CN105267228A - Application of pharmaceutical compositions in preparation of drugs for treating neuropsychic disturbance dermatosis - Google Patents
Application of pharmaceutical compositions in preparation of drugs for treating neuropsychic disturbance dermatosis Download PDFInfo
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- CN105267228A CN105267228A CN201410343670.3A CN201410343670A CN105267228A CN 105267228 A CN105267228 A CN 105267228A CN 201410343670 A CN201410343670 A CN 201410343670A CN 105267228 A CN105267228 A CN 105267228A
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Abstract
The invention relates to kushenin (oxymatrine, matrine and isomatrine) and glycyrrhizic acid or their pharmaceutically acceptable forms or derivatives and a kit containing the compositions, and also relates to matrine glycyrrhizate and kushenin glycyrrhizate. The invention discloses an application of the compositions in preparation of drugs for preventing and treating neuropsychic disturbance dermatosis (pruritus, lichen simplex chronicus, prurigo, nodular prurigo, prurigo pigmentosa and lichenoid dermatitis).
Description
Technical field
The invention belongs to field of medicaments, relate to a kind of pharmaceutical composition for the preparation of the application in prevention and therapy neuropsychiatric disorders dermatoses.Described pharmaceutical composition contains kurarinone (oxymatrine, matrine, Iosmatrine) and glycyrrhizic acid or the pharmaceutically acceptable form both it or the derivant both it and the medicine box containing these compositionss, comprises glycyrrhizic acid matrine salt and glycyrrhizic acid kurarinone salt in addition.
Background technology
The skin dermatosis kind relevant with neuropsychiatric is a lot, its not yet unification so far of classifying.Neuropsychiatric disorders dermatoses of the present invention is mainly common relevant disease, comprises pruritus, lichen chronicus simplex, prurigo, prurigo nodularis, pigmentosa prurigo and lichenoid dermatitis.The dermatosis clinically without primary cutaneous infringement based on pruritus of pruritus.Pruritus is divided into following a few class by Twycross etc.: skin source property pruritus, neuropathic itch, neurogenic pruritus, heart source property pruritus, Combination pruritus.The receptor of mediation pruritus is positioned at dermal papilla and epidermis without on the favourable nerve ending of marrow fiber C.These sensors specific bond can cause the factor of itching, and after being caused factor stimulation of itching, impulsion is reached the cornu dorsale of spinal cord by a species specific fiber C, then by the flaggy core of the thalamus of spinothalamic tract, finally arrives cerebral cortex, causes pruritus.Lichen chronicus simplex has another name called neurodermatitis, is sick with the chronic inflammatory skin that paroxysmal play is itched and skin lichenification is feature.Its cause of disease and pathogenesis it be unclear that, and it is generally acknowledged that and inhibit feature excited with cerebral cortex is lacked of proper care relevant.Prurigo is one group of acute or chronic inflammatory skin is sick general name.Its major determinant is welt sample pimple, tuberosity and Secondary cases skin lesion, very itches unbearably.The cause of disease there is no final conclusion.Most scholar thinks relevant with allergy.Prurigo nodularis is the infringement of excipuliform nodositas.The cause of disease and pathogenesis are not yet illustrated.Some patients sees the sequela that mosquito, Cimex bedbug or other insects bite, and also may have certain relation with gastrointestinal dysfunction and dyshormonia.
This kind of disease mainly comprises hormone in treatment, antihistaminic, immunosuppressant, calming soporific class medicine are interior or topical, can apply the medicines such as procaine hydrochloride vein is closed, Thalidomide in addition.Also can Applied Physics therapy as cold therapy, chemotherapy, phototherapy, photodynamic therapy and x-ray radiotherapy etc.But this type of disease often to treatment opposing, is easy to recurrence and increases the weight of.
Kurarinone has direct antiinflammatory action, immunoregulation effect, Tumor suppression propagation, differentiation-inducing and apoptotic effect, anti-virus sterilizing effect, anti-hypoxia, expansion blood vessel, blood fat reducing, arrhythmia, calmness, antipyretic, lower the temperature, improve hemorheological indexes effect.For the etiology and pathogenesis of the diseases related morbidity of cutaneous lymphoid hyperplasia, central nervous system, oxymatrine have calmness, analgesia, antipyretic, cooling effect, can suppress to cause itch the factor stimulate after, neural impulse reaches cerebral cortex, causes pruritus; Oxymatrine, matrine have hormone-like effect and without the powerful anti-inflammatory agent of hormone side effect; Have stronger immunoregulation effect, the impact by the change of the antibody horizontal on host, immunocyte, cytokine and other inflammatory mediators plays its antiinflammatory action; Kurarinone has anti-allergy action, can suppress the generation that metamorphosis reacts.But there is the side effect such as diuresis row sodium, the unsuitable life-time service of the patient causing urine volume too much clinical in the effective extract of Radix Sophorae Flavescentis or matrine.The effect such as glycyrrhizic acid has antiinflammatory, antiallergic action, antiviral, protect the liver, for the etiology and pathogenesis of neuropsychiatric disorders dermatoses morbidity, the steroid sample effect of glycyrrhizic acid has remarkable effect to the anti-inflammatory effect of neuropsychiatric disorders dermatoses and antiallergic action.But the steroid sample effect of glycyrrhizic acid, the effective component extracts of long-term a large amount of oral Radix Glycyrrhizae or glycyrrhizic acid and derivant thereof can make patient there is the serious adverse reactions such as water-sodium retention, hypertension and hypokalemia.
