phase B; the Chinese medicine extract is added to phase B and stirred evenly to obtain phase C; phase A is added to phase C and stirred evenly to obtain.

[0044] Based on the present invention, the patch is prepared by the following method: the traditional Chinese medicine composition and the pharmaceutical excipients are mixed evenly, coated on a backing material to form a paste layer, and finally covered with a protective film; the amount of the external traditional Chinese medicine composition added is 10-30% of the total mass of the gel; the traditional Chinese medicine composition is an ethanol extract of aconite, notoginseng, white cloud ginseng, and panax notoginseng, and the pharmaceutical excipients include NP700, aluminum glycolate, kaolin, glycerin, tartaric acid, PVP K90, water, a penetration enhancer and a preservative.

[0045] In some embodiments, the mass ratio of NP700, aluminum glycolate, kaolin, glycerol, tartaric acid, PVP K90, water, penetration enhancer and preservative is (7-11): (0.6-0.8): (1.0-2.0): (30-40): (0.8-1.2): (4.0-8.0): (20-30): (1-5): (2-4).

[0046] In some embodiments, the penetration enhancer is any one of propylene glycol, azone and menthol; preferably, propylene glycol.

[0047] In some embodiments, the support body is composed of a raw material including a fiber sheet, and the fiber sheet is composed of a woven or non-woven fabric of natural fibers and / or synthetic fibers.

[0048] The embodiments of the present invention will be described in detail below in conjunction with the examples, but it will be appreciated by those skilled in the art that the following examples are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. If no specific conditions are specified in the examples, the conditions are carried out according to normal conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be obtained commercially.

[0049] Animal grouping and administration: 60 KM mice were randomly divided into 6 groups, with 10 mice in each group, namely model group, diclofenac sodium gel group (DS-G), Hulishan gel patch high-dose group (HLS-GP-H), Hulishan gel patch medium-dose group (HLS-GP-M), and Hulishan gel patch low-dose group (HLS-GP-L). The drugs were administered to the navel and fixed with medical tape once a day for 7 consecutive days.

[0050] Model group: given blank gel patch;

[0051] DS-G group: given diclofenac sodium gel;

[0052] HLS-GP-L group: 1.75 cm × 2.5 cm gel patch (dose 230 mg / kg);

[0053] HLS-GP-M group: 1.75 cm × 2.5 cm gel patch (dosage 460 mg / kg);

[0054] HLS-GP-H group: 1.75 cm × 2.5 cm gel patch (dosage: 920 mg / kg) was administered.

[0055] Example 1 Investigating the Effect of Gel Patch on Body Weight and Organ Index

[0056] The weight changes of mice were recorded within 7 days. The results showed that there was no significant difference in the weight of mice in each group on the first day. Within 7 days of administration, the weight of mice showed an increasing trend, and there was no significant difference in the weight of mice on the seventh day (P>0.05). There was no significant difference in the liver and kidney indexes of mice in each group (P>0.05). The results are shown in Table 1.

[0057] Table 1 Body weight and organ index of mice in each group ( n=10)

[0058]

[0059] Example 2 Investigating the effect of gel patch on ear swelling inhibition

[0060] 2 hours after the last administration, the mice were lightly anesthetized with ether, and 30 μL of xylene was dripped and applied to the front and back of each mouse's right ear to cause mouse ear swelling. The left ear was not treated, and the normal group was coated with an equal amount of saline. After blood collection, the mice were killed, two ears were cut off along the auricle baseline, and bilateral ear samples were collected using a biopsy punch with a diameter of 8 mm and weighed. The swelling inhibition rate and relative swelling inhibition rate were calculated. Swelling rate = (right ear swelling - left ear swelling) / left ear swelling × 100%, relative swelling inhibition rate = (average swelling rate of the model group - average swelling rate of the drug group) / average swelling rate of the model group × 100%.

[0061] The results of swelling inhibition rate showed that after administration of xylene, the right ear of the model group mice was significantly swollen compared with the normal group (P < 0.05). Compared with the model group, after administration of the drug, the swelling of the right ear of the mice in each group was significantly reduced (P < 0.01). The swelling inhibition rate of each group of mice was ranked as follows: HLS-GP-H > DS-G > HLS-GP-M > HLS-GP-L. The results are shown in Table 2.

