Pharmaceutical combination for treating hyperlipemia

Abstract

The invention relates to a pharmaceutical composition for treating hyperlipidemia. The invention relates to the field of medicines, in particular to a pharmaceutical composition of probucol and statins, a pharmaceutical composition or a medicine box containing probucol and statins, and application of the pharmaceutical composition, the pharmaceutical composition or the medicine box in preparation of medicines for treating hyperlipidemia, in particular severe hypertriglyceridemia and severe hypercholesteremia, and application of the pharmaceutical composition, the pharmaceutical composition or the medicine box in preparation of medicines for treating hyperlipidemia, in particular severe hypertriglyceridemia and severe hypercholesteremia. The pharmaceutical composition, the pharmaceutical composition containing the probucol and the statins or the medicine box is characterized in that the pharmaceutical composition, the pharmaceutical composition containing the probucol and the statins or the medicine box containing the probucol and the statins contains a small dose of the probucol and the statins, and the probucol and the statins are configured to be in a form of simultaneous administration.

Description

[0001] Citation of Related Applications This application claims priority to Chinese patent application with application number 202410164131.7, application date February 5, 2024 and invention name “Drug Combination for Treating Severe Hypertriglyceridemia”, and Chinese patent application with application number 202411662172.5, application date November 20, 2024 and invention name “Drug Combination for Treating Hyperlipidemia”, and the two Chinese patent applications are incorporated herein in their entirety. Technical Field

[0002] The present invention relates to a drug combination of probucol and a statin, a drug composition comprising probucol and a statin, and use of the drug combination and the drug composition for treating hyperlipidemia, in particular severe hypertriglyceridemia and severe hypercholesterolemia. Background Art

[0003] Severe hypertriglyceridemia is a special type of hyperlipidemia. In addition to cardiovascular damage, it can also induce pancreatitis. There are many drugs for the treatment of hyperlipidemia, but the drugs for severe hypertriglyceridemia are relatively single. There are only three oral drugs: fibrates, high-dose fish oil Omega-3, and niacin. In clinical practice, fibrates are the first-line drugs of choice, and fish oil is an auxiliary drug. It takes a long time to take effect and is inferior to fibrates, and niacin is even worse. It is not uncommon for patients to be intolerant to fibrates, such as myolysis, liver and kidney damage, etc. If toxic side effects occur, there is no alternative drug, and the prognosis is very poor, which is a current clinical treatment problem. Other treatment options include biological agents and plasma adsorption, but biological agents are difficult to promote due to side effects and other reasons. Plasma adsorption cannot be widely used due to high technical requirements, high costs, and prominent side effects. In addition, patients with severe hypertriglyceridemia are often accompanied by ASCVD risks or combined with hypercholesterolemia, and need to be treated with statins at the same time. The combination of statins and fibrates enhances toxic side effects. Therefore, there is an urgent clinical need for drugs or drug combinations that can replace fibrates in the treatment of severe hypertriglyceridemia and significantly reduce low-density lipoprotein-C (LDL-C) and cholesterol with low side effects and good tolerability.

[0004] LDL-C is recognized as the most important risk factor for cardiovascular disease. Statins are very effective in controlling low-density cholesterol, but some patients still respond poorly to statins. The benefits of increasing statins are limited, the side effects increase, and other drugs need to be combined. According to the 2023 Chinese Lipid Management Guidelines, when LDL-C is not up to standard after statin treatment, consider combining statins with cholesterol absorption inhibitors (such as ezetimibe) and / or PCSK9 inhibitors. Statins combined with ezetimibe can further reduce LDL-C levels by 18-20% (Chinese Lipid Management Guidelines (2023), Joint Expert Committee for the Revision of the Chinese Lipid Management Guidelines, Chinese Journal of Circulation, March 2023, Vol. 38, No. 3, pp. 237-271). Therefore, there is an urgent clinical need for drugs or drug combinations that can further significantly reduce LDL-C when statin treatment is ineffective or inefficient.

[0005] In addition, regardless of cholesterol or triglyceride indicators, some people have poor responses to existing lipid-lowering drugs and need two or more lipid-lowering drugs in combination. The drugs used in combination are usually at their original doses, which may lead to enhanced toxic and side effects of combined use. Therefore, there is an urgent need for a combination of lipid-lowering drugs with low doses, ideal effects, and low side effects in clinical practice.

[0006] Statins, also known as 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase) inhibitors, can significantly reduce TC and LDL-C, and can also slightly reduce serum TG levels. Statins are suitable for the prevention and treatment of hypercholesterolemia, mixed hyperlipidemia and ASCVD. They have poor effects on significant hypertriglyceridemia and chylomicronemia and are not used to treat severe hypertriglyceridemia. The existing statins require different doses of statins to achieve the same lipid-lowering goals. It should be noted that doubling the dose of statins will only increase the LDL-C reduction by 6% (the so-called "6% effect of statin efficacy"), see "Guidelines for the Prevention and Treatment of Dyslipidemia in Adults in China (Revised Edition 2016)". Whether the target value can be achieved depends not only on the dose of statins, but also on the patient's baseline LDL-C level. For example, if the LDL-C is 188 mg / dl, it is difficult to achieve the target of <70 mg / dl even with a dose of 80 mg / day of atorvastatin. Moreover, when the dose of statins is doubled, the side effects increase with the dose.

[0007] Probucol (also known as Probucol, Probucol, CAS No.: 23288-49-5) is a bisphenol lipid-lowering compound, and its structure is shown below: Probucol has little effect on triglycerides and is only suitable for hypercholesterolemia with high LDL. The usual dosage is 0.5g / time, twice a day (i.e., a daily dose of 1000 mg). Literature reports that 1 gram per day can reduce cholesterol by 9-29% and LDL-C by 10-15% (Edited by Li Jiatai, Clinical Pharmacology, People's Medical Publishing House, 3rd edition, page 1531). According to the 2023 Chinese Lipid Management Guidelines, probucol is mainly suitable for patients with familial hypercholesterolemia (FH) and xanthomas. There is no mention of lowering triglycerides, let alone the benefits of combined therapy from lowering triglycerides, especially in severe hypertriglyceridemia, and no mention of the benefits of combining statins to further reduce LDL-C.

[0008] The combination of statins and probucol is mainly used to treat hypercholesterolemia, and there are no reports on the treatment of severe hypertriglyceridemia. Statins are not ideal for severe hypercholesterolemia.

[0009] CN106176717A discloses a probucol and lovavastatin compound composition and a preparation method thereof. The ratio of probucol and lovavastatin in the disclosed compound composition is as follows: Probucol Lovastatin Number of copies 15-20 1-3 15 2 20 3 17 1 18 2 Each tablet, mg 100-200 8-15 100 8 100 10 150 13 200 15 The patent application combines two drugs, probucol and lovastatin, to minimize the amount of pharmaceutical excipients. The patent application does not recognize that probucol can produce synergistic effects with statins in terms of therapeutic effects, nor does it recognize that the combination of probucol and statins can be used to treat severe hypertriglyceridemia and severe hypercholesterolemia and effectively reduce the LDL-C level of ASCVD high-risk, very high-risk and ultra-high-risk patients, thereby preventing or treating hypercholesterolemia described in this article.

[0010] CN101411703A discloses a pharmaceutical composition for treating cardiovascular diseases. The ratio of atorvastatin calcium (molecular weight 1155.342) and probucol in the disclosed composition is as follows: Atorvastatin calcium Probucol 5-100 mg 100-1000 mg 10-40 mg 200-500 mg 10 mg 500 mg The patent application only generally points out that the composition can not only improve the effect of atorvastatin calcium and probucol alone in treating cardiovascular diseases, but also has a synergistic effect. After the pharmaceutical composition is prepared into a pharmaceutical preparation, it can improve the patient's compliance. At the same time, the patent application also claims that the stability test proves that the pharmaceutical composition of atorvastatin calcium and probucol has good stability when preparing the pharmaceutical preparation. The combination of atorvastatin calcium and probucol enhances the stability of atorvastatin calcium in the pharmaceutical preparation. Although the patent application claims a synergistic effect, it does not further explain this, nor does it provide any evidence to illustrate the synergistic effect. From the description of the patent application, the synergistic effect is likely to mean that probucol enhances the stability of atorvastatin calcium in the pharmaceutical preparation. This patent application does not recognize that probucol can have a synergistic therapeutic effect with statins, nor does it recognize that the combination of probucol and statins can be used to treat severe hypertriglyceridemia and severe hypercholesterolemia and effectively reduce the LDL-C level of patients with high risk, very high risk and ultra-high risk of ASCVD, thereby preventing or treating hypercholesterolemia described in this article.

[0011] CN101766594A discloses a lipid-lowering pharmaceutical composition, in which the ratio of atorvastatin to probucol is as follows: Atorvastatin Probucol 5-80 mg 50-500 mg 5-30 mg 100-500 mg 10 mg 300 mg / 500 mg The patent application uses a hyperlipidemia rat model. From its experimental data, it can be seen that the patent application does not realize that probucol can produce a synergistic effect with statins in terms of therapeutic effects, nor does it realize that the combination of probucol and statins can be used to treat severe hypertriglyceridemia and severe hypercholesterolemia and effectively reduce the LDL-C level of ASCVD high-risk, very high-risk and ultra-high-risk patients, thereby preventing or treating hypercholesterolemia described in this article.

[0012] CN101455842A discloses a pharmaceutical composition for treating cardiovascular diseases. The ratio of HMG-CoA reductase inhibitor (selected from lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin) and probucol in the disclosed composition is as follows: HMG-CoA reductase inhibitors Probucol 1-200 mg 100-1000 mg 2-100 mg 200-500 mg 5-50 mg 500 mg Rosuvastatin 5 mg 500 mg Fluvastatin 20 mg 500 mg This patent application does not recognize that probucol can have a synergistic therapeutic effect with statins, nor does it recognize that the combination of probucol and statins can be used to treat severe hypertriglyceridemia and severe hypercholesterolemia and effectively reduce the LDL-C level of patients with high risk, very high risk and ultra-high risk of ASCVD, thereby preventing or treating hypercholesterolemia described in this article.

[0013] In the above-mentioned Chinese patent application, from the dosage relationship between statins and probucol, probucol is usually used at a conventional dose and statins are used at a dose lower than the conventional dose. There is no prior art report on the combination of statins and probucol for the treatment of severe hypertriglyceridemia and severe hypercholesterolemia, nor on how to use probucol to improve the effect of statins in lowering LDL-C levels to treat hypercholesterolemia. In addition, in the above-mentioned Chinese patent application, either no biological test data are disclosed, or the disclosed biological test data are based on rodent animal models, and these animal models cannot reliably prove the efficacy of the combination of statins and probucol for humans.

[0014] When statins are ineffective, guidelines and textbooks recommend a variety of combined drugs, such as ezetimibe, PCSK9 monoclonal antibody, fibrate (the side effects of the combination of the two increase, but they are still recommended), niacin, and even health supplement fish oil; the instructions for ezetimibe, PCSK9 monoclonal antibody, fibrate, niacin, and fish oil also include instructions for combining statins. Unfortunately, authoritative guidelines at home and abroad do not recommend combining with probucol, and the instructions for probucol do not include instructions for combining with statins. According to the conventional dosage method, probucol is 0.5g each time, twice a day, and taken before bedtime with statins. The combination of two cholesterol-lowering drugs has no effect on improving severe triglyceridemia.

