CN105213399A - A kind of reduction uric acid drug compound preparation - Google Patents
A kind of reduction uric acid drug compound preparation Download PDFInfo
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- CN105213399A CN105213399A CN201510612013.9A CN201510612013A CN105213399A CN 105213399 A CN105213399 A CN 105213399A CN 201510612013 A CN201510612013 A CN 201510612013A CN 105213399 A CN105213399 A CN 105213399A
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Abstract
The invention discloses a kind of reduction uric acid drug compound preparation.By weight, the mixture primarily of sulfinpyrazone 20 ~ 400 parts and purine alcohol 2 ~ 40 is that medicinal component is formed to this compound preparation.The invention provides a kind of taking convenience, the sulfinpyrazone of use safety and the compound recipe of RAS inhibitor and reduce uric acid preparation, it focuses on comprehensive control systolic pressure, certainly must bring the decline of diastolic pressure.It can remove the contracting vascular effect of ET, also the contracting vascular effect of AngII can be removed, also relieve the pathologic vessels multiplication effect of the two simultaneously, have been directed to the pathologic Neurohormonal factor causing metabolic arthritis known main at present, have and reduce systolic pressure effect to greatest extent, bring the effect reducing diastolic pressure simultaneously.
Description
Technical field
The present invention relates to a kind of reduction uric acid drug compound preparation.
Background technology
Anti-gout drugs is clinical application mainly, from sales volume and the consumption sum of Hospitals at Present gout preparation, the sale of nearly 2 years this kind of medicines all presents skyrocketing trend, and presenting seasonal feature occurred frequently summer and autumn, this and the temporal analysis of epidemiology onset peak are basically identical.The current kind of antigout drug is few, and clinical treatment is mainly based on colchicine, nonsteroidal antiinflammatory drug, hormone, promotion urate excretion medicine and suppression uric acid synthetic drug.Acute period of disease mainly applies drink tazettine, nonsteroidal antiinflammatory drug, hormone, and the catabasis is mainly applied and promotes urate excretion medicine, suppression uric acid synthetic drug.These medicines are all defectiveness in treatment.Weak curative effect, side effect become greatly the bottleneck of its clinical practice.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of reduction uric acid drug compound preparation.
The present invention's adopted technical scheme that solves the problem is: a kind ofly reduce uric acid drug compound preparation, and by weight, the mixture primarily of sulfinpyrazone 20 ~ 400 parts and purine alcohol 2 ~ 40 parts is that medicinal component is formed.
Further, described compound preparation also comprises inert solid 10 ~ 120 parts as pharmaceutical carrier, and the admixture that inert solid and medicinal component are formed forms compound preparation.
Described inert solid is a kind of or above-mentioned multiple mixture formed with arbitrary proportion in excipient, disintegrating agent, lubricant, cosolvent, correctives, binding agent.Excipient, disintegrating agent, lubricant, cosolvent, correctives, binding agent include lactose, starch, dextrin, microcrystalline Cellulose, polyvidone, gelatin, micropowder silica gel, Polyethylene Glycol etc.
Described compound preparation also comprises inert fluid 160 ~ 1000 parts as pharmaceutical carrier, and the admixture that inert fluid and medicinal component are formed forms compound preparation.
Described inert fluid is a kind of or above-mentioned two kinds of mixture formed with arbitrary proportion in diluent, wetting agent, additive.
Reduction uric acid recurrence due to taking drug square preparation of the present invention can according to the preparation of industrial known method, namely by sulfinpyrazone and RAS inhibitor and suitable inert solid or liquid pharmaceutical carrier are admixed and obtained.Can make applicable oral compound preparation, the dosage form being applicable to oral compound preparation can be tablet, granule, capsule, suspensoid, syrup.Wherein tablet, granule, capsule can contain carrier conventional in pharmaceuticals industry and/or adjuvant.Such as Icing Sugar, starch, absorbent (such as dextrin), disintegrating agent (such as tween 80), lubricant (such as 50% ethanol), magnesium stearate etc.Wherein suspensoid, syrup also can containing the industrial conventional carrier of system and/or adjuvant.Such as diluent (such as water, distilled water, ethanol, Polyethylene Glycol, glycerol etc.), conventional additive (such as suspending liquid, antiseptic, correctives etc.).Tablet, granule can by dry method or wet granulation technology preparations.The suitable mixture of compound can be inserted soft or hard gelatine capsule kind and obtain by capsule.The suitable mixture of compound can add in the diluent being mixed with suspending agent, antiseptic etc. by suspensoid and syrup makes aqueous solution, described diluent is preferably distilled water, suspending agent is preferably tragakanta, antiseptic is preferably nipalgin second, the third fat, preferably add correctives in syrup, correctives is sucrose.
