WO2014187185A1

WO2014187185A1 - Use of pharmaceutical composition in treating dermatitis and eczema

Info

Publication number: WO2014187185A1
Application number: PCT/CN2014/073135
Authority: WO
Inventors: 施惠娟
Original assignee: Shi Huijuan
Priority date: 2013-05-20
Filing date: 2014-03-10
Publication date: 2014-11-27
Also published as: CN104161763B; CN104161763A

Abstract

Disclosed are a pharmaceutical composition comprising kushenin and glycyrrhizic acid or derivatives thereof and the use of the composition in preparing a drug for preventing and treating dermatitis and eczema, wherein the weight ratio of the kushenin or a derivative thereof to the glycyrrhizic acid or a derivative thereof is 10:1-1:10.

Description

Description of a pharmaceutical composition as a preparation for the treatment of dermatitis and eczema

The invention belongs to the field of medicine and relates to the application of a pharmaceutical composition for preparing and preventing dermatitis and eczema. The pharmaceutical composition comprises a pharmaceutically acceptable form of oxymatrine (oxymatrine, matrine, isomatrine) and glycyrrhizic acid or both, and derivatives thereof, and compositions containing the same The kit further includes a glycyrrhizic acid matrine salt and a glycyrrhizic acid ginseng salt.

Background technique

As we all know, dermatitis and eczema skin diseases are common diseases in dermatology. The etiology and pathogenesis of dermatitis and eczema are not clear. The cause is quite complicated. Most of them are caused by allergies. It is an allergic reaction caused by the interaction of various internal and external factors. However, some dermatitis and eczema are not related to allergies. Changes in patient reactivity often involve a variety of factors, some of which are unclear and yet to be studied in the future. (1) Genetic factors: Some types of eczema are closely related to heredity. Eczema patients often have certain allergies and family history of allergic diseases. It is prone to allergic diseases such as contact dermatitis and drug reaction; (2) Environmental factors; the influence of environmental factors mainly refers to the increasing and complex environmental allergens; (3) Infectious factors: some eczema and microbial infections related. These microorganisms include Staphylococcus aureus, Malassezia, airborne fungi such as Alternaria, Fusarium, Penicillium, Aspergillus fumigatus, Fusarium, Penicillium chrysogenum, Aspergillus niger and Rhizopus oryzae. (4) Dietary factors: There are many kinds of human foods, which can be generally divided into plants, animals, minerals. In modern foods, some chemically synthesized foods such as saccharin, acetic acid, citric acid, and flavors are often used. Synthetic dyeing Materials and so on. These foods can cause allergic reactions in food, which can lead to eczema; (5) Drug factors: Some drugs can cause eczema; (6) Other factors: Eczema can be caused by depression, fatigue, anxiety, nervousness, emotional excitement, Insomnia and other neuropsychiatric factors and climate, physical factors such as sunlight, ultraviolet light, cold, dampness, dryness, friction, etc. induce eczema or make eczema worse. In addition, chronic gastrointestinal diseases, gastrointestinal dysfunction, malnutrition, chronic alcoholism, intestinal parasites, metabolic disorders, endocrine disorders and other factors are the causes of eczema. The external factors of eczema may be various physical and chemical stimuli, such as eczema induced by sun exposure; cold can make the skin dry and chapped; when hot, the skin is sweaty and easy to be impregnated, and itching and scratching. Excessive use of soap, detergent, etc. in life can damage the barrier function of the skin, lose its protective function, and cause certain irritants or sensitizers to enter the body and cause eczema. Eczema is a delayed type of allergic reaction, and mast cells play a key role in the pathogenesis. Degranulation of mast cells causes classical rapid allergic reactions on the one hand, and eosinophils, chemokines, leukotrienes and arachidonic acid-derived organisms released on the other hand, in 4-8 hours. After infiltrating the polymorphonuclear cells in the original degranulated cells, after 24-48 hours, the polymorphonuclear cells were gradually replaced by mononuclear cell infiltration by the inhibitory factor released by them, and with macrophages. The infiltration of cells and fibroblasts together forms a delayed type of allergic reaction, which causes tissue damage to increase the stress of the mucosa, and is easy to respond to specific and non-specific stimuli, resulting in repeated episodes of eczema.

At present, there is no good method for dermatitis and eczema. The common treatment methods are as follows: 1. Basic treatment: (1) Avoid induced and aggravated factors; (2) Restore and maintain skin barrier function. 2, drug treatment with local treatment: (1) glucocorticoids: topical topical external use Glucocorticoids, together with moisturizers, are currently the usual treatments for dermatitis and eczema. Long-term use can cause certain skin adverse reactions (such as skin atrophy, telangiectasia, dilatation, hirsutism, glucocorticoid acne, bacterial infection, purpura, etc.), long-term large-area application can sometimes cause systemic adverse reactions ( Iatrogenic adrenal insufficiency, Cushing's syndrome, psychotic symptoms, glaucoma, cataracts, and menstrual cycle disorders, etc.).

(2) Calcineurin inhibitors: These drugs include tacrolimus ointment and pimecrolimus cream, which have good curative effect on dermatitis and eczema, and have strong selective anti-inflammatory effects, which can be relatively long-term. Use it for all affected areas. The adverse reactions were mainly a short-term cauterization and irritation after administration, and no obvious systemic adverse reactions were found, and no adverse reactions of glucocorticoids were observed. (3) Topical antibiotic preparations: Since bacteria or fungi can induce or aggravate the condition by producing superantigen or as an allergen, when glucocorticoids are used, especially when exudative skin lesions are treated, early antibiotics are added. Bacterial or antifungal drugs can help control the condition, but should be avoided for long-term use. (4) Antipruritic: 5% Doxepin cream or non-steroidal anti-inflammatory drugs can effectively reduce the symptoms of rash in a short period of time, and can be used interchangeably with glucocorticoid preparation or calcineurin inhibitor. (5) Others: Depending on the disease and skin lesions, wet compress, zinc oxide oil (paste), tar, black bean distillate, etc. may be selected. 3, drug treatment with systemic treatment: (1) antihistamines and cell membrane stabilizers: According to different conditions and medications, first- or second-generation antihistamines can be selected. (2) Anti-infective drugs: For patients with severe disease (especially those with exudation) or those who have confirmed secondary bacterial or fungal infections, anti-infective drugs can be given for a short period of time. (3) Glucocorticoids: For patients with severe disease, short-term and medium-dose medications can be given. After the condition is improved, the drug should be gradually reduced and stopped in time to avoid adverse reactions caused by long-term use or to stop the drug too quickly and cause the disease to rebound. (4) Allergen-specific desensitization therapy: It is a main antigenic substance that cannot be avoided and confirmed or suspected by skin test or other methods, and is made into a certain concentration of leachate, and is injected by gradually increasing the dose and concentration, and repeatedly injecting a specific antigen to the patient to promote the body. Produce the corresponding antibody. (5) Immunosuppressive agents: For patients with severe disease and difficult to control conventional therapy, cyclosporine, azathioprine and mycophenolate mofetil may be used as appropriate. (6) anti-leukotriene treatment: can be divided into leukotriene antagonist (LTAA) and leukotriene inhibitor. The sensitization and inflammation of cysteine leukotrienes released by mast cells and eosinophils are inhibited by antagonizing the leukotriene receptor on the cell surface. (7) Others: Tranilast, glycyrrhizic acid and multivitamins can be used for the treatment of dermatitis and eczema. It is helpful to use interferon for dermatitis and eczema treatment, but it is often necessary to maintain medication for a longer period of time. 4, Chinese medicine treatment: According to clinical symptoms and signs, TCM syndrome differentiation and treatment. 5, physical therapy: ultraviolet light, phototherapy. There are many treatments mentioned above, but they all have their limitations and adverse reactions. For example, long-term topical use of glucocorticoids can cause certain skin adverse reactions (such as skin atrophy, telangiectasia, dilatation, hirsutism, glucocorticoid acne, bacteria). Infection, purpura, etc., long-term extensive external or oral systemic adverse reactions (iatrogenic adrenal insufficiency, Cushing's syndrome, psychotic symptoms, glaucoma, cataracts and menstrual cycle disorders, etc.).