[0015] Li Dongjun et al. (Observation on the efficacy of rosuvastatin combined with probucol in the treatment of hyperlipidemia, "Jilin Medicine" July 2014, Vol. 35, No. 21: 4633-4634) compared the efficacy of rosuvastatin combined with probucol with that of rosuvastatin alone in patients with hyperlipidemia. In the observation group using rosuvastatin and probucol together: rosuvastatin 10 mg, oral administration on an empty stomach in the morning, once a day, probucol 0.5 g, oral administration, twice a day. This treatment method does not use low-dose probucol, nor does it give statins and probucol at the same time, and the indications targeted do not include severe hypertriglyceridemia and severe hypercholesterolemia involved in the present invention. Li Li et al. (Analysis of the effects of rosuvastatin combined with probucol on carotid plaques and inflammatory factors in patients with hyperlipidemia, "Northern Pharmacy" Vol. 14, No. 5, 2017: 53) treated patients with hyperlipidemia and carotid plaques by taking rosuvastatin combined with probucol orally, including: rosuvastatin 10 mg orally, qn, probucol 250 mg orally, bid. This treatment method uses a 500 mg / day dose of probucol and a 10 mg / day dose of rosuvastatin, but does not give statins and probucol at the same time, and the indications targeted do not include severe hypertriglyceridemia and severe hypercholesterolemia involved in the present invention. Wang Xifu (Effects of probucol combined with rosuvastatin on carotid artery plaques and inflammatory factors in patients with hyperlipidemia, Anhui Medicine, 2013 May, 17(5): 836-838) pointed out that the combined use of statins and probucol can further reduce the cholesterol level of patients with hyperlipidemia, and on this basis, observed the advantages of the combined use of probucol and rosuvastatin over the use of rosuvastatin alone in the treatment of carotid artery plaques in patients with hyperlipidemia, thereby confirming the clinical efficacy of the combined use of the two drugs. The treatment method includes: rosuvastatin 10 mg, once a night, probucol 250 mg, twice a day. The treatment method does not administer statins and probucol at the same time, and the indications targeted do not include severe hypertriglyceridemia and severe hypercholesterolemia involved in the present invention. Zhou Xiangling (Effect of probucol combined with atorvastatin on vascular endothelial function in patients with hyperlipidemia, "Guangdong Trace Element Science: 2016 Vol. 23 No. 11: 34-37) analyzed the effect of probucol combined with atorvastatin on vascular endothelial function in patients with hyperlipidemia, where atorvastatin (Wuhan Zhongyou Pharmaceutical Co., Ltd., National Medicine Standard H20123064) was 1 time / d, 20 mg / time, and probucol (Jingfukang Pharmaceutical Group Co., Ltd., National Medicine Standard H10960161), 3 times / d, 0.25 mg / time. This treatment method does not administer statins and probucol at the same time, and the indications targeted do not include severe hypertriglyceridemia and severe hypercholesterolemia involved in the present invention.Shi Yujie (Analysis of the efficacy of simvastatin combined with probucol in the treatment of mixed hyperlipidemia, "Medical World" May 2009, Vol. 11, No. 5: 132-133) used simvastatin combined with probucol to treat patients with mixed hyperlipidemia, including simvastatin 20 mg, taken orally with dinner every day, and probucol 500 mg, taken orally with breakfast and meals every day. Shi Yujie specifically pointed out that probucol can reduce TC and LDL-C, but has little effect on TG. Patients with mixed hyperlipidemia can be treated with high-dose statins, but the lipid-lowering effect of statins is very limited after doubling the dose, and adverse reactions increase linearly with increasing doses. Mixed hyperlipidemia: If TC and LDL-C are mainly increased, statins are the first choice; if TG is mainly increased, fibrates are selected; if TC, LDL-C, and TG are all significantly increased, combined medication can be considered. Probucol has no effect on reducing TG, while simvastatin has a TG-lowering effect. The advantages complement each other and reduce adverse reactions, which is worth recommending. This treatment method does not use low-dose probucol, nor does it give statins and probucol at the same time, and the indications targeted do not include severe hypertriglyceridemia and severe hypercholesterolemia involved in the present invention. Zhao Xudong (Clinical Observation of Probucol Combined with Atorvastatin in the Treatment of Coronary Heart Disease and Hypercholesterolemia, "China Medical Innovation" Vol. 9, No. 9 (Total No. 219): 116-117) studied the therapeutic effect of probucol combined with atorvastatin on coronary heart disease and hypercholesterolemia. The subjects treated are patients with coronary heart disease, but the patient's indicators do not meet the standards of "Guidelines for the Prevention and Treatment of Dyslipidemia in Adults in China (2007)". The treatment method includes: administering probucol 250 mg / d (trade name Zhile, Shandong Qilu Pharmaceutical Co., Ltd.) plus atorvastatin 20 mg / d (trade name Lipitor, Pfizer Pharmaceutical Co., Ltd.), and it is not explicitly disclosed that probucol and atorvastatin are administered simultaneously, and the indications targeted do not include severe hypertriglyceridemia and severe hypercholesterolemia involved in the present invention. Luo Qin (Observation on the efficacy of atorvastatin calcium combined with probucol in the treatment of coronary heart disease with hyperlipidemia, "Modern Instruments and Medical Treatment" Vol. 19, No. 5, 2013: 83-85) used atorvastatin calcium combined with probucol to treat patients with coronary heart disease and hyperlipidemia, including: oral atorvastatin calcium, dosage 20 mg / d, once a day, and probucol 500 mg / d, twice a day. The treatment method does not administer statins and probucol simultaneously, and the indications targeted do not include severe hypertriglyceridemia and severe hypercholesterolemia involved in the present invention.Lian Rui (Effects of rosuvastatin combined with probucol on IMT, plaque area, IL-6, and TNF-α in patients with hyperlipidemia and carotid plaques, "Capital Food and Medicine" July 2017, second half: 76-77) observed and discussed the effects of rosuvastatin combined with probucol on IMT, plaque area, IL-6, and TNF-α in patients with hyperlipidemia and carotid plaques. The treatment method includes: rosuvastatin treatment, 10 mg / time, 1 time / d, taken before bedtime, probucol 250 mg / d, 2 times / d. This treatment method does not administer statins and probucol at the same time, and the indications targeted do not include severe hypertriglyceridemia and severe hypercholesterolemia involved in the present invention. Shen Yang et al. (Effects of probucol combined with rosuvastatin on NO, ET-1 and carotid atherosclerotic plaques in patients with hyperlipidemia, Journal of Cardiovascular Diseases of Integrated Traditional Chinese and Western Medicine, Vol. 13, No. 18, December 2015: 2100-2102) used probucol combined with rosuvastatin calcium to treat hyperlipidemia and observed its effects on vascular endothelial function and carotid atherosclerotic plaques in patients with hyperlipidemia. The treatment method includes oral administration of probucol tablets (trade name Zhile, Qilu Pharmaceutical Co., Ltd.) 0.25g, 3 times a day, and rosuvastatin calcium (trade name Tuotu, Nanjing Zhengda Tianqing Pharmaceutical Co., Ltd.) 10mg, once every night. This treatment method does not administer statins and probucol at the same time, and the indications targeted do not include severe hypertriglyceridemia and severe hypercholesterolemia involved in the present invention. The above documents teach the combined administration of probucol and statins, but there is still no document teaching the simultaneous administration of the two and the synergistic benefits of simultaneous administration. These documents at most teach the 1+1=2 effect of the combination of probucol and statins, and they do not realize that the effects of taking the two together and taking them separately are very different, and that the simultaneous combination of the two can achieve the effect of 1+1>2. These documents also do not recognize that the combination of probucol and statins can also be used to treat severe hypertriglyceridemia and severe hypercholesterolemia. The therapeutic effects reported in these documents, such as further reducing LDL-C by nearly 20% and vascular protection, have not been confirmed by guidelines, textbooks, and drug instructions. The guidelines recommend as many as 5 drugs combined with statins, but probucol is missing. What is puzzling is that the extent to which the guidelines recommend ezetimibe to reduce LDL-C is consistent with these literature reports.

[0016] The results of foreign studies on statin combined with probucol treatment are different from those in China. Regarding further reduction of LDL-C: Joseph L et al. reported that the effect of lovastatin and probucol combined treatment on reducing low-density lipoprotein is not better than lovastatin alone. The drugs used in this literature are: lovastatin alone 20mgBID; lovastatin 20mBID combined with probucol 500mgBID. (Joseph L. Witztum, MD, et al. Intensive combination drug therapy of familial hypercholesterolemia with lovastatin, probucol, and colestipolhydrochloride. Circulation Vol 79, No 1, January 1989). Regarding vascular protection: The PROSPECTIVE study enrolled 876 ASCVD patients who took statins and other lipid-lowering drugs for more than 8 weeks (statins accounted for 92.7% of the total cases). They were divided into two groups: continuing the original treatment and combining probucol 250 mg BID with the original treatment. The follow-up was more than 3 years. The probucol group had no statistically significant effect in reducing cardiovascular and cerebrovascular events and carotid intima-media thickness, and the results remained negative (Toshiyuki Ishibashi, et al. Probucol Trial for Secondary Prevention of Atherosclerotic Events in Patients with Coronary Heart Disease (PROSPECTIVE) J Astheroscler Thromb, 2021;28:103-123).

[0017] The above research results have led to domestic and foreign guidelines, textbooks and drug instructions not recommending the combination of statins and probucol to further reduce LDL-C. For example, the instructions for pravastatin state that "although there is no increase in adverse events when pravastatin is combined with probucol, it does not increase the LDL-lowering efficacy." Existing technologies have no obvious benefits in reducing high triglycerides or further reducing LDL-C in severe hypertriglyceridemia. Summary of the invention

[0018] The inventors unexpectedly discovered that a drug combination comprising a low dose of probucol and a statin can significantly reduce hypertriglyceridemia in severe hypertriglyceridemia, with an effect no less than that of fibrates; it can further reduce cholesterol and low-density lipoprotein, with an effect no less than that of statins combined with ezetimibe; it can be used to treat severe hypertriglyceridemia or to treat severe hypertriglyceridemia and hypercholesterolemia at the same time, and is a broad-spectrum lipid-lowering drug; it also reduces the risk of ASVCD and the side effects of the drug, thereby meeting the above clinical needs. Surprisingly, if probucol and statins are taken separately, or taken together but with an increased dose of probucol, the unexpected effect disappears.

[0019] In a first aspect of the present invention, a pharmaceutical combination is provided, comprising probucol and a statin.

[0020] In a second aspect of the present invention, a pharmaceutical composition is provided, comprising probucol, a statin and a pharmaceutically acceptable carrier.

[0021] In a third aspect of the present invention, a kit is provided, comprising a first composition containing probucol and a second composition containing a statin.

[0022] In a fourth aspect of the present invention, there is provided use of probucol and statins in the preparation of a medicament for treating hyperlipidemia.

[0023] In a fifth aspect of the present invention, a pharmaceutical combination comprising probucol and a statin or a pharmaceutical composition comprising probucol, a statin and a pharmaceutically acceptable carrier is provided for use in treating hyperlipidemia.

[0024] In a sixth aspect of the present invention, a method for treating hyperlipidemia is provided, comprising administering a therapeutically effective amount of probucol and a therapeutically effective amount of a statin to a subject in need thereof.

[0025] In the above aspects, the statin is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor selected from atorvastatin, rosuvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, and simvastatin.

[0026] In the fourth, fifth and sixth aspects above, the hyperlipidemia is severe hypertriglyceridemia, or severe hypertriglyceridemia and hypercholesterolemia.

[0027] Specifically, the present invention provides the following technical solutions: 1. Use of a drug combination in the preparation of a drug for treating hyperlipidemia in a subject in need of treatment, wherein the drug combination comprises probucol and a statin; or the drug combination is selected from (1) probucol + statin, (2) fibrate + statin (such as fenofibrate 0.2g QD + rosuvastatin 10mg-40mg QD), (3) statin + cholesterol absorption inhibitor (simvastatin 20-40mg QD + ezetimibe 20mg QD), (4) statin + statin (atorvastatin 5mg-40mg QD + rosuvastatin 5mg-40mg QD), (5) fish oil + statin (rosuvastatin 10-40mg QD + fish oil 1-4g QD); Preferably, probucol and the statin are configured in the drug in a form that can be administered simultaneously, or the components of the above-mentioned drug combination (1)-(5) are configured in the drug in a form that can be administered simultaneously or some of the drugs are configured in a form that can be administered simultaneously; Preferably, the hyperlipidemia satisfies one of the following requirements (1)-(6): (1) The TG level of the subject is: TG ≥ 5.6 mmol / L, and / or the LDL-C level of the subject is: LDL-C>4.9mmol / L; (2) The subject's LDL-C level is 1.49-7.34 mmol / L, and the subject's TC and TG levels meet the following conditions: the TC / LDL-C ratio is 1.3-2.4; the product of TG×LDL-C is 2.6-25 (mmol 2 / L 2 ); (3) The subject is an extremely high-risk patient for ASCVD and meets one of the following conditions: (3.1) LDL-C level greater than 1.8 mmol / L; (3.2) The subject has received statin therapy, and / or has received statin combined with cholesterol absorption inhibitor, statin combined with PCSK9 monoclonal antibody, or statin combined with cholesterol absorption inhibitor and PCSK9 monoclonal antibody, and the LDL-C level is greater than 1.8 mmol / L; (3.3) The subject has received statin therapy, and / or has received statin combined with cholesterol absorption inhibitor, statin combined with PCSK9 monoclonal antibody, or statin combined with cholesterol absorption inhibitor and PCSK9 monoclonal antibody, and The subject's LDL-C level after treatment decreased by <50% compared with baseline; or Patients who have severe side effects from statins and need to reduce the dose; or Patients who need to stop taking statins combined with cholesterol absorption inhibitors or statins combined with PCSK9 monoclonal antibodies or statins combined with cholesterol absorption inhibitors and PCSK9 monoclonal antibodies have severe side effects; (4) The subject is an ASCVD ultra-high-risk patient and meets one of the following conditions: (4.1) LDL-C level greater than 1.4 mmol / L; (4.2) The subject has received statin therapy, and / or has received statin combined with cholesterol absorption inhibitor, statin combined with PCSK9 monoclonal antibody, or statin combined with cholesterol absorption inhibitor and PCSK9 monoclonal antibody, and the LDL-C level is greater than 1.4 mmol / L; (4.3) The subject has received statin therapy, and / or has received statin combined with cholesterol absorption inhibitor, statin combined with PCSK9 monoclonal antibody, or statin combined with cholesterol absorption inhibitor and PCSK9 monoclonal antibody, and The subject's LDL-C level after treatment decreased by <50% compared with baseline; or Patients who have severe side effects from statins and need to reduce the dose; or Patients who need to stop taking statins combined with cholesterol absorption inhibitors or statins combined with PCSK9 monoclonal antibodies or statins combined with cholesterol absorption inhibitors and PCSK9 monoclonal antibodies have severe side effects; (5) The subject is a high-risk ASCVD patient and meets one of the following conditions: (5.1) LDL-C level greater than 2.6 mmol / L; (5.2) The subject has received statin therapy, and / or has received statin combined with cholesterol absorption inhibitor, statin combined with PCSK9 monoclonal antibody, or statin combined with cholesterol absorption inhibitor and PCSK9 monoclonal antibody, and the LDL-C level is greater than 2.6 mmol / L; (5.3) The subject has received statin therapy, and / or has received statin combined with cholesterol absorption inhibitor, statin combined with PCSK9 monoclonal antibody, or statin combined with cholesterol absorption inhibitor and PCSK9 monoclonal antibody, and The subject's LDL-C level after treatment decreased by <50% compared with baseline; or Patients who have severe side effects from statins and need to reduce the dose; or Patients who need to stop taking statins combined with cholesterol absorption inhibitors or statins combined with PCSK9 monoclonal antibodies or statins combined with cholesterol absorption inhibitors and PCSK9 monoclonal antibodies have severe side effects; (6) The subject's TC>6.22 mmol / L and / or LDL-C>4.14 mmol / L, and / or the subject's TG>1.7 mmol / L; The ASCVD extremely high-risk patients, ASCVD ultra-high-risk patients, and ASCVD high-risk patients mentioned here are divided according to the standards of the "China Blood Lipid Management Guidelines (2023)".

[0028] 2. Use of a drug combination comprising probucol and a statin for the preparation of a medicament for treating (severe) hypertriglyceridemia, (severe) hypercholesterolemia (including familial), or a combination of (severe) hypertriglyceridemia and (severe) hypercholesterolemia in a subject in need of such treatment; preferably, probucol and the statin are configured in the medicament in a form that can be administered simultaneously.

[0029] 3. Use of a drug combination comprising probucol and a statin in the preparation of a medicament for treating hyperlipidemia that is ineffective or ineffective with statins, or hyperlipidemia that is intolerant or unresponsive to fibrates in a subject in need of such treatment; preferably, probucol and the statin are configured in the medicament in a form that allows for simultaneous administration.

[0030] 4. Use of a drug combination comprising probucol and a statin in the preparation of a medicament for treating (severe) hypercholesterolemia that is ineffective or inefficiently treated with statins, or (severe) hypercholesterolemia that is intolerant of or unresponsive to fibrates in a subject in need of such treatment; preferably, probucol and the statin are formulated in the medicament in a form that allows for simultaneous administration.

[0031] 5. Use of a drug combination comprising probucol and a statin in the preparation of a medicament for treating (severe) hypertriglyceridemia that is ineffective or ineffective with statins, or (severe) hypertriglyceridemia that is intolerant or unresponsive to fibrates in a subject in need of such treatment; preferably, probucol and the statin are configured in the medicament in a form that allows for simultaneous administration.

[0032] 6. Use of a drug combination comprising probucol and a statin in the preparation of a medicament for treating a combination of severe hypertriglyceridemia and hypercholesterolemia, a combination of hypertriglyceridemia and severe hypercholesterolemia, a combination of severe hypertriglyceridemia and severe hypercholesterolemia, severe hypertriglyceridemia for which statins are ineffective or ineffective, or severe hypertriglyceridemia for which fibrates are intolerant or unresponsive, severe hypercholesterolemia for which statins are ineffective or ineffective, or severe hypercholesterolemia for which fibrates are intolerant or unresponsive in a subject in need of such treatment; preferably, probucol and the statin are configured in the medicament in a form that allows for simultaneous administration.