The present invention by experiment, provides to have for neuropsychiatric disorders dermatoses and adds with synergism and the lower brand-new drug regimen of toxic and side effects, and for the preparation of the application in treatment neuropsychiatric disorders dermatoses.
Summary of the invention
This invention people be surprised to find by experiment, the pharmaceutical composition of kurarinone (oxymatrine, matrine) or derivatives thereof and glycyrrhizic acid or derivatives thereof can provide treatment neuropsychiatric disorders dermatoses effect useful especially, and does not observe obvious side effect.And this pharmaceutical composition is particularly suitable for the treatment for the treatment of neuropsychiatric disorders dermatoses (comprising pruritus, lichen chronicus simplex, prurigo, prurigo nodularis, pigmentosa prurigo and lichenoid dermatitis).This medicine technology that also can combine existing treatment neuropsychiatric disorders dermatoses is as hormone, antihistaminic, chemotherapy, immunization therapy, biological response modifier, naturopathy, radiotherapy, phototherapy, photochemotherapy and optical dynamic therapy.
The object of this invention is to provide a kind of pharmaceutical composition for the treatment of neuropsychiatric disorders dermatoses, belonging to pharmaceutical composition comprise order and give or give simultaneously pharmaceutically acceptable amount, or medicine effective dose kurarinone or derivatives thereof and glycyrrhizic acid or derivatives thereof, especially pharmaceutical acceptable form or its pharmaceutical salts.Also comprise glycyrrhizic acid matrine salt and glycyrrhizic acid kurarinone salt.
In compositions, the weight proportion of kurarinone or derivatives thereof and glycyrrhizic acid or derivatives thereof is 10:1 ~ 1:10, preferably 5:1 ~ 1:5, more preferably 5:1 ~ 1:2.Wherein kurarinone or derivatives thereof content is 50 ~ 2000mg, more preferably 100 ~ 1500mg, is more preferably 300 ~ 1000mg; Glycyrrhizic acid or derivatives thereof content is 30 ~ 2000mg, more preferably 30 ~ 1500mg, is more preferably 100 ~ 1000mg.
Simultaneously administration comprises and gives kurarinone or derivatives thereof and glycyrrhizic acid or derivatives thereof, or by the administration simultaneously substantially of the independent preparation of often kind of activating agent.Order refers to and in chronological sequence gives kurarinone or derivatives thereof, glycyrrhizic acid or derivatives thereof according to clinical treatment.The kurarinone or derivatives thereof that the present invention provides and glycyrrhizic acid or derivatives thereof medicine scalar, provide about compound itself, the such as kurarinone of 100mg hydrochloride form refers to the hydrochlorate amount containing 50mg kurarinone.
In the present invention, active medicine preferred with the form administration of pharmaceutical composition, this compositions can comprise multi-medicament or only a kind of medicine.Described pharmaceutical composition can by by the kurarinone or derivatives thereof of above-mentioned content range and glycyrrhizic acid or derivatives thereof after appropriate pharmaceutically acceptable form mixes with acceptable carrier, prepared by the preparation method of pharmaceutical preparation conveniently.
Kurarinone or derivatives thereof and glycyrrhizic acid or derivatives thereof (comprise pharmaceutically acceptable salt, ester and solvate) as pharmaceutically active agents administration in the form of pharmaceutical acceptable respectively.Kurarinone or derivatives thereof of the present invention comprises kurarinone, oxymatrine, matrine, Iosmatrine or its officinal salt (comprising hydrochlorate, sulfate, acetate, phosphate, fumarate and various amino acid salts).Glycyrrhizic acid or derivatives thereof comprises glycyrrhizic acid, glycyrrhizin, Isoglycyrrhiza acid, Isoglycyrrhiza acid salt, glycyrrhetate etc., and glycyrrhetate comprises glycyrrhizin can medication salt, monoammonium glycyrrhizinate, diammonium glycyrrhizinate, glycyrrhizic glycoside, sodium glycyrrhetate, potassium glycyrrhizana and glycyrrhizic acid calcium salt etc.Also comprise glycyrrhizic acid matrine salt and glycyrrhizic acid kurarinone salt.
Described pharmaceutical composition can be added corresponding adjuvant by described quality proportioning, make applicable oral administration, dosage form that drug administration by injection, percutaneous dosing, through mucous membrane absorb administration or other dosage forms.Described pharmaceutical composition can be prepared into the dosage form such as injection, freeze-dried powder, aseptic powder subpackage that is large or low capacity, also can be that tablet, capsule, powder, drop pill, micropill, granule, lozenge, suppository, oral liquid or sterile parenteral solutions or suspension formulation form or other dosage forms are as Emulsion, unguentum etc.Oral liquid can be the form such as Emulsion, syrup, also can exist as dry products, reconstitutes before using with water or other suitable carriers again.Adjuvant comprises (being not limited to) physiologically acceptable pharmaceutical excipient and pharmaceutic adjuvant.Wherein pharmaceutic adjuvant comprises one or more in sodium chloride, mannitol, PVP K30, glucose, lactose and combines.
In order to reach the concordance of administration, the present composition is preferably unit dose form.
