Application of pharmaceutical composition in transdermal drug delivery preparation

Abstract

The invention discloses an application of a pharmaceutical composition consisting of total glucosides of paeony and a non-steroidal anti-inflammatory drug in a transdermal drug delivery preparation. The application of the composition in a transdermal drug delivery preparation has the advantages that (1) the active epidermal barrier and the cuticle barrier of the skin are main barriers of transdermal absorption of total glucosides of paeony; the non-steroidal anti-inflammatory drug in the composition can reversibly open the active epidermal barrier of the skin, and if the non-steroidal anti-inflammatory drug is matched with a penetration enhancer for opening the cuticle barrier of the skin, the transdermal permeability of the total glucosides of paeony in the transdermal drug delivery preparation can be remarkably improved; the method has the characteristics of simple preparation process, easiness in industrial production and non-invasive skin, and can safely and efficiently improve the percutaneous permeability of the total glucosides of paeony; and (2) the total glucosides of paeony and the non-steroidal anti-inflammatory drug in the transdermal drug delivery preparation are combined for use, so that the total glucosides of paeony and the non-steroidal anti-inflammatory drug have an obvious synergistic effect in the aspect of curative effect on primary dysmenorrhea and rheumatoid arthritis, and the curative effect is excellent.

Description

Technical Field

[0001] The invention belongs to the technical field of transdermal drug delivery preparations, and specifically relates to an application of a pharmaceutical composition consisting of total glucosides of white paeony and non-steroidal anti-inflammatory drugs in transdermal drug delivery preparations. Background Art

[0002] Dysmenorrhea is one of the common clinical diseases in gynecology. It can be divided into primary dysmenorrhea (PD) and secondary dysmenorrhea according to whether the patient's reproductive organs have organic lesions. Among them, primary dysmenorrhea, also known as functional dysmenorrhea, accounts for more than 90% of dysmenorrhea. It refers to the patient's reproductive organs without organic lesions. Lower abdominal pain and swelling occur before, during and after menstruation, and are usually accompanied by headaches, fatigue, backache and other discomfort symptoms, which seriously affect the patient's quality of life and work. The earliest record of dysmenorrhea was found in "Golden Chamber Synopsis: Miscellaneous Diseases of Women, Pulse Symptoms and Treatments": "Leucorrhea, menstrual flow is not smooth, and young women have fullness and pain." Zhang Zhongjing pointed out that women's menstrual pain is closely related to poor blood flow. Traditional medicine believes that primary dysmenorrhea belongs to the category of "menstrual abdominal pain". The fundamental cause of primary dysmenorrhea is the obstruction of Qi and blood circulation, which causes "pain due to obstruction" or the lack of nourishment of Chong and Ren meridians and the uterus, which causes "pain due to lack of nourishment". It can be seen that the occurrence of primary dysmenorrhea is closely related to the cyclical physiological changes of Chong and Ren meridians and the uterus. Improving the symptoms of menstrual blood deficiency, lack of nourishment of Chong and Ren meridians and the uterus during menstruation, or unblocking the flow of Qi and blood in Chong and Ren meridians and the uterus during menstruation is the fundamental treatment of primary dysmenorrhea. Modern medicine believes that endogenous substances such as endometrial prostaglandin F2α (PGF2α), estrogen, progesterone, endothelin, nitric oxide, β-endorphin, calcium ions and oxygen free radicals can jointly promote the formation and development of primary dysmenorrhea through different pathways.

[0003] The traditional Chinese medicine Wenjing Decoction, Taohong Siwu Decoction, Aiqi Decoction, Shengyu Decoction, Xuanyu Tongjing Decoction and other classic prescriptions for the treatment of primary dysmenorrhea all contain white peony root in their drug composition, which shows that it has a good effect in the treatment of primary dysmenorrhea. According to Chinese medicine, the liver and spleen are closely related to the biochemistry and operation of qi and blood. The liver is responsible for storing blood and regulating blood flow; the spleen is responsible for transportation and transformation, and is the source of qi and blood biochemistry, with hematopoietic function. White peony root enters the liver and spleen meridians and is good at nourishing blood and regulating menstruation. It can nourish the Chongren and Baogong, and can fundamentally improve the "pain caused by lack of nourishment" of reduced uterine blood flow, uterine tissue ischemia, and hypoxia, and play a role in the treatment of primary dysmenorrhea. In addition, qi stagnation leads to blood stasis, and qi movement leads to blood movement. White peony root enters the liver meridian and mainly regulates qi, relieves liver qi and depression, and by promoting blood flow and activating blood circulation and removing blood stasis, it can fundamentally treat primary dysmenorrhea caused by poor blood circulation and blood stasis blocking the uterus. Total glucosides of paeony (TGP) is the main active ingredient of the traditional Chinese medicine white peony for the treatment of primary dysmenorrhea. Modern pharmacological studies have shown that TGP can treat primary dysmenorrhea in a variety of ways: 1) Paeoniflorin can inhibit the generation of prothrombin, inhibit platelet aggregation, dilate veins and peripheral small blood vessels, improve blood microcirculation and other biological effects, and can improve the symptoms of dysmenorrhea caused by uterine ischemia and hypoxia by promoting blood circulation, replenishing blood, relieving spasms and relieving pain; 2) TGP can reduce the content of PGF2α in mouse uterine tissue, thereby inhibiting the spasmodic contraction of uterine smooth muscle and relieving the symptoms of primary dysmenorrhea; 3) TGP can increase the NO level in the rat uterus, inhibit excessive contraction of the rat uterus, promote blood flow, and inhibit the production of anaerobic metabolites, thereby relieving the symptoms of primary dysmenorrhea; 4) TGP can inhibit the production of extracellular Ca 2+ The influx of calcium and the release of intracellular calcium stores relax uterine smooth muscle and relieve pain; 5) Paeoniflorin and paeoniflorin may exert analgesic effects by increasing the level of β-EP in serum and cerebral cortex, activating endogenous analgesic mechanisms, inhibiting pain conduction and the excitation of nociceptors.

[0004] Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovitis and cartilage destruction. It mainly manifests as polyarticular and symmetrical joint inflammation of the small joints of the hands and feet. In severe cases, it can cause cartilage damage and joint destruction, leading to joint deformity and even loss of function. It is highly disabling and seriously affects the patient's living conditions and work quality. Traditional medicine believes that rheumatoid arthritis is consistent with the common cause of Bi syndrome, and belongs to the category of "Bi syndrome" in traditional Chinese medicine. It has the pathogenic characteristics of liver and kidney deficiency, qi and blood deficiency as internal factors, and wind, cold and dampness as inducing factors. Rheumatoid arthritis patients have their own qi and blood deficiency, damaged yang qi, resulting in empty pores and weak defense. At this time, wind, cold and dampness are more likely to invade the skin, joints, and meridians, resulting in obstruction of qi and blood circulation, swelling and pain in the affected area, and joint deformation and stiffness. It can be seen that the occurrence of rheumatoid arthritis is closely related to the deficiency of the liver, kidney and spleen. The medication should be based on tonifying the liver and kidney, soothing the liver and regulating qi, and invigorating qi and activating blood circulation. Modern medicine believes that multiple factors such as immune cells (synovial B cells, synovial macrophages, neutrophils, etc.), cytokines (IL-1, IL-6, IL-17, TNF-α, etc.), autoantigens and intestinal flora may cause the occurrence and development of rheumatoid arthritis.