[0033] 7. Use of a drug combination comprising probucol and a statin in the preparation of a drug for treating / preventing atherosclerotic vascular lesions, reducing ischemic stroke, reducing lower limb arteriosclerosis occlusion, reducing ischemic kidney lesions, or reducing cardiovascular events in a subject in need thereof; preferably, probucol and the statin are configured in the drug in a form that can be administered simultaneously.

[0034] 8. The use of any one of technical solutions 1-7, characterized in that the probucol and the statin in the drug combination are prepared in a form suitable for simultaneous oral administration.

[0035] 9. The use of any one of technical solutions 1-7, characterized in that The amount of probucol is a / 2b of the maximum daily dose of probucol for lowering cholesterol recommended in the "Guidelines for Blood Lipid Management in China (2023)", where a and b are integers of 1-16, and a≤b, The amount of statins is c / d of the maximum daily dose of statins for lowering cholesterol recommended in the "Guidelines for Chinese Lipid Management (2023)", where c and d are integers of 1-16, and c≤d, for example c≤d / 2.

[0036] 10. The use of any one of technical solutions 1-7, characterized in that The amount of probucol is 3a / 4b or 5a / 16b of the maximum daily dose of probucol for lowering cholesterol recommended in the "Guidelines for Blood Lipid Management in China (2023)", wherein a and b are integers of 1-16, and a≤b, The amount of statins is c / d of the maximum daily dose of statins for lowering cholesterol recommended in the "Guidelines for Chinese Lipid Management (2023)", where c and d are integers of 1-16, and c≤d, for example c≤d / 2.

[0037] 11. The use of any one of technical solutions 1-7, characterized in that the statin is selected from atorvastatin, rosuvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, and simvastatin.

[0038] 12. The use of technical solution 11, characterized in that the drug combination comprises: Probucol and lovastatin in a weight ratio of (3-40):1; or Probucol and pravastatin in a weight ratio of (6-10):1; or Probucol and simvastatin in a weight ratio of (1-15):1; or Probucol and fluvastatin in a weight ratio of (1-4):1; or Probucol and atorvastatin in a weight ratio of (3-25):1; or Probucol and rosuvastatin in a weight ratio of (5-60):1; or The weight ratio of probucol to pitavastatin is (80-150):1.

[0039] 13. The use of technical solution 11 is characterized in that The drug combination comprises 20-400 mg of probucol; and 1-80 mg of a statin.

[0040] 14. The use of technical solution 11 is characterized in that The drug combination comprises 20-400 mg of probucol; and 10-80 mg of lovastatin, or 10-80 mg of pravastatin, or 5-80 mg of simvastatin, or 20-80 mg of fluvastatin, or 10-80 mg of atorvastatin, or 5-40 mg of rosuvastatin, or 1-4 mg of pitavastatin.

[0041] 15. The use of technical solution 11, characterized in that The drug combination comprises 20-400 mg of probucol; and 10-40 mg of lovastatin, or 20-80 mg of pravastatin, or 20-80 mg of simvastatin, or 20-80 mg of fluvastatin, or 5-40 mg of atorvastatin, or 10-40 mg of rosuvastatin, or 2-4 mg of pitavastatin.

[0042] 16. The use of technical solution 11, characterized in that The drug combination comprises 20-400 mg of probucol; and 20-40 mg of lovastatin, or 20-400 mg of pravastatin, or 20-40 mg of simvastatin, or 40-80 mg of fluvastatin, or 10-20 mg of atorvastatin, or 5-10 mg of rosuvastatin, or 2-3 mg of pitavastatin.

[0043] 17. The use of technical solution 11 is characterized in that The weight ratio of probucol to lovastatin is not greater than 50 / 2; or The weight ratio of probucol to pravastatin is not greater than 50 / 4; or The weight ratio of probucol to simvastatin is not greater than 50 / 2; or The weight ratio of probucol to fluvastatin is not greater than 50 / 8; or The weight ratio of probucol to atorvastatin is not greater than 50 / 1; or The weight ratio of probucol to rosuvastatin is not greater than 50 / 1; or The weight ratio of probucol to pitavastatin is no greater than 500 / 2; or The weight ratio of probucol to lovastatin is not greater than 37.5 / 2; or The weight ratio of probucol to pravastatin is not greater than 37.5 / 4; or The weight ratio of probucol to simvastatin is not greater than 37.5 / 2; or The weight ratio of probucol to fluvastatin is not greater than 37.5 / 8; or The weight ratio of probucol to atorvastatin is not greater than 37.5 / 1; or The weight ratio of probucol to rosuvastatin is not greater than 37.5 / 1; or The weight ratio of probucol to pitavastatin is no greater than 375 / 2; or, The weight ratio of probucol to lovastatin is not greater than 37.5 / 1; or The weight ratio of probucol to pravastatin is not greater than 37.5 / 2; or The weight ratio of probucol to simvastatin is not greater than 37.5 / 1; or The weight ratio of probucol to fluvastatin is not greater than 37.5 / 4; or The weight ratio of probucol to atorvastatin is not greater than 75 / 1; or The weight ratio of probucol to rosuvastatin is not greater than 75 / 1; or The weight ratio of probucol to pitavastatin is no greater than 375 / 1; or The weight ratio of probucol to lovastatin is not greater than 31.25 / 2; or The weight ratio of probucol to pravastatin is not greater than 31.25 / 4; or The weight ratio of probucol to simvastatin is not greater than 31.25 / 2; or The weight ratio of probucol to fluvastatin is not greater than 31.25 / 8; or The weight ratio of probucol to atorvastatin is not greater than 31.25 / 1; or The weight ratio of probucol to rosuvastatin is not greater than 31.25 / 1; or The weight ratio of probucol to pitavastatin is no greater than 312.5 / 2; or, The weight ratio of probucol to lovastatin is not greater than 31.25 / 1; or The weight ratio of probucol to pravastatin is not greater than 31.25 / 2; or The weight ratio of probucol to simvastatin is not greater than 31.25 / 1; or The weight ratio of probucol to fluvastatin is not greater than 31.25 / 4; or The weight ratio of probucol to atorvastatin is not greater than 62.5 / 1; or The weight ratio of probucol to rosuvastatin is not greater than 62.5 / 1; or The weight ratio of probucol to pitavastatin is no greater than 625 / 2; or, The weight ratio of probucol to lovastatin is not greater than 25 / 2; or The weight ratio of probucol to pravastatin is not greater than 25 / 4; or The weight ratio of probucol to simvastatin is not greater than 25 / 2; or The weight ratio of probucol to fluvastatin is not greater than 25 / 8; or The weight ratio of probucol to atorvastatin is not greater than 25 / 1; or The weight ratio of probucol to rosuvastatin is not greater than 25 / 1; or The weight ratio of probucol to pitavastatin is no greater than 125 / 1; or, The weight ratio of probucol to lovastatin is not greater than 20 / 2; or The weight ratio of probucol to pravastatin is not greater than 20 / 4; or The weight ratio of probucol to simvastatin is not greater than 20 / 2; or The weight ratio of probucol to fluvastatin is not greater than 20 / 8; or The weight ratio of probucol to atorvastatin is not greater than 20 / 1; or The weight ratio of probucol to rosuvastatin is not greater than 20 / 1; or The weight ratio of probucol to pitavastatin is no greater than 200 / 2; or, The weight ratio of probucol to lovastatin is not greater than 25 / 4; or The weight ratio of probucol to pravastatin is not greater than 25 / 8; or The weight ratio of probucol to simvastatin is not greater than 25 / 4; or The weight ratio of probucol to fluvastatin is not greater than 25 / 16; or The weight ratio of probucol to atorvastatin is not greater than 25 / 2; or The weight ratio of probucol to rosuvastatin is not greater than 25 / 2; or The weight ratio of probucol to pitavastatin is no greater than 125 / 2; or, Probucol and lovastatin in a weight ratio not greater than 25 / 1; or Probucol and pravastatin in a weight ratio not greater than 25 / 3; or Probucol and simvastatin in a weight ratio not greater than 25 / 2; or Probucol and fluvastatin in a weight ratio not greater than 25 / 8; or Probucol and atorvastatin in a weight ratio not greater than 25 / 1; or Probucol and rosuvastatin in a weight ratio not greater than 50 / 1; or Probucol and pitavastatin in a weight ratio no greater than 125 / 1.

[0044] 18. The use of any one of technical solutions 12-17, characterized in that The weight ratio of probucol to lovastatin is not less than 5 / 2; or The weight ratio of probucol to pravastatin is not less than 5 / 4; or The weight ratio of probucol to simvastatin is not less than 5 / 2; or The weight ratio of probucol to fluvastatin is not less than 5 / 8; or The weight ratio of probucol to atorvastatin is not less than 5 / 1; or The weight ratio of probucol to rosuvastatin is not less than 5 / 1; or The weight ratio of probucol to pitavastatin is not less than 50 / 2.

[0045] 19. The use of any one of technical solutions 12-17, characterized in that The weight ratio of probucol to lovastatin is not less than 10 / 2; or The weight ratio of probucol to pravastatin is not less than 10 / 4; or The weight ratio of probucol to simvastatin is not less than 10 / 2; or The weight ratio of probucol to fluvastatin is not less than 10 / 8; or The weight ratio of probucol to atorvastatin is not less than 10 / 1; or The weight ratio of probucol to rosuvastatin is not less than 10 / 1; or The weight ratio of probucol to pitavastatin is not less than 100 / 2.

[0046] 20. A drug combination, characterized in that the drug combination comprises probucol and a statin, Preferably, probucol and the statin in the drug combination are formulated in a form that can be administered simultaneously; Optionally, the drug combination does not include the following combinations 1-69: combination Probucol / weight Lovastatin / weight 1 15 1 2 15 3 3 20 1 4 20 3 5 15 2 6 20 3 7 17 1 8 18 2 combination Probucol / mg Lovastatin / mg 9 100 8 10 100 15 11 200 8 12 200 15 13 100 8 14 100 10 15 150 13 16 200 15 combination Probucol / mg Atorvastatin calcium / mg 17 100 5 18 100 10 19 100 40 20 100 100 21 1000 5 22 1000 10 23 1000 40 24 1000 100 25 200 5 26 200 10 27 200 40 28 200 100 29 500 5 30 500 10 31 500 40 32 500 100 combination Probucol / mg Atorvastatin / mg 33 50 5 34 50 80 35 500 5 36 500 80 37 100 5 38 100 30 39 500 5 40 500 30 41 500 10 42 300 10 43 250 20 combination Probucol / mg Statins / mg 44 100 1 45 100 2 46 100 5 47 100 50 48 100 100 49 100 200 50 200 1 51 200 2 52 200 5 53 200 50 54 200 100 55 200 200 56 500 1 57 500 2 58 500 5 59 500 50 60 500 100 61 500 200 62 1000 1 63 1000 2 64 1000 5 65 1000 50 66 1000 100 67 1000 200 combination Probucol / mg Rosuvastatin / mg 68 500 5 combination Probucol / mg Fluvastatin / mg 69 500 20。 21. The drug combination of technical solution 20, wherein The amount of probucol is a / 2b of the maximum daily dose of probucol for lowering cholesterol recommended in the "Guidelines for Blood Lipid Management in China (2023)", where a and b are integers of 1-16, and a≤b, The amount of statins is c / d of the maximum daily dose of statins for lowering cholesterol recommended in the "Guidelines for Chinese Lipid Management (2023)", where c and d are integers of 1-16, and c≤d, for example c≤d / 2.

[0047] 22. The drug combination of any one of technical solutions 20-21, wherein The amount of probucol is 3a / 4b or 5a / 16b of the maximum daily dose of probucol for lowering cholesterol recommended in the "Guidelines for Blood Lipid Management in China (2023)", wherein a and b are integers of 1-16, and a≤b, The amount of statins is c / d of the maximum daily dose of statins for lowering cholesterol recommended in the "Guidelines for Chinese Lipid Management (2023)", where c and d are integers of 1-16, and c≤d, for example c≤d / 2.