Due to the complicated etiology of dermatitis and eczema, although there are many treatment methods, they have their limitations and adverse reactions, and the treatment effect is not very satisfactory.

Matrine is a potent anti-inflammatory drug with hormone-like effects and no hormonal side effects. Studies have shown that it mainly inhibits leukocyte migration, stabilizes lysosomal membranes, promotes free radical scavenging, and inhibits the synthesis of inflammatory mediators such as histamine and lymphokines. Or release and inhibit inflammatory activity; oxymatrine has strong immunomodulatory effects, can be through the host antibody levels, immune cells The effects of changes, cytokines and other inflammatory regulatory factors exert their anti-inflammatory effects; however, effective extracts of matrine or matrine have side effects such as diuretic sodium in the clinic, which may cause patients with excessive urine output to be unsuitable. Glycyrrhizin has anti-inflammatory, anti-allergic, anti-viral, liver-protecting effects, etc., but the steroid-like effect of glycyrrhizic acid, long-term oral administration of active ingredients extract of licorice or glycyrrhizic acid and its derivatives may cause sodium and water retention in patients. Serious adverse reactions such as high blood pressure and hypokalemia.

The present invention provides a novel drug combination which has additive and synergistic effects on dermatitis and eczema and has a lower toxic side effect, and its preparation for the treatment of dermatitis and eczema. Summary of the invention

The inventors have surprisingly found through experiments that a pharmaceutical composition of oxymatrine (oxymatrine, matrine) or a derivative thereof and glycyrrhizic acid or a derivative thereof can provide a particularly beneficial therapeutic effect on dermatitis and eczema without Obvious side effects were observed. This pharmaceutical composition is particularly suitable for the treatment of dermatitis and eczema, including neurodermatitis, eczema (acute, subacute and chronic eczema), atopic dermatitis, seborrheic dermatitis, pruritus, contact dermatitis, urticaria , chronic lichen-like dermatitis, auto-sensitive dermatitis, infectious eczema-like dermatitis, stasis dermatitis, pruritus, nodular pruritus, photoperceptive dermatitis. This pharmaceutical composition can also be combined with existing techniques for treating dermatitis and eczema such as: ultraviolet radiation, red and blue light irradiation, antihistamines and topical ointment applications.

It is an object of the present invention to provide a pharmaceutical composition for treating dermatitis and eczema, the pharmaceutical composition comprising the sequential or simultaneous administration of a pharmaceutically acceptable amount, or a pharmaceutically effective dose of oxymatrine or a derivative thereof and glycyrrhizic acid or a derivative thereof Or a pharmaceutically acceptable form or a pharmaceutically acceptable salt thereof. Also included are the glycyrrhizic acid matrine salt and the glycyrrhizic acid ginseng salt. The weight ratio of oxymatrine or its derivative to glycyrrhizic acid or its derivative in the composition is

10: 1-1: 10, preferably 5: 1-1: 5, more preferably 5: 1-1: 2. The content of oxymatrine or a derivative thereof is 50 to 2000 mg, more preferably 100 to 1500 mg, still more preferably 300 to 1000 mg, and the content of glycyrrhizic acid or a derivative thereof is 30 to 2000 mg, more preferably 30 to 1500 mg, still more preferably 100~1000mg.

Simultaneous administration includes administration of oxymatrine or a derivative thereof and glycyrrhizic acid or a derivative thereof, or administration of a separate preparation of each active agent substantially simultaneously. Sequential administration refers to administration of oxymatrine or a derivative thereof, glycyrrhizic acid or a derivative thereof according to a clinical treatment schedule in chronological order. The scalar amount of oxymatrine or its derivative and glycyrrhizic acid or its derivative given by the present invention is given with respect to the compound itself, for example, 100 mg of the hydrochloride form of oxymatrine means hydrochloric acid containing 50 mg of oxymatrine. The amount of salt.

In the present invention, the active drug is preferably administered in the form of a pharmaceutical composition, and the composition may include a plurality of drugs or only one drug. The pharmaceutical composition can be prepared according to a conventional pharmaceutical preparation by mixing the above content range of oxymatrine or a derivative thereof and glycyrrhizic acid or a derivative thereof in an appropriate amount in a pharmaceutically acceptable form with an acceptable carrier. preparation.

Oxymatrine or a derivative thereof and glycyrrhizic acid or a derivative thereof are administered as pharmaceutically active agents, respectively, in pharmaceutically acceptable forms thereof, including pharmaceutically acceptable salts, esters and solvates. The oxymatrine or a derivative thereof of the present invention comprises oxymatrine, oxymatrine, matrine, isoporcine or a pharmaceutically acceptable salt thereof (including hydrochloride, sulfate, acetate, phosphate, Fumarate and various amino acid salts). Glycyrrhizic acid or a derivative thereof includes glycyrrhizic acid, glycyrrhizin, isoglycyrrhizic acid, isoglycyrrhizinate, glycyrrhizinate, etc., glycyrrhizinate includes glycyrrhizin Usable salts, monoammonium glycyrrhizinate, diammonium glycyrrhizinate, glycyrrhizin, sodium glycyrrhizinate, potassium glycyrrhizinate and calcium glycyrrhizinate. Also included are the glycyrrhizic acid matrine salt and the glycyrrhizic acid ginseng salt.

The pharmaceutical composition may be formulated in a form suitable for oral administration, injection administration, transdermal administration, transmucosal absorption administration or other dosage forms in the form of the above-mentioned mass ratios. The pharmaceutical composition can be prepared into a large or small volume injection, a lyophilized powder, a sterile powder, or the like, or can be a tablet, a capsule, a powder, a dropping pill, a pellet, a granule, a lozenge, In the form of a suppository, oral solution or sterile parenteral solution or suspension, or other dosage forms such as emulsions, ointments and the like. The oral liquid preparation may be in the form of an emulsion, a sugar paddle or the like, or may be present as a dry product, and reconstituted with water or other suitable carrier before use. Excipients include, without limitation, physiologically acceptable pharmaceutically acceptable excipients and pharmaceutically acceptable excipients. The medicinal excipients include one or more of sodium chloride, mannitol, povidone K30, glucose, and lactose, and combinations thereof.

In order to achieve uniformity of administration, the compositions of the invention are preferably in a single dosage form.

