CN112370473A

CN112370473A - Statin composition and application thereof in preparation of medicine for treating hyperuricemia

Info

Publication number: CN112370473A
Application number: CN202011403555.2A
Authority: CN
Inventors: 刘丽宏; 刘河; 宫丽丽; 任路路; 万子睿; 于晓佳; 王华光
Original assignee: Beijing Chaoyang Hospital
Current assignee: Beijing Chaoyang Hospital
Priority date: 2020-12-04
Filing date: 2020-12-04
Publication date: 2021-02-19

Abstract

The invention discloses a statin composition, which comprises: the feed comprises the following raw materials in parts by weight: 1-10 parts of HMG-CoA reductase inhibitor, 20000 units of vitamin D1000-. The invention also discloses application of the statin composition in preparing a medicine for treating hyperuricemia. The invention has better treatment effect on hyperlipidemia and hyperuricemia, can reduce adverse reaction of combined medication, does not increase toxicity, and reduces the use amount of main drugs.

Description

Statin composition and application thereof in preparation of medicine for treating hyperuricemia

Technical Field

The present invention relates to medicine. More specifically, the invention relates to a statin composition and application thereof in preparing a medicament for treating hyperuricemia.

Background

Along with the improvement of living standard and the change of dietary structure of people, more and more patients with hyperlipidemia and hyperuricemia are suffering. Hyperuricemia is an independent risk factor of hypertension, cerebral apoplexy, renal failure, metabolic syndrome and the like, and is closely related to the occurrence of cardiovascular and cerebrovascular diseases. Total cholesterol and low-density lipoprotein in blood of a patient with hyperlipidemia are independent risk factors of coronary artery pathological changes and are one of inducers of various cardiovascular and cerebrovascular diseases. Two diseases commonly occur in clinic, the existing treatment of hyperlipemia and hyperuricemia is generally divided into two treatments, and the medicines for regulating lipid and reducing blood uric acid are respectively taken, so that adverse reactions with different degrees, such as nausea, vomiting, transaminase rise and the like, exist. For patients with hyperlipidemia complicated with hyperuricemia, how to ensure the curative effect and safe medication is an important clinical problem.

Disclosure of Invention

An object of the present invention is to solve at least the above problems and to provide at least the advantages described later.

The invention also aims to provide a statin composition and application thereof in preparing a medicament for treating hyperuricemia, wherein the statin composition can have better treatment effects on hyperlipidemia and hyperuricemia, can reduce adverse reactions of combined medication, does not increase toxicity, and reduces the use amount of main medicaments.

To achieve these objects and other advantages in accordance with the present invention, there is provided a statin composition comprising: the feed comprises the following raw materials in parts by weight: 1-10 parts of HMG-CoA reductase inhibitor, 20000 units of vitamin D1000-.

Preferably, it comprises a therapeutically effective amount of an HMG-CoA reductase inhibitor, vitamin D, febuxostat, folic acid, hippophae rhamnoides extract and a pharmaceutically acceptable carrier.

Preferably, the HMG-CoA reductase inhibitor comprises lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin, or pitavastatin.

Preferably, the medicament is formulated into a pharmaceutically acceptable dosage form.

Preferably, the dosage form comprises tablets, capsules, granules, disintegrating agents, dispersing agents, pills, oral liquid and films.

The statin composition is used for preparing a medicament for reducing blood fat and blood uric acid and reducing adverse reactions.

Preferably, the adverse reaction is emesis, elevated transaminase.

The invention at least comprises the following beneficial effects:

firstly, the formula of the invention has synergistic effect, can improve the curative effect of statins on hyperlipemia and the curative effect of febuxostat on reducing uric acid, does not increase toxicity, and simultaneously reduces the use amount of statins and febuxostat and reduces the medication cost;

secondly, the invention can reduce the adverse reaction of combined medication of statin and febuxostat, and is superior to the combination of statin and febuxostat which is singly used.

Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention.

Detailed Description

The present invention is described in further detail below with reference to specific details so that those skilled in the art can practice the invention with reference to the description.

It will be understood that terms such as "having," "including," and "comprising," as used herein, do not preclude the presence or addition of one or more other elements or groups thereof.

It is to be noted that the experimental methods described in the following embodiments are all conventional methods unless otherwise specified, and the reagents and materials are commercially available unless otherwise specified.