[0005] The traditional Chinese medicine commonly used classic prescriptions for the treatment of rheumatoid arthritis, such as Shaoyao Gancao Decoction, Huangqi Guizhi Wuwu Decoction, Guizhi Shaoyao Zhimu Decoction, etc., all contain white peony in their drug composition, which shows that it has a good effect in the treatment of rheumatoid arthritis. According to Chinese medicine, if the liver qi is stagnant and the qi is not smooth, it can affect the circulation of qi and blood and aggravate arthralgia. White peony enters the liver meridian, and the liver governs the tendons. By nourishing the liver blood, it can nourish the tendons and veins, which helps to relieve symptoms such as joint pain, cramps, and flexion and extension difficulties. In addition, the liver governs the release of qi and can regulate the qi. White peony can soothe the liver and regulate qi, make the qi smooth, promote the circulation of qi and blood, and help treat arthralgia. White peony enters the spleen meridian and can strengthen the spleen and nourish blood, so that the qi and blood biochemical activity is active, providing a material basis for joint repair. Patients with rheumatoid arthritis often suffer from unbearable joint pain, and the sour and cold nature of white peony can astringe qi and blood, relieve pain, and has a good therapeutic effect on symptoms such as joint pain and muscle spasm caused by arthralgia. Similarly, TGP is also the main active ingredient of white peony root for the treatment of rheumatoid arthritis. Modern pharmacological studies have shown that TGP can treat rheumatoid arthritis in a variety of ways: 1) TGP plays an anti-inflammatory role, inhibiting the proliferation of fibroblast-like synoviocytes (FLS) and promoting FLS cell apoptosis, thereby reducing the release of inflammatory factors, playing an anti-inflammatory role and relieving the symptoms of rheumatoid arthritis; 2) TGP plays an anti-thrombotic role, making blood flow unobstructed, which is helpful for the nourishment of tendons and veins and the repair of damaged joints, thereby achieving the effect of treating rheumatoid arthritis; 3) TGP plays an immunomodulatory role, by reducing the proportion of CD4+ cells in the spleen and lymph nodes, CD4+ Cells / CD8 + cell ratio and IFN-γ level, increase CD8 + 4) It regulates the immune function by increasing the phagocytic effect of macrophages on foreign cells, thereby balancing the immune system and improving the symptoms of rheumatoid arthritis; 5) It regulates the function of osteoclasts and osteoblasts. TGP inhibits the proliferation and differentiation of osteoclasts and protects the maturation and differentiation of osteoblasts to treat rheumatoid arthritis; 6) It regulates the intestinal flora of patients with rheumatoid arthritis. It significantly increases the function of flora related to the immune system and significantly reduces the function of flora related to immune system diseases to inhibit the occurrence of inflammatory response and improve the symptoms of rheumatoid arthritis.

[0006] Although the above-mentioned TGP has the efficacy of treating primary dysmenorrhea and rheumatoid arthritis symptoms, it actually has obvious problems. At present, the commonly used dosage form of TGP is mainly oral capsules, which have the following problems: 1) Due to the combined influence of multiple factors such as the first-pass effect of the liver, the binding of P-glycoprotein and TGP, and the poor lipid solubility of TGP itself, TGP has poor oral absorption and low absolute bioavailability of only 3% to 4%; 2) The blood concentration of TGP capsules is unstable, and the drug half-life is short, the duration of drug effect is short, and multiple doses are required, and patient compliance is poor; 3) The local blood concentration of oral TGP is low, and it is impossible to produce a large blood concentration in the uterus or synovial area of ​​the joint to exert a local therapeutic effect. In contrast, making TGP into a transdermal preparation has the advantages of being free from the first-pass effect of the liver, high bioavailability, long drug half-life, stable blood concentration, and being able to exert local efficacy. However, the skin is a huge barrier for drugs to enter the body through skin absorption. Due to the high water solubility of TGP, it is difficult to achieve percutaneous absorption. Although there are methods for improving the transdermal performance of TGP, there are the following problems: 1) Adding penetration enhancers such as propylene glycol, oleic acid, and berberine hydrochloride. The advantage of this method is that it can improve the transdermal performance of TGP to a certain extent, and the preparation process is relatively simple. However, the disadvantage is that although these penetration enhancers can effectively open the stratum corneum barrier of the skin, they cannot open the active epidermal barrier of the skin, and the existence of the active epidermal barrier still leads to the limited transdermal permeation of TGP. Therefore, the use of these penetration enhancers alone has a very limited effect on the improvement of TGP transdermal performance, and the penetration multiple is usually only 1.5 to 2.5 times; 2) Using ion introduction, microneedle and other physical methods. The advantage of this method is that it can improve the transdermal performance of TGP, but the disadvantage is that the preparation process is relatively complicated, and the use of these skin invasive preparations also has the risk of skin infection; 3) Use new carriers such as liposomes, nanoparticles, and nanogels. The advantage of this type of method is that it can improve the transdermal performance of TGP, but the disadvantages are high production cost, high requirements for production equipment, and complex preparation process. Therefore, based on the above problems, how to make the TGP transdermal drug delivery preparation have the characteristics of simple preparation process, easy industrial production, and non-invasive to the skin, and can safely and efficiently improve the transdermal permeability of TGP is of vital importance.

[0007] Nonsteroidal anti-inflammatory drugs (NSAIDs) are also commonly used drugs for the clinical treatment of primary dysmenorrhea and rheumatoid arthritis, with the characteristics of rapid onset of efficacy. NSAIDs refer to antipyretic, analgesic and anti-inflammatory drugs that do not contain steroidal structures, including nimesulide, indomethacin, flufenamic acid, meloxicam, aspirin and other drugs. Modern pharmacological studies have shown that in the treatment of primary dysmenorrhea, high concentrations of PGF2α can act on the PGF2α receptors on the walls of spiral arterioles, leading to spasmodic contraction of uterine smooth muscle, a large accumulation of acidic products in the uterine myometrium, causing dysmenorrhea, and at the same time increasing the sensitivity of pelvic nerves to pain and amplifying pain. NSAIDs are highly effective prostaglandin synthase inhibitors, which can block the synthesis of prostaglandins by efficiently inhibiting cyclooxygenase and reducing the content of PGF2α, thereby quickly inhibiting the spasmodic contraction of endometrial smooth muscle and treating primary dysmenorrhea. In the treatment of rheumatoid arthritis, NSAIDs can inhibit the synthesis of inflammatory mediators such as prostaglandins, prostaglandins and thromboxane A2 by arachidonic acid by inhibiting the activity of cyclooxygenase, thereby playing an anti-inflammatory, anti-swelling and analgesic role in the synovial tissue of the joints, thereby exerting the therapeutic effect of treating rheumatoid arthritis. However, although NSAIDs have the effect of quickly relieving the pain of primary dysmenorrhea and rheumatoid arthritis, their short half-life and short duration of efficacy require frequent use of the drug, and the problem of easy recurrence after discontinuation of the drug also leads to the limitations of NSAIDs in the clinical treatment of primary dysmenorrhea and rheumatoid arthritis. Summary of the invention

[0008] Purpose of the invention: The purpose of the present invention is to provide an application of a pharmaceutical composition in a transdermal drug delivery preparation, which is used to effectively improve the transdermal permeability of total glucosides of white paeony, and at the same time can produce a better synergistic therapeutic effect on primary dysmenorrhea and rheumatoid arthritis.