For oral administration, it may contain pharmaceutically acceptable excipients such as binders, such as sugar paddle, gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, hypromellose, dextrin. , polyethylene glycol, etc.; fillers, such as lactose, sugar, corn starch, calcium phosphate, sorbitol, glycine, etc.; tableting lubricants, such as magnesium stearate, polyethylene glycol, etc.; disintegrating agents, such as starch , polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; pharmaceutically acceptable wetting agent, such as sodium decyl sulfate; suspension agents, such as sorbitol, sugar paddle, methyl cellulose, gelatin , hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible ester; etc.; emulsifiers, such as lecithin, sorbitan monooleate, gum arabic, etc.; anhydrous carrier (may include Edible oil), such as almond oil, distilled coconut oil, Or oily esters; preservatives such as methylparaben, propyl ester, sorbic acid, etc.; flavoring and sweeteners, such as rebaudioside, aspartame, stevioside, xylitol, menthol, Orange flavor, etc.; coloring agents can also be added. The preparation method employs a preparation method conventional in the art. For parenteral administration, particularly injections, the two active ingredients can be prepared in unit liquid form, respectively, in a sterile vehicle, and are suspended or dissolved in the carrier depending on the concentration employed. In the preparation of the liquid, the active ingredient can be dissolved in water for injection and sterilized by filtration, and then poured into a container and sealed for storage. Advantageously, adjuvants commonly used in injections such as preservatives, buffers, pH adjusters, osmo-regulators, solubilizers, stabilizers, antioxidants and the like may be added for intravenous administration.

Further, the single-flavor active preparation or the pharmaceutical composition in the pharmaceutical composition can be formulated into a sustained-release preparation such as sustained-release pellets or controlled-release pellets according to a conventional method.

The pharmaceutical composition is preferably formulated in unit doses in an amount suitable for the relevant daily dose. It can be administered 1 to 6 times a day, but it is most preferably administered once a day (injection administration) or 3 times (oral administration and external administration).

The sum of the contents of oxymatrine or a derivative thereof and glycyrrhizic acid or a derivative thereof in the composition may be from 0.1% to 99%, preferably from 1% to 60%, based on the total amount of the administration and the requirements of the preparation.

The present invention has proved by a large number of experiments that a pharmaceutical composition of oxymatrine or a derivative thereof and glycyrrhizic acid or a derivative thereof has a particularly remarkable effect for treating dermatitis and eczema, and has a lower toxic side effect. Detailed ways

Hereinafter, the present invention will be specifically described with reference to the examples. The following examples are merely illustrative of the technical solutions of the present invention and are not intended to limit the present invention. Example 1 Comparison of Acute Toxicity of Oxymatrine, Glycyrrhizic Acid and Their Compositions in Kunming Kunming mice were randomly divided into a normal control group and a test drug group, each group consisting of ten, half male and half female. Except the normal control group, the test group was intraperitoneally injected (ip) with a large dose of oxymatrine, glycyrrhizin, and a combination of the two components once for 7 days, and the death time and number of deaths of the animals were recorded. The results showed that when the dose of oxymatrine was 950 mg/kg, it was highly toxic, 9 of 10 mice died, and when the dose of glycyrrhizin was 950 mg/kg, 2 of 10 mice died and oxidized. Sophora flavescens: licorice is 1 : 1 and the combined dose is 950mg/kg and oxymatrine: glycyrrhizin is 2: 1 and the combined dose is 950mg/kg, no animal death, oxymatrine reduction: licorice sweet When the dosage was 3:1 and the combined dose was 950mg/kg, 2 animals died, indicating that the combination of oxymatrine and glycyrrhizin was significantly reduced in toxicity, and oxymatrine and glycyrrhizin were as follows: 1 and 2: 1 ratio is less than 3: 1 ratio. Table 1 Comparison of acute toxicity of oxymatrine, glycyrrhizic acid and their compositions (ip-time) on mice

Remarks: "bitter": indicates oxymatrine; "gan": indicates glycyrrhizin

Example 2 Therapeutic effect of compound glycyrrhizin combined with oxymatrine on generalized eczema

1 Materials and methods

1.1 Clinical data The clinical diagnosis is consistent with patients with generalized eczema, and the clinical diagnosis is in accordance with acute wetness. 40 patients with acute episodes of rash, subacute eczema or chronic eczema, 20 males and 20 females, aged 20-50 years, have not received treatment within one month, no severe visceral diseases such as liver and kidney dysfunction, no activity Tuberculosis, hypertension, diabetes, history of cataract, eradication of pregnancy, lactation women. The patients were randomly divided into four groups: oxymatrine treatment group (group A), compound glycyrrhizin treatment group (group B), oxymatrine combined with compound glycyrrhizin treatment group (group C), and control group (D). Group), 10 cases in each group, half male and half female. There were no significant differences in age, gender, and severity of the four groups (P > 0.05).

1. 2 treatment group A intravenous infusion of oxymatrine injection 0. 6gl00ml / d; group B intravenous infusion of compound glycyrrhizin injection 120mg / d; group C given intravenous infusion of oxymatrine injection 0 6gl00ml/d, compound glycyrrhizin injection 120mg/d; control group given left cetirizine capsule 5mg orally; all four groups were combined with triamcinolone acetonazole cream for external use, all for 2 weeks as a course of treatment The efficacy is judged after the end of the treatment. The symptoms and signs of the patients were observed on the day of the first visit and after two weeks of treatment (including itching, erythema, papules, exudation, erosion, infiltration or lichenification, keratinized desquamation, etc.), and each indicator was pressed at each evaluation. The 4-level scoring method is performed: 0=none, 1=slight, 2=moderate, 3=severe. Score, evaluate efficacy, and observe side effects.

1.3 Efficacy evaluation criteria: The integral value calculation formula is: Integral value = (Total score of the initial diagnosis day - Total of points after 2 weeks of treatment) / Total score of the initial diagnosis day X 100%. Cure: Integral value reduction > 95%; Significant effect: The integral value is reduced by 61%~95%; Better: The integral value is reduced by 20~60%; The integral value is reduced by <20%.

1.4 Safety evaluation Both groups were examined for hematuria and biochemical routines (including liver and kidney function, blood glucose, electrolytes and blood lipids) before and after each treatment, and the treatment period was recorded. Adverse reactions occurred, serious adverse reactions occurred and the observer was judged to be ineffective.

2 results

Table 2 Comparison of four groups of efficacy (%) effective

Number of cases - efficient progress n (%) invalid n (%) P n

Healing n (%) markedly effective n (%) (%)

Group A 10 2(20.0) 5(50.0) 70.0 2(10.0) 1 (0.0)

Group B 10 3(30.0) 4(40.0) 70.0 3(30.0) 0(0.0)

, ' <0.001

Group C 10 6(60.0) 4(40.0) 100.0 0(0.0) 0(0.0)

Group D 10 0(0.0) 2(20.0) 20.0 3(30.0) 5(50.0)

Group A = oxymatrine treatment group; Group B = compound glycyrrhizin treatment group; Group C = oxymatrine combined with compound glycyrrhizin treatment group; Group 0 = control group.

Adverse reactions in group A 2 cases of self-reported urine volume increased; group B in 3 cases of fatigue, mild abdominal distension, 1 case of hypokalemia, 2 cases of mild edema symptoms; group C and group D did not appear adverse reactions; A Both B and B did not affect treatment. There were no obvious abnormalities in the four groups of hematuria before and after treatment. 3 Conclusions Oxymatrine combined with compound glycyrrhizin has a significant effect on the treatment of generalized eczema, with an effective rate of 100% and no adverse reactions. Example 3 Oxymatrine 200mg Diammonium glycyrrhizinate 150mg NaCl 0.9g Water for injection

Take NaCl in 100 ml each, stir and dissolve with water for injection, and then add oxymatrine and ganto, respectively. Diammonium oxalate, completely dissolved when stirring, add water for injection to the total amount, filter to clear, canned, sterilized, that is.

