CN109381465A - Wo Nuolazan is preparing the application in antigout preparation - Google Patents

Abstract

The invention discloses the purposes that the Wo Nuolazan of free form or pharmaceutically acceptable salt form is used to prepare antigout preparation.Have the beneficial effect that the Wo Nuolazan of free form or pharmaceutically acceptable salt form is able to suppress the activity of xanthine oxidase, hypoxanthine and xanthine is prevented to be metabolized as uric acid, to reduce the generation of uric acid, it can effectively prevent the gout symptom as caused by hyperuricemia.

Description

Wo Nuolazan is preparing the application in antigout preparation

Technical field

The present invention relates to pharmaceutical fields, are preparing the application in antigout preparation more particularly, to Wo Nuolazan.

Background technique

Gout is a kind of because of disorders of purine metabolism, makes disease caused by uric acid accumulation, belongs to arthritic one kind, also known as Metabolic arthritis.Clinical signs are hyperuricemia, gouty acute arthritis, tophaceous deposition, the chronic pass of characteristic Section inflammation and arthritis deformans, often involve kidney, cause arteriosclerotic kidney and kidney calculus urate.Epidemiology shows, American-European ground The illness rate of area's gout is 0.2%-1.7%.In China, the disease incidence of gout is in rising trend in recent years, China general population Illness rate about 1.14%.The gout disease incidence of China areas of well-being is apparently higher than rural area.Gout has seriously affected patient's Quality of life.Currently, clinically the current kind of gout suppressant is few, the drug of western medical treatment gout mainly has colchicin, non- Steroidal anti-inflammatory medicine, glucocorticoid, cortex hormone of aadrenaline, Glucosamine and IL inhibitor.These drugs are in the treatment All defective, weak curative effect, side effect become greatly the bottleneck of its clinical application.

Summary of the invention

The object of the present invention is to provide Wo Nuolazan to prepare the application in antigout preparation, prepared antigout preparation The gout symptom as caused by hyperuricemia can effectively be prevented.

Specifically, the Wo Nuolazan that the present invention provides free form or pharmaceutically acceptable salt form be used to prepare it is anti- The purposes of gout preparations.Free form or the Wo Nuolazan of pharmaceutically acceptable salt form are able to suppress xanthine oxidase Activity inhibits hypoxanthine and xanthine to be metabolized as the reaction rate of uric acid, to reduce the generation of uric acid.

Preferably, free form or the Wo Nuolazan of pharmaceutically acceptable salt form are applied as stand-alone product.

Preferably, free form or the Wo Nuolazan of pharmaceutically acceptable salt form and one or more other health cares Preparation combines application.Gout is a kind of multifactor disease for participating in morbidity, a kind of antigout preparation is used alone, just for one The treatment of factor improves antigout effect by can achieve the effect for many factors in conjunction with application.

Preferably, being carried out in the case where being applied in the presence of at least one formulation auxiliary agents.Formulation auxiliary agents there are the case where Under, processing performance, mechanical property, optical property, ageing properties and the surface property of preparation, Neng Gouti can be effectively improved The quality of high preparation, it is with good economic efficiency.

Preferably, formulation auxiliary agents are selected from the mixture of one or more of filler, disintegrating agent and lubricant.

Preferably, filler is Lactis Anhydrous.But the type of filler of the present invention is not limited to this, art technology The filler that personnel approve is within the scope of the present invention.The Lactis Anhydrous being added can not only increase tablet and glue The weight and volume of wafer, while the mobility of tablets and capsules compound can be improved, fill die hole uniformly, and Lactis Anhydrous has high stability in air, can with long term storage, easily operated grasp, also not with most of active ingredients Ingredient works.

Preferably, disintegrating agent is crospovidone.But the type of disintegrating agent of the present invention is not limited to this, this field skill The disintegrating agent that art personnel approve is within the scope of the present invention.Crospovidone has very high capillary activity and excellent Water can be promptly absorbed into antigout preparation by different hydration capability, make internal pressure rapidly and be more than the intensity of preparation and fast Speed disintegration.

Preferably, lubricant is silica.Using silica as lubricant, Wo Nuolazan and die wall are reduced Frictional force between hole, while can prevent Wo Nuolazan from sticking together the substance with punch head surface, and reduce rubbing between particle Power is wiped, the processing performance of Wo Nuolazan is significantly improved.

Preferably, the Wo Nuolazan of pharmaceutically acceptable salt form is Vonoprazan fumarate.Pass through free form Wo Nuolazan reacted with pharmaceutically acceptable fumaric acid be made Vonoprazan fumarate, compared with Wo Nuolazan, fumaric acid Wo Nuolazan is stronger to the inhibiting effect of xanthine oxidase.