[0009] Technical solution: The pharmaceutical composition of the present invention comprises total glucosides of white paeony and non-steroidal anti-inflammatory drugs.

[0010] The pharmaceutical composition comprises total glucosides of white paeony and non-steroidal anti-inflammatory drugs as active ingredients.

[0011] In the composition, the total glucosides of white peony are terpene glycosides of white peony, including one or more of paeoniflorin, paeoniflorin lactones, oxidized paeoniflorin, benzoyl paeoniflorin, and galloyl paeoniflorin, or are extracts containing terpene glycosides of white peony extracted from traditional Chinese medicine or plants. Further, the traditional Chinese medicine or plants include red peony root and peony bark.

[0012] The composition, the non-steroidal anti-inflammatory drug includes diclofenac, indomethacin, flurbiprofen, flufenamic acid, nabumetone, meloxicam, rofecoxib, celecoxib, mefenamic acid, nimesulide, loxoprofen, etoricoxib and one or more of their pharmaceutically acceptable salts or derivatives.

[0013] The pharmaceutical composition is used in preparing medicines for treating primary dysmenorrhea and rheumatoid arthritis.

[0014] Application of nonsteroidal anti-inflammatory drugs in improving the transdermal performance of total glycosides of white paeony.

[0015] Furthermore, nonsteroidal anti-inflammatory drugs are used in combination with total glucosides of white paeony in transdermal preparations.

[0016] The transdermal preparation is prepared by adding pharmaceutically acceptable excipients to the pharmaceutical composition.

[0017] The pharmaceutically acceptable excipients of the transdermal preparation include a chemical penetration enhancer. Further preferably, the transdermal preparation contains a pharmaceutically acceptable chemical penetration enhancer for enhancing the ability of the drug to penetrate the stratum corneum barrier.

[0018] The transdermal drug delivery preparation comprises one or more of pepper oil, peppermint oil, galangal oil, mustard oil, 1,8-cineole, evodia rutaecarpa oil, dried ginger oil and clove oil.

[0019] The transdermal preparation is selected from the group consisting of patches, emulsions, plasters, ointments, plasters, pastes, coatings, gels, powder sprays, aerosols, sprays, oils, lotions, glycerin, liniments, suspensions, solutions, sols, tinctures and spirits.

[0020] More preferably, when the transdermal preparation is a patch, it contains 11-18 mg / cm 2 , containing nonsteroidal anti-inflammatory drugs 4-7mg / cm 2 .

[0021] In a specific implementation, the nonsteroidal anti-inflammatory drug in the pharmaceutical composition can improve the transdermal permeability of total glucosides of white paeony.

[0022] In a specific implementation, the total glucosides of white paeony and non-steroidal anti-inflammatory drugs in the pharmaceutical composition have obvious synergistic effects in the treatment of primary dysmenorrhea and rheumatoid arthritis.

[0023] After a long series of studies, the applicant of this patent has found that the combined use of total glucosides of white paeony and non-steroidal anti-inflammatory drugs in transdermal preparations not only improves the bioavailability of drugs, prolongs the half-life of drugs, maintains stable blood drug concentrations, and exerts local therapeutic effects, but more importantly, the non-steroidal anti-inflammatory drugs in the pharmaceutical composition can significantly improve the transdermal permeability of total glucosides of white paeony, and the combination of the two has a significant synergistic effect in the treatment of primary dysmenorrhea and rheumatoid arthritis. The specific value analysis of the combination of non-steroidal anti-inflammatory drugs and total glucosides of white paeony in the transdermal preparation is as follows: (1) In terms of improving the transdermal permeability of total glucosides of white paeony, non-steroidal anti-inflammatory drugs can reversibly open the tight junctions of the active epidermis of the skin, and the use of them in combination with penetration enhancers that open the stratum corneum barrier can significantly enhance the transdermal permeability of total glucosides of white paeony. Therefore, the method of improving the transdermal permeability of total glucosides of white paeony by combining nonsteroidal anti-inflammatory drugs can solve the problems existing in the prior art, and has the advantages of effectively improving the transdermal permeability of total glucosides of white paeony, simple preparation process, safe and non-damaging to the skin, and easy industrial production; (2) In terms of the efficacy of nonsteroidal anti-inflammatory drugs themselves, nonsteroidal anti-inflammatory drugs have a rapid onset of action and have the efficacy of quickly improving the symptoms of primary dysmenorrhea and rheumatoid arthritis, but their drug half-life is short, the duration of drug effect is short, frequent medication is required, and the problem of easy recurrence after drug withdrawal also leads to the limitations of nonsteroidal anti-inflammatory drugs in the clinical treatment of primary dysmenorrhea and rheumatoid arthritis. Compared with total glucosides of white paeony, although nonsteroidal anti-inflammatory drugs do not have the efficacy of total glucosides of white paeony to continuously exert therapeutic effects, they have the characteristic of rapid onset of efficacy that total glucosides of white paeony do not have. Therefore, the combination of non-steroidal anti-inflammatory drugs and total glucosides of white paeony has obvious synergistic effect. The combination of the two can have the advantages of rapid onset of action and sustained and long-term efficacy in the treatment of primary dysmenorrhea and rheumatoid arthritis.

[0024] Beneficial effects: Compared with the prior art, the present invention has the following advantages: (1) The transdermal preparation prepared by the pharmaceutical composition provided by the present invention can significantly improve the transdermal permeability of total glucosides of white paeony. Compared with the existing methods for enhancing the transdermal permeability of total glucosides of white paeony, the application of the composition in transdermal preparations is a method that has the characteristics of simple preparation process, easy industrial production, and non-invasiveness to the skin and can safely and efficiently improve the transdermal permeability of total glucosides of white paeony. (2) The combined use of the pharmaceutical composition in the transdermal preparation provided by the present invention has a significant synergistic effect in the treatment of primary dysmenorrhea and rheumatoid arthritis, and has excellent therapeutic effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 The graph shows the results of the permeation enhancement of paeoniflorin by flufenamic acid;

[0026] Figure 2The figure shows the results of celecoxib enhancing the permeation of paeoniflorin;

[0027] Figure 3 The graph shows the results of the enhancement of the permeation of paeoniflorin by flurbiprofen;

[0028] Figure 4 The graph shows the permeation enhancement results of nimesulide on albiflorin. DETAILED DESCRIPTION

[0029] The present invention will be further described below in conjunction with specific embodiments, it should be understood that these embodiments are illustrative, are only used to illustrate the present invention, and are not intended to limit the scope of the invention of the present invention. The pharmaceutical composition, composition patch, and comparison patch provided in the following specific embodiments are all obtained by laboratory self-production, and any imitation, modification or change made without departing from the drug combination ideas and types provided by the present invention all belong to the protection scope of the present invention. Raw materials and equipment used in the present invention are all known products, obtained by purchasing commercially available products.

[0030] Example 1

[0031] This embodiment provides a pharmaceutical composition consisting of flufenamic acid and paeoniflorin, named as Composition 1; the weight ratio of flufenamic acid to paeoniflorin is 1:1, mixed evenly, and the composition is prepared in a laboratory.

[0032] Example 2

[0033] This embodiment provides a pharmaceutical composition consisting of celecoxib and paeoniflorin, named as composition 2; the weight ratio of celecoxib to paeoniflorin is 1:1, mixed evenly, and the composition is prepared in the laboratory.

