Pharmaceutical composition containing thyroxine receptor stimulant and folic acid substances

Abstract

The invention provides a pharmaceutical composition. The pharmaceutical composition is composed of a thyroxine receptor beta agonist, folic acid substances and pharmaceutically acceptable auxiliary materials. The invention also relates to application of the composition in preparation of drugs for treating chronic fatty liver diseases. The pharmaceutical composition has the advantages that the pharmaceutical composition can be used for treating the fatty liver accompanied by hypothyroidism, and adverse reactions generated by independently taking a thyroid receptor beta agonist can be reduced.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition containing a thyroid hormone receptor agonist and a folic acid substance, which is used for treating chronic fatty liver disease, and is particularly suitable for treating fatty liver associated with hypothyroidism. The present invention belongs to the field of pharmacy. Background Art

[0002] Thyroid hormone (TH) is a substance secreted by thyroid epithelial cells, which plays a key role in regulating many physiological processes such as neural development and energy metabolism. Thyroid hormone can act on the liver and adipose tissue to regulate lipid metabolism. Therefore, hypothyroidism (hypothyroidism) is usually associated with abnormal lipid metabolism, which may cause fat accumulation in the liver, leading to insulin resistance in the liver, and further may lead to non-alcoholic fatty liver disease (NAFLD). Although hypothyroidism and NAFLD seem to have some common pathophysiological mechanisms, there is no direct causal relationship between the two diseases.

[0003] After thyroid hormone is released into the blood, it exerts its effects by binding to receptors on target tissues. Thyroid hormone receptors (THR) are mainly divided into two subtypes, α and β. When thyroid hormone binds to receptor α (THR-α), it mainly regulates body temperature, basal metabolism, etc., while when it binds to receptor β (THR-β), it promotes the expression of thyrotropin-releasing hormone (TRH) in the liver and improves lipid metabolism. Therefore, in theory, THR-β selective agonists can be tried for the treatment of NAFLD because of their multiple regulatory functions of liver lipid metabolism. However, the current THR-β agonists are not ideal in their selectivity for receptor β, and there are varying degrees of receptor α activation. In addition to affecting body temperature and basal metabolism, they also have side effects such as cardiotoxicity, including tachycardia, atrial arrhythmia, heart failure, muscle atrophy, osteoporosis, fatigue, etc. If we can find a way to balance effectiveness and safety, THR-β agonists have great development potential. Summary of the invention

[0004] In order to solve the shortcomings of the above-mentioned THR-β agonists and meet clinical needs, the present invention provides a pharmaceutical composition containing a thyroxine receptor β agonist and a folic acid substance, and the specific technical scheme involved is:

[0005] A pharmaceutical composition comprising:

[0006] (1) a therapeutically effective amount of folic acid,

[0007] (2) a therapeutically effective amount of a thyroxine receptor β agonist,

[0008] (3) Pharmaceutically acceptable excipients.

[0009] In the present invention, the mass ratio of the thyroid hormone receptor β agonist to the folic acid substance is 0.1-500:0.02-5. As a preferred embodiment, the mass ratio of the folic acid substance to the thyroid hormone receptor agonist is 1-300:0.2-1

[0010] In the pharmaceutical composition of the present invention, the folic acid substance is 0.02-5 mg, and the thyroid receptor agonist is 0.1-500 mg; preferably, the folic acid substance is 0.1-1 mg, and the thyroid receptor agonist is 2-100 mg.

[0011] In the pharmaceutical composition of the present invention, the folic acid substance is selected from one of 5-methyltetrahydrofolate, formyltetrahydrofolate, active metabolites of folic acid or folate, and substances that can release / generate folic acid in vivo.

[0012] In the pharmaceutical composition of the present invention, the folic acid substance is preferably folic acid or 5-methyltetrahydrofolate.

[0013] In the pharmaceutical composition of the present invention, the thyroid hormone receptor β agonist comprises: ilotirole in an amount of 20-100 mg, resmetirole in an amount of 20-100 mg, and sobetirome in an amount of 50-100 mg.