Preferably, the dosage form of antigout preparation is tablet or capsule or pulvis or granule.Wo Nuolazan is made After different dosage forms, patient is easy to use, is easy to receive, and not only preparation dosage is accurate, while increasing the stability of preparation, subtracts Lack toxic side effect, is also convenient for the storage, transport and carrying of preparation.

Compared with prior art, the invention has the benefit that free form or pharmaceutically acceptable salt form it is fertile Nola praises the activity for being able to suppress xanthine oxidase, prevents hypoxanthine and xanthine from being metabolized as uric acid, to reduce urine The generation of acid, can effectively prevent gout symptom；Gout is a kind of multifactor disease for participating in morbidity, and a kind of anti-pain is used alone Wind preparation improves antigout by can achieve the effect for many factors in conjunction with application just for the treatment of a factor Effect；In the presence of formulation auxiliary agents, the processing performance of preparation, mechanical property, optical property, old can be effectively improved Change performance and surface property, can be improved the quality of preparation, it is with good economic efficiency；Wo Nuolazan is made different After dosage form, patient is easy to use, is easy to receive, and not only preparation dosage is accurate, while increasing the stability of preparation, reduces poison Side effect is also convenient for the storage, transport and carrying of preparation.

Specific embodiment

It is described in further detail by the following examples:

Embodiment 1: influence of the Vonoprazan fumarate to Studies on Animal Models of Hyperuricemic Mice

Experimental animal grouping and dosage: by weight 20-25g mouse 60,6 groups are randomly divided into, every group 10, i.e. sky White control group, model group, drug control group (Allopurinol), antigout injection low, middle and high dose groups.Each group gastric infusion, just The physiological saline 0.2mL, drug control group Allopurinol 1.875g mL of the normal capacity such as group and model group stomach-filling^-1, medicine group presses respectively Mass ratio 4.6875%, 9.375%, 18.75%, it is 0.2mL that daily stomach-filling is primary, continuous 5d；

Modeling: to 5d, after the completion of last stomach-filling, through 1h, in addition to blank group, remaining each group mouse carries out abdomen with uric acid Chamber injects (500mg/Kg), induces Gout Model, blank group injects the physiology salt of isometric(al), after the completion of injection again after 1h to small Mouse carries out eyeball and takes blood；

Blood uric acid value measurement: blood is placed in a centrifuge with 3000rmin^-1It is centrifuged 5min, supernatant is taken to add No. two examinations Agent 2.0mL is mixed, in 3000rmin after 10min^-1Lower centrifugation 5min, takes supernatant, adds No. three, No. four each 0.5mL of reagent, mixes It closes uniformly, with wavelength 690nm, 1cm optical path after 10min, blank tube zeroing measures the absorbance value of each pipe and calculates blood As a result as shown in table 1 below uric acid level is known by 1 knot of table, be administered within continuous oral 5 days, Vonoprazan fumarate uric acid with higher Inhibiting rate has good curative effect to gout.

The influence of 1 Vonoprazan fumarate mouse blood uric acid of table

Group	Uric acid inhibiting rate (%)
		High dose group	67.5
Middle dose group	56.5
		Low dose group	46.4
Model group	/
		Blank control group	/
Allopurinol group	53.7

Note: compared with blank group: △ P < 0.01；The * P < 0.01 compared with model group, * * * * P < 0.01.

A kind of embodiment 2: preparation method of antigout preparation: by 4 parts of citric acids, 8 parts of potassium citrates and 6 parts of citric acids Sodium sieving, mixing obtain premix；By 6 parts of Vonoprazan fumarates, premix, 1 part of Lactis Anhydrous, 1 part of crospovidone, 5 Part silica mixing, adds 0.3 part of magnesium stearate mixing, and tabletting obtains antigout preparation；The citric acid that is added, lemon Sour potassium and sodium citrate can alkalize uric acid, promote uric acid excretion, to reduce uric acid level.

Embodiment 3: a kind of preparation method of antigout preparation: 7 parts of Vonoprazan fumarates and 1 part of crospovidone are mixed It closes, adds 0.2 part of magnesium stearate mixing, tabletting obtains antigout preparation, and the crospovidone being added has very high capillary Water can be promptly absorbed into antigout preparation by pipe activity and excellent hydration capability, and make internal pressure is more than preparation rapidly Intensity and fater disintegration；And prepared antigout preparation is able to suppress kidney proximal tubule and promotes to urinate to the reabsorption of uric acid The excretion of acid, while may additionally facilitate renal tubule to the secreting function of uric acid, the intracorporal uric acid level of people is greatly reduced, is not only kept away Exempt from the generation of chronic gout, and also has certain treatment to diseases such as kidney stone, diabetes, hypertension, hyperlipidemia, heart diseases Effect.