Example 4

Oxymatrine 200g

Glycyrrhizin 150g

Sodium Hydroxymethyl Starch 10g

Lactose 50g

Magnesium stearate 0.5g

Pure water

Made into 1000 pieces

The oxymatrine and glycyrrhizin are pre-pulverized through an 80 mesh sieve, and the lactose is sieved through an 80 mesh sieve for use. The above-mentioned fine powder which has been sieved is weighed according to the above prescription, and uniformly mixed. The mixed powder is placed in a mixer, and pure water is added while stirring, and stirred for 15 minutes to obtain a soft material, granulation, and wet granules 50 to 60. Dry at °C, whole grain, add sodium hydroxymethyl starch, magnesium stearate, mix and compress, then obtain.

Example 5

Oxymatrine 200mg

Diammonium glycyrrhizinate 150mg

Microcrystalline cellulose 27.5mg

Milk candy monohydrate

Magnesium stearate 0.5mg

Production After the above raw materials and auxiliary materials are uniformly mixed, they are granulated according to a conventional wet method, dried, and tableted. Example 6 18β-Glycyrrhizic Acid Matrine Salt

165g of 18β-glycyrrhizic acid and 49.7g of matrine were added to an appropriate amount of anhydrous methanol, and dissolved at room temperature. Stirring was continued for several minutes, then slowly added to vigorously stirred 3000 ml of acetone, and a large amount of white crystalline powder was washed out and filtered. After drying at 0<c>C under vacuum, 172 g of a white crystalline powder was obtained with a yield of 80.1%.

Mp: 204 ° C decomposition

[C] = +24.5 (1% ethanol)

Elemental analysis Determination value (%) Calculated value (%)

C 63.88 63.91

H 8.12 8.09

N 2.70 2.61 Example 7 18β-Glycyrrhizin

Take 18β-glycyrrhizic acid 165g and oxymatrine 106g into an appropriate amount of anhydrous methanol, stir and dissolve at room temperature, continue stirring for a few minutes, slowly add vigorously stirred 3000ml of acetone, wash out a large amount of white crystalline powder, filter, at 60 ° C was vacuum dried to obtain 188 g of a white crystalline powder, yield: 69.4%.

Mp: decomposition at 206 ° C

[C] = +42.4 (1% ethanol)

Elemental analysis Determination value (%) Calculated value (%)

C 63.91 63.98

H 8.31 8.20 N 4.12 4.15 Example 8 18α-Glycyrrhizic acid matrine salt

Take 165g of 18α-glycyrrhizic acid and 49.7g of matrine in an appropriate amount of anhydrous methanol, stir and dissolve at room temperature, continue stirring for a few minutes, slowly add vigorously stirred 3000 ml of acetone, wash out a large amount of white crystalline powder, filter, at 60 Drying under vacuum at °C gave a white crystalline powder (yield: 180 g).

Mp: 208 ° C decomposition

[C] = +23.6 (1% ethanol)

Elemental analysis Determination value (%) Calculated value (%)

C 63.88 63.91

H 8.10 8.09

N 2.59 2.61 Example 9 18α-Glycyrrhizin

165g of 18α-glycyrrhizic acid and 106g of matrine were added to an appropriate amount of anhydrous methanol, and dissolved at room temperature. Stirring was continued for several minutes, and then slowly added to vigorously stirred 3000 ml of acetone to precipitate a large amount of white crystalline powder, which was filtered at 60 ° C. Drying in vacuo gave 190 g of a white crystalline powder, yield 73.1%.

Mp: 210 ° C decomposition

[C] ^D ₂ . =+24.2 (1% ethanol)

Elemental analysis Determination value (%) Calculated value (%)

C 63.79 63.98

H 8.31 8.20 N 4. 19 4. 15 Example 10 Preparation of lyophilized powder of glycyrrhizic acid oxymatrine complex salt

In a 100 ml reaction flask, add 2.00 g (2.33 匪ol) of glycyrrhizic acid, 1.372 g (4.86 匪ol) of oleoresin, add 30 ml of deionized water, stir to dissolve, filter, and freeze the filtrate. 3%。 The lyophilized powder 3. 26g, yield 99. 3%.

Example 11 Preparation of lyophilized powder of glycyrrhizic acid trisporin compound salt

In a 100 ml reaction flask, add 2.00 g (2.33 匪ol) of glycyrrhizic acid, 2. 06 g (7. 29 匪ol) of oleic acid, add 30 ml of deionized water, stir to dissolve, filter, and freeze the filtrate. 8%。 The lyophilized powder 3. 88g, yield 98. 8%.

Example 12 Preparation of a composite salt of glycyrrhizic acid and oxymatrine

In a 100 ml reaction flask, 40 ml of deionized water was added, and at a normal temperature, glycyrrhizic acid (2.0 g (2.33 mmol), oleoresin 0. 686 g (2.33 mmol), dissolved in a water bath at 60 ° C was added. The pump was depressurized (20 mmHg) and concentrated to 10 ml. The acetone was slowly added dropwise with stirring to dissolve the precipitated white oily turbid precipitate. When acetone was added dropwise to 20 ml, the precipitated white oily turbid precipitate no longer dissolved, and the acetone was suspended. Stir to a white oily precipitate and convert to a white solid crystal. It takes about 30 minutes to 1 hour. Continue to add acetone to 60 ml in 30 minutes, stir in a water bath at 50 ° C for 1 hour, then naturally cool to room temperature and stir for 2 hours. , 3%。 The yield was 83.3%. The yield was 83.3%.

Table 3 Elemental analysis results (C ₄₂ H ₆₂ 0 ₁₆ . C ₁₅ H ₂₄ N ₂ 0 ₂ )

C weight content H weight content N weight content

62. 96% 7. 97% 2. 57% Experimental value 62. 43% 7. 88% 2. 48%

Example 13 Preparation of Powder Injection of Compound Salt of Glycyrrhizic Acid and Oxymatrine

In the aseptic batching room, weigh 4g of mannitol into a suitable amount of container, 800ml of water for injection, stir to dissolve it fully, add 50g of compound salt of glycyrrhizic acid and oxymatrine to stir and dissolve, add water for injection to 1000ml, no Under the conditions of bacteria, filter with 0.22μηι microporous membrane and then dispense, the dosage is 10ml per bottle, freeze-dry, add sterilized plug and roll the outer cover.

Example 14 Preparation of a lyophilized powder of a composition

Oxymatrine and glycyrrhizin composition (1~10: 1~10), matrine and glycyrrhizin composition (1~10: 1~10), oxymatrine and glycyrrhizic acid diamine composition (1~10: 1~10), matrine and glycyrrhizic acid diamine composition (1~10: 1~10), glycyrrhizin oxymatrine complex salt, glycyrrhizic acid oxymatrine complex salt, glycyrrhizic acid Oxymatrine complex salt, 18α-glycyrrhizin salt, 18α-glycyrrhizic acid matrine salt, 18β-glycyrrhizic acid matrine salt, 18β-glycyrrhizic acid, at room temperature and pressure, one of the above components is added to the reagent In the bottle, an appropriate amount of deionized water known in the art is added to stir, and after fully dissolving, the dissolved system is concentrated under reduced pressure. Secondly, a water-soluble solvent is added dropwise under stirring to precipitate a white precipitate; finally, at 50 ° C, respectively. Stirring under water bath conditions, crystal transformation and stirring at room temperature to complete crystallization, followed by filtration, washing, vacuum drying at 50 ° C, etc. to obtain white crystals of one of the above components; or an aqueous solution prepared as described above Freeze-dried to obtain a lyophilized powder.