[0048] 23. The drug combination of any one of technical solutions 20-22, wherein The drug combination comprises 20-400 mg of probucol; and 1-80 mg of a statin; Or the drug combination comprises Probucol and lovastatin in a weight ratio of (3-40):1; or Probucol and pravastatin in a weight ratio of (6-10):1; or Probucol and simvastatin in a weight ratio of (1-15):1; or Probucol and fluvastatin in a weight ratio of (1-4):1; or Probucol and atorvastatin in a weight ratio of (3-25):1; or Probucol and rosuvastatin in a weight ratio of (5-60):1; or Probucol and pitavastatin in a weight ratio of (80-150):1; Or the pharmaceutical combination comprises 20-400 mg of probucol; and 10-80 mg of lovastatin, or 10-80 mg of pravastatin, or 5-80 mg of simvastatin, or 20-80 mg of fluvastatin, or 10-80 mg of atorvastatin, or 5-40 mg of rosuvastatin, or 1-4 mg of pitavastatin; Or the pharmaceutical combination comprises 20-400 mg of probucol; and 10-40 mg of lovastatin, or 20-80 mg of pravastatin, or 20-80 mg of simvastatin, or 20-80 mg of fluvastatin, or 5-40 mg of atorvastatin, or 10-40 mg of rosuvastatin, or 2-4 mg of pitavastatin; Or the pharmaceutical combination comprises 20-400 mg of probucol; and 20-40 mg of lovastatin, or 20-400 mg of pravastatin, or 20-40 mg of simvastatin, or 40-80 mg of fluvastatin, or 10-20 mg of atorvastatin, or 5-10 mg of rosuvastatin, or 2-3 mg of pitavastatin; Or the pharmaceutical combination comprises 20-400 mg of probucol; and 10-40 mg of lovastatin, or 10-40 mg of pravastatin, or 10-40 mg of simvastatin, or 20-80 mg of fluvastatin, or 10-40 mg of atorvastatin, or 5-20 mg of rosuvastatin, or 1-4 mg of pitavastatin; Or the pharmaceutical combination comprises 20-400 mg of probucol; and 10-20 mg of lovastatin, or 10-20 mg of pravastatin, or 20-40 mg of simvastatin, or 40-80 mg of fluvastatin, or 10-20 mg of atorvastatin, or 5-10 mg of rosuvastatin, or 2-4 mg of pitavastatin; or in the drug combination The weight ratio of probucol to lovastatin is not greater than 50 / 2; or The weight ratio of probucol to pravastatin is not greater than 50 / 4; or The weight ratio of probucol to simvastatin is not greater than 50 / 2; or The weight ratio of probucol to fluvastatin is not greater than 50 / 8; or The weight ratio of probucol to atorvastatin is not greater than 50 / 1; or The weight ratio of probucol to rosuvastatin is not greater than 50 / 1; or The weight ratio of probucol to pitavastatin is no greater than 500 / 2; or in the drug combination The weight ratio of probucol to lovastatin is not greater than 37.5 / 2; or The weight ratio of probucol to pravastatin is not greater than 37.5 / 4; or The weight ratio of probucol to simvastatin is not greater than 37.5 / 2; or The weight ratio of probucol to fluvastatin is not greater than 37.5 / 8; or The weight ratio of probucol to atorvastatin is not greater than 37.5 / 1; or The weight ratio of probucol to rosuvastatin is not greater than 37.5 / 1; or The weight ratio of probucol to pitavastatin is no greater than 375 / 2; or in the drug combination The weight ratio of probucol to lovastatin is not greater than 37.5 / 1; or The weight ratio of probucol to pravastatin is not greater than 37.5 / 2; or The weight ratio of probucol to simvastatin is not greater than 37.5 / 1; or The weight ratio of probucol to fluvastatin is not greater than 37.5 / 4; or The weight ratio of probucol to atorvastatin is not greater than 75 / 1; or The weight ratio of probucol to rosuvastatin is not greater than 75 / 1; or The weight ratio of probucol to pitavastatin is no greater than 375 / 1; or in the drug combination The weight ratio of probucol to lovastatin is not greater than 31.25 / 2; or The weight ratio of probucol to pravastatin is not greater than 31.25 / 4; or The weight ratio of probucol to simvastatin is not greater than 31.25 / 2; or The weight ratio of probucol to fluvastatin is not greater than 31.25 / 8; or The weight ratio of probucol to atorvastatin is not greater than 31.25 / 1; or The weight ratio of probucol to rosuvastatin is not greater than 31.25 / 1; or The weight ratio of probucol to pitavastatin is no greater than 312.5 / 2; or in the drug combination The weight ratio of probucol to lovastatin is not greater than 31.25 / 1; or The weight ratio of probucol to pravastatin is not greater than 31.25 / 2; or The weight ratio of probucol to simvastatin is not greater than 31.25 / 1; or The weight ratio of probucol to fluvastatin is not greater than 31.25 / 4; or The weight ratio of probucol to atorvastatin is not greater than 62.5 / 1; or The weight ratio of probucol to rosuvastatin is not greater than 62.5 / 1; or The weight ratio of probucol to pitavastatin is no greater than 625 / 2; Or the drug combination comprises Probucol and lovastatin in a weight ratio not greater than 25 / 1; or Probucol and pravastatin in a weight ratio not greater than 25 / 3; or Probucol and simvastatin in a weight ratio not greater than 25 / 2; or Probucol and fluvastatin in a weight ratio not greater than 25 / 8; or Probucol and atorvastatin in a weight ratio not greater than 25 / 1; or Probucol and rosuvastatin in a weight ratio not greater than 50 / 1; or Probucol and pitavastatin in a weight ratio not greater than 125 / 1; Optionally: The weight ratio of probucol to lovastatin is not less than 5 / 2; or The weight ratio of probucol to pravastatin is not less than 5 / 4; or The weight ratio of probucol to simvastatin is not less than 5 / 2; or The weight ratio of probucol to fluvastatin is not less than 5 / 8; or The weight ratio of probucol to atorvastatin is not less than 5 / 1; or The weight ratio of probucol to rosuvastatin is not less than 5 / 1; or The weight ratio of probucol to pitavastatin is not less than 50 / 2; Or optionally: The weight ratio of probucol to lovastatin is not less than 10 / 2; or The weight ratio of probucol to pravastatin is not less than 10 / 4; or The weight ratio of probucol to simvastatin is not less than 10 / 2; or The weight ratio of probucol to fluvastatin is not less than 10 / 8; or The weight ratio of probucol to atorvastatin is not less than 10 / 1; or The weight ratio of probucol to rosuvastatin is not less than 10 / 1; or The weight ratio of probucol to pitavastatin is not less than 100 / 2.

[0049] 24. The drug combination of any one of technical solutions 20-23, wherein the amount of probucol as the active ingredient is 20 mg, 25 mg, 30 mg, 31.25 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 62.5 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 187.5 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 230 mg mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg or 400 mg.

[0050] 25. The drug combination of any one of technical solutions 20-23, wherein the amount of probucol as an active ingredient is 20-400 mg, excluding 20 mg, 25 mg, 30 mg, 31.25 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 62.5 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 187.5 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg 220 mg mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg and / or 400 mg.

[0051] 26. The drug combination of any one of technical solutions 20-25, wherein the drug combination does not include other active ingredients except probucol and statins.

[0052] 27. A pharmaceutical composition, wherein the pharmaceutical composition comprises the drug combination of any one of technical solutions 20-26 and a pharmaceutically acceptable carrier, characterized in that the form of simultaneous administration is in the form of an oral unit dosage form selected from tablets, capsules, granules, pellets, and micropills, and the oral unit dosage form contains probucol and a statin, for example, the tablet is a two-layer or multi-layer tablet, wherein at least one layer contains probucol and a pharmaceutically acceptable carrier thereof, and at least another layer contains a statin and a pharmaceutically acceptable carrier thereof.

[0053] 28. A medicine kit, wherein the medicine kit has the drug combination of any one of technical solutions 20-26, the amount of probucol and the amount of statin contained in the medicine kit are as described in any one of technical solutions 21-25, and probucol and statin are provided in the form of a single composition in the medicine kit.

[0054] 29. A medicine box, wherein the medicine box has the drug combination of any one of technical solutions 20-26, and the medicine box includes one or more identical drug units isolated from the external environment, each drug unit contains a first drug composition containing probucol and a second drug composition containing a statin, the amount of probucol in the first drug composition and the amount of statin in the second drug composition are as described in any one of technical solutions 21-25, and the first drug composition and the second drug composition are each in an oral unit dosage form, The opening of each pharmaceutical unit exposes the first pharmaceutical composition and the second pharmaceutical composition to the external environment simultaneously.

[0055] 30. A medicine kit comprising probucol and a statin as active ingredients, preferably, probucol and the statin are configured in the medicine kit to be administered simultaneously; more preferably, the medicine kit comprises one or more identical medicine units isolated from the external environment, and one, two or three, preferably one or two medicine units can be opened simultaneously for each administration, each medicine unit comprising the probucol and the statin of the present invention, and the opening of each medicine unit can expose the probucol and the statin of the present invention to the external environment at the same time.

[0056] 31. The drug kit of technical solution 30, wherein the amount or ratio of probucol and statin in each drug unit is as described in any one of technical solutions 21-25.

[0057] 32. Use of the drug combination of any one of Technical Solutions 20-26, the drug composition of Technical Solution 27, or the drug kit of any one of Technical Solutions 28-31 in the preparation of a drug for treating hyperlipidemia, preferably, the use is the use of any one of Technical Solutions 1-7. DETAILED DESCRIPTION

[0058] Unless defined otherwise, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0059] As used herein, the term "combination" refers to two or more drugs that are administered simultaneously, separately or sequentially. In some embodiments, "combination" refers to simultaneous administration, for example, two drugs are administered in a single dosage form. In other embodiments, "combination" refers to separate administration, for example, two drugs are administered in separate dosage forms, but are administered substantially simultaneously, with an interval of less than 30 minutes between administrations. In still other embodiments, "combination" refers to sequential administration, for example, one drug is administered first, followed by another drug after a certain time interval, for example, greater than 30 minutes.

[0060] The term "effective amount" or "therapeutically effective amount" as used herein refers to the amount of a compound or combination of compounds that provides an expected clinical or therapeutic benefit in a subject being treated. The therapeutically effective amount will depend on factors such as the general condition (e.g., weight, age, and sex) of the subject being treated, the severity of the disease, the specific compound being administered, the dosing regimen, the use of concomitant medications, and can be determined by the prescribing physician according to routine practice. In this article, unless otherwise indicated, the effective amount, therapeutically effective amount, and content of probucol are all calculated in terms of probucol free phenol, and the effective amount, therapeutically effective amount, and content of statins are all calculated in terms of statins in non-salt form.

[0061] The term "low dose / low dosage" as used herein means that the daily dose of probucol is less than the commonly used daily dose of 1000 mg / day, see "Guidelines for the Prevention and Treatment of Dyslipidemia in Adults in China (2016 Revised Edition)", for example, the daily dose is not more than 800 mg / day, preferably not more than 400 mg / day.

[0062] As used herein, the term "about" may allow for a certain degree of variability in a value or range, for example, within ±10%, within ±5%, or within ±1% of a stated value or a stated limit of a range.

[0063] As used herein, the term "treat" refers to at least partially alleviating, controlling and / or ameliorating a disease or its symptoms.

[0064] The term "subject" as used herein refers to a human subject to whom administration of the pharmaceutical combination or pharmaceutical composition of the present invention is intended.

[0065] As used herein, the term "QD" means once daily.

[0066] As used herein, the term "BID" means twice daily.

[0067] The term "pharmaceutically acceptable" as used herein refers to those substances or materials which are, within the scope of sound medical judgment, suitable for contact with subjects such as human tissues without causing excessive toxicity, irritation, allergic response or other problems, and with a commensurate benefit / risk ratio.

[0068] The term "pharmaceutically acceptable salt" as used herein refers to an addition salt formed with a pharmaceutically acceptable acid or base, including, for example, hydrochloride, acetate, hydrobromide, sulfate, bisulfate, carbonate, bicarbonate, sulfite, phosphate, hydrogen phosphate, oxalate, malonate, valerate, borate, p-toluenesulfonate, methanesulfonate, tartrate, benzoate, lactate, citrate, maleate, fumarate, malate, salicylate, mandelate, succinate, gluconate, lactobionate, alkali metal salts (e.g., lithium, sodium, potassium, rubidium, cesium salts), alkaline earth metal salts (e.g., magnesium, calcium, strontium, barium salts), aluminum salts, etc. The salts can be prepared by methods well known to those skilled in the art.

[0069] The term "pharmaceutically acceptable carrier" as used herein refers to a carrier (or excipient) that does not cause significant irritation to an organism and does not eliminate the biological activity and properties of the administered compound. Any commonly used pharmaceutically acceptable carrier can be used, and its selection depends on factors such as the specific mode of administration, the effect of the carrier on solubility and stability, and the nature of the dosage form and is within the ordinary skills of those skilled in the art. Examples of pharmaceutically acceptable carriers include, but are not limited to: fillers, such as lactose, sucrose, mannitol or sorbitol, cellulose derivatives and / or calcium phosphate; binders, such as corn, wheat or potato starch, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and / or polyvinyl pyrrolidone; disintegrants, such as starch, carboxymethyl starch, cross-linked polyvinyl pyrrolidone, alginic acid or its salts; lubricants, such as silicic acid, talc, stearic acid or its salts, and / or polyethylene glycol or its derivatives, etc.

[0070] The term "hyperlipidemia" used herein refers to abnormal blood lipids in which the levels of total cholesterol (TC) and / or triglyceride (TG) in serum are elevated.

[0071] The term "hypercholesterolemia" as used herein refers to hyperlipidemia with TC>6.22 mmol / L or 240 mg / dL, and / or LDL-C>4.14 mmol / L or 160 mg / dL, including familial (severe) hypercholesterolemia.

[0072] The term "severe hypercholesterolemia" as used herein refers to hyperlipidemia with LDL-C>4.9mmol / L.

[0073] The term "hypertriglyceridemia" as used herein refers to hyperlipidemia with TG>1.7 mmol / L or>150 mg / dL.

[0074] The term "severe hypertriglyceridemia" as used herein refers to hyperlipidemia with TG ≥ 5.6 mmol / L (500 mg / dL).

[0075] The term "fibrate-intolerant or -unresponsive hyperlipidemia" as used herein refers to hyperlipidemia in which fibrate treatment causes liver and kidney damage, elevated muscle enzymes, or TG remains greater than 5.6 mmol / L after fibrate treatment.

[0076] The term "hyperlipidemia that is ineffective or ineffective in statin treatment" used in this article refers to hyperlipidemia that does not reach the target value recommended by the "Chinese Lipid Management Guidelines (2023)" after statin treatment.

[0077] Hypercholesterolemia, severe hypercholesterolemia, hypertriglyceridemia, severe hypertriglyceridemia, fibrate-intolerant or non-responsive hyperlipidemia, and statin-refractory or ineffective hyperlipidemia are defined above. Similar definitions can be used for the following terms: Combination of hypertriglyceridemia and hypercholesterolemia Hypercholesterolemia that is ineffective or ineffective with statins, or hypercholesterolemia that is intolerant or unresponsive to fibrates Hypertriglyceridemia that is ineffective or ineffective with statins, or hypertriglyceridemia that is intolerant or unresponsive to fibrates Combination of severe hypertriglyceridemia and hypercholesterolemia, Combination of hypertriglyceridemia and severe hypercholesterolemia, Combination of severe hypertriglyceridemia and severe hypercholesterolemia, Severe hypertriglyceridemia that is ineffective or ineffective with statins, severe hypertriglyceridemia that is intolerant of or unresponsive to fibrates, Severe hypercholesterolemia that is ineffective or ineffective with statins, or intolerant or unresponsive to fibrates.

[0078] The "probucol" mentioned herein includes probucol and pharmaceutically acceptable salts or esters thereof, such as probucol disuccinate and the like.

[0079] The "statins" mentioned herein include statins and pharmaceutically acceptable salts thereof, such as sodium salts, calcium salts, and the like.

[0080] A first aspect of the present invention provides a pharmaceutical combination comprising probucol and a statin.

[0081] The statin is selected from atorvastatin, rosuvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, and simvastatin.

[0082] In some embodiments, the drug combination comprises a therapeutically effective amount of probucol and a therapeutically effective amount of a statin. In some embodiments, the therapeutically effective amount of probucol is about 10 mg to about 1000 mg (preferably, excluding the endpoint value of 1000 mg). In some embodiments, the therapeutically effective amount of probucol is about 20 mg to about 800 mg. In some embodiments, the therapeutically effective amount of probucol is about 20 mg to about 400 mg. In some embodiments, the therapeutically effective amount of probucol is about 40 mg to about 400 mg. In some embodiments, the therapeutically effective amount of probucol is about 60 mg to about 250 mg. In some embodiments, the therapeutically effective amount of probucol is about 20 mg, 25 mg, 30 mg, 31.25 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 62.5 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 187.5 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 In some embodiments, the therapeutically effective amount of probucol is about 62.5 mg to about 250 mg, or about 125 mg to about 250 mg. The "therapeutically effective amount" in this paragraph refers to the dose administered to a subject (or patient) in a single day, and can be administered once or more (such as 2 or 3 times) per day.

[0083] In some embodiments, the drug combination comprises a therapeutically effective amount of a statin. In some embodiments, the therapeutically effective amount of a statin is about 1 mg to about 80 mg. In some embodiments, the therapeutically effective amount of a statin is about 2 mg to about 80 mg. In some embodiments, the therapeutically effective amount of a statin is about 5 to about 80 mg. In some embodiments, the therapeutically effective amount of a statin is about 10 to about 80 mg. In some embodiments, the therapeutically effective amount of a statin is about 20 to about 80 mg. In some embodiments, the therapeutically effective amount of a statin is about 5 to about 40 mg. In some embodiments, the therapeutically effective amount of a statin is about 20 to about 40 mg. In some embodiments, the therapeutically effective amount of a statin is about 10 to about 20 mg. In some embodiments, the therapeutically effective amount of a statin is about 1 to about 5 mg. In preferred embodiments, the therapeutically effective amount of a statin is about 1 mg to about 80 mg, or about 2 mg to about 80 mg. The "therapeutically effective amount" in this paragraph refers to the dose administered to a subject (or patient) in a single day, and may be administered once or more (eg, twice or three times) per day.