For oral administration, can containing pharmaceutically conventional excipient as binding agent, such as syrup, arabic gum, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, hypromellose, dextrin, Polyethylene Glycol etc.; Filler, such as lactose, sugar, corn starch, calcium phosphate, sorbitol, glycine etc.; Tableting lubricant, such as magnesium stearate, Polyethylene Glycol etc.; Disintegrating agent, such as starch, polyvinylpyrrolidone, Explotab or microcrystalline Cellulose; Pharmaceutically acceptable wetting agent, as sodium lauryl sulphate etc.; Suspending agent, such as sorbitol, syrup, methylcellulose, gelatin, hydroxyethyl-cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenation eat ester etc.; Emulsifying agent, such as lecithin, anhydro sorbitol-oleate, arabic gum etc.; Anhydrous carrier (can edible oil be comprised), such as almond oil, heating up in a steamer Oleum Cocois or oily ester; Antiseptic, such as methyl parahydroxybenzoate, propyl ester, sorbic acid etc.; Correctives and sweeting agent, as stevioside, aspartame, steviosin, xylitol, menthol, flavoring orange essence etc.; Also coloring agent etc. can be added.Preparation method adopts the preparation method of this area routine.
For parenteral, particularly injection, can utilize two kinds of active components to prepare unit liquid dosage form respectively at sterile carrier, and suspended according to concentration used or be dissolved in carrier.When preparing liquid, by solubilize active ingredients in water for injection and filtration sterilization, sealing in container can be filled into afterwards and preserve.Advantageously, in order to applicable intravenous injection can add injection conventional adjuvant such as antiseptic, buffer agent, acidity-basicity regulator, Osmolyte regulator, solubilizing agent, stabilizing agent, antioxidant etc.
Also conventionally the single active ingredient in pharmaceutical composition or pharmaceutical composition can be made sustained-release preparation, as slow-release micro-pill or controlled release micro pill in addition.
Described pharmaceutical composition preferably makes unit dose with the amount suitable to relevant daily dose.Can administration every day 1 ~ 6 time, but most preferably administration every day 1 time (drug administration by injection) or 3 times (oral administration and topical administration).
According to the difference of administering mode and formulation requirements, in said composition, kurarinone or derivatives thereof and glycyrrhizic acid or derivatives thereof content sum can be 0.1% ~ 99% of total amounts, are preferably 1% ~ 60%.
The present invention is by experimental results demonstrate, the medicine composite for curing neuropsychiatric disorders dermatoses of kurarinone or derivatives thereof and glycyrrhizic acid or derivatives thereof has significant especially effect, and toxic and side effects is lower.
Detailed description of the invention
We illustrate the present invention in conjunction with the embodiments below.Following examples only for illustration of technical scheme of the present invention, are not intended to limit the present invention.
embodiment 1
oxymatrine, glycyrrhizic acid and compositions thereof are to the comparison of Mouse Acute Toxicity effect
Kunming mice is divided into Normal group and test medicine group at random, often organizes ten, male and female half and half.Except Normal group, once, Continuous Observation 7 days, records death time and the death toll of animal to the compositions of test medicine group difference lumbar injection (ip) heavy dose of oxymatrine, glycyrrhizin and two kinds of components.
Result shows, when the dosage of oxymatrine is 950mg/kg, there is larger toxicity, 9 death in 10 mices, when glycyrrhizin dosage is 950mg/kg, 2 death in 10 mices, and Oxymatrine subtracts: glycyrrhizin is 1:1 and share dosage is 950mg/kg and kurarinone: glycyrrhizin is 2:1 and share dosage when being 950mg/kg, without animal dead, Oxymatrine subtracts: glycyrrhizin is 3:1 and share dosage when being 950mg/kg, 2 animal deads, illustrate that oxymatrine and glycyrrhizin carry out proportioning combination, its toxicity obviously reduces, and oxymatrine, glycyrrhizin is less than 3:1 proportioning by its toxicity of 1:1 and 2:1 proportioning.
Table 1 oxymatrine, glycyrrhizic acid and compositions (ip once) comparison to Mouse Acute Toxicity effect thereof
| Group | Dosage (mg/kg) | Death toll/sum |
| Normal group | 0 | 0/10 |
| Bitter | 950 | 9/10 |
| Sweet | 950 | 2/10 |
| Bitter+sweet (1:1) | 950 | 0/10 |
| Bitter+sweet (2:1) | 950 | 0/10 |
| Bitter+sweet (3:1) | 950 | 2/10 |
Remarks: " hardship ": represent oxymatrine; " sweet ": represent glycyrrhizin
embodiment 2
the observation of curative effect of SNMC co-oxidation Sophorcarpidine Treating lichen chronicus simplex
1 data and method
1.1 clinical data clinical diagnosises meet the 40 routine patients of general property lichen chronicus simplex, man 20 example, female 20 example, 23 ~ 55 years old age, treatment was not accepted in January, without serious viscera diseases such as hepatic and renal function injure, without active tuberculosis, hypertension, diabetes, cataract medical history, reject trimester of pregnancy, women breast-feeding their children.Patient is divided into four groups at random: Oxymatrine Treating group (A group), SNMC in Treatment group (B group), oxymatrine associating SNMC in Treatment group (C group), matched group (D group), often organize ten examples, men and women half and half.Four groups of equal no difference of science of statistics (P ﹥ 0.05) on age, sex, coincident with severity degree of condition.