Example 15 Preparation of Injection of Composition

Oxymatrine and glycyrrhizin composition (1~10: 1~10), matrine and licorice sweet Composition (1~10: 1~10), oxymatrine and glycyrrhizic acid diamine composition (1~10: 1~10), matrine and glycyrrhizic acid diamine composition (1~10: 1) ~10), glycyrrhizin oxymatrine complex salt, glycyrrhizic acid oxymatrine complex salt, glycyrrhizic acid trisporin compound salt, 18α-glycyrrhizin saponin salt, 18α-glycyrrhizic acid matrine salt, 18β- Glycyrrhizic acid matrine salt, 18β-glycyrrhizic acid 50g of one of the above ingredients is added to a suitable container, adding about 85% of the total volume of water for injection, stirring and dissolving, measuring the pH value, adjusting the pH with hydrochloric acid solution or sodium hydroxide solution Value is about 6.0~6.5, add 900g, stir to dissolve, add water for injection to 10L, stir evenly and then filter with 0.22μηι microporous membrane, flush nitrogen, potting, autoclave sterilization at 115 °C for 30 minutes, lamp Inspection, inspection, packaging.

Example 16

Oxymatrine 600mg

Glycyrrhizic acid diamine 150mg

NaCl 0.9g

Water for injection

Sodium chloride is stirred and dissolved with water for injection, and then oxymatrine and diamine glycyrrhizinate are separately added, and the stirring is continued to completely dissolve the water for injection to the total amount, filtered to clear, sealed, and sterilized.

Example 17 Tablet Preparation of Composition

Oxymatrine and glycyrrhizin composition (1~10: 1~10), matrine and glycyrrhizin composition (1~10: 1~10), oxymatrine and glycyrrhizic acid diamine composition (1~10: 1~10), Matrine and Glycyrrhizic Acid Diamine Composition (1~10: 1~10), Glycyrrhizin Salt, glycyrrhizic acid oxymatrine complex salt, glycyrrhizic acid oxymatrine complex salt, 18α-glycyrrhizin oxymatrine salt, 18α-glycyrrhizic acid matrine salt, 18β-glycyrrhizic acid matrine salt, 18β- Glycyrrhizinate

One of the above ingredients 50g

Pregelatinized starch 2g

Hydroxypropyl cellulose 4g

Sodium Carboxymethyl Starch 3.5g

Microcrystalline cellulose lg

Magnesium stearate

One of the above ingredients and the above-mentioned auxiliary materials are respectively sieved through an 80 mesh sieve, uniformly mixed, and the povidone is made into a soft material, granulated with a 14-mesh nylon sieve, dried at 50 to 60 ° C, and sieved to a uniform size of 14 mesh, and uniformly mixed. After the tableting is made.

Example 18 Preparation of granules of the composition

Oxymatrine and glycyrrhizin composition (1~10: 1~10), matrine and glycyrrhizin composition (1~10: 1~10), oxymatrine and glycyrrhizic acid diamine composition (1~10: 1~10), matrine and glycyrrhizic acid diamine composition (1~10: 1-10), glycyrrhizin oxymatrine complex salt, glycyrrhizic acid oxymatrine complex salt, glycyrrhizic acid Oxymatrine complex salt, 18α-glycyrrhizin salt, 18α-glycyrrhizic acid matrine salt, 18β-glycyrrhizic acid matrine salt, 18β-glycyrrhizin oxymatrine salt,

One of the above ingredients 50g

Sodium cyclamate 8g

Lactose 8g Si

Dissolve one of the above ingredients in water, add 80g of starch, 20g of sugar powder, add appropriate amount of flavor, mix well, granulate with 14~16 mesh, dry at 60 °C, and package.

Example 19 Capsule Preparation of Composition

Oxymatrine and glycyrrhizin composition (1~10: 1~10), matrine and glycyrrhizin composition (1~10: 1~10), oxymatrine and glycyrrhizic acid diamine composition (1~10: 1~10), glycyrrhizin oxymatrine complex salt, glycyrrhizic acid oxymatrine complex salt, glycyrrhizic acid dysentery compound salt, 18α-glycyrrhizin oxymatrine salt, 18α-glycyrrhizin Alkali salt, 18β-glycyrrhizic acid matrine salt, 18β-glycyrrhizin oxymatrine salt,

One of the above ingredients 50g

Starch 5g

Microcrystalline cellulose 2g

Hard hidden beauty H

One of the above components is separately sieved with each of the above-mentioned excipients, and uniformly mixed, and packaged in a hard capsule, that is, obtained.

Example 20 Oral Liquid Preparation of Composition

Oxymatrine and glycyrrhizin composition (1~10: 1~10), matrine and glycyrrhizin composition (1~10: 1~10), oxymatrine and glycyrrhizic acid diamine composition (1~10: 1~10), matrine and glycyrrhizic acid diamine composition (1~10: 1~10), glycyrrhizin oxymatrine complex salt, glycyrrhizic acid oxymatrine complex salt, glycyrrhizic acid Oxymatrine complex salt, 18α-glycyrrhizin salt, 18α-glycyrrhizic acid matrine salt, 18β-glycyrrhizic acid matrine salt, 18β-glycyrrhizic acid One of the above ingredients 50g

Propylene glycol 5g

Glycerin ig

Gelatin 2g

Sucrose 10g

Sodium benzoate o.ig

Citric acid 0.5g

Fragrance

Pure water 100a

One of the above components and the above-mentioned auxiliary materials are added to pure water, stirred and dissolved, and obtained by dispensing. Example 21 Preparation of sustained release pellets of the composition

Sustained release part of the prescription (pill 1)

Pill core prescription

Oxymatrine 200g

Glycyrrhizin 150g

Microcrystalline cellulose 15g

Hypromellose 5g

Pure water 200ml

Made of 1000 capsules

Coating prescription Made of 1000 tablets.

Microcrystalline cellulose, oxymatrine and glycyrrhizin were pre-pulverized through an 80 mesh sieve, and weighed according to the prescription of the pellet 1 and mixed uniformly. The aqueous solution of hydroxypropylmethylcellulose was used as a binder to prepare pellets. Dry at 50~60°C, 20~30 mesh pellets, spare.

The prepared and selected pellets are placed in a fluidized bed, and are sprayed by hot air suspension using a bottom spray method. The inlet air temperature is 55 ° C, and the bed temperature is controlled at 30 ° C, and the peristaltic pump is adjusted. The coating liquid was supplied at a rate of 5 g of the slurry per minute, and the atomization pressure was 2 bar. The flow of the pellet was continuously sprayed. After the nozzle was finished, the air volume was reduced, and the pellet was dried at 40 ° C for a while under a slight boiling state. After taking out, it was dried in an oven at 40 ° C for 24 hours, and the weight gain was about 18%.

Example 22

Effects of oxymatrine combined with glycyrrhizic acid diamine on serum IL-2 and TNF-α levels in mice with acute dermatitis and eczema.

The aim of this study was to investigate the effects of oxymatrine and glycyrrhizic acid diamine on serum IL-2 and TNF- ct levels in mice with acute dermatitis and eczema, and to explore the mechanism of protecting acute dermatitis and eczema mice. Methods The animal model of acute dermatitis and eczema was replicated by external application of 1% DNFB50ul to stimulate the skin tissue of mice. All mice were evenly coated with l% DNFB10ul on both sides of the right ear and the left ear was coated with an equal amount of 4:1 acetone olive oil. The mixture was administered with different doses of oxymatrine and glycyrrhizic acid diamine. After 5 days of experiment, the thickness of the ears of the mice was measured, the redness of the ears was scored, and the thickness of the ears of the mice was measured by electronic digital calipers. Blood was taken from the eyeball, serum was taken after blood coagulation, and serum was taken to determine the contents of IL-2 and TNF-a. Results Oxymatrine, glycyrrhizin diamine, oxymatrine and glycyrrhizic acid diamine could protect acute dermatitis and eczema in mice, and reduce serum IL-2 and TNF- ct levels in mice. Alkali combined with glycyrrhizic acid diamine compared to oxymatrine, glycyrrhizic acid Diamine has a stronger protective effect on acute dermatitis and eczema in mice. Compared with oxymatrine and glycyrrhizin diamine, the content of IL-2 and TNF- ct in serum is more significant. Conclusion The combination of oxymatrine and glycyrrhizic acid diamine has protective effects on acute dermatitis and eczema in mice, which may improve the inflammatory reaction of skin and decrease the levels of serum IL-2 and TNF-α.

