阅读说明：本技术 一种治疗肾结石的药物组合物及其用途 (Pharmaceutical composition for treating kidney stone and application thereof ) 是由 马明 徐芳 张景欣 于 2020-07-20 设计创作，主要内容包括：本发明公开了一种治疗肾结石的药物组合物及其用途。特别地,本发明提供的治疗肾结石的药物组合物是以5-甲基-4-[({(1R,2R)-2-[4-(3-甲基-1H-吡唑-5-基)苯甲酰基]-环己基}羰基)氨基]-1H-吡唑-3-甲酰胺为有效成分制成的固体分散体。本发明还涉及所述化合物在制备用于治疗肾结石的药物中的用途。(The invention discloses a pharmaceutical composition for treating kidney stone and application thereof. Particularly, the pharmaceutical composition for treating kidney stones provided by the invention is a solid dispersion prepared by using 5-methyl-4- [ ({ (1R,2R) -2- [4- (3-methyl-1H-pyrazol-5-yl) benzoyl ] -cyclohexyl } carbonyl) amino ] -1H-pyrazole-3-formamide as an active ingredient. The invention also relates to the use of said compounds for producing medicaments for treating kidney stones.)

1. The pharmaceutical composition for treating kidney stones is characterized in that the pharmaceutical composition is in the form of solid dispersion, the solid dispersion is prepared by taking a compound shown in a formula I, polyoxyethylene 40 hydrogenated castor oil, PEG6000, poloxamer 188, microcrystalline cellulose and copovidone as raw materials, wherein the mass ratio of the compound shown in the formula I, the polyoxyethylene 40 hydrogenated castor oil, the PEG6000, the poloxamer 188, the microcrystalline cellulose and the copovidone is 0.5-2:0.2-0.8:1-4:0.2-0.8:1-4:0.3-1.2

2. The pharmaceutical composition for treating kidney stones according to claim 1, characterized in that the mass ratio between the compound of formula I, polyoxyethylene 40 hydrogenated castor oil, PEG6000, poloxamer 188, microcrystalline cellulose and copovidone is 0.5-2:0.4:2:0.4:2: 0.6.

3. A process for preparing a pharmaceutical composition for the treatment of kidney stones according to claim 1 or 2 comprising the steps of:

(1) dissolving the compound of the formula I and PEG6000 in a proper amount of solvent, then sequentially adding polyoxyethylene 40 hydrogenated castor oil and poloxamer 188, dissolving and uniformly mixing to obtain a solution;

(2) and (2) adding microcrystalline cellulose and copovidone into a fluidized bed, spraying the solution obtained in the step (1) into the fluidized bed in a top spraying mode for granulation, drying and sieving to obtain the pharmaceutical composition.

4. The process of claim 3, the solvent is selected from the group consisting of ethanol, acetone, dichloromethane, tetrahydrofuran, and mixtures thereof.

5. The method of claim 4, wherein the solvent is ethanol-dichloromethane in a volume ratio of 3: 1.

6. A pharmaceutical formulation for treating kidney stones, consisting of the pharmaceutical composition for treating kidney stones according to claim 1 or 2 and a pharmaceutically acceptable carrier.

7. The pharmaceutical formulation for treating kidney stones according to claim 6, wherein the pharmaceutical formulation is solid and the pharmaceutically acceptable carrier is selected from a mixture of one or more of conventional pharmaceutical fillers, disintegrants, binders, lubricants.

8. Use of a compound of formula I for the preparation of a medicament for the treatment of kidney stones

9. The use according to claim 8, wherein the kidney stone is a kidney stone whose main component is calcium oxalate.

Technical Field

The invention relates to the technical field of medicines, in particular to a pharmaceutical composition for treating kidney stones and application thereof.

Background

Renal calculus (renal calculi) is a disease caused by abnormal accumulation of crystal substances in the kidney, is a common disease and frequently-occurring disease of the urinary system, and preferably occurs in young and middle-aged people, wherein nearly 80 percent of the renal calculus is calcium oxalate calculus, 15 percent of the renal calculus is calcium phosphate calculus, and the balance is uric acid calculus, cystine calculus, infectious calculus and the like. The process of forming kidney stones can be attributed to that certain factors cause the concentration of crystal substances in urine to be increased or the solubility of the crystal substances to be reduced, and the crystal substances are in a supersaturated state, so that crystals are separated out and locally grow and accumulate to finally form stones. About 40% to 75% of kidney stone patients have different levels of lumbago, mainly manifested as soreness and discomfort in the waist, or dull pain when physical activity increases. If the treatment is not performed in time, urinary tract obstruction, kidney tissue injury, urinary infection and even renal failure and other adverse effects are easily caused.

The forming mechanism of kidney stones is not completely clear, and abnormal biochemical indexes, renal tubular epithelial cell injury, nanobacteria biomineralization, abnormal cell signal transduction, metabolic diseases and the like are considered as possible factors for forming the stones. In addition, nutritional deficiencies (vitamin B6 deficiency, magnesium-deficient diet), prolonged bed rest, urinary tract obstruction, infection, foreign body and drug use are also common causes of calculus formation.