1.2 Therapeutic Method A group intravenous drip Oxymatrine Injection 0.6g100ml/d; B group intravenous drip Compound Glycyrrhizin Injection Concomitant 120mg/d; C group gives intravenous drip Oxymatrine Injection 0.6g100ml/d, Compound Glycyrrhizin Injection Concomitant 120mg/d; It is oral that matched group awards levocetirizine capsule 5mg; Four groups coordinate the externals of triamcinolone acetonide benefit bran azoles emulsifiable paste all simultaneously, are all a course for the treatment of with 4 weeks, carry out efficacy determination after terminating after the course for the treatment of.Respectively at after first visit same day and treatment surrounding, (comprise pruritus, erythema, pimple, ooze out, rotten to the corn, infiltrate or lichenization, keratinization desquamation etc.) was observed to patients symptomatic and sign, each index is all undertaken by 4 grades of point systems when each assessment: 0=without, 1=is slight, 2=moderate, 3=severe.Make scoring, Estimating curative effect, and observe side effect.
1.3 the standard of curative effect evaluations: integrated value computing formula is: integrated value=(first visit day integration add up to ﹣ treat the integration after 2 weeks add up to)/first visit day integration add up to × 100%.Cure: integrated value reduces > 95%; Effective: integrated value reduces 61% ~ 95%; Take a turn for the better: integrated value reduces 20 ~ 60%; Integrated value reduces < 20%.
1.4 safety evaluatios two groups all with treatment before, each course for the treatment of terminates rear inspection hematuria conventional, biochemical conventional (comprising hepatic and renal function, blood glucose, electrolyte and blood fat), and record treatments period occur untoward reaction, occur serious adverse reaction exit observer be judged to invalid.
2 results
Table 2 four groups of comparitive study examples (%)
A group=Oxymatrine Treating group; B group=SNMC in Treatment group; C group=oxymatrine associating SNMC in Treatment group; D group=matched group.
3. the routine readme urine volume of untoward reaction A group 2 increases, and 1 routine times of defecation is by being increased to every day 2 times once a day; B group 3 example occurs weak, slight abdominal distention, and hypokalemia appears in 1 example, and Mild edema symptom appears in 2 examples; All there is not untoward reaction in C group and D group; A, B two groups does not all affect treatment.Before and after treatment, four groups of hematuria routines are showed no obvious exception.
3. conclusion
Oxymatrine associating SNMC in Treatment lichen chronicus simplex Be very effective, effective percentage reaches 100%, and untoward reaction does not occur.
embodiment 3
the clinical observation of SNMC co-oxidation Sophorcarpidine Treating prurigo nodularis
1 data and method
1.1 clinical data clinical diagnosises meet 40 routine patients of prurigo nodularis, man 20 example, female 20 example, 35 ~ 51 years old age, treatment was not accepted in January, without serious viscera diseases such as hepatic and renal function injure, without active tuberculosis, hypertension, diabetes, cataract medical history, reject trimester of pregnancy, women breast-feeding their children.Patient is divided into four groups at random: Oxymatrine Treating group (A group), SNMC in Treatment group (B group), oxymatrine associating SNMC in Treatment group (C group), matched group (D group), often organize ten examples, men and women half and half.Four groups of equal no difference of science of statistics (P ﹥ 0.05) on age, sex, coincident with severity degree of condition.
1.2 Therapeutic Method A group intravenous drip Oxymatrine Injection 0.6g100ml/d; B group intravenous drip Compound Glycyrrhizin Injection Concomitant 120mg/d; C group gives intravenous drip Oxymatrine Injection 0.6g100ml/d, Compound Glycyrrhizin Injection Concomitant 120mg/d; It is oral that matched group awards levocetirizine capsule 5mg; Four groups coordinate the externals of triamcinolone acetonide benefit bran azoles emulsifiable paste all simultaneously, are all a course for the treatment of with 4 weeks, carry out efficacy determination after terminating after the course for the treatment of.Respectively at after first visit same day and treatment surrounding, (comprise pruritus, erythema, pimple, ooze out, rotten to the corn, infiltrate or lichenization, keratinization desquamation etc.) was observed to patients symptomatic and sign, each index is all undertaken by 4 grades of point systems when each assessment: 0=without, 1=is slight, 2=moderate, 3=severe.Make scoring, Estimating curative effect, and observe side effect.
1.3 the standard of curative effect evaluations: integrated value computing formula is: integrated value=(first visit day integration add up to ﹣ treat the integration after 2 weeks add up to)/first visit day integration add up to × 100%.Cure: integrated value reduces > 95%; Effective: integrated value reduces 61% ~ 95%; Take a turn for the better: integrated value reduces 20 ~ 60%; Integrated value reduces < 20%.
1.4 safety evaluatios two groups all with treatment before, each course for the treatment of terminates rear inspection hematuria conventional, biochemical conventional (comprising hepatic and renal function, blood glucose, electrolyte and blood fat), and record treatments period occur untoward reaction, occur serious adverse reaction exit observer be judged to invalid.
2 results
Table 2 four groups of comparitive study examples (%)
A group=Oxymatrine Treating group; B group=SNMC in Treatment group; C group=oxymatrine associating SNMC in Treatment group; D group=matched group.
3. the routine readme urine volume of untoward reaction A group 3 increases; B group 3 example occurs weak, slight abdominal distention, and hypokalemia appears in 1 example, and Mild edema symptom appears in 2 examples; All there is not untoward reaction in C group and D group; A, B two groups does not all affect treatment.Before and after treatment, four groups of hematuria routines are showed no obvious exception.