Table 4 Effect of oxymatrine combined with glycyrrhizic acid diamine on serum IL-2 and TNF-α levels in mice with acute eczema

5", _n = 30)

Drug dose

IL-2 (ng/ml) TNF- a (ng/ml)

(mg.kg-1)

Normal pair

NS 10.41±2.11 1.69±0.38 Model NS 31.84±4.35** 2.74±0.49**

Group and object 40 19.64±3.71** ^ΔΔΑΑ 1.79±0.28 ^ΔΔΑ

ΟΜΤ 40 26.56±4.01** ^ΔΔ 1.86±0.32 ^ΔΔ

Glycyrrhizinate

40 25.97 ±6.29** ^ΔΔ 1.95±0.36 ^ΔΔ

Diamine

Compared with the normal control group, *Ρ<0.05, **Ρ<0.01; compared with the model group, ^Δ Ρ<0.05, ^ΔΔ Ρ<0.01; the composition group compared with guanidine and glycyrrhizic acid diamine ^Α Ρ<0.05, ^ΑΑ Ρ<0.01 .

Example 23

Effect of 18β-glycyrrhizic acid matrine on serum IL-2 and TNF-α levels in mice with acute dermatitis and eczema.

The aim was to investigate the effects of 18β-glycyrrhizic acid matrine on serum IL-2 and TNF-a levels in mice with acute dermatitis and eczema, and to explore the mechanism of protecting acute dermatitis and eczema mice. Methods The animal model of acute dermatitis and eczema was replicated by external application of 1% DNFB50ul to stimulate the skin tissue of mice. All mice were evenly coated with l% DNFB10ul on both sides of the right ear and the left ear was coated with an equal amount of 4:1 acetone olive oil. The mixture was administered with different doses of 18β-glycyrrhizic acid matrine. After 5 days of experiment, the thickness of the ears of the mice was measured, the redness of the ears was scored, and the thickness of the ears of the mice was measured by electronic digital calipers. Blood, serum was taken after blood coagulation, and serum was taken to determine the contents of IL-2 and TNF-a. Results 18β-glycyrrhizic acid matrine salts 90, 60 and 30mg.kg-l can be used for acute dermatitis in mice. Eczema has a protective effect and reduces serum IL-2 and TNF-α levels in mice. Conclusion 18β-glycyrrhizic acid matrine has protective effects on acute dermatitis and eczema in mice, which may improve the inflammatory reaction of skin and decrease the levels of serum IL-2 and TNF-a.

Table 5 Effect of 18β-glycyrrhizic acid matrine on serum IL-2 and TNF-a levels in estrogen-cycle vaginal epithelial mitotic mice (± S,

Drug dose

Group o IL-2 (ng/ml) TNF- a (ng/ml)

(mg.kg-l)

Normal pair

NS 10.41±2.11 1.69±0.38 Model NS 31.84±4.35** 2.74±0.49**

Dexame

1 18.97±3.76** ^ΔΔ 2.21 ±0.20**

Pine

Test group 90 19.63±3.71** ^ΔΔ 1.78±0.28 ^ΔΔΑΑ

60 22.54±4.01** ^ΔΔΑ 1.87±0.32 ^ΔΔΑ

30 23.91 ±6.29** ^ΔΔΑ 1.94±0.36 ^ΔΔΑ

Compared with the normal control group, *Ρ<0.05, **Ρ<0.01; compared with the model group, ^Δ Ρ<0.05, ^ΔΔ Ρ<0.01; compared with the dexamethasone group, ^Α Ρ<0.05, ^ΑΑ Ρ<0.01.

Example 24 Antagonistic effect of glycyrrhizic acid and oxymatrine complex salt on oxidative stress in a mouse model of chronic dermatitis and eczemaObjective To investigate the antagonism of glycyrrhizic acid and oxymatrine complex salt on oxidative stress in a mouse model of chronic dermatitis and eczema The mechanism of prevention and treatment of chronic dermatitis and eczema. Methods The mouse model of chronic dermatitis and eczema was replicated by external application of 1% DNFB50ul to stimulate the skin tissue of the abdomen. The mice were treated with different doses of glycyrrhizic acid and oxymatrine compound. After 15 days, the serum of the mice was determined by SOD. , MDA, GSH, T-AOC and NO content, and observed the effect of glycyrrhizic acid and oxymatrine complex salt on chronic dermatitis and eczema in mice. Results Glycyrrhizin and oxymatrine complex salts 80, 40 and 20 mg.kg- ¹ can all protect acute dermatitis and eczema in mice. Glycyrrhizin and oxymatrine complex salt 80mg/kg can increase chronic dermatitis and eczema. Serum serum SOD and T-AOC content (P<0.05, P<0.01), decreased MDA, GSH and NO content (PO.Ol); glycyrrhizic acid oxymatrine combined salt 40mg/kg can reduce serum MDA and NO content in mice with chronic dermatitis and eczema (P<0.05) , P <0.01). Conclusion The combination of glycyrrhizin and oxymatrine complex salt has protective effect on experimental chronic dermatitis and eczema. This effect may be related to lowering serum MDA, GSH and NO content and increasing SOD and T-AOC content.

Table 6 Effect of glycyrrhizic acid and oxymatrine complex salt on serum SOD, MDA, GSH, T-AOC and NO in mice with chronic dermatitis and eczema (± S, n=30) The amount of drug group SOD/U.mL- ¹ MDA/nmol-mL GSH/mg-L T- AOC/U+ml/ ¹ NO/umol-L" ¹ (mg/kg)

284.44 ± 21.71 ± 8.62 82.38 ± 14.45 control group NS 109.28 ± 9.95 4.09 ± 1.63

56.70

412.47 ± 10.32 ± 3.75** 126.48 ± 15.05 * Model group NS 77.76 ± 16.45 ^: .20 ± 2. IT

94.82" dexamethas 389.45 士 13.79±4.51** ^Δ 121.53± 14.87*

1 99.44±13.32: 6.02 ±2.32

Pine Group 93.96"

316.30 + 15.76±4.67** ^ΔΔ 107.65± 10.25* Composition 80 90.63±11.93 ^: 4.52±2.01

68.77 ^ΔΔΑ

374.21 士 11.77±3.08" 110.51 ± 12.53*

40 86.45 ±9.97 5.97±2.34:

78.68"

361.77 士 11.08±2.99" 118.19±6.05**

20 86.23±9.25 ^: 6.85 ±3.16"

70.45 Compared with the normal control group, 'Ρ<0. 05, **Ρ<0. 01; compared with the model group ^Δ Ρ<0. 05,,<0. 01; compared with the ΜΤΧ group ^Α Ρ<0. 05, "Ρ <0. 01. Example 25 Therapeutic effect of magnesium isoglycyrrhizinate combined with oxymatrine on generalized neurodermatitis

1 Materials and methods

1.1 Clinical data The clinical diagnosis is consistent with patients with generalized neurodermatitis. The clinical diagnosis is consistent with 40 patients with generalized neurodermatitis. There are 20 males and 20 females, aged 20-56 years old. They have not received treatment within one month. There are no serious visceral diseases such as liver and kidney dysfunction, no active tuberculosis, hypertension, diabetes, cataract history, and women who are pregnant or lactating. The patients were randomly divided into four groups: oxymatrine treatment group (Α group), magnesium isoglycyrrhizinate treatment group (Β group), oxymatrine combined with magnesium isoglycyrrhizinate treatment group (group C), and control group (group D), each group of ten cases. Both men and women. There were no statistical differences in age, sex, and severity of the four groups (Ρ > 0.05).