[0084] In some embodiments, the statin is lovastatin, and its therapeutically effective amount is about 5 mg to about 40 mg, about 10 mg to about 40 mg, or about 10 mg to about 20 mg. In some embodiments, the therapeutically effective amount of lovastatin is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg. In a preferred embodiment, the therapeutically effective amount of lovastatin is about 5 mg to about 40 mg, or about 10 mg to about 20 mg. The "therapeutically effective amount" in this paragraph refers to the dose administered to the subject (or patient) in a single day, and can be administered once or more (such as 2 or 3 times) per day.

[0085] In some embodiments, the statin is pravastatin, and its therapeutically effective amount is about 5 mg to about 40 mg, about 10 mg to about 40 mg, or about 10 mg to about 20 mg. In some embodiments, the therapeutically effective amount of pravastatin is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg. In a preferred embodiment, the therapeutically effective amount of pravastatin is about 7.5 mg to about 40 mg, such as 30 mg, or about 15 mg. The "therapeutically effective amount" in this paragraph refers to the dose administered to the subject (or patient) in a single day, and can be administered once or more (such as 2 or 3 times) per day.

[0086] In some embodiments, the statin is simvastatin, and its therapeutically effective amount is about 10 mg to about 80 mg, about 5 mg to about 40 mg, about 10 mg to about 40 mg, or about 20 mg to about 40 mg. In some embodiments, the therapeutically effective amount of simvastatin is about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg. In a preferred embodiment, the therapeutically effective amount of simvastatin is about 10 mg to about 40 mg, or about 20 mg to about 40 mg. The "therapeutically effective amount" in this paragraph refers to the dose administered to the subject (or patient) in a single day, and can be administered once or more (such as 2 or 3 times) per day.

[0087] In some embodiments, the statin is fluvastatin, and its therapeutically effective amount is about 10 mg to about 80 mg, about 20 mg to about 80 mg, about 10 mg to about 60 mg, or about 20 mg to about 40 mg. In some embodiments, the therapeutically effective amount of fluvastatin is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, or about 80 mg. In a preferred embodiment, the therapeutically effective amount of fluvastatin is about 20 mg to about 80 mg, or about 40 mg to about 80 mg. The "therapeutically effective amount" in this paragraph refers to the dose administered to the subject (or patient) in a single day, and can be administered once or more (such as 2 or 3 times) per day.

[0088] In some embodiments, the statin is atorvastatin, and its therapeutically effective amount is about 5 mg to about 80 mg, about 10 mg to about 80 mg, about 5 mg to about 40 mg, about 10 mg to about 40 mg, or about 10 mg to about 20 mg. In some embodiments, the therapeutically effective amount of atorvastatin is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, or about 80 mg. In a preferred embodiment, the therapeutically effective amount of atorvastatin is about 5 mg to about 40 mg, or about 10 mg to about 20 mg. The "therapeutically effective amount" in this paragraph refers to the dose administered to the subject (or patient) in a single day, and can be administered once or more (such as 2 or 3 times) per day.

[0089] In some embodiments, the statin is rosuvastatin, and its therapeutically effective amount is about 2.5 mg to about 20 mg, about 5 mg to about 20 mg, or about 10 mg to about 20 mg. In some embodiments, the therapeutically effective amount of rosuvastatin is about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 20 mg. In a preferred embodiment, the therapeutically effective amount of rosuvastatin is about 5 mg to about 20 mg, or about 5 mg to about 10 mg. The "therapeutically effective amount" in this paragraph refers to the dose administered to the subject (or patient) in a single day, and can be administered 1 or more times (such as 2 or 3 times) per day.

[0090] In some embodiments, the statin is pitavastatin, and its therapeutically effective amount is about 0.5 mg to about 4 mg, about 1 mg to about 4 mg, about 2 mg to about 4 mg, about 2.5 mg to about 4 mg, about 3 mg to about 4 mg, or about 3.5 mg to about 4 mg. In some embodiments, the therapeutically effective amount of pitavastatin is about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, or about 4 mg. In a preferred embodiment, the therapeutically effective amount of pitavastatin is about 1 mg to about 4 mg, or about 2 mg to about 4 mg. The "therapeutically effective amount" in this paragraph refers to the dose administered to the subject (or patient) in a single day, and can be administered once or more (such as 2 or 3 times) per day.

[0091] Any weight of the therapeutically effective amount of probucol within the above range and any weight of the therapeutically effective amount of any one of the statins within the above range may constitute the pharmaceutical composition mentioned in the present invention.

[0092] In the present invention, the drug combination comprises a therapeutically effective amount of probucol and a therapeutically effective amount of a statin, wherein the therapeutically effective amount of probucol and the therapeutically effective amount of a statin are such amounts: the amount of probucol is 3a / 4b or 5a / 16b or a / 2b of the maximum daily dose of probucol for lowering cholesterol recommended in the "Guidelines for Blood Lipid Management in China (2023)", wherein a and b are integers of 1-16, and a≤b; the amount of statin is c / d of the maximum daily dose of statins for lowering cholesterol recommended in the "Guidelines for Blood Lipid Management in China (2023)", wherein c and d are integers of 1-16, and c≤d, for example, c≤d / 2.

[0093] With the development of medicine and the changes in human physique, if new conventional daily doses of probucol for lowering cholesterol and conventional daily doses of statins for lowering cholesterol are updated or proposed in the future "Guidelines for Chinese Blood Lipid Management" or other authoritative guidelines, the amount of probucol shall be 3a / 4b or 5a / 16b or a / 2b of the maximum daily dose of probucol for lowering cholesterol recommended in the updated "Guidelines for Chinese Blood Lipid Management", wherein a and b are integers of 1-16 and a≤b, and the amount of statins shall be c / d of the maximum daily dose of statins for lowering cholesterol recommended in the updated "Guidelines for Chinese Blood Lipid Management", wherein c and d are integers of 1-16 and c≤d, for example, c≤d / 2.

[0094] The amount of probucol is a / 2b of the maximum daily dose of probucol for lowering cholesterol recommended in the Guidelines for Blood Lipid Management in China (2023), wherein a and b are integers from 1 to 16, and a≤b, and the amount of statin is c / d of the maximum daily dose of statin for lowering cholesterol recommended in the Guidelines for Blood Lipid Management in China (2023), wherein c and d are integers from 1 to 16, and c≤d, for example, c≤d / 2; or The amount of probucol is 3a / 4b or 5a / 16b of the maximum daily dose of probucol for lowering cholesterol recommended in the "Guidelines for Blood Lipid Management in China (2023)", wherein a and b are integers of 1-16, and a≤b, and the amount of statins is c / d of the maximum daily dose of statins for lowering cholesterol recommended in the "Guidelines for Blood Lipid Management in China (2023)", wherein c and d are integers of 1-16, and c≤d, for example, c≤d / 2.

[0095] The maximum daily dose of probucol for cholesterol-lowering and the maximum daily dose of statins for cholesterol-lowering recommended by the "Guidelines for Chinese Blood Lipid Management (2023)" are (see Section 9.1.4 and Table 12 of the "Guidelines for Chinese Blood Lipid Management (2023)"): probucol: 1000 mg, pravastatin: 40 mg, simvastatin: 40 mg, fluvastatin: 80 mg, atorvastatin: 80 mg, rosuvastatin: 20 mg, and pitavastatin: 4 mg.

[0096] In some embodiments, the pharmaceutical combination comprises a therapeutically effective amount of probucol and a therapeutically effective amount of lovastatin, wherein the weight ratio of probucol to lovastatin is about (0.25-80):1. In some embodiments, the weight ratio of probucol to lovastatin is about (0.5-80):1. In some embodiments, the weight ratio of probucol to lovastatin is about (0.5-50):1. In some embodiments, the weight ratio of probucol to lovastatin is about (1-40):1. In some embodiments, the weight ratio of probucol to lovastatin is about (1-25):1. In some embodiments, the weight ratio of probucol to lovastatin is about (3-40):1. In some embodiments, the weight ratio of probucol to lovastatin is about 0.25:1, 0.5:1, 1:1, 2:1, 3:1, 3.125:1, 4:1, 5:1, 6:1, 6.25:1, 7:1, 8:1, 9:1, 9.375:1, 10:1, 11:1, 12:1, 12.5:1, 13:1, 14:1, 15:1, 15.625:1, 16:1, 17:1, 18:1, 18.75:1, 19:1, 20:1, 21:1, 21.875:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1, 39:1, or 40:1.

[0097] In some embodiments, the drug combination comprises a therapeutically effective amount of probucol and a therapeutically effective amount of lovastatin, wherein the drug combination comprises about 20 to about 800 mg of probucol and about 5 to about 40 mg of lovastatin. In some embodiments, the drug combination comprises about 20 to about 400 mg of probucol and about 10 to about 40 mg of lovastatin. In some embodiments, the drug combination comprises about 40 to about 400 mg of probucol and about 10 to about 40 mg of lovastatin. In some embodiments, the drug combination comprises about 60 to about 250 mg of probucol and about 10 to about 40 mg of lovastatin. In some embodiments, the drug combination comprises about 62.5 mg to about 250 mg, or about 125 mg to about 250 mg of probucol and about 5 mg to about 40 mg, or about 10 mg to about 20 mg of lovastatin. In some embodiments, the drug combination comprises about 125 mg of probucol and about 5 mg of lovastatin. In some embodiments, the drug combination comprises about 125 mg of probucol and about 10 mg of lovastatin. In some embodiments, the drug combination comprises about 125 mg of probucol and about 20 mg of lovastatin. In some embodiments, the drug combination comprises about 250 mg of probucol and about 5 mg of lovastatin. In some embodiments, the drug combination comprises about 250 mg of probucol and about 10 mg of lovastatin. In some embodiments, the drug combination comprises about 250 mg of probucol and about 20 mg of lovastatin. The "therapeutically effective amount" in this paragraph refers to the dose administered to the subject (or patient) in a single day, and can be administered once or more (such as 2 or 3 times) per day.

[0098] In some embodiments, the pharmaceutical combination comprises a therapeutically effective amount of probucol and a therapeutically effective amount of pravastatin, wherein the weight ratio of probucol to pravastatin is about (0.25-80):1. In some embodiments, the weight ratio of probucol to pravastatin is about (0.5-80):1. In some embodiments, the weight ratio of probucol to pravastatin is about (0.5-50):1. In some embodiments, the weight ratio of probucol to pravastatin is about (1-40):1. In some embodiments, the weight ratio of probucol to pravastatin is about (1-25):1. In some embodiments, the weight ratio of probucol to pravastatin is about (6-10):1. In some embodiments, the weight ratio of probucol to pravastatin is about 0.25:1, 0.5:1, 1:1, 2:1, 3:1, 3.125:1, 4:1, 5:1, 6:1, 6.25:1, 7:1, 8:1, 25:3, 9:1, 9.375:1, 10:1, 11:1, 12:1, 12.5:1, 13:1, 14:1, 15:1, 15.625:1, 16:1, 17:1, 18:1, 18.75:1, 19:1, 20:1, 21:1, 21.875:1, 22:1, 23:1, 24:1, or 25:1.

[0099] In some embodiments, the drug combination comprises a therapeutically effective amount of probucol and a therapeutically effective amount of pravastatin, wherein the drug combination comprises about 20 to about 800 mg of probucol and about 5 to about 40 mg of pravastatin. In some embodiments, the drug combination comprises about 20 to about 400 mg of probucol and about 10 to about 40 mg of pravastatin. In some embodiments, the drug combination comprises about 40 to about 400 mg of probucol and about 10 to about 40 mg of pravastatin. In some embodiments, the drug combination comprises about 60 to about 250 mg of probucol and about 10 to about 40 mg of pravastatin. In some embodiments, the drug combination comprises about 62.5 mg to about 250 mg, or about 125 mg to about 250 mg of probucol and about 7.5 mg to about 30 mg, or about 15 mg of pravastatin. In some embodiments, the drug combination comprises about 125 mg of probucol and about 10 mg of pravastatin. In some embodiments, the drug combination comprises about 125 mg of probucol and about 15 mg of pravastatin. In some embodiments, the drug combination comprises about 125 mg of probucol and about 20 mg of pravastatin. In some embodiments, the drug combination comprises about 250 mg of probucol and about 10 mg of pravastatin. In some embodiments, the drug combination comprises about 250 mg of probucol and about 15 mg of pravastatin. In some embodiments, the drug combination comprises about 250 mg of probucol and about 20 mg of pravastatin. The "therapeutically effective amount" in this paragraph refers to the dose administered to the subject (or patient) in a single day, and can be administered once or more (such as 2 or 3 times) per day.

[0100] In some embodiments, the pharmaceutical combination comprises a therapeutically effective amount of probucol and a therapeutically effective amount of simvastatin, wherein the weight ratio of probucol to simvastatin is about (0.25-160):1. In some embodiments, the weight ratio of probucol to simvastatin is about (0.5-160):1. In some embodiments, the weight ratio of probucol to simvastatin is about (0.5-80):1. In some embodiments, the weight ratio of probucol to simvastatin is about (1-40):1. In some embodiments, the weight ratio of probucol to simvastatin is about (1-25):1. In some embodiments, the weight ratio of probucol to simvastatin is about (1-15):1. In some embodiments, the weight ratio of probucol to simvastatin is about 0.25:1, 0.5:1, 1:1, 25:16, 2:1, 3:1, 3.125:1, 4:1, 5:1, 6:1, 6.25:1, 7:1, 8:1, 9:1, 9.375:1, 10:1, 11:1, 12:1, 12.5:1, 13:1, 14:1, 15:1, 15.625:1, 16:1, 17:1, 18:1, 18.75:1, 19:1, 20:1, 21:1, 21.875:1, 22:1, 23:1, 24:1, or 25:1.