[0014] In the pharmaceutical composition of the present invention, the pharmaceutical composition can be prepared into oral preparations, including tablets, capsules or granules.

[0015] In the pharmaceutical composition of the present invention, the pharmaceutical composition is used in preparing a product for treating chronic fatty liver disease (fatty liver). Chronic fatty liver disease includes alcoholic fatty liver and non-alcoholic fatty liver.

[0016] In the pharmaceutical composition of the present invention, the pharmaceutical composition is used in preparing a product for treating fatty liver disease associated with hypothyroidism.

[0017] Advantages of the present invention: The present invention provides a composition containing a thyroid receptor β agonist and folic acid substances. On the basis of effectively improving hypothyroidism and regulating liver fat metabolism, the folic acid in the composition can synergistically reduce liver blood lipid levels and reduce liver fat accumulation, and can also improve cardiovascular function damage caused by the use of a single thyroid receptor agonist. It has significant synergistic and toxicity-reducing effects, making up for the shortcomings of existing drugs for treating fatty liver. Therefore, it is a more suitable product with clinical application value.

[0018] The present invention is further described below in conjunction with specific implementation modes, which is not intended to limit the present invention. Any equivalent replacements in the art made according to the contents of the present invention shall fall within the protection scope of the present invention. Detailed implementation mode

[0019] Example 1: Effect of the composition of the present invention on rats with hypothyroidism-induced fatty liver model

[0020] Wistar rats, SPF grade, were included in the experiment after 7 days of quarantine. 10 rats were selected as the control group, and the remaining rats were given intragastric administration of 0.1% propylthiouracil (PTU) at a dose of 10 mg / kg / d. The control group was given intragastric administration of an equal volume of normal saline. After 4 weeks of administration, a rat model of hypothyroidism-induced fatty liver was established. At the end of 4 weeks, blood was taken from the orbital vein for model evaluation. After the model was successfully established, the corresponding test substances were given by intragastric administration according to the following groups, and the intragastric administration volume was calculated according to 10 ml / kg. Once a day, after continuous administration for 8 weeks, all rats were sacrificed, blood was taken to detect the levels of serum total thyroxine (TT4), alanine aminotransferase (ALT), and aspartate aminotransferase (AST), the liver was removed, and the levels of serum total cholesterol (TC) and low-density lipoprotein (LDL-C) in the liver tissue were detected, and the liver index was measured.

[0021] Effect analysis of the pharmacodynamic effects between two components using Jin Zhengjun's Q value method.

[0022] Jin Zhengjun's Q value method [Jin Zhengjun, Zhang Xiaowen, A new method for estimating the combined effect of drugs with equal probability sum curve and Q5e-, Acta Academiae Medicinae Shanghai Secondae, 1981] is also called the probability addition method. According to the pharmacological effects of the combination of two drugs and the pharmacological effects of the two drugs used alone in the dose-effect curve area, Q = E A+B / (E A + E B - E A * E B ), where the numerator represents the "measured combined effect" and the denominator represents the "expected combined effect". (To satisfy the analysis of the pharmacological action relationship of the components and the composition, their pharmacological actions are transformed into effects that can intuitively reflect the strength of the pharmacological action. The calculation formula: E i = 1 - P i / P 模型组 , Pi is the pharmacological index of each component, and P 模型组 is the pharmacological index of the model group), and Q is the ratio of the two. When Q < 0.85, it is considered that the combination of the two drugs is an antagonistic effect; when 0.85 < Q < 1.15, it is considered an additive effect; when Q > 1.15, it is considered a synergistic effect. The liver was removed and weighed, and the liver index was calculated (liver wet weight / body weight × 100%)).

[0023] Table 1: Comparison of TT4 levels in serum and TC and LDL levels in liver tissue of rats in each group after 8 weeks of administration ( n = 9 - 10)

[0024]

[0025]

[0026] Note: Compared with the control group, ## P<0.01; compared with the model group, ** P<0.01.