1. 2 treatment methods Α group intravenous infusion of oxymatrine glucose injection 0. 6g, 100ml / d; group B intravenous infusion of magnesium isoglycyrrhizinate 150mg / d _; group C given intravenous infusion of oxymatrine glucose injection 0. 6g, 100ml/d, magnesium isoglycyrrhizinate injection 120mg/d; the control group was given 5mg of levocetirizine capsule orally; the four groups were combined with triamcinolone acetonide cream for external use, all for 2 weeks as a course of treatment. After the end, the efficacy was judged. The symptoms and signs of the patients (including itching, erythema, papules, exudation, erosion, infiltration or lichenification, keratinized desquamation, etc.) were observed on the day of the first diagnosis and two weeks after the treatment, and each indicator was pressed at each evaluation. The 4-level scoring method is performed: 0=none, 1=slight, 2=moderate, 3=severe. Score, evaluate efficacy, and observe side effects.

1.3 Efficacy evaluation criteria: The integral value calculation formula is: Integral value = (Total score of the initial diagnosis day - Total points after 2 weeks of treatment) / Total score of the first day of diagnosis is 100%. Cure: Integral value reduction >95%; Significant effect: The integral value is reduced by 61%~95%; Improved: The integral value is reduced by 20~60%; The integral value is reduced by <20%.

1.4 Safety evaluation Both groups were examined for hematuria and biochemical routines (including liver and kidney function, blood glucose, electrolytes and blood lipids) before and after treatment, and the adverse reactions occurred during the treatment were recorded. Serious adverse reactions occurred and the observer was judged. Invalid.

2 results

Table 7 Four groups of effects are more effective

Number of cases - efficient progress n (%) invalid n (%) P n

Healing n (%) markedly effective n (%) (%)

Group A 10 2(20.0) 5(50.0) 70.0 2(10.0) 1 (0.0)

Group B 10 3(30.0) 4(40.0) 70.0 3(30.0) 0(0.0)

, ' <0.001

Group C 10 6(60.0) 4(40.0) 100.0 0(0.0) 0(0.0)

Group D 10 0(0.0) 2(20.0) 20.0 3(30.0) 5(50.0)

Group A = oxymatrine treatment group; 13 groups = magnesium isoglycyrrhizinate treatment group; (group = oxymatrine combined with magnesium isoglycyrrhizinate treatment group; group 0 = control group.

Adverse reactions A group of 2 cases of self-reported urine volume increased; group B 2 cases of fatigue, mild abdominal distension, 1 case of hypokalemia, 2 cases of mild edema symptoms; group C and group D did not appear adverse reactions; A Both B and B did not affect treatment. There were no obvious abnormalities in the four groups of hematuria before and after treatment. 3 Conclusions The effect of oxymatrine combined with magnesium isoglycyrrhizinate on generalized neurodermatitis is significant, with an effective rate of 100% and no adverse reactions. Example 26 Oral administration of oxymatrine and glycyrrhizic acid diamine for the treatment of seborrheic dermatitis 1 data and method 1.1 Clinical data The clinical diagnosis of 8 patients with seborrheic dermatitis, 4 males and 4 females, aged 25 to 46 years, had no treatment within one month, no serious visceral diseases such as liver and kidney dysfunction, no activity Tuberculosis, hypertension, diabetes, history of cataract, eradication of pregnancy, lactation women. Patients were randomly divided into treatment group and control group: 4 cases in each group, half male and half female. There were no significant differences in age, gender, and severity of disease between the two groups (P > 0.05).

1. 2 treatment methods in the treatment group oral combination tablets (oxymatrine 0. 6g + glycyrrhizic acid diamine 1.35 combination / d); control group given oral levocetirizine capsule 5mg, once a day, treatment for 4 weeks After a course of treatment, the effect is judged after the end of the course of treatment. The symptoms and signs of the patients were observed on the day of the first diagnosis and 4 weeks after treatment (including itching, erythema, papules, exudation, erosion, infiltration or lichenification, keratinized desquamation, etc.), and each indicator was pressed at each evaluation. The 4-level scoring method is performed: 0=none, 1=slight, 2=moderate, 3=severe. Score, evaluate efficacy, and observe side effects.

2 results

Table 8 Comparison of four groups of efficacy (%) effective

Number of cases - efficient progress n (%) invalid n (%) P

Π

Healing n (%) markedly effective n (%) (%)

Treatment group 4 1 (50.0) 3(50.0) 100.0 0(00.0) 0(0.0)

, ' <0.001 control group 4 0 (0.0) 1 (25.0) 25.0 1 (25.0) 2 (50.0)

Adverse reactions: No adverse reactions were observed.

3 Conclusions The combination of oxymatrine and glycyrrhizic acid diamine has a significant effect on seborrheic dermatitis, with an effective rate of 100%. No adverse reactions occurred.

Example 27 Oral solution made of oxymatrine and glycyrrhizin for the treatment of stasis dermatitis

1 Materials and methods

1.1 Clinical data The clinical diagnosis of 20 patients with stasis dermatitis, male and female, aged 20 to 55 years, no systemic treatment within one month, no serious visceral diseases such as liver and kidney dysfunction, no active tuberculosis, hypertension Disease, diabetes, cataract history, eradication of pregnancy, lactating women. Patients were randomly divided into treatment group and control group: 4 cases in each group, male and female. There were no significant differences in age, gender, and severity of disease between the two groups (P > 0.05).

1. 2 Therapeutic methods The oral liquid made of oxymatrine and glycyrrhizin in the treatment group (0.6g of oxymatrine and 0.45g of glycyrrhizin) _; 5mg of levocetirizine capsule, once a day, for 4 weeks After a course of treatment, the effect is judged after the end of the course of treatment. The symptoms and signs of the patients were observed on the day of the first visit and after 4 weeks of treatment (including itching, erythema, papules, exudation, erosion, infiltration or lichenification, keratinized desquamation, etc.), and each indicator was pressed at each evaluation. The 4-level scoring method is performed: 0=none, 1=slight, 2=moderate, 3=severe. Score, evaluate efficacy, and observe side effects. 1.3 Efficacy evaluation criteria: The integral value calculation formula is: integral value = (total score of the initial diagnosis day - total of points after 2 weeks of treatment) / total score of the initial diagnosis day X 100%. Cure: Integral value reduction >95%; Significant effect: The integral value is reduced by 61%~95%; Improved: The integral value is reduced by 20~60%; The integral value is reduced by <20%.

2 results

Table 9 Four groups of effects are more effective

Number of cases - efficient progress n (%) invalid n (%) P

Π

Healing n (%) markedly effective n (%) (%)

Treatment group 10 3(30.0) 7(70.0) 100.0 0(00.0) 0(0.0)

, ' <0.001 control group 10 0 (0.0) 3 (30.0) 30.0 2 (20.0) 3 (30.0)

Adverse reactions: No adverse reactions were observed.

