CN112294969A - Statin composition and application thereof in preparation of lipid-lowering medicines for inhibiting liver and kidney toxicity - Google Patents

Abstract

The invention discloses a statin composition which 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 lipid-lowering medicines for inhibiting liver and kidney toxicity. The invention has better hyperlipemia treatment effect, can reduce the liver and kidney toxicity of statins, does not increase the toxicity and reduces the using amount of statins.

Description

Statin composition and application thereof in preparation of lipid-lowering medicines for inhibiting liver and kidney toxicity

Technical Field

The present invention relates to medicine. More specifically, the invention relates to an application of a statin composition in preparing a lipid-lowering medicament for inhibiting liver and kidney toxicity.

Background

The statins are HMG-CoA reductase inhibitors with a naphthyl ester ring skeleton structure, namely HMG-CoA reductase inhibitors, and represent drugs such as lovastatin, pravastatin, simvastatin and the like. Statins have good curative effect on patients with hyperlipidemia, but in clinical application for more than 20 years, statins show various toxic and side effects, particularly the liver and kidney toxicity, and can cause asymptomatic transaminase rise, cholestasis, hepatitis, even acute liver failure, proteinuria and the like. For patients taking statins for a long time, how to ensure the safety and effectiveness of 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 the application of the statin composition in preparing lipid-lowering medicines for inhibiting liver and kidney toxicity, which can have better treatment effect on hyperlipidemia, and simultaneously can reduce the liver and kidney toxicity of statins without increasing toxicity and reduce the using amount of statins.

To achieve these objects and other advantages in accordance with the present invention, there is provided a statin composition comprising 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, pachyman, Acorus gramineus extract and a pharmaceutically acceptable carrier.

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

Preferably, the composition 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 lipid-lowering medicines for inhibiting liver and kidney toxicity.

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, does not increase toxicity, and simultaneously reduces the using amount of statins and the medication cost;

secondly, the invention can reduce the liver and kidney toxicity of statins, improve the BUN, UA, ALT, AST, GSH-Px, MDA and kidney index level, and is superior to the combination of statin and vitamin D which is singly used;

thirdly, the invention can reduce the damage of the liver and the kidney through clinical trial, and the functions of the liver and the kidney are effectively improved after the drug is taken for reexamination.

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 further described in detail below with reference to examples to enable those skilled in the art to 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, pachyman 0.3mg, and rhizoma Acori Graminei extract 0.02 mg. The daily dosage is 20 mg/day.

< example 2>

The statin composition comprises the following raw materials in parts by weight: lovastatin 10mg, vitamin D20000 unit, pachyman 0.5mg, and rhizoma Acori Graminei extract 0.02 mg. The daily dosage is 40 mg/day.

< example 3>

The statin composition comprises the following raw materials in parts by weight: pitavastatin 1mg, vitamin D1000 units, pachyman 0.1mg, Acorus gramineus soland extract 0.01 mg. The daily dose is 2 mg/day.

< comparative example 1>

The statin composition comprises the following raw materials in parts by weight: simvastatin 5mg, vitamin D10000 units.

< comparative example 2>

The statin composition comprises the following raw materials in parts by weight: simvastatin 5mg, vitamin D10000 units, pachyman 0.03 mg.

< comparative example 3>

The statin composition comprises the following raw materials in parts by weight: simvastatin 5mg, vitamin D3000 unit, and grassleaved sweetflag rhizome extract 0.002 mg.