[0034] Example 3

[0035] This embodiment provides a pharmaceutical composition consisting of flurbiprofen and paeoniflorin, named as composition 3; the weight ratio of flurbiprofen to paeoniflorin is 1:1, mixed evenly, and the composition is prepared in the laboratory.

[0036] Example 4

[0037] This embodiment provides a pharmaceutical composition consisting of nimesulide and albiflorin, named as composition 4; the weight ratio of nimesulide to albiflorin is 1:1, mixed evenly, and the composition is prepared in the laboratory.

[0038] Example 5

[0039] This embodiment provides a transdermal patch, which is composed of Composition 5 (peony lactone glycosides, mefenamic acid) and other pharmaceutical excipients, named as Example 5 patch, which is made in the laboratory. The specific preparation method is as follows:

[0040] 5.1 Prescription preparation

[0041] The following components are all in parts by weight:

[0042]

[0043] Among them, paeoniflorin is a component of total glucosides of white peony; mefenamic acid is a component of non-steroidal anti-inflammatory drugs; hydroxypropyl cellulose is used as a skeleton material; triethyl citrate is used as a plasticizer; butyl acrylate-acrylic acid copolymer is used as an adhesive; polyvinyl pyrrolidone is used as a moisturizer; magnesium aluminum silicate is used as a cross-linking agent; ascorbic acid is used as an antioxidant and cross-linking regulator; and clove oil is used as a stratum corneum penetration enhancer.

[0044] 5.2 Preparation method

[0045] (1) fully swelling and uniformly dispersing paeoniflorin, mefenamic acid, hydroxypropyl cellulose, triethyl citrate and an appropriate amount of water phase to obtain a mixture a;

[0046] (2) uniformly mixing butyl acrylate-acrylic acid copolymer, polyvinyl pyrrolidone, clove oil and an appropriate amount of water to obtain a mixture b;

[0047] (3) mixing and dissolving magnesium aluminum silicate, ascorbic acid and the remaining water to obtain a mixture C;

[0048] (4) Mixtures a, b, and c are combined and stirred thoroughly, and the resulting total mixture is placed between a coating machine backing layer (non-woven fabric) and a protective layer (ethylene-vinyl acetate copolymer), and extruded to obtain a patch containing composition 5;

[0049] (5) The obtained patch was placed in a drying machine and baked for 30 minutes. The finished product had a moisture content of about 7.4%. After being taken out, it was cut into 3 cm × 3 cm patches and packaged. HPLC determination showed that the content of 18.5 mg / cm 2 The patch of composition 5 (containing 12.58 mg / cm 2 , containing mefenamic acid 5.92mg / cm 2 ).

[0050] Example 6

[0051] This embodiment provides a transdermal patch, which is composed of composition 6 (benzoylpeonidin, galloylpeonidin, diclofenac) and other pharmaceutical excipients, named as Example 6 patch, which is made in the laboratory. The specific preparation method is as follows:

[0052] 6.1 Prescription preparation

[0053] The following components are all in parts by weight:

[0054]

[0055] Among them, benzoylpeonidin and galloylpeonidin are components of total glycosides of white peony; diclofenac is a non-steroidal anti-inflammatory drug component; polyacrylate is used as a skeleton material; triethyl citrate is used as a plasticizer; hydroxypropyl methylcellulose is used as a binder; sodium hyaluronate is used as a moisturizer; magnesium aluminum silicate is used as a cross-linking agent; lipoic acid is used as an antioxidant; ethylenediaminetetraacetic acid is used as a cross-linking regulator; and galangal oil is used as a stratum corneum penetration enhancer.

[0056] 6.2 Preparation method

[0057] (1) fully swelling and uniformly dispersing benzoylpeonidin, galloylpeonidin, diclofenac, polyacrylate, triethyl citrate and an appropriate amount of water to obtain a mixture I;

[0058] (2) uniformly mixing hydroxypropyl methylcellulose, sodium hyaluronate, lipoic acid, galangal oil and an appropriate amount of water to obtain a mixture II;

[0059] (3) mixing and dissolving magnesium aluminum silicate, ethylenediaminetetraacetic acid and the remaining water phase to obtain a mixture III;

[0060] (4) After the mixtures I, II and III are combined and stirred thoroughly, the total mixture is placed between the coating machine lining layer (non-woven fabric) and the protective layer (aluminum foil-polyethylene composite film), and extruded to obtain a patch containing composition 6;

[0061] (5) The obtained patch was placed in a drying machine and baked for 30 minutes. The finished product had a moisture content of about 8.5%. After being taken out, it was cut into 3 cm × 3 cm patches and packaged. HPLC determination showed that it contained 22.5 mg / cm 2 Composition 6 patch (containing 11.25 mg / cm 2 , containing galloylpeonidin 5.25mg / cm 2 , containing diclofenac 6.00mg / cm 2 ).

[0062] Comparative Example 1

[0063] This comparative example provides a patch, named as the patch of comparative example 1. The difference between the patch and the patch of Example 5 is that the patch of comparative example 1 does not contain paeoniflorin, and the reduced mass is proportionally distributed to the mass of mefenamic acid, and the other components and contents remain unchanged.

[0064] The preparation method is similar to that of Example 5.

[0065] Comparative Example 2

[0066] This comparative example provides a patch, named as the patch of comparative example 2. The only difference between the patch of comparative example 2 and the patch of example 5 is that the patch of comparative example 2 does not contain mefenamic acid, and its reduced mass is proportionally distributed to the mass of paeoniflorin, and other components and contents remain unchanged.

[0067] The preparation method is similar to that of Example 5.

[0068] Comparative Example 3

[0069] This comparative example provides a patch, named as the patch of comparative example 3. The only difference between the patch of comparative example 3 and the patch of example 5 is that the patch of comparative example 3 is a matrix patch without the component 5 of composition (peonidin and mefenamic acid), and the reduced mass of the two components is proportionally distributed to the mass of other components.

[0070] The preparation method is similar to that of Example 5.

[0071] Comparative Example 4

[0072] This comparative example provides a patch, named as the patch of comparative example 4. The only difference between the patch of comparative example 4 and the patch of example 6 is that the patch of comparative example 4 does not contain benzoylpeonidin and galloylpeonidin, and the reduced mass of the two is proportionally distributed to the mass of diclofenac, and the other components and contents remain unchanged.

[0073] The preparation method is similar to that of Example 6.

[0074] Comparative Example 5

[0075] This comparative example provides a patch, named as the patch of comparative example 5. The only difference between the patch of comparative example 5 and the patch of example 6 is that the patch of comparative example 5 does not contain diclofenac, and its reduced mass is proportionally distributed to the mass of benzoylpeonidin and galloylpeonidin, and other components and contents remain unchanged.

[0076] The preparation method is similar to that of Example 6.

[0077] Comparative Example 6

[0078] This comparative example provides a patch, named as Comparative Example 6 patch. The only difference between the patch and the patch of Example 6 is that the patch of Comparative Example 6 is a matrix patch without the components of composition 6 (benzoylpeonidin, galloylpeonidin and diclofenac), and the reduced mass of the three components is proportionally distributed to the mass of other components.

[0079] The preparation method is similar to that of Example 6.