[0101] In some embodiments, the drug combination comprises a therapeutically effective amount of probucol and a therapeutically effective amount of simvastatin, wherein the drug combination comprises about 20 to about 800 mg of probucol and about 2.5 to about 40 mg of simvastatin. In some embodiments, the drug combination comprises about 20 to about 400 mg of probucol and about 5 to about 40 mg of simvastatin. In some embodiments, the drug combination comprises about 40 to about 400 mg of probucol and about 5 to about 40 mg of simvastatin. In some embodiments, the drug combination comprises about 60 to about 250 mg of probucol and about 10 to about 40 mg of simvastatin. In some embodiments, the drug combination comprises about 62.5 mg to about 250 mg, or about 125 mg to about 250 mg of probucol and about 10 mg to about 40 mg, or about 20 mg to about 40 mg of simvastatin. In some embodiments, the drug combination comprises about 62.5 mg of probucol and about 40 mg of simvastatin. In some embodiments, the drug combination comprises about 125 mg of probucol and about 10 mg of simvastatin. In some embodiments, the drug combination comprises about 125 mg of probucol and about 20 mg of simvastatin. In some embodiments, the drug combination comprises about 125 mg of probucol and about 40 mg of simvastatin. In some embodiments, the drug combination comprises about 250 mg of probucol and about 10 mg of simvastatin. In some embodiments, the drug combination comprises about 250 mg of probucol and about 20 mg of simvastatin. In some embodiments, the drug combination comprises about 250 mg of probucol and about 40 mg of simvastatin.

[0102] In some embodiments, the pharmaceutical combination comprises a therapeutically effective amount of probucol and a therapeutically effective amount of fluvastatin, wherein the weight ratio of probucol to fluvastatin is about (0.125-40):1. In some embodiments, the weight ratio of probucol to fluvastatin is about (0.125-20):1. In some embodiments, the weight ratio of probucol to fluvastatin is about (0.25-20):1. In some embodiments, the weight ratio of probucol to fluvastatin is about (0.5-20):1. In some embodiments, the weight ratio of probucol to fluvastatin is about (0.5-10):1. In some embodiments, the weight ratio of probucol to fluvastatin is about (0.5-8):1. In some embodiments, the weight ratio of probucol to fluvastatin is about (1-4):1. In some embodiments, the weight ratio of probucol to fluvastatin is about 0.25:1, 0.5:1, 1:1, 25:16, 2:1, 3:1, 3.125:1, 4:1, 5:1, 6:1, 6.25:1, 7:1, 8:1, 9:1, 9.375:1, 10:1, 11:1, 12:1, 12.5:1, 13:1, 14:1, 15:1, 15.625:1, 16:1, 17:1, 18:1, 18.75:1, 19:1, 20:1, 21:1, 21.875:1, 22:1, 23:1, 24:1, or 25:1.

[0103] In some embodiments, the pharmaceutical combination comprises a therapeutically effective amount of probucol and a therapeutically effective amount of fluvastatin, wherein the pharmaceutical combination comprises about 20 to about 800 mg of probucol and about 10 to about 80 mg of fluvastatin. In some embodiments, the pharmaceutical combination comprises about 20 to about 400 mg of probucol and about 20 to about 80 mg of fluvastatin. In some embodiments, the pharmaceutical combination comprises about 40 to about 400 mg of probucol and about 20 to about 80 mg of fluvastatin. In some embodiments, the pharmaceutical combination comprises about 60 to about 250 mg of probucol and about 30 to about 80 mg of fluvastatin. In some embodiments, the pharmaceutical combination comprises about 62.5 mg to about 250 mg, or about 125 mg to about 250 mg of probucol and about 20 mg to about 80 mg, or about 40 mg to about 80 mg of fluvastatin. In some embodiments, the drug combination comprises about 125 mg of probucol and about 40 mg of fluvastatin. In some embodiments, the drug combination comprises about 125 mg of probucol and about 60 mg of fluvastatin. In some embodiments, the drug combination comprises about 125 mg of probucol and about 80 mg of fluvastatin. In some embodiments, the drug combination comprises about 250 mg of probucol and about 40 mg of fluvastatin. In some embodiments, the drug combination comprises about 250 mg of probucol and about 60 mg of fluvastatin. In some embodiments, the drug combination comprises about 250 mg of probucol and about 80 mg of fluvastatin. The "therapeutically effective amount" in this paragraph refers to the dose administered to the subject (or patient) in a single day, and can be administered once or more (such as 2 or 3 times) per day.

[0104] In some embodiments, the pharmaceutical combination comprises a therapeutically effective amount of probucol and a therapeutically effective amount of atorvastatin, wherein the weight ratio of probucol to atorvastatin is about (0.5-80): 1. In some embodiments, the weight ratio of probucol to atorvastatin is about (0.5-50): 1. In some embodiments, the weight ratio of probucol to atorvastatin is about (1-40): 1. In some embodiments, the weight ratio of probucol to atorvastatin is about (3-25): 1. In some embodiments, the weight ratio of probucol to atorvastatin is about (2-25): 1. In some embodiments, the weight ratio of probucol to atorvastatin is about 0.5:1, 1:1, 2:1, 3:1, 3.125:1, 4:1, 5:1, 6:1, 6.25:1, 7:1, 8:1, 9:1, 9.375:1, 10:1, 11:1, 12:1, 12.5:1, 13:1, 14:1, 15:1, 15.625:1, 16:1, 17:1, 18:1, 18.75:1, 19:1, 20:1, 21:1, 21.875:1, 22:1, 23:1, 24:1, or 25:1.

[0105] In some embodiments, the pharmaceutical combination comprises a therapeutically effective amount of probucol and a therapeutically effective amount of atorvastatin, wherein the pharmaceutical combination comprises about 20 to about 800 mg of probucol and about 5 to about 80 mg of atorvastatin. In some embodiments, the pharmaceutical combination comprises about 20 to about 400 mg of probucol and about 10 to about 80 mg of atorvastatin. In some embodiments, the pharmaceutical combination comprises about 40 to about 400 mg of probucol and about 10 to about 80 mg of atorvastatin. In some embodiments, the pharmaceutical combination comprises about 60 to about 250 mg of probucol and about 10 to about 40 mg of atorvastatin. In some embodiments, the pharmaceutical combination comprises about 62.5 mg to about 250 mg, or about 125 mg to about 250 mg of probucol and about 5 mg to about 40 mg, or about 10 mg to about 20 mg of atorvastatin. In some embodiments, the drug combination comprises about 62.5 mg of probucol and about 20 mg of atorvastatin. In some embodiments, the drug combination comprises about 125 mg of probucol and about 10 mg of atorvastatin. In some embodiments, the drug combination comprises about 125 mg of probucol and about 15 mg of atorvastatin. In some embodiments, the drug combination comprises about 125 mg of probucol and about 20 mg of atorvastatin. In some embodiments, the drug combination comprises about 250 mg of probucol and about 10 mg of atorvastatin. In some embodiments, the drug combination comprises about 250 mg of probucol and about 15 mg of atorvastatin. In some embodiments, the drug combination comprises about 250 mg of probucol and about 20 mg of atorvastatin. The "therapeutically effective amount" in this paragraph refers to the dose administered to a subject (or patient) in a single day, and may be administered once or more (eg, twice or three times) per day.

[0106] In some embodiments, the pharmaceutical combination comprises a therapeutically effective amount of probucol and a therapeutically effective amount of rosuvastatin, wherein the weight ratio of probucol to rosuvastatin is about (1-160): 1. In some embodiments, the weight ratio of probucol to rosuvastatin is about (1-80): 1. In some embodiments, the weight ratio of probucol to rosuvastatin is about (1-60): 1. In some embodiments, the weight ratio of probucol to rosuvastatin is about (1-50): 1. In some embodiments, the weight ratio of probucol to rosuvastatin is about (5-60): 1. In some embodiments, the weight ratio of probucol to rosuvastatin is about 1:1, 2:1, 3:1, 3.125:1, 4:1, 5:1, 6:1, 6.25:1, 7:1, 8:1, 9:1, 9.375:1, 10:1, 11:1, 12:1, 12.5:1, 13:1, 14:1, 15:1, 15.625:1, 16:1, 17:1, 18:1 , 18.75:1, 19:1, 20:1, 21:1, 21.875:1, 22:1, 23:1, 24:1, 25:1, 26:1, 28:1, 30:1, 32:1, 34:1, 36:1, 38:1, 40:1, 42:1, 44:1, 46:1, 48:1, 50:1, 52:1, 54:1, 56:1, 58:1, or 60:1.

[0107] In some embodiments, the drug combination comprises a therapeutically effective amount of probucol and a therapeutically effective amount of rosuvastatin, wherein the drug combination comprises about 20 to about 800 mg of probucol and about 2.5 to about 20 mg of rosuvastatin. In some embodiments, the drug combination comprises about 20 to about 400 mg of probucol and about 5 to about 20 mg of rosuvastatin. In some embodiments, the drug combination comprises about 40 to about 400 mg of probucol and about 5 to about 20 mg of rosuvastatin. In some embodiments, the drug combination comprises about 60 to about 250 mg of probucol and about 5 to about 20 mg of rosuvastatin. In some embodiments, the drug combination comprises about 62.5 mg to about 250 mg, or about 125 mg to about 250 mg of probucol and about 2.5 mg to about 20 mg, or about 5 mg to about 10 mg of rosuvastatin. In some embodiments, the drug combination comprises about 62.5 mg of probucol and about 10 mg of rosuvastatin. In some embodiments, the drug combination comprises about 125 mg of probucol and about 5 mg of rosuvastatin. In some embodiments, the drug combination comprises about 125 mg of probucol and about 10 mg of rosuvastatin. In some embodiments, the drug combination comprises about 125 mg of probucol and about 15 mg of rosuvastatin. In some embodiments, the drug combination comprises about 250 mg of probucol and about 5 mg of rosuvastatin. In some embodiments, the drug combination comprises about 250 mg of probucol and about 10 mg of rosuvastatin. In some embodiments, the drug combination comprises about 250 mg of probucol and about 15 mg of rosuvastatin. The "therapeutically effective amount" in this paragraph refers to the dose administered to a subject (or patient) in a single day, and may be administered once or more (eg, twice or three times) per day.

[0108] In some embodiments, the pharmaceutical combination comprises a therapeutically effective amount of probucol and a therapeutically effective amount of pitavastatin, wherein the weight ratio of probucol to pitavastatin is about (10-400): 1. In some embodiments, the weight ratio of probucol to pitavastatin is about (15-250): 1. In some embodiments, the weight ratio of probucol to pitavastatin is about (20-200): 1. In some embodiments, the weight ratio of probucol to pitavastatin is about (30-125): 1. In some embodiments, the weight ratio of probucol to pitavastatin is about (80-150): 1. In some embodiments, the weight ratio of probucol to pitavastatin is about 10:1, 15:1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, 55:1, 60:1, 65:1, 70:1, 75:1, 80:1, 85:1, 90:1, 95:1, 100:1, 125:1, 150:1, 200:1, or 250:1.

[0109] In some embodiments, the drug combination comprises a therapeutically effective amount of probucol and a therapeutically effective amount of rosuvastatin, wherein the drug combination comprises about 20 to about 800 mg of probucol and about 1 to about 4 mg of pitavastatin. In some embodiments, the drug combination comprises about 20 to about 400 mg of probucol and about 2 to about 4 mg of pitavastatin. In some embodiments, the drug combination comprises about 40 to about 400 mg of probucol and about 2 to about 4 mg of pitavastatin. In some embodiments, the drug combination comprises about 60 to about 250 mg of probucol and about 1 to about 3 mg of pitavastatin. In some embodiments, the drug combination comprises about 62.5 mg to about 250 mg, or about 125 mg to about 250 mg of probucol and about 0.5 mg to about 4 mg, about 1 mg to about 4 mg, or about 2 mg to about 4 mg of pitavastatin. In some embodiments, the drug combination comprises about 125 mg of probucol and about 2 mg of pitavastatin. In some embodiments, the drug combination comprises about 125 mg of probucol and about 3 mg of pitavastatin. In some embodiments, the drug combination comprises about 125 mg of probucol and about 4 mg of pitavastatin. In some embodiments, the drug combination comprises about 250 mg of probucol and about 2 mg of pitavastatin. In some embodiments, the drug combination comprises about 250 mg of probucol and about 3 mg of pitavastatin. In some embodiments, the drug combination comprises about 250 mg of probucol and about 4 mg of pitavastatin. The "therapeutically effective amount" in this paragraph refers to the dose administered to the subject (or patient) in a single day, and can be administered once or more (such as 2 or 3 times) per day.

[0110] In some embodiments, probucol or a pharmaceutically acceptable salt thereof and a statin are provided in separate formulations. In some embodiments, probucol is provided in the form of a probucol tablet. In some embodiments, a statin is provided in the form of a tablet, capsule, or granule.

[0111] In some embodiments, probucol and statins are provided in a single composition, such as in a single tablet, capsule or granule. In some embodiments, probucol and statins can also be provided in a plurality of (e.g., 2, 3, 4, 5, 6, 7, 8, 9) compositions, such as in a plurality of (e.g., 2, 3, 4, 5, 6, 7, 8, 9) tablets, capsules or granules, wherein the therapeutically effective amount of probucol and the therapeutically effective amount of statins are evenly distributed in the plurality of (e.g., 2, 3, 4, 5, 6, 7, 8, 9) compositions (e.g., tablets, capsules or granules). The form of the composition is not limited to the tablets, capsules or granules described above.

[0112] The second aspect of the present invention provides a pharmaceutical composition comprising probucol, a statin and a pharmaceutically acceptable carrier.

[0113] In the present invention, the amount of probucol and the amount of statin in the pharmaceutical composition are such amounts: the amount of probucol is 3a / 4b or 5a / 16b or a / 2b of the maximum daily dose of probucol for lowering cholesterol recommended in the "Guidelines for Blood Lipid Management in China (2023)", wherein a and b are integers of 1-16, and a≤b; the amount of statin is c / d of the maximum daily dose of statin for lowering cholesterol recommended in the "Guidelines for Blood Lipid Management in China (2023)", wherein c and d are integers of 1-16, and c≤d, for example, c≤d / 2. With the development of medicine and the changes in human physique, if new conventional daily doses of probucol for lowering cholesterol and conventional daily doses of statins for lowering cholesterol are updated or proposed in the future "Guidelines for Chinese Blood Lipid Management" or other authoritative guidelines, the amount of probucol shall be 3a / 4b or 5a / 16b or a / 2b of the maximum daily dose of probucol for lowering cholesterol recommended in the updated "Guidelines for Chinese Blood Lipid Management", wherein a and b are integers of 1-16 and a≤b, and the amount of statins shall be c / d of the maximum daily dose of statins for lowering cholesterol recommended in the updated "Guidelines for Chinese Blood Lipid Management", wherein c and d are integers of 1-16 and c≤d, for example, c≤d / 2.