The solid preparation for oral administration of the medicine can be in the forms of tablets, capsules, granules, disintegrating agents, dispersing agents, pills, films and the like. The above dosage forms are mixed with three active ingredients and at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, agar, pectin, magnesium aluminosilicate, etc., and other adjuvants, such as lubricant such as magnesium stearate, disintegrating agent such as calcium cellulose glycolate, stabilizer such as lactose, etc., cosolvent such as glutamic acid or aspartic acid, etc., and sugar coating such as sucrose, gelatin, hypromellose, etc., or gastric or enteric film can be coated on the outside. Liquid preparations for oral administration may be in the form of oral liquids, emulsions, suspensions, syrups, and the like. The above dosage forms incorporate the three active ingredients together with at least one inert diluent, such as purified water, ethanol, etc., and may further contain other adjuvants, such as wetting agents, suspending agents, sweetening, flavoring, perfuming, and preservative agents, etc.

< example 1>

The statin composition comprises the following raw materials in parts by weight: simvastatin 5mg, vitamin D10000 units, febuxostat 0.5mg, folic acid 1mg and sea buckthorn extract 0.3 mg. The daily dosage is 20 mg/day.

< example 2>

The statin composition comprises the following raw materials in parts by weight: 10mg of lovastatin, 20000 units of vitamin D, 5mg of febuxostat, 0.1mg of folic acid and 0.1mg of sea buckthorn extract. The daily dosage is 40 mg/day.

< example 3>

The statin composition comprises the following raw materials in parts by weight: 1mg of pitavastatin, 1000 units of vitamin D, 4mg of febuxostat, 0.5mg of folic acid and 0.5mg of sea buckthorn extract. The daily dosage is 2 mg/day.

< toxicity test in mice >

C57 male mice 8 weeks old, half male and female, and 18-22g in body weight were randomly divided into an administration group and a control group, each of which was 20 mice each, half male and female, and the drugs prepared in examples 1-3 were used in the administration groups, respectively, and the daily dose was 6 times/day. Before the test, the mice were fasted for 12 hours, the appearance and activity of the mice were observed and recorded, the mice were weighed, and each group of mice was gavaged for 7 days. Immediately observing the toxic reaction of the mice after administration, continuously recording for seven days, including whether the mice have abnormalities of five sense organs, four limbs, behaviors, spirit, appetite, excrement and urine and the like, and timely performing autopsy for pathological examination if the mice die.

The results show that the mice are normal in diet, activity and hair color excrement after drenching the drug, and no animal dies. The body weight of mice in the administration group is not obviously changed compared with that of the control group. After the test is finished, the spinal cord of the mouse is pulled off and dissected, no abnormality is found in the internal organs such as heart, liver, spleen, lung, kidney and the like, and no abnormality and tumor is found in the tissues, organs and abdominal cavity. As can be seen, the administration amount of the gavage of the mice is 3 times higher than the clinical dosage, and no acute toxic reaction is seen.

< test of therapeutic efficacy of hypertriglyceridemia with hyperuricemia >

8-week-old C57 male mice, each half of male and female, weighing 18-22g, were randomly divided into blank control group, model control group, simvastatin + febuxostat group, example 1 drug group, lovastatin + febuxostat group, example 2 drug group, pitavastatin + febuxostat group, example 3 drug group, 5 animals per group, each half of male and female, wherein in addition to the blank control group, other groups were fed with hyperuricemic feed (with animal uric acid and uricase inhibitor), and molding of hyperuricemia animals was performed (see Life Science of the periodic study, "Substituted cyclic acetic acid potential-gout agents") for 3 weeks, fasting for 12 hours, blood drawing assay TC, TG, BUA levels were elevated, and TC was not greatly changed. The statistical difference (p is less than 0.05), the model forming is successful, namely the characteristic of hypertriglyceridemia accompanied by hyperuricemia is realized, the dosage of simvastatin + febuxostat group is the same as that of the medicine group in the example 1, the dosage of lovastatin + febuxostat group is the same as that of the medicine group in the example 2, the dosage of pitavastatin + febuxostat group is the same as that of the medicine group in the example 3, and the daily dosage is 2 times/day. Each group of mice was gavaged for 56 consecutive days. Then, blood was collected intravenously, and TC (total cholesterol), TG (triglyceride), BUA (blood uric acid) were measured, and the measurement calculation results are shown in table 1.