< 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 hyperlipemia >

Using 8-week-old C57 male mice each half of male and female mice, weighing 18-22g, randomly dividing into blank control group, model control group, simvastatin group, example 1 drug group, lovastatin group, example 2 drug group, pitavastatin group, example 3 drug group and comparative example 2-3 group, each group having 5 mice each half of male and female mice, wherein except blank control group fed with normal feed, other groups are fed with high fat feed for modeling, continuously fed for 6 weeks, and blood is drawn for assaying TC, TG, HDL-C, LDL-C levels, TC, TG, LDL-C levels are all increased, HDL-C levels are decreased, statistical difference (p < 0.05) is existed, modeling is successful, simvastatin group and comparative example 2-3 group are administered with example 1 drug group, lovastatin group is administered with example 2 drug group, pitavastatin group is administered with example 3 drug group, the daily dose is 2 times per day, and the administration is continued for 56 days. Each group of mice was gavaged for 56 consecutive days. Then, blood was collected intravenously, and TC (total cholesterol), TG (triglyceride), HDL-C (high density lipoprotein), LDL-C (low density lipoprotein) levels were measured, and the results of measurement and calculation are shown in Table 1.

TABLE 1

Compared with a model control group, the TC, TG and LDL-C levels of all groups are obviously reduced, the HDL-C level is obviously increased, 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 statin drugs is slightly lower, which shows that the statin drugs and statin combined drugs can improve hyperlipidemia and the statin combined drug treatment effect is better. The levels of comparative examples 2-3 were close to those of simvastatin group and slightly worse than those of the drug group of example 1, probably due to the synergistic effect of the formulations of simvastatin, vitamin D, pachyman, and acorus gramineus extract, and the components like pachyman and asarone can increase the density of hepatic LDL receptor, which is beneficial to the degradation of cholesterol, and at the same time, there is no significant side effect when combined with statins.

< test for suppressing hepatotoxicity and Kidney >

8-week-old C57 male mice were randomly divided into a blank control group, a model control group, a simvastatin group, a drug group of example 1, a lovastatin group, a drug group of example 2, a pitavastatin group, a drug group of example 3 and a comparative example 1, wherein each group had 5 animals each half of male and female, and except for the blank control group fed with normal feed, the other groups were fed with high-fat feed for high-fat animal molding and were continuously fed for 6 weeks, and the levels of TC, TG and HDL-C, LDL-C were all increased, HDL-C was decreased, and were statistically different (p < 0.05), and the molding was successful, and the amount of administered in the simvastatin group was the same as that in the drug group of example 1, the amount of administered in the lovastatin group was the same as that in the drug group of example 2, the amount of pitavastatin group was the same as that in the drug group of example 3, and the daily amount of administration was 2 times/day. Each group of mice was gavaged for 56 consecutive days. Then, blood is collected intravenously, the levels of serum urea (BUN), Uric Acid (UA), glutamic-pyruvic transaminase (ALT) and glutamic-oxaloacetic transaminase (AST) are measured, then weighing is carried out, the body weight is recorded and killed, the left kidney is taken and cleaned, the surface moisture is absorbed, weighing is carried out, the kidney index is calculated, the kidney index is the weight of the left kidney/the body weight, the result is shown in the table 2-3, the left kidney is taken for homogenate, the supernatant is taken, and the contents of glutathione peroxidase (GSH-Px) and Malondialdehyde (MDA) are measured and measured by a colorimetric method and a thiobarbituric acid (TBA) method respectively, and the result is shown in the table 4.

TABLE 2

Group of	ALT(U/L)	AST(U/L)
			Blank control group	43.67±0.66	90.20±0.56
Model control group	62.45±0.43	138.75±0.72
			Simvastatin group	53.27±0.55	114.87±0.29
Example 1 drug group	46.08±0.43	101.25±0.38
			Comparative example 1 group	50.27±0.22	108.35±0.81
Lovastatin group	54.13±0.41	115.25±0.68
			Example 2 drug group	45.62±0.14	102.55±0.62
Pitavastatin group	51.89±0.30	113.21±0.27
			Example 3 drug group	44.80±0.32	101.35±0.80