The treatment of kidney stone is a problem which is difficult in medical field because the cause of kidney stone is not clear and the recurrence rate is high after 3-5 years. At present, in clinical medicine, the renal calculus is mainly treated by means of open operation calculus removal, percutaneous nephroscope calculus removal, laparoscopic calculus removal, ureteroscope calculus removal, ultrasonic calculus removal and the like. However, these treatments are highly damaging to the body, prone to bleeding during the operation, and have a high recurrence rate. Therefore, there is an urgent need in the art to find non-invasive litholytic therapies.

Disclosure of Invention

The technical problem to be solved by the invention is to overcome the defects of the prior art and to find a medicine which can be used for treating kidney stones by non-invasive administration.

Through intensive studies, the inventors of the present application found that 5-methyl-4- [ ({ (1R,2R) -2- [4- (3-methyl-1H-pyrazol-5-yl) benzoyl ] -cyclohexyl } carbonyl) amino ] -1H-pyrazole-3-carboxamide, particularly a solid dispersion preparation thereof, has a better therapeutic effect on kidney stone model rats, and thus completed the present invention.

Accordingly, the invention provides a pharmaceutical composition for treating kidney stones and application thereof. Specifically, the pharmaceutical composition for treating kidney stones provided by the invention is a solid dispersion prepared from 5-methyl-4- [ ({ (1R,2R) -2- [4- (3-methyl-1H-pyrazol-5-yl) benzoyl ] -cyclohexyl } carbonyl) amino ] -1H-pyrazole-3-carboxamide (hereinafter referred to as "compound of formula I") as an active ingredient.

Accordingly, in one embodiment, the present invention provides a pharmaceutical composition for treating kidney stones, which is characterized in that the pharmaceutical composition is in the form of a solid dispersion prepared from the compound of formula I, polyoxyethylene 40 hydrogenated castor oil, PEG6000, poloxamer 188, microcrystalline cellulose, and copovidone as raw materials, wherein the mass ratio between the compound of formula I, the polyoxyethylene 40 hydrogenated castor oil, the PEG6000, the poloxamer 188, the microcrystalline cellulose, and the copovidone is 0.5-2:0.2-0.8:1-4:0.2-0.8:1-4: 0.3-1.2.

For example, in one embodiment, the mass ratio between the compound of formula I, polyoxyethylene 40 hydrogenated castor oil, PEG6000, poloxamer 188, microcrystalline cellulose and copovidone is 0.5-2:0.4:2:0.4:2: 0.6.

In one embodiment, the present invention also provides a method for preparing the pharmaceutical composition for treating kidney stones, comprising the steps of:

(1) dissolving the compound of the formula I and PEG6000 in a proper amount of solvent, then sequentially adding polyoxyethylene 40 hydrogenated castor oil and poloxamer 188, dissolving and uniformly mixing to obtain a solution;

(2) and (2) adding microcrystalline cellulose and copovidone into a fluidized bed, spraying the solution obtained in the step (1) into the fluidized bed in a top spraying mode for granulation, drying and sieving to obtain the pharmaceutical composition.

In a preferred embodiment, the solvent is selected from the group consisting of ethanol, acetone, dichloromethane, tetrahydrofuran and mixtures thereof, preferably ethanol-dichloromethane in a volume ratio of 3: 1.

By "suitable amount" is meant an amount sufficient to dissolve all materials including the compound of formula I, polyoxyethylene 40 hydrogenated castor oil, PEG6000, poloxamer 188, microcrystalline cellulose and copovidone. This amount is readily determined by one skilled in the art in accordance with conventional pharmaceutical practice.

In another aspect of the present invention, a pharmaceutical preparation for treating kidney stones is provided, which comprises the above pharmaceutical composition (solid dispersion) and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical formulation is a solid and the pharmaceutically acceptable carrier is selected from a mixture of one or more of conventional pharmaceutical fillers, disintegrants, binders, lubricants.

The structural formula of the active ingredient 5-methyl-4- [ ({ (1R,2R) -2- [4- (3-methyl-1H-pyrazol-5-yl) benzoyl ] -cyclohexyl } carbonyl) amino ] -1H-pyrazole-3-carboxamide in the pharmaceutical composition for treating kidney stones of the present invention is as follows:

this compound is disclosed in International patent publication No. WO2016/177703A1 (see example 22). This patent document relates generally to novel pyrazole derivatives that inhibit 5-lipoxygenase activating protein and thus the production of leukotrienes. It is believed that the compounds may be used in the treatment and/or prevention of cardiovascular diseases such as arteriosclerosis, coronary heart disease, heart failure, coronary artery disease and abdominal aortic aneurysm. However, this patent document does not mention the use of said compounds for the treatment of kidney stones, which constitutes an unexpected finding of the present invention.

A further aspect of the invention relates to the novel pharmaceutical use of the compounds of formula I, namely the use of the compounds of formula I for the preparation of a medicament for the treatment of kidney stones. Preferably, the kidney stone is a kidney stone whose main component is calcium oxalate.

Preferred embodiments of the present invention and effects thereof will be described below with reference to specific embodiments. However, it should be understood that the description of these preferred embodiments is only for further elaboration of the advantages and effects of the invention, and is in no way intended to limit the scope of the claims.

Detailed Description