TABLE 1

Compared with a model control group, TC and BUA levels of all groups are obviously reduced, TG level changes are small, wherein the drug effects of the drug group in example 1, the drug group in example 2 and the drug group in example 3 are better under the condition that the dosage of main drugs of statin and febuxostat is slightly low, which shows that the statin drugs and statin combined drugs can improve high triglyceride and the statin combined drug has better treatment effect. The level of the comparative example 1 group is close to that of the simvastatin group and is slightly worse than that of the drug group in the example 1, which is probably because the formula of simvastatin, vitamin D, febuxostat, folic acid and sea buckthorn extract has synergistic effect, which is beneficial to the degradation of cholesterol and the effect of reducing serum uric acid, and has no obvious side effect when being combined with statins. According to clinical research, the hyperuricemia, the hypertension and the hyperlipidemia are closely related, and the cooperative treatment of the medicines for reducing the blood fat and the uric acid can be more beneficial to the treatment of diseases, so that the control and the treatment of the uric acid are required to be paid attention to when the relevant metabolic diseases are treated, and the medicines can play a complementary role.

< adverse reaction test >

8-week-old C57 male mice, each half of male and female, weighing 18-22g, were randomly divided into blank control group, model control group, simvastatin + febuxostat group, example 1 drug group, lovastatin + febuxostat group, example 2 drug group, pitavastatin + febuxostat group, example 3 drug group, 10 animals each, and each half of male and female, wherein except for blank control group, other groups were fed with hyperuricemic feed (with animal uric acid and uricase inhibitor), and were continuously fed for 3 weeks, fasted for 12h, and blood test TC, TG, BUA levels, and TC changes little. The statistical difference (p is less than 0.05), the model forming is successful, namely the characteristic of hypertriglyceridemia accompanied by hyperuricemia is realized, the dosage of simvastatin + febuxostat group is the same as that of the medicine group in the example 1, the dosage of lovastatin + febuxostat group is the same as that of the medicine group in the example 2, the dosage of pitavastatin + febuxostat group is the same as that of the medicine group in the example 3, and the daily dosage is 2 times/day. Each group of mice was gavaged for 56 consecutive days. Then, blood was collected intravenously, ALT (alanine aminotransferase) and AST (aspartate aminotransferase) were measured, and the measurement results are shown in table 2. Dissecting, cutting antrum tissue, washing with normal saline, soaking in 10% neutral formalin solution, taking out, dehydrating antrum tissue with ethanol, removing xylene, soaking in paraffin, embedding in paraffin, slicing into 4 μm, HE staining, and observing pathological result. EGF (epidermal growth factor) was measured in the mucosa of antral tissue by radioimmunoassay and the measurement and calculation are shown in Table 3.

TABLE 2

Group of	ALT(U/L)	AST(U/L)
			Blank control group	41.24±8.56	134.23±32.48
Model control group	54.36±5.45	151.36±21.76
			Simvastatin + febuxostat group	76.78±10.32	183.57±26.34
Example 1 drug group	60.23±6.49	157.50±17.25
			Lovastatin + febuxostat group	70.59±8.49	188.75±31.26
Example 2 drug group	57.99±6.54	160.37±30.47
			Pitavastatin + febuxostat group	72.73±8.58	190.67±25.66
Example 3 drug group	58.50±7.44	166.89±16.25

Compared with a blank control group, the ALT and AST of the drug group in example 1, the drug group in example 2 and the drug group in example 3 are reduced compared with the ALT and AST of the simvastatin + febuxostat group, the lovastatin + febuxostat group and the pitavastatin + febuxostat group, which indicates that the combined medication of statin and febuxostat may cause the increase of transaminase, and the drug group in example 1, the drug group in example 2 and the drug group in example 3 can effectively reduce ALT and AST and reduce adverse reactions.

The mucosa of the blank control group is pink and glossy, the surface of the mucosa fold is smooth and has a regular trend, the mucosa of the model control group is reddish and not glossy, the surface of the mucosa fold is thinned and flattened, and the trend is irregular, the mucosa of the simvastatin + febuxostat group, the lovastatin + febuxostat group and the pitavastatin + febuxostat group are tragic and white, the mucosa is dull, the surface of the mucosa fold is atrophious and disordered, and the mucosa of the drug group in example 1, the drug group in example 2 and the drug group in example 3 is pale, and a new tissue is generated on the surface of the fold, so that the gastrointestinal tissue is repaired.