[0080] Experimental Example 1. Effect of Flufenamic Acid on the Transdermal Performance of Paeoniflorin

[0081] 1.1 Main experimental drugs, reagents and instruments

[0082] Drugs and reagents: paeoniflorin, composition 1, peppermint oil, urethane, phosphoric acid, acetonitrile, physiological saline, anhydrous ethanol.

[0083] Instruments: Transdermal diffusion tester, high performance liquid chromatography, high speed centrifuge.

[0084] 1.2 Experimental animals

[0085] 5 female ordinary New Zealand rabbits, weighing 2-3 kg.

[0086] 1.3 Analysis methods

[0087] 1.3.1 HPLC conditions

[0088] Chromatographic column: Luna C18 column (150*4.6mm, 5μm); mobile phase: acetonitrile: 0.1% phosphoric acid aqueous solution (14:68, V / V); flow rate: 1.0mL / min; detection wavelength: 230nm; temperature: 30℃; injection volume: 20μL.

[0089] 1.3.2 Preparation of standard solution and establishment of standard curve

[0090] Accurately weigh the paeoniflorin reference substance, add ethanol to make up the volume, and shake well to obtain the standard solution. Linear regression is performed with the mass concentration of paeoniflorin as the horizontal axis and the peak area as the vertical axis.

[0091] 1.4 Rabbit skin in vitro transdermal diffusion test method

[0092] 1.4.1 Preparation of ex vivo rabbit skin

[0093] After the rabbits were anesthetized by injection of urethane solution, the hair on the abdomen of the rabbits was removed with a shaver. Each rabbit was killed, and the abdominal skin was cut, washed with saline, and stored in an ice bath for later use.

[0094] 1.4.2 Transdermal test

[0095] The skin of each rabbit was randomly divided into two groups, namely the control group and the experimental group. Franz diffusion cell was used, and PBS solution was used as the receiving solution; the control group was supplied with OP-10 solution containing 5% paeoniflorin (containing 7% peppermint oil); the experimental group was supplied with OP-10 solution containing 5% paeoniflorin (peoniflorin + flufenamic acid) (containing 7% peppermint oil). The skin of each group was placed in a transdermal diffusion instrument at 32°C and 600rpm under continuous stirring. 0.5mL was sampled from the receiving cell after 1, 2, 4, 5, and 6 hours, and an equal amount of fresh receiving solution at the same temperature was immediately added.

[0096] 1.4.3 Data processing

[0097] The above samples were placed in a high-speed centrifuge at 12000 r·min- 1 The samples were centrifuged for 10 min under the same conditions, and the content of paeoniflorin in the supernatant was determined according to the chromatographic conditions in item "1.3.1", and the cumulative transdermal drug amount per unit area (Q n ).

[0098] 1.5 Experimental Results and Analysis

[0099] The results are shown in Table 1. Figure 1 As shown. Compared with the control group, the experimental group can significantly increase the cumulative permeation of paeoniflorin through the skin (P<0.001). The above results show that when flufenamic acid and peppermint oil are used together, the effect of promoting the permeation of paeoniflorin is significantly better than that of peppermint oil alone. The reason is that although peppermint oil can effectively open the stratum corneum barrier of the skin, it cannot open the active epidermal barrier of the skin, while flufenamic acid can open the active epidermal barrier. Therefore, the co-use of flufenamic acid and peppermint oil can significantly enhance the transdermal performance of paeoniflorin.

[0100] Table 1 The penetration-enhancing results of paeoniflorin ( n=5)

[0101]

[0102] Note: Compared with the control group, * P<0.05, ** P<0.01, *** P < 0.001, **** P<0.0001.

[0103] Experimental Example 2. Effect of celecoxib on the transdermal performance of paeoniflorin

[0104] 2.1 Main experimental drugs, reagents and instruments:

[0105] The composition 1 under item "1.1" was replaced by the composition 2, the peppermint oil was replaced by the galangal oil, and the other experimental drugs, reagents and instruments were the same as those in Experimental Example 1.

[0106] 2.2 Experimental animals, analytical methods, and preparation of ex vivo rabbit skin

[0107] Same as Test Example 1.

[0108] 2.3 Rabbit skin in vitro transdermal diffusion test method

[0109] 2.3.1 Transdermal test

[0110] The skin of each rabbit was randomly divided into two groups, namely the control group and the experimental group. Franz diffusion cell was used, and PBS solution was used as the receiving solution; the control group was supplied with OP-10 solution containing 5% paeoniflorin (containing 7% galangal oil); the experimental group was supplied with OP-10 solution containing 5% paeoniflorin (peoniflorin + celecoxib) (containing 7% galangal oil). The transdermal experimental method and operation were the same as those in Experimental Example 1.

[0111] 2.3.2 Data processing

[0112] The data processing method is the same as that of Experimental Example 1.

[0113] 2.4 Experimental Results and Analysis

[0114] The results are shown in Table 2. Figure 2 As shown. Compared with the control group, the experimental group can significantly increase the cumulative permeation of paeoniflorin through the skin (P<0.001). The above results show that when celecoxib and galangal oil are used together, the effect of promoting the permeation of paeoniflorin is significantly better than that of galangal oil alone. The reason is that although galangal oil can effectively open the stratum corneum barrier of the skin, it cannot open the active epidermal barrier of the skin, while celecoxib can open the active epidermal barrier. Therefore, the co-use of celecoxib and galangal oil can significantly enhance the transdermal performance of paeoniflorin.

[0115] Table 2 The results of promoting the penetration of paeoniflorin ( n=5)

[0116]

[0117] Note: Compared with the control group, * P<0.05, ** P<0.01, *** P < 0.001, **** P<0.0001.

[0118] Experimental Example 3. Effect of Flurbiprofen on the Transdermal Performance of Paeoniflorin

[0119] 3.1 Main experimental drugs, reagents and instruments:

[0120] The paeoniflorin under item "1.1" was replaced with paeoniflorin, composition 1 was replaced with composition 3, peppermint oil was replaced with 1,8-cineole, and other experimental drugs, reagents and instruments were the same as those in Experimental Example 1.

[0121] 3.2 Experimental animals

[0122] Same as Test Example 1.

[0123] 3.3 Analysis methods

[0124] 3.3.1 HPLC conditions

[0125] Chromatographic column: Luna C18 column (150*4.6mm, 5μm); mobile phase: acetonitrile: 0.1% phosphoric acid aqueous solution (13:87, V / V); flow rate: 1.0mL / min; detection wavelength: 233nm; temperature: 30℃; injection volume: 20μL.

[0126] 3.3.2 Preparation of standard solution and establishment of standard curve

[0127] Weigh the peony lactone glycosides, add ethanol to make up the volume, and shake well to obtain the standard solution. Perform linear regression with the mass concentration of peony lactone glycosides as the horizontal axis and the peak area as the vertical axis.

[0128] 3.4 In vitro transdermal diffusion test method of rabbit skin

[0129] 3.4.1 Preparation of ex vivo rabbit skin

[0130] The preparation method of ex vivo rabbit skin is the same as that of Experimental Example 1.

[0131] 3.4.2 Transdermal test

[0132] The skin of each rabbit was randomly divided into two groups, namely the control group and the experimental group. Franz diffusion cell was used, and PBS solution was used as the receiving solution; the control group was supplied with OP-10 solution containing 5% of paeoniflorin (containing 7% of 1,8-cineole); the experimental group was supplied with OP-10 solution containing 5% of paeoniflorin (paeoniflorin + flurbiprofen) (containing 7% of 1,8-cineole). The transdermal experimental method and operation were the same as those in Experimental Example 1.