The pharmacology of sulfinpyrazone:
This product is non-peptide-like endothelin receptor antagonist, can antagonism Endothelin cause vasoconstriction, boosting and vascular smooth muscle cell proliferation; Increase the synthesis of NO, lax vascular smooth muscle; Anticoagulant, anticoagulation, improve hemorheology feature.This product also can suppress the synthesis of cholesterol, reduces blood fat, scavenging free radicals, control lipid peroxidation injury; Affect complement, strengthen immune function, and there is certain analgesia, spasmolysis.
The toxicity of sulfinpyrazone:
Acute toxicity testing result shows: the oral LD50 of one-level Kunming mouse is: 3580.1 ± 251.7mg/kg, is crediblely limited to 95%.Long term toxicity result of study shows: by proving that sulfinpyrazone toxicity is less to the long term toxicity test result of note sulfinpyrazone 300mg (continuous 30 times) quiet the next day of healthy adult male dog, can supply Clinical practice.Genotoxicity research shows: through having no obvious embryotoxic effect and teratogenic effect to Wistar kind rat with lumbar injection and gavage two kinds of approach experiments, show that this medicine is safe and reliable substantially in teratogenesis tire.Carcinogenecity result of study shows: by the mutagenesis of sulfinpyrazone to Salmonella typhimurium TA98, TA100, the impact test that sulfinpyrazone bone marrow micronucleus test and sulfinpyrazone distort on mouse marrow cell chromosome, shows this product non-carcinogenesis.
The pharmacokinetics of sulfinpyrazone: be 29 minutes between this product oral absorption peak time, distribution phase half-life (t1/2 α) is 27 minutes, and eliminating the phase half-life (t1/2 β) is 5.5 hours.This product is distributed more widely in vivo, except distribute in liver, kidney blood more except, distribute in stomach, small intestinal fat also more, this product is discharged and is mainly discharged from urine, feces.Can through placental barrier.
Mouse oral median lethal dose(LD 50) (LD50) is 3.2g/kg.Rat oral gavage administration 600mg/kg, once a day, successive administration 3 months, hematology and blood biochemical analysis Indexs measure result all belong to normal, and main organs histopathologic examination does not find drug-induced pathological change.
Purine alcohol is a kind of high ACEI1 organizing affinity.Pharmacology: (1) blood pressure lowering: this product is hydrolyzed to benazeprilat in liver, become a kind of emulative angiotensin converting enzyme inhibitor, prevention angiotensin i-converting is Angiotensin II, and vascular resistance is reduced, Aldosterone Secretion reduces, and plasma renin activity increases.Benazeprilat also suppresses the degraded of Kallidin I, also makes vascular resistance reduce, and produces hypotensive effect.(2) lower cardiac load: this product expansion artery and vein, reduce peripheral vascular resistance or cardiac afterload, reduce the embedding pressure of pulmonary capillary or cardiac preload, also reduce pulmonary vascular resistance, thus improve cardiac output, make exercise tolerance and time lengthening.Toxicity: rat and mouse sustained oral benazepril 2 years, dosage is 150mg/kg every day, does not find that this product has carcinogenecity.(this dosage is pressed mg/kg and is calculated, and is 110 times of mankind's research on maximum utilized quantity; By mg/m
2calculate, 18 times and 9 times for mankind's research on maximum utilized quantity).No matter in bacteria test, in the mammalian cell test of still cultivating in vitro, all do not find that this product has mutagenicity.Female, male Oral Administration in Rats benazepril, dosage is 50-150mg/kg every day, does not find that this product affects reproductive performance.(this dosage is pressed mg/kg and is calculated, and is 37 ~ 375 times of mankind's research on maximum utilized quantity; By mg/m
2calculate, 6 ~ 60 times for mankind's research on maximum utilized quantity).