A kind of embodiment 4: preparation method of antigout preparation: by 7 parts of citric acids, 8 parts of potassium citrates and 6 parts of citric acids Sodium sieving, mixing obtain premix；By 4 parts of Vonoprazan fumarates, premix, 1 part of Lactis Anhydrous, 1 part of crospovidone, 5 Part silica mixing adds 0.3 part of magnesium stearate mixing, controls grain, obtain antigout preparation, using silica as lubrication Agent reduces the frictional force between Wo Nuolazan and punch die cinclides, while can prevent Wo Nuolazan from sticking together and punch head surface Substance, and the frictional force between particle is reduced, significantly improve the processing performance of Wo Nuolazan；It is intracorporal by reducing people Uric acid reduces the generation of uric acid crystal salt, it is suppressed that the combination of uric acid crystal salt and immunoglobulin reduces FC receptor pair The stimulation of blood platelet reduces the agglutination and dissolution of blood platelet, avoids the generation of thrombus and the free factor, to effectively prevent The formation of atherosclerosis.

A kind of embodiment 5: preparation method of antigout preparation: by 7 parts of citric acids, 5 parts of potassium citrates and 4 parts of citric acids Sodium sieving, mixing obtain premix；By 9 parts of Vonoprazan fumarates, premix, 1 part of Lactis Anhydrous, 1 part of crospovidone, 3 Part silica mixing, adds 0.2 part of magnesium stearate, 0.01 part of tetramethylenthanediol and 0.0003 part of 3- methyldiphenyl first Ketone mixing, clays into power, obtains antigout preparation, can not only effectively prevent the generation of gout by reducing the intracorporal uric acid of people, And can reduce damage of the hyperuricemia to pancreatic beta cell, avoid the disorder of glycometabolism；Compared to xanthine oxidase, institute The tetramethylenthanediol and 3- methyl benzophenone of addition improve the competitive inhibitory effect of Vonoprazan fumarate, make to combine The content that the alpha-helix and β-of the xanthine oxidase of Vonoprazan fumarate are delivered increases, the content of beta sheet and random coil It reduces, to improve the tightness of xanthine oxidase secondary structure, it is suppressed that the formation of enzyme active center has interrupted yellow fast Electron transmission in purine oxidation process, reduces the oxidative metabolism of xanthine, to reduce the generation of uric acid, further avoids Depositions of the sodium urate crystals in joint and tissue, effectively prevent the generation of gout.

A kind of embodiment 6: preparation method of antigout preparation: by 5 parts of citric acids, 6 parts of potassium citrates and 1 part of citric acid Sodium sieving, mixing obtain premix；By 4 parts of Vonoprazan fumarates, premix, 1 part of Lactis Anhydrous, 2 parts of crospovidone, 3 Part silica mixing adds 0.1 part of magnesium stearate mixing, capsule is made, obtains antigout preparation.

The above embodiments are only used to illustrate the present invention, and not limitation of the present invention, the ordinary skill people of this field Member can also make a variety of changes and modification without departing from the spirit and scope of the present invention.Therefore, all equivalent Technical solution also belong to scope of the invention, scope of patent protection of the invention should be defined by the claims.

Claims (10)

1. The application of vonoprazan in the preparation of anti-gout preparations, characterized in that the use of vonoprazan in free form or pharmaceutically acceptable salt form for the preparation of anti-gout preparations. 2. The application of vonoprazan in the preparation of anti-gout preparations according to claim 1, wherein the vonoprazan in free form or in pharmaceutically acceptable salt form is administered as an independent product. 3. the application of vonoprazan according to claim 1 in the preparation of anti-gout preparations, it is characterized in that: the vonoprazan of described free form or pharmaceutically acceptable salt form and one or more other Administration in combination with health preparations. 4. The application of vonoprazan according to claim 1 in the preparation of an anti-gout preparation, wherein the vonoprazan in the pharmaceutically acceptable salt form is vonoprazan fumarate. 5 . The application of vonoprazan according to claim 1 in the preparation of anti-gout preparations, wherein the dosage form of the anti-gout preparations is tablet or capsule or powder or granule. 6 . The application of vonoprazan according to claim 2 in the preparation of anti-gout preparations, characterized in that: the administration is carried out in the presence of at least one preparation auxiliary. 7. the application of vonoprazan according to claim 6 in the preparation of anti-gout preparations, it is characterized in that: described preparation auxiliary agent is selected from one or more in filler, disintegrating agent and lubricant mixture. 8 . The application of vonoprazan according to claim 7 in the preparation of anti-gout preparations, wherein the filler is anhydrous lactose. 9 . The application of vonoprazan according to claim 7 in the preparation of anti-gout preparations, wherein the disintegrating agent is crospovidone. 10. The application of vonoprazan according to claim 7 in the preparation of anti-gout preparations, wherein the lubricant is silicon dioxide.