[0133] 3.4.3 Data processing

[0134] The above samples were placed in a high-speed centrifuge and centrifuged at 12000 r·min-1 for 10 min. The supernatant was determined according to the chromatographic conditions under "3.3.1" to determine the content of paeoniflorin in each sample, and the cumulative transdermal amount of the drug per unit area at different time points (Q' n ).

[0135] 3.5 Experimental Results and Analysis

[0136] The results are shown in Table 3. Figure 3As shown. Compared with the control group, the experimental group can significantly increase the cumulative permeation of albiflorin (P<0.001). The above results show that when flurbiprofen and 1,8-cineole are used together, the permeation-enhancing effect of albiflorin is significantly better than that of 1,8-cineole alone. The reason is that although 1,8-cineole can effectively open the stratum corneum barrier of the skin, it cannot open the active epidermal barrier of the skin, while flurbiprofen can open the active epidermal barrier. Therefore, the co-use of flurbiprofen and 1,8-cineole can significantly enhance the transdermal performance of albiflorin.

[0137] Table 3 The results of promoting the penetration of paeoniflorin ( n=5)

[0138]

[0139] Note: Compared with the control group, * P<0.05, ** P<0.01, *** P < 0.001, **** P<0.0001.

[0140] Experimental Example 4. Effect of Nimesulide on the Transdermal Performance of Paeoniflorin

[0141] 4.1 Main experimental drugs, reagents and instruments:

[0142] The composition 3 under item "3.1" was replaced by the composition 4, 1,8-cineole was replaced by evodia rutaecarpa oil, and other experimental drugs, reagents and instruments were the same as those in Experimental Example 3.

[0143] 4.2 Experimental animals, analytical methods, and preparation of ex vivo rabbit skin

[0144] Same as Test Example 1.

[0145] 4.3 In vitro transdermal diffusion test method of rabbit skin

[0146] 4.3.1 Transdermal test

[0147] The skin of each rabbit was randomly divided into two groups, namely the control group and the experimental group. Franz diffusion cell was used, and PBS solution was used as the receiving solution; the control group was supplied with OP-10 solution containing 5% paeoniflorin (containing 7% evodia rutaecarpa oil); the experimental group was supplied with OP-10 solution containing 5% paeoniflorin (peoniflorin + nimesulide) (containing 7% evodia rutaecarpa oil). The transdermal experimental method and operation were the same as those in Experimental Example 1.

[0148] 4.3.2 Data processing

[0149] Same as Test Example 1.

[0150] 4.4 Experimental Results and Analysis

[0151] The results are shown in Table 4. Figure 4 As shown. Compared with the control group, the experimental group can significantly increase the cumulative permeation of albiflorin (P<0.001). The above results show that when nimesulide and evodia oil are used together, the effect of promoting the permeation of albiflorin is significantly better than that of evodia oil alone. The reason is that although evodia oil can effectively open the stratum corneum barrier of the skin, it cannot open the active epidermal barrier of the skin, while nimesulide can open the active epidermal barrier. Therefore, the co-use of nimesulide and evodia oil can significantly enhance the transdermal performance of albiflorin.

[0152] Table 4 The results of promoting the penetration of paeoniflorin ( n=5)

[0153]

[0154] Note: Compared with the control group, * P<0.05, ** P<0.01, *** P < 0.001, **** P<0.0001.

[0155] Test Example 5. Evaluation of the effect of the patch of Example 5 and the patch of Example 6 in treating primary dysmenorrhea in mice

[0156] 5.1 Experimental drugs and reagents

[0157] Loxoprofen sodium tablets, total glucosides of white paeony tablets, patch of Example 5, patch of Comparative Example 1, patch of Comparative Example 2, patch of Comparative Example 3, patch of Example 6, patch of Comparative Example 4, patch of Comparative Example 5, patch of Comparative Example 6, estradiol benzoate injection, and oxytocin injection.

[0158] 5.2 Experimental animals

[0159] Female KM mice, 120, weighing 18-22 g.

[0160] 5.3 Grouping and Dosing

[0161] 120 female KM mice, 10 mice in each group, were randomly divided into normal group, model group, loxoprofen sodium group (100 mg / kg), total glucosides of white peony group (100 mg / kg), patch group of Example 5, patch group of Comparative Example 1, patch group of Comparative Example 2, patch group of Comparative Example 3, patch group of Example 6, patch group of Comparative Example 4, patch group of Comparative Example 5, and patch group of Comparative Example 6. After the above groups were adaptively raised for 4 days, the loxoprofen sodium group and the total glucosides of white peony group were given corresponding doses of drugs, and the normal group and the model group were given equal doses of distilled water; 2 corresponding patches were applied to the abdomen of each patch group, and the drug was continuously administered for 7 days (once a day). Starting from the 5th day, except for the normal group mice which were subcutaneously injected with normal saline, the other groups of mice were subcutaneously injected with estradiol benzoate injection (0.3 mg / kg) at the same time every day, and oxytocin (20 U / kg) was injected intraperitoneally 1 hour after the last administration on the 7th day (the corresponding patch of each patch group was not removed after the last administration). The model was successfully established when the mice showed a twisting reaction with abdominal concavity, extension of hind limbs, and lifting of buttocks.

[0162] 5.4 Detection indicators

[0163] Immediately after oxytocin injection, the mice were placed in an incubator, and the number of writhing reactions of the mice within 0-1h, 3-4h, and 6-7h after oxytocin injection was observed and recorded, and the inhibition rate of the writhing reactions of the mice was calculated.

[0164] The inhibition rate of the number of writhing reactions of mice % = (mean number of writhing reactions of mice in the model group - mean number of writhing reactions of mice in each drug-administered group) / mean number of writhing reactions of mice in the model group × 100%

[0165] 5.5 Experimental Results and Conclusions

[0166] (1) The writhing of mice within 0-1h after oxytocin injection is shown in Table 5. Compared with the normal group, the writhing reaction times of mice in the model group were significantly increased (P<0.0001), indicating that the modeling was successful. Compared with the model group, the writhing reaction times of mice in the loxoprofen sodium group, the total glucosides of white peony group, the patch group of Example 5, the patch group of Comparative Example 1, the patch group of Comparative Example 2, the patch group of Example 6, the patch group of Comparative Example 4, and the patch group of Comparative Example 5 were significantly reduced (P<0.0001, P<0.05, P<0.0001, P<0.0001, P<0.05, P<0.0001, P<0.0001, P<0.05), while the writhing reaction times of mice in the patch group of Comparative Example 3 and the patch group of Comparative Example 6 were similar, with no significant difference (P>0.05).

[0167] (2) The writhing of mice within 3-4 hours after oxytocin injection is shown in Table 6. Compared with the normal group, the writhing reaction times of mice in the model group were significantly increased (P<0.0001), indicating that the modeling was successful. Compared with the model group, the writhing reaction times of mice in the total glucosides of white peony group, the patch group of Example 5, the patch group of Comparative Example 1, the patch group of Comparative Example 2, the patch group of Example 6, the patch group of Comparative Example 4, and the patch group of Comparative Example 5 were significantly reduced (P<0.001, P<0.0001, P<0.05, P<0.01, P<0.0001, P<0.05, P<0.01), while the writhing reaction times of mice in the patch group of Comparative Example 3 and the patch group of Comparative Example 6 were similar, with no significant difference (P>0.05).