TABLE 3

Group of	EGF(ng/L)
		Blank control group	0.50±0.15
Model control group	0.42±0.12
		Simvastatin + febuxostat group	0.36±0.04
Example 1 drug group	0.44±0.13
		Lovastatin + febuxostat group	0.38±0.09
Example 2 drug group	0.46±0.10
		Pitavastatin + febuxostat group	0.35±0.12
Example 3 drug group	0.44±0.14

Compared with the blank control group, the EGF in the drug group in example 1, the drug group in example 2 and the drug group in example 3 is increased compared with the EGF in the simvastatin + febuxostat group, the lovastatin + febuxostat group and the pitavastatin + febuxostat group, which indicates that the combined administration of the statin and the febuxostat may damage the cell growth, and the EGF in the drug group in example 1, the EGF in example 2 and the EGF in example 3 can be effectively increased, the gastric cell proliferation is promoted and the gastrointestinal tract is protected.

< typical cases >

Case 1: a male patient is 78 years old, and patients with hyperlipidemia complicated with hyperuricemia complain about 'discontinuous joint swelling and pain is nearly 5 years'. Serum uric acid 605 mu mol/L (reference range 208-428 mu mol/L). After taking simvastatin 20mg, qd and febuxostat 40mg, qd for 15 days, the liver function is regularly checked, and the liver function abnormality, ALT 298.1U/L and AST 365.3U/L, accompanied with vomiting symptoms, is found. Excluding other causes, considering the possibility of liver damage, adjusting the drugs, taking the drugs according to the drug combination of example 1 for 10 days continuously, reviewing liver function, ALT 120.1U/L, AST 208.3U/L, and normal uric acid: blood uric acid 328 mu mol/L, vomiting symptom disappeared.

Case 2: a male patient aged 49 years is suffering from gout symptoms of patients with hyperlipidemia complicated with hyperuricemia and suffering from fishermen working for a long time, and the uric acid content is about 550 mu mol/L before 3 years. Lovastatin 20mg, qd, febuxostat 40mg, qd were administered. After 10 days, liver function was checked regularly, and "liver function abnormality", ALT 306.1U/L, AST 311.3U/L, and vomiting symptoms were found. Excluding other causes, considering the possibility of liver injury, adjusting the drugs, taking the drugs according to the drug combination of example 2 for 7 days, and reviewing liver function, ALT 168.1U/L, AST 132.3U/L, serum uric acid 315 mu mol/L, and disappearance of vomit symptoms.

The number of apparatuses and the scale of the process described herein are intended to simplify the description of the present invention. Applications, modifications and variations of the present invention will be apparent to those skilled in the art.

While embodiments of the invention have been disclosed above, it is not limited to the applications set forth in the description and the embodiments, which are fully applicable in various fields of endeavor to which the invention pertains, and further modifications may readily be made by those skilled in the art, it being understood that the invention is not limited to the details shown and described herein without departing from the general concept defined by the appended claims and their equivalents.

Claims

1. A statin composition, comprising: the feed comprises the following raw materials in parts by weight: 1-10 parts of HMG-CoA reductase inhibitor, 20000 units of vitamin D1000-.

2. The statin composition of claim 1, comprising a therapeutically effective amount of an HMG-CoA reductase inhibitor, vitamin D, febuxostat, folic acid, a hippophae rhamnoides extract, and a pharmaceutically acceptable carrier.

3. The statin composition of claim 1, wherein the HMG-CoA reductase inhibitor comprises lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin, or pitavastatin.

4. The statin composition of any of claims 1-3, wherein the drug is formulated in a pharmaceutically acceptable dosage form.

5. The statin composition of claim 4, wherein the dosage form comprises a tablet, a capsule, a granule, a disintegrant, a dispersant, a pill, an oral liquid, a film.

6. Use of the statin composition of any of claims 1-5 in the manufacture of a medicament for reducing blood lipid and blood uric acid that reduces adverse effects.

7. The use of claim 6, wherein the adverse reaction is emesis, increased transaminase.