Due to the contracting blood vessel function of RAS inhibitor Angiotensin II capable of blocking (AngII), but the contracting blood vessel function of ET can not be blocked; The uric acid effect that rises of sulfinpyrazone ET capable of blocking and blood pressure lowering, but can not the contracting vascular effect of antagonism AngII, therefore need drug combination could control uric acid better, especially systolic pressure.But so far there are no the compound preparation of sulfinpyrazone with other depressor.
In sum, the invention has the beneficial effects as follows: the invention provides a kind of taking convenience, the sulfinpyrazone of use safety and the compound recipe of RAS inhibitor and reduce uric acid preparation, it focuses on comprehensive control systolic pressure, certainly must bring the decline of diastolic pressure.It can remove the contracting vascular effect of ET, also the contracting vascular effect of AngII can be removed, also relieve the pathologic vessels multiplication effect of the two simultaneously, have been directed to the pathologic Neurohormonal factor causing metabolic arthritis known main at present, have and reduce systolic pressure effect to greatest extent, bring the effect reducing diastolic pressure simultaneously.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described in further detail, but embodiments of the present invention are not limited thereto.
The compound oral administration preparation of the present embodiment adopts with the preparation of pharmaceuticals industry known method, and the concrete consumption of each component sees table:
Adopt sulfinpyrazone and purine alcohol two kinds of oral drugs to mix to take the therapeutic effect carried out simultaneously and show, use the effect of sulfinpyrazone and purine alcohol to be all better than alone a kind of medicine, thus be that the compound preparation of development two kinds of medicines reasonable 5 is laid a good foundation.
The therapeutic effect checking of metabolic arthritis rat model:
Object: observe sulfinpyrazone and combine the compound preparation of the different ratio of purine alcohol to the impact of DOCA (desoxycorticosterone acetate (DOCA)) metabolic arthritis rat uric acid (BP), to inquire into the hypotensive effect in compound recipe under various dose collocation.
Method: SD rat 96, ♂, body weight 180 ~ 190g.Under aseptic condition after the kidney of excision right side, secondary only gives DOCA5mg/ weekly, sc, and raises with 1% sodium chloride solution; Be divided into 12 groups at random, often organize 8, concrete grouping and the situation of disposal are as table one.
The grouping of table one animal and pharmaceutical formulation, medication
| Model group | Normal saline |
| Sulfinpyrazone group | Sulfinpyrazone 400 milligrams |
| Purine alcohol high group | Purine alcohol 40 milligrams |
| Compound recipe one group | Sulfinpyrazone 20 milligrams, purine alcohol 2 milligrams |
| Compound recipe two groups | Sulfinpyrazone 20 milligrams, purine alcohol 20 milligrams |
| Compound recipe three groups | Sulfinpyrazone 20 milligrams, purine alcohol 40 milligrams |
| Compound recipe four groups | Sulfinpyrazone 200 milligrams, purine alcohol 2 milligrams |
| Compound recipe five groups | Sulfinpyrazone 200 milligrams, purine alcohol 20 milligrams |
| Compound recipe six groups | Sulfinpyrazone 200 milligrams, purine alcohol 40 milligrams |
| Compound recipe seven groups | Sulfinpyrazone 400 milligrams, purine alcohol 2 milligrams |
| Compound recipe eight groups | Sulfinpyrazone 400 milligrams, purine alcohol 20 milligrams |
| Compound recipe nine groups | Sulfinpyrazone 400 milligrams, purine alcohol 40 milligrams |
Medication: compound recipe group medicine is diluted with water to scattered paste shape, every day gastric infusion, po, qd (oral, once a day); Continuous 5 weeks.