[0168] (3) The writhing of mice within 6-7 hours after oxytocin injection is shown in Table 7. Compared with the normal group, the writhing reaction times of mice in the model group were significantly increased (P<0.0001), indicating that the modeling was successful. Compared with the model group, the writhing reaction times of mice in the total glucosides of white peony group, the patch group of Example 5, the patch group of Comparative Example 2, the patch group of Example 6, and the patch group of Comparative Example 5 were significantly reduced (P<0.0001, P<0.0001, P<0.05, P<0.0001, P<0.05), while the writhing reaction times of mice in the patch groups of Comparative Example 3 and Comparative Example 6 were similar, with no significant difference (P>0.05).

[0169] The above results show that the patch of Example 5 and the patch of Example 6 can effectively relieve the writhing symptoms of primary dysmenorrhea model mice (the matrix in the patch has no drug effect), and its therapeutic effect is better than the simple use of non-steroidal anti-inflammatory drug control patch, white peony total glucosides control patch or non-steroidal anti-inflammatory drugs, white peony total glucosides gavage. The effect of non-steroidal anti-inflammatory drug control patch or non-steroidal anti-inflammatory drug gavage in relieving the writhing symptoms of dysmenorrhea model mice in the early stage is significant, but the drug effect does not last long, and the effect is soon significantly weakened; although the effect of white peony total glucosides gavage in relieving the writhing symptoms of dysmenorrhea model mice in the later stage of medication is similar to the above two combination patches, but the therapeutic effect in the early stage of medication is obviously not as good as the combination patch; the white peony total glucosides control patch is affected by the active epidermal barrier, and the content that can be permeated through the skin is limited, so it can only exert a weak drug effect, and the efficacy is always limited after medication. The above two composite patches added non-steroidal anti-inflammatory drugs that can reversibly open the active epidermal barrier, which not only greatly increased the transdermal permeation of total glycosides of white paeony, but also made the composite patch have the rapid onset of efficacy of non-steroidal anti-inflammatory drugs. Therefore, the patch of the two composites has the best efficacy and has the advantage of rapidly, continuously and long-term efficacy in treating primary dysmenorrhea in mice.

[0170] Table 5 Statistical table of the number of writhing reactions and the inhibition rate of writhing reactions in each group of mice within 0 to 1 hour ( n=10)

[0171]

[0172] Note: Compared with the model group, * P<0.05, ** P<0.01, *** P < 0.001, **** P<0.0001; compared with the normal group, ### P < 0.001, #### P<0.0001.

[0173] Table 6 Statistical table of the number of writhing reactions and the inhibition rate of writhing reactions in each group of mice within 3 to 4 hours ( n=10)

[0174]

[0175]

[0176] Table notes: Same as table notes in Table 5.

[0177] Table 7 Statistical table of the number of writhing reactions and the inhibition rate of writhing reactions in each group of mice within 5 to 6 hours ( n=10)

[0178]

[0179] Table notes: Same as table notes in Table 5.

[0180] Test Example 6. Evaluation of the effect of the patch of Example 5 and the patch of Example 6 in treating adjuvant arthritis in rats

[0181] 6.1 Experimental drugs and reagents

[0182] Nimesulide tablets, total glucosides of white paeony tablets, patch of Example 5, patch of Comparative Example 1, patch of Comparative Example 2, patch of Comparative Example 3, patch of Example 6, patch of Comparative Example 4, patch of Comparative Example 5, patch of Comparative Example 6, and Freund's complete adjuvant.

[0183] 6.2 Experimental Animals

[0184] 72 male SD rats, weighing 150-180 g.

[0185] 6.3 Grouping, modeling and drug administration

[0186] 72 male rats, 6 rats in each group, were randomly divided into a normal group, a model group, a nimesulide group (150 mg / kg), a total glucosides of white paeony group (150 mg / kg), an Example 5 patch group, a Comparative Example 1 patch group, a Comparative Example 2 patch group, a Comparative Example 3 patch group, an Example 6 patch group, a Comparative Example 4 patch group, a Comparative Example 5 patch group, and a Comparative Example 6 patch group. After one week of adaptive feeding, the rats in the above groups (except the normal group) were intradermally injected with 0.1 mL of complete Freund's adjuvant / each rat into the right hind foot to induce inflammation, and preventive medication was performed on the second day: the normal group and the model group were given equal doses of distilled water; the nimesulide group and the total glucosides of white paeony group were gavaged with corresponding doses of drugs; each patch group applied half a patch on the right hind foot of the rats for 3 consecutive weeks (once a day), and injected with 0.1 mL of complete Freund's adjuvant / each rat again 1 hour after the first medication at the end of the 4th week to stimulate inflammation (the corresponding patch was not removed after the last medication in each patch group).

[0187] 6.4 Detection indicators

[0188] The number of licking of the right hind paw of each group of rats was observed and recorded within 0-0.5h, 3-3.5h and 6-6.5h after inflammation was induced.

[0189] 6.5 Experimental Results and Conclusions

[0190] (1) The results of the number of licking of the right hind paw within 0-0.5h after the rats in each group were stimulated to cause inflammation are shown in Table 8: Compared with the normal group, the number of licking of the rats in the model group was significantly increased (P<0.0001), indicating that the model was successfully established. Compared with the model group, the number of licking of the rats in the nimesulide group, the total glucosides of white paeony group, the patch group of Example 5, the patch group of Comparative Example 1, the patch group of Comparative Example 2, the patch group of Example 6, the patch group of Comparative Example 4, and the patch group of Comparative Example 5 were significantly reduced (P<0.0001, P<0.05, P<0.0001, P<0.0001, P<0.05, P<0.0001, P<0.0001, P<0.05), while the number of licking of the rats in the patch group of Comparative Example 3 and the patch group of Comparative Example 6 was similar to that in the model group, with no significant difference (P>0.05).

[0191] (2) The results of the number of licking of the right hind paw within 3 to 3.5 hours after the rats in each group were stimulated to cause inflammation are shown in Table 8: Compared with the normal group, the number of licking of the rats in the model group was significantly increased (P<0.0001), indicating that the model was successfully established. Compared with the model group, the number of licking of the rats in the total glucosides of white peony group, the patch group of Example 5, the patch group of Comparative Example 1, the patch group of Comparative Example 2, the patch group of Example 6, the patch group of Comparative Example 4, and the patch group of Comparative Example 5 were significantly reduced (P<0.001, P<0.0001, P<0.05, P<0.01, P<0.0001, P<0.05, P<0.01), while the number of licking of the rats in the patch group of Comparative Example 3 and the patch group of Comparative Example 6 was similar to that in the model group, with no significant difference (P>0.05).

[0192] (3) The results of the number of licking of the right hind paw within 6 to 6.5 hours after the rats in each group were stimulated to cause inflammation are shown in Table 8: Compared with the normal group, the number of licking of the rats in the model group was significantly increased (P<0.0001), indicating that the model was successfully established. Compared with the model group, the number of licking of the rats in the total glucosides of white peony group, the patch group of Example 5, the patch group of Comparative Example 2, the patch group of Example 6, and the patch group of Comparative Example 5 was significantly reduced (P<0.0001, P<0.0001, P<0.05, P<0.0001, P<0.05), while the number of licking of the rats in the patch groups of Comparative Example 3 and Comparative Example 6 was similar to that in the model group, with no significant difference (P>0.05).