3. conclusion
Oxymatrine associating SNMC in Treatment lichen chronicus simplex Be very effective, effective percentage reaches 100%, and untoward reaction does not occur.
embodiment 4
Oxymatrine 200mg
Diammonium glycyrrhizinate 150mg
NaCl0.9g
water for injection is appropriate
Often prop up 100ml
Get NaCl, use water for injection stirring and dissolving, then add oxymatrine, diammonium glycyrrhizinate respectively, continue to dissolve completely when stirring, add and inject water to total amount, filter to clear and bright, potting, sterilizing, to obtain final product.
embodiment 5
Oxymatrine 200g
Glycyrrhizin 150g
Sodium Hydroxymethyl Stalcs 10g
Lactose 50g
Magnesium stearate 0.5g
pure water is appropriate
Make 1000
By oxymatrine, glycyrrhizin, pulverized 80 mesh sieves in advance, and got lactose and cross 80 mesh sieves, for subsequent use.Get the above-mentioned fine powder sieved to take by above-mentioned prescription, mix homogeneously, puts into mixer by the powder of mixing, adds pure water while stirring, stir and make soft material, granulation in 15 minutes, wet grain 50 ~ 60 DEG C of dryings, granulate, adds Sodium Hydroxymethyl Stalcs, magnesium stearate, mixing, tabletting, to obtain final product.
embodiment 6
Oxymatrine 200mg
Diammonium glycyrrhizinate 150mg
Microcrystalline Cellulose 27.5mg
Lactose fruit-hydrate is appropriate
magnesium stearate 0.5mg
Film-making
After above-mentioned raw materials, adjuvant mix homogeneously, conveniently wet granulation, dry, tabletting.
embodiment 7
Oxymatrine 200mg
Diammonium glycyrrhizinate 150mg
Microcrystalline Cellulose 27.5mg
Lactose fruit-hydrate is appropriate
magnesium stearate 0.5mg
Film-making
After above-mentioned raw materials, adjuvant mix homogeneously, conveniently wet granulation, dry, tabletting.
embodiment 8, 18 β-glycyrrhizic acid matrine salt
Getting 18 β-glycyrrhizic acid 165g and matrine 49.7g adds in appropriate absolute methanol, stirred at ambient temperature dissolves, slowly add in the 3000ml acetone of vigorous stirring after continuing stirred for several minute, wash out a large amount of white crystalline powder, filter, in 60 DEG C of vacuum dryings, obtain white crystalline powder 172g, yield is 80.1%.
Mp:204 DEG C of decomposition
[C]
d 20=+24.5 (1% ethanol)
| Elementary analysis | Measured value (%) | Value of calculation (%) |
| C | 63.88 | 63.91 |
| H | 8.12 | 8.09 |
| N | 2.70 | 2.61 |
embodiment 9, 18 β-glycyrrhizic acid kurarinone salt
Getting 18 β-glycyrrhizic acid 165g and kurarinone 106g adds in appropriate absolute methanol, stirred at ambient temperature dissolves, slowly add in the 3000ml acetone of vigorous stirring after continuing stirred for several minute, wash out a large amount of white crystalline powder, filter, in 60 DEG C of vacuum dryings, obtain white crystalline powder 188g, yield is 69.4%.
Mp:206 DEG C of decomposition
[C]
d 20=+42.4 (1% ethanol)
| Elementary analysis | Measured value (%) | Value of calculation (%) |
| C | 63.91 | 63.98 |
| H | 8.31 | 8.20 |
| N | 4.12 | 4.15 |
embodiment 10, 18 alpha-liquorice acid matrine salts
Getting 18 alpha-liquorice acid 165g and matrine 49.7g adds in appropriate absolute methanol, stirred at ambient temperature dissolves, slowly add in the 3000ml acetone of vigorous stirring after continuing stirred for several minute, wash out a large amount of white crystalline powder, filter, in 60 DEG C of vacuum dryings, obtain white crystalline powder 180g, yield is 83.8%.
Mp:208 DEG C of decomposition
[C]
d 20=+23.6 (1% ethanol)
| Elementary analysis | Measured value (%) | Value of calculation (%) |
| C | 63.88 | 63.91 |
| H | 8.10 | 8.09 |
| N | 2.59 | 2.61 |
embodiment 11, 18 alpha-liquorice acid kurarinone salt
Getting 18 alpha-liquorice acid 165g and matrine 106g adds in appropriate absolute methanol, stirred at ambient temperature dissolves, slowly add in the 3000ml acetone of vigorous stirring after continuing stirred for several minute, separate out a large amount of white crystalline powder, filter, in 60 DEG C of vacuum dryings, obtain white crystalline powder 190g, yield is 73.1%.