[0062] Table 2 Results of ear swelling inhibition in each group of mice ( n=10)

[0063]

[0064] Note: Compared with CON, ## P<0.01; compared with MOD, * P<0.05, ** P<0.01

[0065] Pathological sections of experimental mouse tissues were performed, such as Figure 1 As shown, no abnormality was found in the normal group mice, while the model group mice had obvious edema and obvious inflammatory cell infiltration in the ear tissues. After administration, the inflammatory cell infiltration in the ear tissues of mice in each group decreased, and the degree of swelling was significantly reduced. With the increase of the dose in the HLS-GP group, the degree of swelling inhibition increased significantly, and the ear swelling degree of the HLS-GP-H group was equivalent to that of the CON group, which was better than the positive drug DS-G group. It can be seen that HLS-GP has an inhibitory effect on xylene-induced mouse ear swelling.

[0066] Example 3 Investigating the effect of gel patch on the expression of inflammatory factors in mouse serum

[0067] Anesthetized and blood was collected, allowed to stand, centrifuged at 3000r / min for 15min, serum was separated into EP tubes, stored in a -80℃ refrigerator for standby use, and the levels of IL-6, IL-1β, and TNF-α in mouse serum were detected by enzyme-linked immunosorbent assay. The results showed that compared with the normal group, the levels of IL-1β, IL-6, and TNF-α in the serum of the model group mice were significantly increased (P<0.01), compared with the model group, the levels of IL-1β in the serum of the low, medium, and high dose groups of Hulisan gel patch mice were significantly reduced, the levels of IL-6 in the serum of the medium and high dose groups of Hulisan gel patch mice were significantly reduced, and the levels of TNF-α in the serum of the low and high dose groups of Hulisan gel patch mice were significantly reduced (P<0.05, P<0.01), the results are shown in Table 3.

[0068] Table 3 Changes in serum IL-6, IL-1β, and TNF-α levels in each group of mice ( n=10)

[0069]

[0070] Note: Compared with CON, ## P<0.01; compared with MOD, * P<0.05, ** P<0.01

[0071] Example 4: Results of the study on the effect of the gel patch on the writhing reaction of mice

[0072] 2 hours after the last administration, 0.7% glacial acetic acid 10mL / kg was injected intraperitoneally, and the latency period and the number of twisting times within 15 minutes of the mice were observed (twisting standard: abdominal cavity concavity, hind limb extension, buttocks raised), and the analgesic rate was calculated. Analgesic rate = (average number of twisting times in the model group - average number of twisting times in the drug administration group) / average number of twisting times in the model group × 100%.

[0073] The results showed that after intraperitoneal injection of acetic acid, the latency of mice in each group was significantly prolonged and the number of writhing times was significantly reduced compared with the model group (P < 0.05). The analgesic rates of the drug-administered groups were as follows: HLS-GP-H>HLS-GP-M>DS-G>HLS-GP-L, as shown in Table 4.

[0074] Table 4 Results of writhing reaction of mice in each group ( n=10)

[0075]

[0076] Note: Compared with MOD, * P<0.05, ** P<0.01

[0077] Example 5 Investigating the effect of the gel patch on the expression of 5-HT, IL-1β, and PGE2 in mouse serum

[0078] After the acetic acid writhing reaction test, the mice were anesthetized and blood was collected. The mice were allowed to stand and centrifuged at 5000 r / min for 15 min. The serum was separated into EP tubes and stored in a -80°C refrigerator for later use. The levels of 5-HT, IL-1β, and PGE2 in mouse serum were detected by enzyme-linked immunosorbent assay. The results are shown in Table 5.

[0079] Table 5 Results of writhing reaction of mice in each group

[0080]

[0081] Example 6

[0082] Tartaric acid and PVPK90 are dissolved in water and swelled overnight to obtain phase A; aluminum glycolate, NP700, and kaolin are added to glycerol and stirred evenly to obtain phase B; Chinese herbal medicine extract is added to phase B and stirred evenly to obtain phase C; phase A is added to phase C and stirred evenly to obtain a gel preparation;

[0083] Among them, the Chinese medicine extract was prepared by the following method: take 75 weight parts of processed Aconitum kusnezoffii, 10 weight parts of Panax notoginseng, 15 weight parts of Panax notoginseng, and 5 weight parts of Panax notoginseng, crush and mix, add 10 times the amount of 60% ethanol to reflux and extract for 2 hours, filter, add 10 times the amount of 60% ethanol to the residue, reflux and extract for 2 hours, filter, combine the two filtrates, recover ethanol under reduced pressure, and concentrate to 2 g / mL to obtain the Chinese medicine extract.