[0114] In some embodiments, the pharmaceutical composition comprises about 0.1% by weight to 99.5% by weight of active ingredients (i.e., probucol and statins), preferably about 0.5% by weight to 99.5% by weight, more preferably about 1% by weight to 50% by weight, for example, about 1%, about 1.5%, about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30% by weight or about 50% by weight of active ingredients. The remainder of the pharmaceutical composition is a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises two, three or more pharmaceutically acceptable carriers. Examples of the pharmaceutically acceptable carrier include, but are not limited to, conventional diluents in the pharmaceutical field (such as, but not limited to, water, ethanol, propylene glycol, glycerol, lactose, dextrose, sucrose, cellulose, corn starch, potato starch), excipients (such as, but not limited to, sodium citrate, calcium carbonate, calcium phosphate), fillers (such as, but not limited to, lactose, high molecular weight polyethylene glycol), binders (such as, but not limited to, polyvinyl pyrrolidone, sucrose, gelatin, gum arabic, starch, methylcellulose, carboxymethyl cellulose), wetting agents (such as, but not limited to, lecithin, polysorbate, lauryl sulfate), disintegrants (such as, but not limited to, starch, alginic acid, alginates, sodium starch glycolate), lubricants (such as, but not limited to, sodium lauryl sulfate, talc, silicon dioxide, stearic acid, magnesium stearate, calcium stearate, polyethylene glycol), colorants, flavors, absorption promoters, surfactants, adsorption carriers, etc.

[0115] In some embodiments, the pharmaceutical composition comprises probucol and lovastatin as active ingredients, wherein the weight ratio of probucol to lovastatin is about (0.5-80):1, about (0.5-50):1, about (1-40):1, about (3-40):1, or about (1-25):1. In some embodiments, the weight ratio of probucol to lovastatin is about 0.25:1, 0.5:1, 1:1, 2:1, 3:1, 3.125:1, 4:1, 5:1, 6:1, 6.25:1, 7:1, 8:1, 9:1, 9.375:1, 10:1, 11:1, 12:1, 12.5:1, 13:1, 14:1, 15:1, 15.625:1, 16:1, 17:1, 18:1, 18.75:1, 19:1, 20:1, 21:1, 21.875:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1, 39:1, or 40:1.

[0116] In some embodiments, the pharmaceutical composition comprises probucol and pravastatin as active ingredients, wherein the weight ratio of probucol to pravastatin is about (0.5-80):1, about (0.5-50):1, about (1-40):1, about (6-10):1 or about (1-25):1. In some embodiments, the weight ratio of probucol to pravastatin is about 0.25:1, 0.5:1, 1:1, 2:1, 3:1, 3.125:1, 4:1, 5:1, 6:1, 6.25:1, 7:1, 8:1, 25:3, 9:1, 9.375:1, 10:1, 11:1, 12:1, 12.5:1, 13:1, 14:1, 15:1, 15.625:1, 16:1, 17:1, 18:1, 18.75:1, 19:1, 20:1, 21:1, 21.875:1, 22:1, 23:1, 24:1, or 25:1.

[0117] In some embodiments, the pharmaceutical composition comprises probucol and simvastatin as active ingredients, wherein the weight ratio of probucol to simvastatin is about (0.5-160):1, about (0.5-80):1, about (1-40):1, about (1-25):1 or about (1-15):1. In some embodiments, the weight ratio of probucol to simvastatin is about 0.25:1, 0.5:1, 1:1, 25:16, 2:1, 3:1, 3.125:1, 4:1, 5:1, 6:1, 6.25:1, 7:1, 8:1, 9:1, 9.375:1, 10:1, 11:1, 12:1, 12.5:1, 13:1, 14:1, 15:1, 15.625:1, 16:1, 17:1, 18:1, 18.75:1, 19:1, 20:1, 21:1, 21.875:1, 22:1, 23:1, 24:1, or 25:1.

[0118] In some embodiments, the pharmaceutical composition comprises probucol and fluvastatin as active ingredients, wherein the weight ratio of probucol to fluvastatin is (0.125-40):1, about (0.125-20):1, about (0.25-20):1, about (0.5-20):1, about (0.5-10):1, about (1-4):1 or about (0.5-8):1. In some embodiments, the weight ratio of probucol to fluvastatin is about 0.25:1, 0.5:1, 1:1, 25:16, 2:1, 3:1, 3.125:1, 4:1, 5:1, 6:1, 6.25:1, 7:1, 8:1, 9:1, 9.375:1, 10:1, 11:1, 12:1, 12.5:1, 13:1, 14:1, 15:1, 15.625:1, 16:1, 17:1, 18:1, 18.75:1, 19:1, 20:1, 21:1, 21.875:1, 22:1, 23:1, 24:1, or 25:1.

[0119] In some embodiments, the pharmaceutical composition comprises probucol and atorvastatin as active ingredients, wherein the weight ratio of probucol to atorvastatin is about (0.5-80):1, about (0.5-50):1, about (1-40):1, about (3-25):1 or about (2-25):1. In some embodiments, the weight ratio of probucol to atorvastatin is about 0.25:1, 0.5:1, 1:1, 2:1, 3:1, 3.125:1, 4:1, 5:1, 6:1, 6.25:1, 7:1, 8:1, 9:1, 9.375:1, 10:1, 11:1, 12:1, 12.5:1, 13:1, 14:1, 15:1, 15.625:1, 16:1, 17:1, 18:1, 18.75:1, 19:1, 20:1, 21:1, 21.875:1, 22:1, 23:1, 24:1, or 25:1.

[0120] In some embodiments, the pharmaceutical composition comprises probucol and rosuvastatin as active ingredients, wherein the weight ratio of probucol to rosuvastatin is about (1-160):1, about (1-80):1, about (1-60):1, about (1-50):1, or about (5-60):1. In some embodiments, the weight ratio of probucol to rosuvastatin is about 0.25:1, 0.5:1, 1:1, 2:1, 3:1, 3.125:1, 4:1, 5:1, 6:1, 6.25:1, 7:1, 8:1, 9:1, 9.375:1, 10:1, 11:1, 12:1, 12.5:1, 13:1, 14:1, 15:1, 15.625:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1 :1, 18:1, 18.75:1, 19:1, 20:1, 21:1, 21.875:1, 22:1, 23:1, 24:1 or 25:1, 26:1, 28:1, 30:1, 32:1, 34:1, 36:1, 38:1, 40:1, 42:1, 44:1, 46:1, 48:1, 50:1, 52:1, 54:1, 56:1, 58:1, or 60:1.

[0121] In some embodiments, the pharmaceutical composition comprises probucol and pitavastatin as active ingredients, wherein the weight ratio of probucol to pitavastatin is about (10-400): 1, about (15-250): 1, about (20-200): 1, about (30-125): 1, or about (80-150): 1. In some embodiments, the weight ratio of probucol to pitavastatin is about 10: 1, 15: 1, 20: 1, 25: 1, 30: 1, 35: 1, 40: 1, 45: 1, 50: 1, 55: 1, 60: 1, 65: 1, 70: 1, 75: 1, 80: 1, 85: 1, 90: 1, 95: 1, 100: 1, 125: 1, 150: 1, 200: 1, or 250: 1.

[0122] In some embodiments, the pharmaceutical composition is prepared into a pharmaceutically acceptable dosage form. For example, in some embodiments, probucol and statins can be mixed with one or more pharmaceutically acceptable carriers and prepared into a pharmaceutically acceptable dosage form according to conventional production methods in the pharmaceutical field. Examples of the pharmaceutically acceptable dosage form include, but are not limited to, conventional solid dosage forms in the pharmaceutical field (such as, but not limited to, tablets (including ordinary tablets, coated tablets, chewable tablets, enteric-coated tablets, sustained-release tablets, controlled-release tablets, orally disintegrating tablets, dispersible tablets, effervescent tablets, etc.), capsules (including hard capsules, soft capsules, enteric-coated capsules, sustained-release capsules, controlled-release capsules, etc.), granules (including soluble granules, suspension granules, enteric-coated granules, sustained-release granules, controlled-release granules, effervescent granules, etc.), pills, micropills, etc.), liquid dosage forms (such as, but not limited to, solutions, syrups, suspensions, emulsions, etc.), etc.

[0123] In some embodiments, the pharmaceutical composition is presented as a unit dosage form suitable for oral administration, such as a tablet, capsule, or granule, each of which contains a predetermined amount of active ingredient. In some embodiments, the pharmaceutical composition is a capsule. In some embodiments, the pharmaceutical composition is a tablet. In some embodiments, the pharmaceutical composition is a chewable tablet. In some embodiments, the pharmaceutical composition is a multilayer tablet, such as a bilayer tablet, wherein the first layer contains probucol and a pharmaceutically acceptable carrier, and the second layer contains a statin and a pharmaceutically acceptable carrier.

[0124] In some embodiments, the pharmaceutical composition is an oral unit dosage form, which contains a therapeutically effective amount of probucol, a statin, and a pharmaceutically acceptable carrier. In some embodiments, the content of probucol in the oral unit dosage form can vary in the range of about 10 mg to about 1000 mg, such as about 20 mg to about 800 mg, about 20 mg to about 400 mg, about 40 mg to about 400 mg, about 60 mg to about 250 mg, about 31.25 mg, about 62.5 mg, about 125 mg, about 187.5 mg, about 250 mg, about 312.5 mg, or about 375 mg. In some embodiments, the content of statins in the oral unit dosage form can vary in the range of about 1 mg to about 80 mg, such as about 5 mg to about 80 mg, about 5 mg to about 40 mg, about 5 mg to about 20 mg, or about 1 mg to about 5 mg. In a preferred embodiment, in the oral unit dosage form, the content of probucol may be about 62.5 mg to about 250 mg, or about 125 mg to about 250 mg; the content of statin may be about 1 mg to about 80 mg, or about 2 mg to about 80 mg.

[0125] In some embodiments, the oral unit dosage form contains about 20 mg to about 400 mg of probucol and about 5 mg to about 40 mg of lovastatin. In some embodiments, the oral unit dosage form contains about 40 mg to about 400 mg of probucol and about 5 mg to about 40 mg of lovastatin. In some embodiments, the oral unit dosage form contains about 62.5 mg to about 375 mg of probucol and about 10 mg to about 20 mg of lovastatin. In some embodiments, the oral unit dosage form contains about 62.5 mg of probucol and about 20 mg of lovastatin. In some embodiments, the oral unit dosage form contains about 125 mg of probucol and about 20 mg of lovastatin. In some embodiments, the oral unit dosage form contains about 250 mg of probucol and about 10 mg of lovastatin. In some embodiments, the oral unit dosage form contains about 250 mg of probucol and about 20 mg of lovastatin. In a preferred embodiment, in the oral unit dosage form, the content of probucol may be about 62.5 mg to about 250 mg, or about 125 mg to about 250 mg; the content of lovastatin may be about 5 mg to about 40 mg, or about 10 mg to about 20 mg.

[0126] In some embodiments, the oral unit dosage form contains about 20 mg to about 400 mg of probucol and about 5 mg to about 40 mg of pravastatin. In some embodiments, the oral unit dosage form contains about 40 mg to about 400 mg of probucol and about 5 mg to about 40 mg of pravastatin. In some embodiments, the oral unit dosage form contains about 62.5 mg to about 375 mg of probucol and about 10 mg to about 40 mg of pravastatin. In some embodiments, the oral unit dosage form contains about 62.5 mg of probucol and about 15 mg of pravastatin. In some embodiments, the oral unit dosage form contains about 125 mg of probucol and about 15 mg of pravastatin. In some embodiments, the oral unit dosage form contains about 250 mg of probucol and about 15 mg of pravastatin. In a preferred embodiment, in the oral unit dosage form, the content of probucol may be about 62.5 mg to about 250 mg, or about 125 mg to about 250 mg; the content of pravastatin may be about 7.5 mg to about 30 mg, or about 15 mg.

[0127] In some embodiments, the oral unit dosage form contains about 20 mg to about 400 mg of probucol and about 2.5 mg to about 40 mg of simvastatin. In some embodiments, the oral unit dosage form contains about 40 mg to about 400 mg of probucol and about 2.5 mg to about 40 mg of simvastatin. In some embodiments, the oral unit dosage form contains about 62.5 mg to about 375 mg of probucol and about 10 mg to about 40 mg of simvastatin. In some embodiments, the oral unit dosage form contains about 62.5 mg to about 40 mg of probucol and about 40 mg of simvastatin. In some embodiments, the oral unit dosage form contains about 125 mg of probucol and about 40 mg of simvastatin. In some embodiments, the oral unit dosage form contains about 250 mg of probucol and about 40 mg of simvastatin. In some embodiments, the oral unit dosage form contains about 250 mg of probucol and about 20 mg of simvastatin. In a preferred embodiment, in the oral unit dosage form, the content of probucol may be about 62.5 mg to about 250 mg, or about 125 mg to about 250 mg; the content of simvastatin may be about 10 mg to about 80 mg, or about 20 mg to about 40 mg.

[0128] In some embodiments, the oral unit dosage form contains about 20 mg to about 400 mg of probucol and about 10 mg to about 80 mg of fluvastatin. In some embodiments, the oral unit dosage form contains about 40 mg to about 400 mg of probucol and about 10 mg to about 80 mg of fluvastatin. In some embodiments, the oral unit dosage form contains about 62.5 mg to about 375 mg of probucol and about 20 mg to about 40 mg of fluvastatin. In some embodiments, the oral unit dosage form contains about 62.5 mg of probucol and about 40 mg of fluvastatin. In some embodiments, the oral unit dosage form contains about 125 mg of probucol and about 40 mg of fluvastatin. In some embodiments, the oral unit dosage form contains about 125 mg of probucol and about 80 mg of fluvastatin. In some embodiments, the oral unit dosage form contains about 250 mg of probucol and about 40 mg of fluvastatin. In a preferred embodiment, in the oral unit dosage form, the content of probucol may be about 62.5 mg to about 250 mg, or about 125 mg to about 250 mg; the content of fluvastatin may be about 20 mg to about 80 mg, or about 40 mg to about 80 mg.

[0129] In some embodiments, the oral unit dosage form contains about 20 mg to about 400 mg of probucol and about 5 mg to about 80 mg of atorvastatin. In some embodiments, the oral unit dosage form contains about 40 mg to about 400 mg of probucol and about 5 mg to about 80 mg of atorvastatin. In some embodiments, the oral unit dosage form contains about 62.5 mg to about 375 mg of probucol and about 10 mg to about 40 mg of atorvastatin. In some embodiments, the oral unit dosage form contains about 62.5 mg of probucol and about 20 mg of atorvastatin. In some embodiments, the oral unit dosage form contains about 125 mg of probucol and about 20 mg of atorvastatin. In some embodiments, the oral unit dosage form contains about 250 mg of probucol and about 20 mg of atorvastatin. In some embodiments, the oral unit dosage form contains about 250 mg of probucol and about 10 mg of atorvastatin. In preferred embodiments, in the oral unit dosage form, the content of probucol can be about 62.5 mg to about 250 mg, or about 125 mg to about 250 mg; the content of atorvastatin can be about 5 mg to about 40 mg, or about 10 mg to about 20 mg.