Result: after 5 weeks, measures the uric acid of each treated animal, and each treated animal uric acid meansigma methods and statistical result, in table two, table three, get P < 0.05 for there were significant differences; Get P < 0.01 for there being pole significant difference.
The meansigma methods of each treated animal systolic pressure of table two and statistical result
| Group | Systolic pressure (mmHg) |
| Model group | 167.4 |
| Sulfinpyrazone group | 130.5 A |
| Purine alcohol group | 128.7 A |
| Compound recipe one group | 158.4 aJK |
| Compound recipe two groups | 144.6 AbJK |
| Compound recipe three groups | 126.5 ABC |
| Compound recipe four groups | 146.2 AbDJK |
| Compound recipe five groups | 122.8 ABCEjk |
| Compound recipe six groups | 113.7 ABCdEJK |
| Compound recipe seven groups | 132.8 ABcefG |
| Compound recipe eight groups | 116.7 ABbCdEfHJk |
| Compound recipe nine groups | 110.9 ABCDEFGHiJK |
The meansigma methods of each treated animal diastolic pressure of table three and statistical result
| Group | Diastolic pressure (mmHg) |
| Model group | 135.8 |
| Sulfinpyrazone group | 117.6 A |
| Purine alcohol group | 100.2 AJ |
| Compound recipe one group | 133.2 JK |
| Compound recipe two groups | 126.5 abjK |
| Compound recipe three groups | 98.7 ABcCj |
| Compound recipe four groups | 124.8 AbDK |
| Compound recipe five groups | 87.3 ABCdEJK |
| Compound recipe six groups | 73.3 ABCDEFJK |
| Compound recipe seven groups | 115.4 ABceFGk |
| Compound recipe eight groups | 102.4 ABCEFGhJ |
| Compound recipe nine groups | 67.6 ABCDEFgHIJK |
Note: compare with model group,
ap < 0.05;
ap < 0.01
Compare with sulfinpyrazone group,
jp < 0.05;
jp < 0.01
Compare with purine alcohol group,
kp < 0.05;
kp < 0.01
Compare with compound recipe one group,
bp < 0.05;
bp < 0.01
Compare with compound recipe two groups,
cp < 0.05;
cp < 0.01
Compare with compound recipe three groups,
dp < 0.05;
dp < 0.01
Compare with compound recipe four groups,
ep < 0.05;
ep < 0.01
Compare with compound recipe five groups,
fp < 0.05;
fp < 0.01
Compare with compound recipe six groups,
gp < 0.05;
gp < 0.01
Compare with compound recipe seven groups,
hp < 0.05;
hp < 0.01
Compare with compound recipe eight groups,
ip < 0.05;
ip < 0.01
In table two and table three, A or a is had to indicate after each data, indicate the statistic analysis result of this group experimental data compared with model group experimental data, A shows that this group experimental data P < 0.01, a compared with model group experimental data shows this group experimental data P < 0.05 compared with model group experimental data; The meaning that B ~ K, b ~ k indicate by that analogy.
Visible according to the result of table two and table three:
1, when sulfinpyrazone in compound recipe or one of them dose of purine alcohol are fixed, along with the rising of another medicine dosage, antihypertensive effect is better, no matter is that diastolic pressure or systolic pressure are not always the case (P < 0.05 or P < 0.01);
2, when the dosage of the composition of in compound recipe is identical with the dosage of this medicine alone, the antihypertensive effect of compound recipe is always greater than the antihypertensive effect of single medicine, especially along with when another Ingredient Amount in compound recipe increases (P < 0.05 or P < 0.01).