[0084] The above method was used to prepare Chinese medicine extracts. The component types and usage amounts of the gel preparations in Examples 6.1-6.23 are shown in Table 6:

[0085] Table 6 Effect of matrix dosage on drug loading

[0086]

[0087]

[0088] The above products were subjected to performance tests and scored by sensory evaluation (fabric penetration, uniformity, skin follow-up, spreadability, repeated adhesion and film residue). The test results are shown in Table 7.

[0089] Table 7 Effect of matrix dosage changes on gel patch formation

[0090]

[0091]

[0092] From the above table, it can be seen that the drug loading of the present invention can reach 41.72% by scientifically adjusting the components of the gel matrix, and the drug loading is good, the drug has a sustained effect, and the drug has good skin followability. It can be seen that as NP700 is used as a skeleton material, the degree of cross-linking of the paste increases with the increase in the amount of NP700, resulting in increased cohesion, reduced viscosity, and poor spreadability. At the same time, the uniformity and skin followability of the paste also decrease accordingly.

[0093] As the amount of aluminum glycolate increases, the spreadability and skin followability of the paste gradually decrease. The reason may be that aluminum glycolate is a cross-linking agent. As its amount increases, the degree of cross-linking of the paste increases, the cohesion of the paste increases, and the strips break during coating, the viscosity decreases, and the skin followability becomes worse; as the amount of glycerol increases, the scores of various evaluation indicators gradually increase. The reason may be that as the amount of glycerol increases, the softness of the paste becomes better, and the spreadability, uniformity, skin followability, repeated adhesion and film residue are getting better and better, but the degree of cross-linking is not enough, the spatial structure is not firm, and the degree of penetration becomes more and more serious;

[0094] As the amount of tartaric acid increases, the more carboxyl groups there are, the more 3+ The more stable the complex formed, the better the Al 3+ The harder it is to dissociate from the complex, the slower the cross-linking speed, making it difficult to cross-link with NP700, resulting in a longer curing time and poor paste cohesion; however, a lower tartaric acid dosage will result in fewer carboxyl groups, faster paste cross-linking, and a hard paste that is difficult to apply;

[0095] As the amount of PVPK90 increases, the degree of penetration and skin follow-up are getting better, but the uniformity is gradually reduced. The reason is that PVPK90 is a viscosity enhancer. When the amount is small, the paste is not sticky enough, which makes it difficult to apply. As the amount increases, the paste viscosity increases, but when the amount is large, the degree of cross-linking decreases and the cohesion of the paste decreases.

[0096] Example 7

[0097] Different amounts of penetration enhancers were added to the traditional Chinese medicine extract prepared in Example 6.1. The types and addition amounts of penetration enhancers in Examples 7.1-7.9 are shown in Table 8:

[0098] Table 8

[0099] Serial number Azone (AZ) Propylene glycol (PG) Menthol (MT) Example 7.1 1％ - - Example 7.2 3％ - - Example 7.3 5％ - - Example 7.4 - 1％ - Example 7.5 - 3％ - Example 7.6 - 5％ - Example 7.7 - - 1％ Example 7.8 - - 3％ Example 7.9 - - 5％

[0100] In vitro percutaneous penetration tests were performed on the above products:

[0101] Experimental materials: Male SD rats were depilated with depilatory cream. After 24 hours of adaptive feeding, the rats were anesthetized and killed by cervical dislocation. Immediately after killing, the abdominal skin of the rats was removed, and the subcutaneous tissue and fat were gently separated with scissors and tweezers without damaging the skin. The skin was repeatedly rinsed with saline until it was clean, and the intact skin was immersed in saline and frozen at -20℃ for later use.

[0102] Experimental method: Take the treated rat skin and thaw it, fix it on one end of the dry heating automatic transdermal system, make the skin surface face the supply chamber, place a gel patch of appropriate size, fill the receiving chamber with the receiving medium, make sure there is no gap between it and the dermis, keep the temperature at (32±0.5)℃, stir with magnetic force at 600r / min, take out all the receiving solution at 1, 2, 4, 6, 8, 10, 12, 24h, and fill up the original solution volume. Determine the cumulative permeation per unit area Q of Lobactin (LOB), Notoginsenoside R1 (NG-R1), Ginsenoside Rg1 (G-Rg1), 8-deacetyl-Yanconitine (8D-YNA), Yanconitine (YNA), and Ginsenoside Rb1 (G-Rb1). The test results are shown in Tables 9-14 below:

[0103]

[0104] ER=Js / Jo

[0105] Q is the cumulative permeation per unit area, V is the volume of the receiving solution, Cn is the drug concentration measured at the nth sampling point, A is the permeation area of ​​the diffusion cell, Js is the steady-state transdermal rate after adding a permeation enhancer, and Jo is the steady-state transdermal rate without adding a permeation enhancer.