Mp:210 DEG C of decomposition
[C]
d 20=+24.2 (1% ethanol)
| Elementary analysis | Measured value (%) | Value of calculation (%) |
| C | 63.79 | 63.98 |
| H | 8.31 | 8.20 |
| N | 4.19 | 4.15 |
embodiment 12:the lyophilized powder preparation of the two kushenin compound salt of glycyrrhizic acid
In 100ml reaction bulb, add glycyrrhizic acid 2.00g(2.43mmol), a water kurarinone 1.372g (4.86mmol), adds deionized water 30ml, stirring and dissolving, and filter, filtrate lyophilization, obtains freeze-dried powder 3.26g, yield 99.3%.
embodiment 13:the lyophilized powder preparation of glycyrrhizic acid three kushenin compound salt
In 100ml reaction bulb, add glycyrrhizic acid 2.00g(2.43mmol), a water kurarinone 2.06g (7.29mmol), adds deionized water 30ml, stirring and dissolving, and filter, filtrate lyophilization, obtains freeze-dried powder 3.88g, yield 98.8%.
embodiment 14:the preparation of the complex salt of glycyrrhizic acid and kurarinone
In 100ml reaction bulb, add deionized water 40ml, at normal temperatures, add glycyrrhizic acid 2.00g(2.43mmol), one water kurarinone 0.686g (2.43mmol), stirring and dissolving, water-bath 60 DEG C is rushed pump decompression (20mmHg) with water and is concentrated into 10ml, slowly acetone is dripped under stirring, the white oil turbidity sediment of separating out is dissolved, when dripping acetone to 20ml, the white oil turbidity sediment of separating out no longer dissolves, suspend and drip acetone, be stirred to white oil precipitation and be converted into white crystalline solid, about need 30 minutes to 1 hour, continue to drip acetone to 60ml in 30 minutes, in 50 DEG C of stirred in water bath 1 hour, then stirring at room temperature is naturally cooled to 2 hours, filter, washing with acetone, in 50 DEG C of vacuum dryings, obtain white crystals 2.2g, m.p:202-204 DEG C, yield is 83.3%.
Table. results of elemental analyses (C
42h
62o
16.C
15h
24n
2o
2)
| C weight content | H weight content | N weight content | |
| Value of calculation | 62.96% | 7.97% | 2.57% |
| Experiment value | 62.43% | 7.88% | 2.48% |
embodiment 15: the injectable powder preparation of the complex salt of glycyrrhizic acid and kurarinone
In aseptic weighing area, claim 4g mannitol to add in appropriate container, add 800ml water for injection, stir and make it abundant dissolving, add the complex salt stirring and dissolving of 50g glycyrrhizic acid and kurarinone, inject water to 1000ml, aseptically, carry out subpackage with after 0.22 μm of filtering with microporous membrane, loading amount is every bottle of 10ml, lyophilization, adds sterilizing plug and rolls enclosing cover, to obtain final product.
embodiment 16: the preparation of the lyophilized powder of compositions
Oxymatrine and glycyrrhizin compositions (1 ~ 10:1 ~ 10), matrine and glycyrrhizin compositions (1 ~ 10:1 ~ 10), oxymatrine and Diammonium Glycyrrhizinate compositions (1 ~ 10:1 ~ 10), matrine and Diammonium Glycyrrhizinate compositions (1 ~ 10:1 ~ 10), glycyrrhizic acid kushenin compound salt, the two kushenin compound salt of glycyrrhizic acid, glycyrrhizic acid three kushenin compound salt, 18 alpha-liquorice acid kurarinone salt, 18 alpha-liquorice acid matrine salts, 18 β-glycyrrhizic acid matrine salt, 18 β-glycyrrhizic acid kurarinone salt,
At normal temperatures and pressures, one of mentioned component is added in reagent bottle, then add appropriate deionized water and stirring well-known in the art, to dissolution system concentrating under reduced pressure after fully dissolving; Secondly, instill water-soluble solvent under agitation, separate out white precipitate; Finally, carry out respectively stirring under stirring makes transformation of crystal and room temperature condition under 50 DEG C of water bath condition crystallize is completed, filter afterwards, washing, the operating procedures such as 50 DEG C of vacuum dryings obtain the white crystals of one of mentioned component; Or obtain lyophilized powder by above-mentioned obtained aqueous solution lyophilization.
embodiment 17: the injection preparation of compositions
Oxymatrine and glycyrrhizin compositions (1 ~ 10:1 ~ 10), matrine and glycyrrhizin compositions (1 ~ 10:1 ~ 10), oxymatrine and Diammonium Glycyrrhizinate compositions (1 ~ 10:1 ~ 10), matrine and Diammonium Glycyrrhizinate compositions (1 ~ 10:1 ~ 10), glycyrrhizic acid kushenin compound salt, the two kushenin compound salt of glycyrrhizic acid, glycyrrhizic acid three kushenin compound salt, 18 alpha-liquorice acid kurarinone salt, 18 alpha-liquorice acid matrine salts, 18 β-glycyrrhizic acid matrine salt, 18 β-glycyrrhizic acid kurarinone salt
One of mentioned component 50g is joined in appropriate containers, adds the water for injection of cumulative volume about 85%, stirring and dissolving, survey pH value, regulate pH value about 6.0 ~ 6.5 with hydrochloric acid solution or sodium hydroxide solution, add 900g, stirring makes it to dissolve, and injects water to 10L, stirs and makes evenly with 0.22 μm of filtering with microporous membrane, rush nitrogen, embedding, 115 DEG C of pressure sterilizings 30 minutes, lamp inspection, inspection, packaging.
embodiment 18:
Oxymatrine 600mg
Diammonium Glycyrrhizinate 150mg
NaCl0.9g
water for injection is appropriate
Get sodium chloride water for injection stirring and dissolving, then add oxymatrine, Diammonium Glycyrrhizinate respectively, continuing stirring is dissolve sky completely to inject water to total amount, and filter to clear and bright, embedding, sterilizing, to obtain final product.