[0193] The above results show that the patch of Example 5 and the patch of Example 6 can effectively relieve the paw licking symptoms of adjuvant arthritis rats (the matrix in the patch has no medicinal effect), and its therapeutic effect is significantly better than the use of non-steroidal anti-inflammatory drug control patch, white paeony total glucosides control patch or non-steroidal anti-inflammatory drugs, white paeony total glucosides gavage. The effect of the NSAID control patch or the NSAID gavage in relieving the licking symptoms of adjuvant arthritis rats in the early stage is significant, but the duration of the drug effect is not long, and the effect is soon significantly weakened; although the effect of the total glycosides of white peony gavage in relieving the licking symptoms of adjuvant arthritis rats in the later stage of medication is similar to that of the above two combination patches, the therapeutic effect in the early stage of medication is obviously not as good as the combination patch; the total glycosides of white peony control patch is limited in the amount that can be permeated through the skin due to the active epidermal barrier, so it can only play a weak drug effect, and the efficacy is always limited after medication, and the above two combination patches add non-steroidal anti-inflammatory drugs with reversible opening of the active epidermal barrier, which not only greatly increases the percutaneous permeation of the total glycosides of white peony, but also makes the combination patch have the rapid onset of the drug effect of non-steroidal anti-inflammatory drugs. Therefore, the patch of the two combinations has the best efficacy, and has the advantage of quickly, continuously and long-term exerting the efficacy of treating adjuvant arthritis rats.

[0194] Table 8 Statistics of the number of licking feet of rats in each group ( n=6)

[0195]

[0196] Table notes: Same as table notes in Table 5.

[0197] Test Example 7. Evaluation of skin irritation of the patch of Example 5 and the patch of Example 6

[0198] 7.1 Main drugs and reagents

[0199] The patch of Example 5, the patch of Example 6, the patch of Comparative Example 3, the patch of Comparative Example 6, and normal saline.

[0200] 7.2 Experimental Animals

[0201] 20 ordinary New Zealand rabbits, half male and half female, weighing 2-3kg.

[0202] 7.3 Skin irritation test

[0203] 7.3.1 Rabbit hair removal

[0204] 24 hours before the experiment, the rabbits were subjected to abdominal hair removal. Before administration, the skin was observed to see if there was any damage. Irritation experiments should not be performed on damaged skin.

[0205] 7.3.2 Grouping and Dosing

[0206] The 20 New Zealand rabbits were randomly divided into 4 groups, half male and half female, with 5 rabbits in each group. The drugs were administered according to the following groups: (1) the patch of Example 5 was applied on the left side of the skin of the rabbit's abdominal depilatory area; (2) the patch of Comparative Example 3 was applied on the right side of the skin of the rabbit's abdominal depilatory area with the same frequency and the same dose; (3) the patch of Example 6 was applied on the left side of the skin of the rabbit's abdominal depilatory area; (4) the patch of Comparative Example 6 was applied on the right side of the skin of the rabbit's abdominal depilatory area with the same frequency and the same dose. Each rabbit was grouped as above, applied once a day, 3 patches each time, and administered continuously for 7 days. One day after the last administration, the patch was gently and slowly torn off, the drug was washed off with warm water, and the rabbit's skin was observed immediately (0 day), and the erythema and swelling of the rabbit's skin were observed and recorded on the 1st, 3rd, 5th, and 7th days.

[0207] 7.4 Evaluation Metrics

[0208] 7.4.1 Skin irritation evaluation standard

[0209] Skin irritation is evaluated by erythema and edema, and the scoring criteria are as follows:

[0210] (1) Erythema: No erythema was 0 points; barely visible mild erythema was 1 point; clearly visible moderate erythema was 2 points; severe erythema was 3 points; purple-red erythema to mild eschar formation was 4 points.

[0211] (2) Edema: No edema was 0 points; mild edema that was barely visible was 1 point; moderate edema with obvious swelling was 2 points; severe edema with skin swelling of 1 mm and clear contours was 3 points; severe edema with skin swelling of more than 1 mm or with blisters or ulcers was 4 points.

[0212] The highest skin irritation score for each rabbit was erythema + edema totaling 8 points.

[0213] 7.4.2 Evaluation criteria for skin irritation intensity

[0214] The mean value of skin irritation intensity of each group of rabbits = (the total score of skin erythema + edema of each group of rabbits) / the number of rabbits in each group. The irritation intensity scoring standard is as follows:

[0215] A mean value of 0 to 0.49 is considered non-irritating; 0.5 to 2.99 is considered mildly irritating; 3.0 to 5.99 is considered moderately irritating; and 6.0 to 8.00 is considered severely irritating.

[0216] 7.5 Skin irritation test results and analysis

[0217] The results are shown in Tables 9 and 10. The rabbit skin irritation intensity evaluation of the patch of Example 5 and the patch of Example 6 is non-irritating. The above research results show that the patch of Example 5 and the patch of Example 6 are non-irritating to the skin when used externally.

[0218] Table 9 Results of the skin irritation rating of the patch of Example 5 on rabbits (n=5)

[0219]

[0220] Table 10 Results of the skin irritation rating of the patch of Example 6 on rabbits (n=5)

[0221]

Claims

1. A pharmaceutical composition, characterized in that Contains total glucosides of paeony and nonsteroidal anti-inflammatory drugs.

2. The pharmaceutical composition according to claim 1, characterized in that Total glucosides of white paeony and nonsteroidal anti-inflammatory drugs are active ingredients.

3. The composition according to claim 1, characterized in that The total glucosides of white peony are terpene glycosides of white peony, including one or more of paeoniflorin, paeoniflorin lactone glycosides, oxidized paeoniflorin, benzoylpaeoniflorin, galloylpaeoniflorin, or are extracts containing terpene glycosides of white peony extracted from traditional Chinese medicine or plants.

4. The composition according to claim 1, characterized in that The non-steroidal anti-inflammatory drugs include diclofenac, indomethacin, flurbiprofen, flufenamic acid, nabumetone, meloxicam, rofecoxib, celecoxib, mefenamic acid, nimesulide, loxoprofen, etoricoxib and one or more of their pharmaceutically acceptable salts or derivatives.

5. Use of the pharmaceutical composition according to claim 1 in the preparation of drugs for treating primary dysmenorrhea and rheumatoid arthritis.

6. Application of non-steroidal anti-inflammatory drugs in improving the transdermal performance of total glycosides of white paeony.

7. A transdermal preparation, characterized in that: The pharmaceutical composition according to claim 1 is prepared by adding pharmaceutically acceptable excipients.

8. The percutaneous drug administration preparation according to claim 7, characterized in that The pharmaceutically acceptable excipients include chemical penetration enhancers.

9. The percutaneous drug administration preparation according to claim 8, characterized in that The chemical penetration enhancer includes one or more of pepper oil, peppermint oil, galangal oil, mustard oil, 1,8-cineole, evodia rutaecarpa oil, dried ginger oil, and clove oil.

10. The transdermal preparation according to claim 7, wherein the dosage form is selected from the group consisting of patches, emulsions, plasters, ointments, plasters, pastes, film coatings, gels, powder sprays, aerosols, sprays, oils, lotions, glycerines, liniments, suspensions, solutions, sols, tinctures and spirits.

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