[0106] Table 9 LOB cumulative permeability per unit area ( n=4)

[0107]

[0108] Table 10 NG-R1 cumulative permeability per unit area ( n=4)

[0109]

[0110]

[0111] Table 11G-Rg1 Cumulative permeability per unit area ( n=4)

[0112]

[0113] Table 12 8D-YNA cumulative penetration per unit area ( n=4)

[0114]

[0115]

[0116] Table 13 YNA cumulative penetration per unit area ( n=4)

[0117]

[0118] Table 14G-Rb1 Cumulative permeability per unit area ( n=4)

[0119]

[0120]

[0121] As can be seen from Tables 9-14, the results show that menthol basically inhibits the percutaneous permeation of the six components in the Chinese medicine extract, while azone and propylene glycol both show different degrees of promotion. From the overall results, it can be seen that propylene glycol shows a better permeation-enhancing effect than AZ, and the optimal permeation-enhancing concentration of propylene glycol is concentrated at 3% and 5%. From the results of the 24h cumulative permeation volume, it can be seen that 5% propylene glycol has a better permeation-enhancing effect on NG-R1, G-Rg1 and G-Rb1 than 3% propylene glycol, and it is the group with the highest 24h cumulative permeation volume among all permeation enhancers, and 5% propylene glycol has a permeation-enhancing effect on LOB, 8D-YNA and YNA.

[0122] Example 8

[0123] The same as Example 7.3, except that the Chinese medicine extract is prepared by the following method: 85 parts by weight of processed Aconitum kusnezoffii, 15 parts by weight of Panax notoginseng, 15 parts by weight of Panax notoginseng, and 10 parts by weight of Panax notoginseng.

[0124] Example 9

[0125] The same as Example 7.3, except that the Chinese medicine extract is prepared by the following method: 65 parts by weight of processed Aconitum kusnezoffii, 5 parts by weight of Panax notoginseng, 10 parts by weight of Panax notoginseng, and 3 parts by weight of Panax notoginseng.

[0126] Example 10

[0127] The same as Example 7.3, except that the Chinese medicine extract is prepared by the following method: 65 parts by weight of processed Aconitum kusnezoffii, 12 parts by weight of Panax notoginseng, 12 parts by weight of Panax notoginseng, and 5 parts by weight of Panax notoginseng.

[0128] Embodiment 11

[0129] The same as Example 7.3, except that the Chinese medicine extract is prepared by the following method: 70 parts by weight of processed Aconitum kusnezoffii, 8 parts by weight of Panax notoginseng, 18 parts by weight of Panax notoginseng, and 7 parts by weight of Panax notoginseng.

[0130] Example 12

[0131] The same as Example 7.3, except that the Chinese medicine extract is prepared by the following method: 80 parts by weight of processed Aconitum kusnezoffii, 10 parts by weight of Panax notoginseng, 30 parts by weight of Panax notoginseng, and 5 parts by weight of Panax notoginseng.

[0132] Clinical application of the external medicinal preparation of the present invention.

[0133] Zhang, male, 60 years old, patient's knee joint is sore and painful, pain has fixed place, there is obvious sense of heaviness or swelling, joint stretch is unfavorable, affects normal life activities, and is diagnosed as knee osteoarthritis after inspection and laboratory testing. Use multiple medicines for the treatment of knee osteoarthritis, all no improvement. After 2 courses of treatment of using the tiger powder gel plaster of embodiment 8, joint swelling and pain are obviously alleviated, and after continuing to take 2 courses of treatment, knee osteoarthritis symptoms are obviously alleviated, and normal activities can be carried out.

[0134] Jia, female, 65 years old, retired employee, suffered from knee osteoarthritis for more than 3 years, limited joint movement, deformed swelling, aggravated after work, pain and other discomforts occurred after sitting or walking for a long time, affecting normal life and activities, and all treatments were ineffective. After 2 courses of treatment with the Hulisan gel plaster of Example 11, the pain was relieved, and the limb movement was improved compared with before treatment. After 2 courses of treatment, the symptoms of knee osteoarthritis such as joint pain and swelling were significantly improved.