embodiment 19: the tablet preparation of compositions
Oxymatrine and glycyrrhizin compositions (1 ~ 10:1 ~ 10), matrine and glycyrrhizin compositions (1 ~ 10:1 ~ 10), oxymatrine and Diammonium Glycyrrhizinate compositions (1 ~ 10:1 ~ 10), matrine and Diammonium Glycyrrhizinate compositions (1 ~ 10:1 ~ 10), glycyrrhizic acid kushenin compound salt, the two kushenin compound salt of glycyrrhizic acid, glycyrrhizic acid three kushenin compound salt, 18 alpha-liquorice acid kurarinone salt, 18 alpha-liquorice acid matrine salts, 18 β-glycyrrhizic acid matrine salt, 18 β-glycyrrhizic acid kurarinone salt
One of mentioned component 50g
Pregelatinized Starch 2g
Hydroxypropyl cellulose 4g
Carboxymethyl starch sodium 3.5g
Microcrystalline Cellulose 1g
magnesium stearate 0.4g
One of mentioned component and above-mentioned each adjuvant are crossed 80 mesh sieves respectively, and mix homogeneously, has polyvidone to make soft material, granulates by 14 order nylon mesh, 50 ~ 60 DEG C of dryings, 14 mesh sieve granulate, carries out tabletting and obtain after mix homogeneously.
embodiment 20: the granule preparation of compositions
Oxymatrine and glycyrrhizin compositions (1 ~ 10:1 ~ 10), matrine and glycyrrhizin compositions (1 ~ 10:1 ~ 10), oxymatrine and Diammonium Glycyrrhizinate compositions (1 ~ 10:1 ~ 10), matrine and Diammonium Glycyrrhizinate compositions (1 ~ 10:1 ~ 10), glycyrrhizic acid kushenin compound salt, the two kushenin compound salt of glycyrrhizic acid, glycyrrhizic acid three kushenin compound salt, 18 alpha-liquorice acid kurarinone salt, 18 alpha-liquorice acid matrine salts, 18 β-glycyrrhizic acid matrine salt, 18 β-glycyrrhizic acid kurarinone salt
One of mentioned component 50g
Cyclamate 8g
Lactose 8g
essence is appropriate
One of mentioned component is water-soluble, and add starch 80g, Icing Sugar 20g, then it is appropriate to add essence, mixing, granulates with 14 ~ 16 mesh sieves, less than 60 DEG C dry, packaging.
embodiment 21: the capsule preparation of compositions
Oxymatrine and glycyrrhizin compositions (1 ~ 10:1 ~ 10), matrine and glycyrrhizin compositions (1 ~ 10:1 ~ 10), oxymatrine and Diammonium Glycyrrhizinate compositions (1 ~ 10:1 ~ 10), glycyrrhizic acid kushenin compound salt, glycyrrhizic acid two kushenin compound salt, glycyrrhizic acid three kushenin compound salt, 18 alpha-liquorice acid kurarinone salt, 18 alpha-liquorice acid matrine salts, 18 β-glycyrrhizic acid matrine salt, 18 β-glycyrrhizic acid kurarinone salt
One of mentioned component 50g
Starch 5g
Microcrystalline Cellulose 2g
magnesium stearate 1g
One of mentioned component and above-mentioned each adjuvant are sieved respectively, and mix homogeneously, be sub-packed in hard capsule, obtain final product.
embodiment 22: the oral liquid preparation of compositions
Oxymatrine and glycyrrhizin compositions (1 ~ 10:1 ~ 10), matrine and glycyrrhizin compositions (1 ~ 10:1 ~ 10), oxymatrine and Diammonium Glycyrrhizinate compositions (1 ~ 10:1 ~ 10), matrine and Diammonium Glycyrrhizinate compositions (1 ~ 10:1 ~ 10), glycyrrhizic acid kushenin compound salt, the two kushenin compound salt of glycyrrhizic acid, glycyrrhizic acid three kushenin compound salt, 18 alpha-liquorice acid kurarinone salt, 18 alpha-liquorice acid matrine salts, 18 β-glycyrrhizic acid matrine salt, 18 β-glycyrrhizic acid kurarinone salt
One of mentioned component 50g
Propylene glycol 5g
Glycerol 1g
Gelatin 2g
Sucrose 10g
Sodium benzoate 0.1g
Citric acid 0.5g
Essence is appropriate
pure water 100g
After one of mentioned component and above-mentioned each adjuvant are added pure water, stirring and dissolving, subpackage and get final product.
embodiment 23: the slow-release micro-pill preparation of compositions
Slow-released part prescription (ball 1)
Ball core prescription
Kurarinone 200g
Glycyrrhizin 150g
Microcrystalline Cellulose 15g
Hypromellose 5g
pure water 200ml
Make 1000
Coating prescription
25% aqueous ethylcellulose falls apart liquid 184g
pure water 123g
Make 1000
Respectively microcrystalline Cellulose, kurarinone, glycyrrhizin were pulverized 80 mesh sieves in advance, take by ball 1 prescription, mix homogeneously, hydroxypropyl methylcellulose aqueous solution makes binding agent, micropill processed, by it in 50 ~ 60 DEG C of dryings, and 20 ~ 30 object pillers, for subsequent use.