3 Conclusion The oral liquid made of oxymatrine and glycyrrhizin has a significant effect on the treatment of dermatitis, with an effective rate of 100%. No adverse reactions have occurred.

Example 28 Capsules made of oxymatrine and glycyrrhizin for treatment of nodular pruritus

1 Materials and methods

1.1 Clinical data The clinical diagnosis of 20 patients with nodular pruritus, male and female, aged 19 to 58 years, no systemic treatment within one month, no serious visceral diseases such as liver and kidney dysfunction, no active tuberculosis, high Blood pressure disease, diabetes, cataract history, eradication of pregnancy, lactating women. Patients were randomly divided into treatment group and control group: 4 cases in each group, male Female half. There were no significant differences in age, gender, and severity of disease between the two groups (P > 0.05).

1. 2 Therapeutic methods The treatment group consists of oxymatrine and glycyrrhizin capsules (oxymatrine 0.6g and glycyrrhizin 0.45g) _; levocetirizine capsule 5mg, once a day, treatment for 4 weeks is a The course of treatment is performed after the end of the course of treatment. The symptoms and signs of the patients were observed on the day of the first visit and after 4 weeks of treatment (including itching, erythema, papules, exudation, erosion, infiltration or lichenification, keratinized desquamation, etc.), and each indicator was pressed at each evaluation. The 4-level scoring method is performed: 0=none, 1=slight, 2=moderate, 3=severe. Score, evaluate efficacy, and observe side effects.

2 results

Table 10 Four groups of effects are more effective

Number of cases - efficient progress n (%) invalid n (%) P

Π

Healing n (%) markedly effective n (%) (%)

Treatment group 10 3(30.0) 7(70.0) 100.0 0(00.0) 0(0.0)

, ' <0.001 control group 10 0 (0.0) 3 (30.0) 30.0 2 (20.0) 3 (30.0)

Adverse reactions: No adverse reactions were observed. 3 Conclusion

Capsules made of oxymatrine and glycyrrhizin have significant effects in treating nodular pruritus, with an effective rate of 100% and no adverse reactions.

Example 29 Combination of oxymatrine and glycyrrhizin for the treatment of progressive pigmentary purpura-like dermatitis

1 Materials and methods

1.1 Clinical data The clinical diagnosis of 10 patients with progressive pigmentary purpura-like dermatitis, male and female, ages 38 to 60 years old, no systemic treatment within one month, no serious visceral diseases such as liver and kidney dysfunction, no Active tuberculosis, hypertension, diabetes, cataract history.

1. 2 treatment method intravenous infusion of oxymatrine injection 0. 6gl00ml / d and compound glycyrrhizin injection 60mg / d, treatment for 4 weeks for a course of treatment, after the end of the course of treatment to determine the effect. The symptoms and signs of the patients were observed on the day of the first diagnosis and after 4 weeks of treatment (including itching, erythema, papules, exudation, erosion, infiltration or lichenification, keratinized desquamation, etc.), and each indicator was pressed at each evaluation. The 4-level scoring method is performed: 0=none, 1=slight, 2=moderate, 3=severe. Score, evaluate efficacy, and observe side effects.

1.4 Safety evaluation Both groups were examined for hematuria and biochemical routines (including liver and kidney function, blood glucose, electrolytes and blood lipids) before and after treatment, and recorded during treatment. Adverse reactions, serious adverse reactions, withdrawal from the observer was judged to be invalid.

2 results

Table 11 Comparison of four groups of efficacy (%) effective

Number of cases - efficient progress n (%) invalid n (%)

Π

Healing n (%) markedly effective n (%) (%)

Treatment group 10 8 (100.0) 2 (00.0) 100.0 0 (00.0) 0 (0.0) Adverse reactions: No adverse reactions were observed.

3. Conclusion

With an effective rate of 100%, no adverse reactions occurred.

Claims

Claim

A pharmaceutical composition comprising a sequential or simultaneous administration of a pharmaceutically acceptable form of a derivative of oxymatrine and glycyrrhizic acid or both.

2. The pharmaceutical composition according to claim 1, wherein the weight ratio of the combined species oxymatrine or a derivative thereof to glycyrrhizic acid or a derivative thereof is 10:1 to 1:10.

The pharmaceutical composition according to any one of claims 1 to 2, wherein the weight ratio of the combination species oxymatrine or a derivative thereof to glycyrrhizic acid or a derivative thereof is 5:1 to 1:5.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the weight ratio of the combination species oxymatrine or a derivative thereof to glycyrrhizic acid or a derivative thereof is 5:1 to 1:2.

The pharmaceutical composition according to any one of claims 1 to 4, wherein the content of oxymatrine or a derivative thereof is 50 to 2000 mg, and the content of glycyrrhizic acid or a derivative thereof is 30 to 2000 mg.

The pharmaceutical composition according to any one of claims 1 to 5, wherein the oxymatrine or a derivative thereof is contained in an amount of from 100 to 1,500 mg, and the glycyrrhizic acid or a derivative thereof is used in an amount of from 30 to 1,500 mg per day.

The pharmaceutical composition according to any one of claims 1 to 6, wherein the content of oxymatrine or a derivative thereof is 300 to 1000 mg, and the content of glycyrrhizic acid or a derivative thereof is 100 to 1000 mg.

The pharmaceutical composition according to any one of claims 1 to 7, wherein the oxymatrine or a derivative thereof is oxymatrine, matrine or a derivative thereof, and isoflavone. In particular, pharmaceutically acceptable salts include hydrochlorides, sulfates, acetates, phosphates, fumarates, and various amino acid salts and the like.

The pharmaceutical composition according to any one of claims 1 to 7, wherein the glycyrrhizic acid or a derivative thereof is glycyrrhizin or a pharmaceutically acceptable salt, ester or solvate thereof.

The pharmaceutical composition according to claim 9, wherein the glycyrrhizic acid or a derivative thereof comprises licorice Acid, glycyrrhizin, isoglycyrrhizic acid, isoglycyrrhizinate, glycyrrhizinate, glycyrrhizinate including glycyrrhizin available medicinal salt, glycyrrhizin, monoammonium glycyrrhizinate, diammonium glycyrrhizinate, sodium glycyrrhizinate, licorice Potassium acid salt and calcium glycyrrhizinate.

The pharmaceutical composition according to any one of claims 1 to 10, which further comprises a glycyrrhizic acid matrine salt and a ginseng glycyrrhizin salt.

The pharmaceutical composition according to any one of claims 1 to 11, wherein the pharmaceutical composition and the form are an injection, a powder injection, a tablet, a sustained release agent, a dropping pill, a granule, a capsule, a sustained release pellet, Nanotechnology for oral liquids, topical creams and emulsions or formulations thereof.

Use of the pharmaceutical composition according to any one of claims 1 to 12 for the preparation of dermatitis and eczema.

The use according to claim 13, wherein the dermatitis eczema comprises neurodermatitis, eczema (acute, subacute and chronic eczema), atopic dermatitis, seborrheic dermatitis, pruritus, contact dermatitis, urticaria , chronic lichen-like dermatitis, auto-sensitive dermatitis, infectious eczema-like dermatitis, stasis dermatitis, pruritus, nodular pruritus, photoperceptive dermatitis.

The use according to claims 1 to 14 can be combined with existing techniques for treating dermatitis and eczema such as ultraviolet irradiation, red-blue irradiation, antihistamines and topical ointment applications.