[0135] He, female, 62 years old, had joint pain, hand pressure pain, morning stiffness and other symptoms for more than 4 years. Going up and down stairs would increase the pain, squatting was difficult, affecting the quality of life. She was diagnosed with knee osteoarthritis by hospital examination. Multiple drug treatments were used without obvious effect. After 4 courses of treatment with the Hulisan gel plaster of Example 9, the symptoms of joint pain and swelling were significantly improved.

[0136] Finally, it should be noted that the above description is only a preferred embodiment of the present invention. Under the guidance of the present invention, those skilled in the art can make a variety of similar expressions without violating the purpose and claims of the present invention, and such changes all fall within the protection scope of the present invention.

Claims

1. A Chinese medicine preparation for external use for anti-inflammatory and analgesic treatment of arthritis, characterized in that: The invention comprises a traditional Chinese medicine composition and pharmaceutical adjuvants acceptable in the art. The traditional Chinese medicine composition comprises 65-85 parts by weight of processed aconite, 5-15 parts of notoginseng, 10-30 parts of white cloud ginseng and 1-10 parts of radix polygoni multiflori.

2. The external Chinese medicine preparation for anti-inflammatory and analgesic treatment of arthritis according to claim 1, characterized in that: The added amount of the traditional Chinese medicine composition is 10-30% of the total mass.

3. The external Chinese medicine preparation for anti-inflammatory and analgesic treatment of arthritis according to claim 1, characterized in that: The Chinese medicine composition comprises: 70-85 parts by weight, or 68-85 parts by weight, or 70-80 parts by weight, or 73-80 parts by weight, or 73-78 parts by weight, such as 75 parts by weight of processed Aconitum kusnezoffii; and 5-12 parts, or 5-10 parts by weight, or 7-10 parts by weight, or 8-15 parts by weight, or 8-12 parts by weight, or 10-12 parts by weight, such as 10 parts by weight, of Panax notoginseng; and 10-25 parts, or 10-22 parts by weight, or 10-20 parts by weight, or 10-18 parts by weight, or 12-28 parts by weight, or 15-25 parts by weight, or 15-20 parts by weight, such as 15 parts by weight of Baiyun ginseng; and The amount of broken ginseng is 3-10 parts, or 3-7 parts by weight, or 3-5 parts by weight, or 5-10 parts by weight, or 1-5 parts by weight, such as 5 parts by weight.

4. The external Chinese medicine preparation according to claim 1, characterized in that: From bottom to top, there are a backing layer, a paste layer and an anti-sticking layer, and the paste layer contains the traditional Chinese medicine composition and the pharmaceutical excipients.

5. A method for preparing a Chinese medicine preparation for external use, characterized in that: The external Chinese medicine preparation according to claim 1 is prepared into a gel and / or a patch according to conventional methods in the art.

6. The preparation method according to claim 5, characterized in that: The gel is prepared by the following method: the traditional Chinese medicine composition is mixed with the pharmaceutical excipients, and the amount of the external Chinese medicine composition added is 10-30% of the total mass of the gel; the traditional Chinese medicine composition is the ethanol extract of Aconitum kusnezoffii, Panax notoginseng, Panax baiyunensis and Panax ginseng, and the pharmaceutical excipients include NP700, aluminum glycolate, kaolin, glycerin, tartaric acid, PVP K90, water, a penetration enhancer and a preservative.

7. The preparation method according to claim 5, characterized in that: The patch is prepared by the following method: the traditional Chinese medicine composition and the pharmaceutical excipients are mixed evenly, coated on a backing material to form a paste layer, and finally covered with a protective film; the amount of the external traditional Chinese medicine composition added is 10-30% of the total mass of the gel; the traditional Chinese medicine composition is an ethanol extract of Aconitum kusnezoffii, Panax notoginseng, Panax baiyunensis, and Panax ginseng, and the pharmaceutical excipients include NP700, aluminum glycolate, kaolin, glycerin, tartaric acid, PVPK90, water, a penetration enhancer, and a preservative.

8. The preparation method according to claim 6 or 7, characterized in that: The mass ratio of NP700, aluminum glycolate, kaolin, glycerol, tartaric acid, PVP K90, water, penetration enhancer and preservative is (7-11): (0.6-0.8): (1.0-2.0): (30-40): (0.8-1.2): (4.0-8.0): (20-30): (1-5): (2-4).

9. The preparation method according to claim 7, characterized in that: The penetration enhancer is any one of propylene glycol, azone and menthol; preferably, propylene glycol.

10. The preparation method according to claim 7, characterized in that: The support body is composed of a raw material including a fiber sheet; the fiber sheet is composed of a woven or non-woven fabric of natural fibers and / or synthetic fibers.

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