To prepare and the micropill chosen, put in fluid bed, adopt end spray mode, by hot-air suspension fluidization, inlet temperature is 55 DEG C, material bed tempertaure controls 30 DEG C time, regulates peristaltic pump to make it provide coating solution by the speed of 5g serosity per minute, atomizing pressure 2bar, start to whitewash continuously to the piller of fluidisation, after whitewashing terminates, reduce air quantity, make micropill under slight boiling condition 40 DEG C of dry a moments.Taking-up to be placed in 40 DEG C of baking ovens dry 24 hours, weightening finish about 18%, measures content, to obtain final product.
Claims (14)
1. a pharmaceutical composition, described pharmaceutical composition comprises the kurarinone and glycyrrhizic acid or the derivant both it that sequentially give or give simultaneously pharmaceutically acceptable form, also comprises glycyrrhizic acid matrine salt and glycyrrhizic acid kurarinone salt.
2. the pharmaceutical composition according to right 1, the weight proportion of combination species kurarinone or derivatives thereof and glycyrrhizic acid or derivatives thereof is 10:1 ~ 1:10.
3. the pharmaceutical composition according to right 1 ~ 2, the weight proportion of combination species kurarinone or derivatives thereof and glycyrrhizic acid or derivatives thereof is 5:1 ~ 1:5.
4. the pharmaceutical composition according to right 1 ~ 3, the weight proportion of combination species kurarinone or derivatives thereof and glycyrrhizic acid or derivatives thereof is 5:1 ~ 1:2.
5. the pharmaceutical composition according to right 1, wherein the content of kurarinone or derivatives thereof is 50 ~ 2000mg, and the content of glycyrrhizic acid or derivatives thereof is 30 ~ 2000mg.
6. the pharmaceutical composition according to right 1 ~ 5, wherein the content of kurarinone or derivatives thereof is 100 ~ 1500mg, and the content of glycyrrhizic acid or derivatives thereof is 30 ~ 1500mg.
7. the pharmaceutical composition according to right 1 ~ 6, wherein the content of kurarinone or derivatives thereof is 300 ~ 1000mg, and the content of glycyrrhizic acid or derivatives thereof is 100 ~ 1000mg.
8. according to the arbitrary described pharmaceutical composition of claim 1 ~ 7, wherein said kurarinone or derivatives thereof is oxymatrine, matrine or derivant, Iosmatrine both it, derivant is officinal salt especially, comprises hydrochlorate, sulfate, acetate, phosphate, fumarate and various amino acid salts.
9., according to the arbitrary described pharmaceutical composition of claim 1 ~ 8, wherein said glycyrrhizic acid or derivatives thereof is glycyrrhizin or its officinal salt, ester and solvate; Also comprise glycyrrhizic acid matrine salt and glycyrrhizic acid kurarinone salt.
10. pharmaceutical composition according to claim 9, glycyrrhizic acid or derivatives thereof comprises glycyrrhizic acid, glycyrrhizin, Isoglycyrrhiza acid, Isoglycyrrhiza acid salt, glycyrrhetate, and glycyrrhetate comprises glycyrrhizin can medication salt, glycyrrhizic glycoside, monoammonium glycyrrhizinate, diammonium glycyrrhizinate, sodium glycyrrhetate, potassium glycyrrhizana and glycyrrhizic acid calcium salt; Comprise glycyrrhizic acid matrine salt and glycyrrhizic acid kurarinone salt.
11. according to the arbitrary described pharmaceutical composition of claim 1 ~ 10, and wherein said drug regimen material and form are the nanotechnology of injection, injectable powder, tablet, slow releasing agent, drop pill, electuary, capsule, slow-release micro-pill, oral liquid, externally used paste and Emulsion or its above preparation.
12. according to the application of the arbitrary described pharmaceutical composition of claim 1 ~ 11 in preparation treatment neuropsychiatric disorders dermatoses medicine.
13. application according to claim 12, described neuropsychiatric disorders dermatoses comprises pruritus, lichen chronicus simplex, prurigo, prurigo nodularis, pigmentosa prurigo and lichenoid dermatitis.
14. application according to claim 12, the technology that can combine existing treatment neuropsychiatric disorders dermatoses is as hormone, antihistaminic, chemotherapy, immunization therapy, biological response modifier, naturopathy, radiotherapy, phototherapy, photochemotherapy and optical dynamic therapy.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410343670.3A CN105267228B (en) | 2014-07-18 | 2014-07-18 | A kind of pharmaceutical composition is as the application in preparation treatment neuropsychiatric disorders dermatoses drug |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410343670.3A CN105267228B (en) | 2014-07-18 | 2014-07-18 | A kind of pharmaceutical composition is as the application in preparation treatment neuropsychiatric disorders dermatoses drug |
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| CN105267228B CN105267228B (en) | 2019-02-26 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1695624A (en) * | 2004-05-12 | 2005-11-16 | 江苏恒瑞医药股份有限公司 | Combination of medication of containing kurarinone and glycyrrhetic acid, and application |
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2014
- 2014-07-18 CN CN201410343670.3A patent/CN105267228B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1695624A (en) * | 2004-05-12 | 2005-11-16 | 江苏恒瑞医药股份有限公司 | Combination of medication of containing kurarinone and glycyrrhetic acid, and application |
Non-Patent Citations (2)
| Title |
|---|
| 吴友良等: "《苦参素联合普鲁卡因治疗全身性皮肤瘙痒疗效观察》", 《西南国防医药》 * |
| 张明发等: "《甘草及其有效成分的皮肤药理和临床应用》", 《药物评价研究》 * |
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