TABLE 3

TABLE 4

Group of	GSH-Px(U/mg proain)	MDA(nmol/mg protain)
			Blank control group	104.31±9.90	3.61±0.56
Model control group	78.22±5.32	6.80±1.21
			Simvastatin group	84.56±3.26	5.94±1.13
Example 1 drug group	95.62±4.57	4.67±0.52
			Comparative example 1 group	88.89±2.61	5.04±2.09
Lovastatin group	87.78±6.50	6.12±1.08
			Example 2 drug group	98.77±5.03	4.90±0.22
Pitavastatin group	82.24±4.17	5.68±0.78
			Example 3 drug group	94.65±4.07	4.46±1.26

As can be seen from Table 2, compared with the blank control group, the mice in the model control group had significantly impaired liver function and significantly increased ALT and AST. ALT and AST levels were significantly reduced after administration of the example 1, example 2, and example 3 drug groups, and were greater in magnitude than the statin group. The group of comparative example 1 had better levels than the simvastatin group, but was slightly worse than the drug group of example 1, probably because the formulations of simvastatin, vitamin D, pachyman, and acorus gramineus extract were synergistic to effectively alleviate liver damage caused by high-fat diet.

As can be seen from Table 3, compared with the blank control group, the kidney function of the mice in the model control group is obviously damaged, and the BUN, UA and kidney index are obviously increased. After the drug group of example 1, the drug group of example 2 and the drug group of example 3 were administered, the levels of BUN, UA and renal index were significantly reduced and the amplitudes were greater than those of the statin group. The group of comparative example 1 was superior to the simvastatin group, but was slightly inferior to the group of the drug of example 1, probably because the formulations of simvastatin, vitamin D, pachyman, and acorus gramineus extract were synergistic to effectively alleviate kidney damage caused by high-fat diet.

As can be seen from Table 4, compared with the blank control group, the kidney function of the mice in the model control group is obviously damaged, the GSH-Px is obviously reduced, and the MDA is obviously increased. After the drug group of example 1, the drug group of example 2 and the drug group of example 3 were administered, GSH-Px was significantly increased, MDA was significantly decreased, and the magnitude was greater than that of the statin group. The group of comparative example 1 has better level than the group of simvastatin, but is slightly worse than the group of the drug of example 1, probably because the formulations of simvastatin, vitamin D, pachyman and acorus gramineus extract, which can reverse redox imbalance to generate anti-oxidation effect in vivo, act synergistically to effectively alleviate kidney injury caused by high-fat diet.

< clinical typical cases >

A female patient is 68 years old and has hyperlipidemia, 20mg and qd of simvastatin are taken for a long time, liver function is checked regularly, and 'liver function abnormality', ALT 221.1U/L and AST 369.3U/L are found. Excluding other causes, considering the possibility of drug-induced liver damage, drugs were adjusted and taken in combination according to example 1 for 7 days, and liver function was reviewed, ALT 101.1U/L, AST 210.3U/L.

A female patient is 70 years old, has the diabetes history of 3 years, is accompanied by hyperlipidemia, takes 20mg and qd of lovastatin for a long time, examines the functions of liver and kidney, and finds that the disease is abnormal in kidney function and BUN is 23.6mmol/L, UA 821.2 mu mol/L, Cr 205.1.1 mu mol/L. Excluding other causes, considering the possibility of renal injury, the drugs were adjusted and taken in combination according to example 2 for 7 days, and the renal function was reviewed for three items, BUN 10.6mmol/L, UA 410.21 mol/L, Cr 109.1.1. mu. mol/L.

A female patient, 55 years old, is hyperlipemia, takes 2mg of pitavastatin and qd for a long time, examines liver and kidney functions, finds 'liver function abnormality', ALT 301.1U/L and AST 401.2U/L. Excluding other causes, considering the possibility of drug-induced liver damage, the drugs were adjusted and taken in combination according to example 3 for 7 days, and liver function was reviewed, ALT 98.1U/L, AST 106.3U/L.

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 (6)

1. The statin composition is characterized by comprising 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, pachyman, an extract of acorus gramineus, 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 composition 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 preparation of a lipid-lowering medicament that inhibits hepatorenal toxicity.