[0027] From the above experimental results, it can be concluded that the TT4 of rats that have been successfully modeled with hypothyroidism was significantly reduced (P<0.01), and the TC and LDL levels were significantly increased (P<0.01), proving that low thyroid hormone levels will lead to an increase in the TC and LDL content in the liver, causing liver fat accumulation. After using different thyroid receptor agonists alone, the serum TT4 level increased significantly, and the TC and LDL levels in the liver tissue decreased significantly. After the combined use of folic acid, each group had the effect of synergistically increasing the serum TT4 level and synergistically reducing the TC and TG levels in the liver tissue.

[0028] Table 2: Comparison of serum ALT and AST levels in rats of each group after 8 weeks of administration ( n=9~10)

[0029]

[0030]

[0031] Note: Compared with the control group, ## P<0.01; compared with the model group, ** P<0.01.

[0032] From the above experimental results, it can be seen that the rats with successful preparation of hypothyroidism-induced fatty liver model had significantly increased serum ALT and AST levels compared with the control group, and the increase was statistically significant (P<0.01). This proves that the liver damage in rats prepared by the model has a tendency to reduce ALT and AST levels when thyroid receptor agonists are used alone. The use of folic acid and 5-methyltetrahydrofolate alone can significantly reduce serum ALT and AST levels, and the increase is statistically significant (P<0.01). The combined use of thyroid receptor agonists and folic acid or 5-methyltetrahydrofolate has a synergistic effect of reducing serum ALT and AST levels (Q>1.15).

[0033] Table 3: Comparison of liver indexes in rats of each group after 8 weeks of administration ( n=9~10)

[0034]

[0035]

[0036] Note: Compared with the control group, ## P<0.01; compared with the model group, * P<0.05, ** P<0.01.

[0037] From the above experimental results, it can be seen that the liver index of rats induced by hypothyroidism with fatty liver modeling is significantly increased, and the liver index is decreased when thyroid receptor agonists and folic acid substances are used alone. The combined use of folic acid substances on the basis of thyroid receptor agonists alone has the effect of further reducing the liver index. From the above experimental results, it can be concluded that the composition provided by the present invention has a significant synergistic effect on improving fatty liver and liver function damage caused by hypothyroidism.

Claims

1. A pharmaceutical composition comprising: (1) a therapeutically effective amount of a thyroxine receptor β agonist, (2) a therapeutically effective amount of folic acid, (3) Pharmaceutically acceptable excipients.

2. The pharmaceutical composition according to claim 1, characterized in that The mass ratio of the thyroid hormone receptor β agonist to the folic acid substance is 0.1-500:0.02-5, preferably 1-300:0.2-1.

3. The pharmaceutical composition according to claim 1, characterized in that The thyroid hormone receptor β agonist is 0.1-500 mg, and the folic acid substance is 0.02-5 mg; preferably, the thyroid hormone receptor β agonist is 2-300 mg, and the folic acid substance is 0.1-1 mg.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The thyroid hormone receptor β agonist is selected from one of the following substances: ilotirole in an amount of 20-100 mg, resmetirole in an amount of 20-100 mg, and sobetirome in an amount of 50-100 mg.

5. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The folic acid substance is selected from one of 5-methyltetrahydrofolate, formyltetrahydrofolate, active metabolites of folic acid or folate, and substances that can release / generate folic acid in vivo.

6. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that The pharmaceutical dosage form of the pharmaceutical composition is an oral preparation, including tablets, capsules or granules.

7. Use of the pharmaceutical composition according to any one of claims 1 to 5 in the preparation of a product for treating chronic fatty liver disease.

8. The use according to claim 7, characterized in that The chronic fatty liver disease includes alcoholic fatty liver disease and non-alcoholic fatty liver disease.

9. Use of the pharmaceutical composition according to any one of claims 1 to 5 in the preparation of a product for treating fatty liver combined with hypothyroidism.

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