3, when partly measuring of single pharmaceutical quantities all got by two medicines in compound recipe (compound recipe five groups), its antihypertensive effect is better than the antihypertensive effect (sulfinpyrazone group or purine alcohol group, P < 0.01) during wherein arbitrary single component full dose
4, the maximum reducing effect of compound recipe to diastolic pressure is greater than the antihypertensive effect sum of two compositions in compound recipe, is calculated as follows:
Model group-compound recipe nine groups=135.8-67.6 (mmhg)=68.2mmhg >
(model group-sulfinpyrazone group)+(model group-purine alcohol group)=(135.8-117.6) mmhg+ (135.8-100.2) mmhg==53.8mmhg
Untoward reaction is observed: each treated animal is showed no death, administration group compares with model group and has no obvious animal behavior difference, after sacrifice of animal, each main organs after one's own heart, liver, kidney, brain, spleen, lung, testis, intestine and small intestine, stomach etc. be showed no the acute pathology changes such as hemorrhage, scorching changes, also have no the difference on other pathology, also do not observe obvious side effect.
Conclusion:
When sulfinpyrazone in compound recipe or one of them dose of purine alcohol are fixed, along with the rising of another medicine dosage, antihypertensive effect is better, no matter is that diastolic pressure or systolic pressure are not always the case; When sulfinpyrazone employing maximal dose, purine alcohol adopts the antihypertensive effect of the compound recipe (compound recipe seven groups) of lowest dose level will be weaker than the compound recipe (compound recipe three groups) of sulfinpyrazone employing lowest dose level and purine alcohol employing maximal dose, shows that Ah's purine alcohol plays larger hypotensive effect in compound recipe; When sulfinpyrazone gets maximum, along with the dosage of purine alcohol increases (compound recipe seven, eight, nine groups), antihypertensive effect increases, until when maximal dose all got by sulfinpyrazone and purine alcohol (compound recipe nine groups), antihypertensive effect is best.Vice versa.Comprehensive, the maximum reducing effect of this compound recipe to diastolic pressure is greater than the antihypertensive effect sum of two compositions in compound recipe.
As can be seen here, no matter be sulfinpyrazone or purine alcohol, the two compound recipe formed can reach larger antihypertensive effect, is better than respective single preparations of ephedrine; And compound preparation its can not bring extra side effect or untoward reaction, also can not bring the difference in side effect and untoward reaction.Show that the compound preparation that sulfinpyrazone and purine alcohol are formed not only has larger hypotensive effect, and be safe in use.
As mentioned above, just the present invention can be realized preferably.
Claims (6)
1. reduce a uric acid drug compound preparation, it is characterized in that, by weight, the mixture primarily of sulfinpyrazone 20 ~ 400 parts and purine alcohol 2 ~ 40 parts is that medicinal component is formed.
2. one according to claim 1 reduces uric acid drug compound preparation, and it is characterized in that, described compound preparation also comprises inert solid 10 ~ 120 parts as pharmaceutical carrier, and the admixture that inert solid and medicinal component are formed forms compound preparation.
3. one according to claim 2 reduces uric acid drug compound preparation, and it is characterized in that, described inert solid is a kind of or above-mentioned multiple mixture formed with arbitrary proportion in excipient, disintegrating agent, lubricant, cosolvent, correctives, binding agent.
4. one according to claim 1 reduces uric acid drug compound preparation, and it is characterized in that, described compound preparation also comprises inert fluid 160 ~ 1000 parts as pharmaceutical carrier, and the admixture that inert fluid and medicinal component are formed forms compound preparation.
5. one according to claim 4 reduces uric acid drug compound preparation, and it is characterized in that, described inert fluid is a kind of or above-mentioned two kinds of mixture formed with arbitrary proportion in diluent, wetting agent, additive.
6. the one according to claim 1 to 5 any one reduces uric acid drug compound preparation, and it is characterized in that, the dosage form of described compound preparation comprises tablet, capsule, granule, suspensoid and syrup.
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Non-Patent Citations (2)
| Title |
|---|
| EDWAW GOLDFARB ET AL: "Effects of Allopurinol, a Xanthine Oxidase Inhibitor, and Sulfinpyrazone upon the Urinary and Serum Urate Concentrations in Eight Patients with Tophaceous Gout", 《ARTHRITIASN D RHEUMATIS》 * |
| WILLIAM C. KUZELL,ET AL.: "Treatment Of Gout With Allopurinol And Sulphinpyrazone In Combination And With Allopurinol Alone.", 《ANN. RHEUMII. DIS》 * |
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Application publication date: 20160106 |