[0130] In some embodiments, the oral unit dosage form contains about 20 mg to about 400 mg of probucol and about 2.5 mg to about 20 mg of rosuvastatin. In some embodiments, the oral unit dosage form contains about 40 mg to about 400 mg of probucol and about 2.5 mg to about 20 mg of rosuvastatin. In some embodiments, the oral unit dosage form contains about 62.5 mg to about 375 mg of probucol and about 5 mg to about 20 mg of rosuvastatin. In some embodiments, the oral unit dosage form contains about 62.5 mg of probucol and about 10 mg of rosuvastatin. In some embodiments, the oral unit dosage form contains about 125 mg of probucol and about 10 mg of rosuvastatin. In some embodiments, the oral unit dosage form contains about 250 mg of probucol and about 10 mg of rosuvastatin. In some embodiments, the oral unit dosage form contains about 250 mg of probucol and about 5 mg of rosuvastatin. In preferred embodiments, in the oral unit dosage form, the content of probucol can be about 62.5 mg to about 250 mg, or about 125 mg to about 250 mg; the content of rosuvastatin can be about 2.5 mg to about 20 mg, or about 5 mg to about 10 mg.

[0131] In some embodiments, the oral unit dosage form contains about 20 mg to about 400 mg of probucol and about 0.5 mg to about 4 mg, about 1 mg to about 4 mg of pitavastatin. In some embodiments, the oral unit dosage form contains about 40 mg to about 400 mg of probucol and about 0.5 mg to about 4 mg, about 1 mg to about 4 mg of pitavastatin. In some embodiments, the oral unit dosage form contains about 62.5 mg to about 375 mg of probucol and about 1 mg to about 2 mg of pitavastatin. In some embodiments, the oral unit dosage form contains about 62.5 mg of probucol and about 2 mg of pitavastatin. In some embodiments, the oral unit dosage form contains about 125 mg of probucol and about 2 mg of pitavastatin. In some embodiments, the oral unit dosage form contains about 250 mg of probucol and about 2 mg of pitavastatin. In preferred embodiments, in the oral unit dosage form, the content of probucol may be about 62.5 mg to about 250 mg, or about 125 mg to about 250 mg; the content of pitavastatin may be about 0.5 mg to about 4 mg, about 1 mg to about 4 mg, or about 2 mg to about 4 mg.

[0132] The third aspect of the present invention provides a medicine kit, which contains probucol and statins; in particular, the active ingredients contained in the medicine kit are probucol and statins.

[0133] In one embodiment of the third aspect, the medicine box comprises a first pharmaceutical composition containing probucol and a second pharmaceutical composition containing a statin. In the present invention, the amount of probucol in the first pharmaceutical composition contained in the medicine box and the amount of statins in the second pharmaceutical composition contained in the medicine box are such amounts: the amount of probucol is 3a / 4b or 5a / 16b or a / 2b of the maximum daily dose of probucol for lowering cholesterol recommended in the "Guidelines for Blood Lipid Management in China (2023)", wherein a and b are integers of 1-16, and a≤b, and the amount of statins is c / d of the maximum daily dose of statins for lowering cholesterol recommended in the "Guidelines for Blood Lipid Management in China (2023)", wherein c and d are integers of 1-16, and c≤d, for example, c≤d / 2. With the development of medicine and the changes in human physique, if new conventional daily doses of probucol for lowering cholesterol and conventional daily doses of statins for lowering cholesterol are updated or proposed in the future "Guidelines for Chinese Blood Lipid Management" or other authoritative guidelines, the amount of probucol shall be 3a / 4b or 5a / 16b or a / 2b of the maximum daily dose of probucol for lowering cholesterol recommended in the updated "Guidelines for Chinese Blood Lipid Management", wherein a and b are integers of 1-16 and a≤b, and the amount of statins shall be c / d of the maximum daily dose of statins for lowering cholesterol recommended in the updated "Guidelines for Chinese Blood Lipid Management", wherein c and d are integers of 1-16 and c≤d, for example, c≤d / 2.

[0134] In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises probucol in an amount of about 10 mg to about 1000 mg and the second pharmaceutical composition comprises a statin in an amount of about 1 mg to about 80 mg.

[0135] In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises probucol in an amount of about 20 mg to about 400 mg, and the second pharmaceutical composition comprises a statin in an amount of about 1 mg to about 80 mg.

[0136] In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises probucol in an amount of about 40 mg to about 400 mg, and the second pharmaceutical composition comprises a statin in an amount of about 1 mg to about 80 mg. In a preferred embodiment, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises probucol in an amount of about 62.5 mg to about 250 mg, or about 125 mg to about 250 mg, and the second pharmaceutical composition comprises a statin in an amount of about 1 mg to about 80 mg, or about 2 mg to about 80 mg.

[0137] In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises probucol in an amount of about 40 mg to about 400 mg, and the second pharmaceutical composition comprises lovastatin in an amount of about 10 mg to about 20 mg. In a preferred embodiment, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises probucol in an amount of about 62.5 mg to about 250 mg, or about 125 mg to about 250 mg, and the second pharmaceutical composition comprises lovastatin in an amount of about 5 mg to about 40 mg, or about 10 mg to about 20 mg.

[0138] In some embodiments, the weight ratio of probucol to lovastatin is about 0.25:1 to 25:1, for example, about 0.25:1, 0.5:1, 1:1, 2:1, 3:1, 3.125:1, 4:1, 5:1, 6:1, 6.25:1, 7:1, 8:1, 9:1, 9.375:1, 10:1, 11:1, 12:1, 12.5:1, 13:1, 14:1, 15:1, 15 .625:1, 16:1, 17:1, 18:1, 18.75:1, 19:1, 20:1, 21:1, 21.875:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1, 39:1, or 40:1.

[0139] In some preferred embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises about 125 mg of probucol and the second pharmaceutical composition comprises about 20 mg of lovastatin.

[0140] In some preferred embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises about 250 mg of probucol and the second pharmaceutical composition comprises about 10 mg of lovastatin.

[0141] In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises probucol in an amount of about 40 mg to about 400 mg, and the second pharmaceutical composition comprises pravastatin in an amount of about 10 mg to about 40 mg. In a preferred embodiment, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises probucol in an amount of about 62.5 mg to about 250 mg, or about 125 mg to about 250 mg, and the second pharmaceutical composition comprises pravastatin in an amount of about 7.5 mg to about 30 mg, or about 15 mg.

[0142] In some embodiments, the weight ratio of probucol to pravastatin is about 0.25:1 to 25:1, for example, about 0.25:1, 0.5:1, 1:1, 2:1, 3:1, 3.125:1, 4:1, 5:1, 6:1, 6.25:1, 7:1, 8:1, 25:3, 9:1, 9.375:1, 10:1, 11:1, 12:1, 12.5:1, 13:1, 14:1, 15:1, 15.625:1, 16:1, 17:1, 18:1, 18.75:1, 19:1, 20:1, 21:1, 21.875:1, 22:1, 23:1, 24:1, or 25:1.

[0143] In some preferred embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises about 250 mg of probucol and the second pharmaceutical composition comprises about 15 mg of pravastatin.

[0144] In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises probucol in an amount of about 40 mg to about 400 mg, and the second pharmaceutical composition comprises simvastatin in an amount of about 10 mg to about 40 mg. In a preferred embodiment, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises probucol in an amount of about 62.5 mg to about 250 mg, or about 125 mg to about 250 mg, and the second pharmaceutical composition comprises simvastatin in an amount of about 10 mg to about 80 mg, or about 20 mg to about 40 mg.

[0145] In some embodiments, the weight ratio of probucol to simvastatin is about 0.25:1 to 25:1, for example, about 0.25:1, 0.5:1, 1:1, 25:16, 2:1, 3:1, 3.125:1, 4:1, 5:1, 6:1, 6.25:1, 7:1, 8:1, 9:1, 9.375:1, 10:1, 11:1, 12:1, 12.5:1, 13:1, 14:1, 15:1, 15.625:1, 16:1, 17:1, 18:1, 18.75:1, 19:1, 20:1, 21:1, 21.875:1, 22:1, 23:1, 24:1, or 25:1.

[0146] In some preferred embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises about 62.5 mg of probucol and the second pharmaceutical composition comprises about 40 mg of simvastatin.

[0147] In some preferred embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises about 125 mg of probucol and the second pharmaceutical composition comprises about 40 mg of simvastatin.

[0148] In some preferred embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises about 250 mg of probucol and the second pharmaceutical composition comprises about 20 mg of simvastatin.

[0149] In some preferred embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises about 250 mg of probucol and the second pharmaceutical composition comprises about 40 mg of simvastatin.

[0150] In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises probucol in an amount of about 40 mg to about 400 mg, and the second pharmaceutical composition comprises fluvastatin in an amount of about 20 mg to about 40 mg. In a preferred embodiment, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises probucol in an amount of about 62.5 mg to about 250 mg, or about 125 mg to about 250 mg, and the second pharmaceutical composition comprises fluvastatin in an amount of about 20 mg to about 80 mg, or about 40 mg to about 80 mg.

[0151] In some embodiments, the weight ratio of probucol to fluvastatin is about 0.25:1 to 25:1, for example, about 0.25:1, 0.5:1, 1:1, 25:16, 2:1, 3:1, 3.125:1, 4:1, 5:1, 6:1, 6.25:1, 7:1, 8:1, 9:1, 9.375:1, 10:1, 11:1, 12:1, 12.5:1, 13:1, 14:1, 15:1, 15.625:1, 16:1, 17:1, 18:1, 18.75:1, 19:1, 20:1, 21:1, 21.875:1, 22:1, 23:1, 24:1, or 25:1.

[0152] In some preferred embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises about 125 mg of probucol and the second pharmaceutical composition comprises about 40 mg of fluvastatin.

[0153] In some preferred embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises about 125 mg of probucol and the second pharmaceutical composition comprises about 80 mg of fluvastatin.

[0154] In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises probucol in an amount of about 40 mg to about 400 mg, and the second pharmaceutical composition comprises atorvastatin in an amount of about 10 mg to about 40 mg. In a preferred embodiment, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises probucol in an amount of about 62.5 mg to about 250 mg, or about 125 mg to about 250 mg, and the second pharmaceutical composition comprises atorvastatin in an amount of about 5 mg to about 40 mg, or about 10 mg to about 20 mg.

[0155] In some embodiments, the weight ratio of probucol to atorvastatin is about 0.5:1 to 25:1, e.g., 0.5:1, 1:1, 2:1, 3:1, 3.125:1, 4:1, 5:1, 6:1, 6.25:1, 7:1, 8:1, 9:1, 9.375:1, 10:1, 11:1, 12:1, 12.5:1, 13:1, 14:1, 15:1, 15.625:1, 16:1, 17:1, 18:1, 18.75:1, 19:1, 20:1, 21:1, 21.875:1, 22:1, 23:1, 24:1, or 25:1.

[0156] In some preferred embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises about 62.5 mg of probucol and the second pharmaceutical composition comprises about 20 mg of atorvastatin.

[0157] In some preferred embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises about 125 mg of probucol and the second pharmaceutical composition comprises about 20 mg of atorvastatin.

[0158] In some preferred embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises about 250 mg of probucol and the second pharmaceutical composition comprises about 10 mg of atorvastatin.

[0159] In some preferred embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises about 250 mg of probucol and the second pharmaceutical composition comprises about 20 mg of atorvastatin.

[0160] In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises probucol in an amount of about 40 mg to about 400 mg, and the second pharmaceutical composition comprises rosuvastatin in an amount of about 5 mg to about 40 mg. In a preferred embodiment, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises probucol in an amount of about 62.5 mg to about 250 mg, or about 125 mg to about 250 mg, and the second pharmaceutical composition comprises rosuvastatin in an amount of about 2.5 mg to about 20 mg, or about 5 mg to about 10 mg.

[0161] In some embodiments, the weight ratio of probucol to rosuvastatin is about 1:1 to 60:1, for example, 1:1, 2:1, 3:1, 3.125:1, 4:1, 5:1, 6:1, 6.25:1, 7:1, 8:1, 9:1, 9.375:1, 10:1, 11:1, 12:1, 12.5:1, 13:1, 14:1, 15:1, 15.625:1, 16:1, 17:1. 1, 18:1, 18.75:1, 19:1, 20:1, 21:1, 21.875:1, 22:1, 23:1, 24:1, 25:1, 26:1, 28:1, 30:1, 32:1, 34:1, 36:1, 38:1, 40:1, 42:1, 44:1, 46:1, 48:1, 50:1, 52:1, 54:1, 56:1, 58:1, or 60:1.

[0162] In some preferred embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises about 62.5 mg of probucol and the second pharmaceutical composition comprises about 10 mg of rosuvastatin.

[0163] In some preferred embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises about 125 mg of probucol and the second pharmaceutical composition comprises about 10 mg of rosuvastatin.

[0164] In some preferred embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises about 250 mg of probucol and the second pharmaceutical composition comprises about 5 mg of rosuvastatin.

[0165] In some preferred embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises about 250 mg of probucol and the second pharmaceutical composition comprises about 10 mg of rosuvastatin.

[0166] In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises probucol in an amount of about 40 mg to about 400 mg, and the second pharmaceutical composition comprises pitavastatin in an amount of about 1 mg to about 2 mg. In a preferred embodiment, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises probucol in an amount of about 62.5 mg to about 250 mg, or about 125 mg to about 250 mg, and the second pharmaceutical composition comprises pitavastatin in an amount of about 0.5 mg to about 4 mg, about 1 mg to about 4 mg, or about 2 mg to about 4 mg.

[0167] In some embodiments, the weight ratio of probucol to pitavastatin is about 10: 1 to 250: 1, for example, about 10: 1, 15: 1, 20: 1, 25: 1, 30: 1, 35: 1, 40: 1, 45: 1, 50: 1, 55: 1, 60: 1, 65: 1, 70: 1, 75: 1, 80: 1, 85: 1, 90: 1, 95: 1, 100: 1, 125: 1, 150: 1, 200: 1, or 250: 1.

[0168] In some preferred embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, wherein the first pharmaceutical composition comprises about 250 mg of probucol and the second pharmaceutical composition comprises about 2 mg of pitavastatin.

[0169] In another embodiment of the third aspect, probucol and statins are provided as a single composition in a kit. In the present invention, the amount of probucol and the amount of statins contained in the single composition in the kit are such amounts: the amount of probucol is 3a / 4b or 5a / 16b or a / 2b of the maximum daily dose of probucol for lowering cholesterol recommended in the "Guidelines for Blood Lipid Management in China (2023)", wherein a and b are integers of 1-16, and a≤b, and the amount of statins is c / d of the maximum daily dose of statins for lowering cholesterol recommended in the "Guidelines for Blood Lipid Management in China (2023)", wherein c and d are integers of 1-16, and c≤d, for example c≤d / 2. With the development of medicine and the changes in human physique, if the conventional daily dose of probucol for lowering cholesterol and the conventional daily dose of statins for lowering cholesterol are updated or proposed in the future "Guidelines for the Management of Blood Lipids in China" or other authoritative guidelines, the amount of probucol is 3a / 4b or 5a / 16b or a / 2b of the maximum daily dose of probucol for lowering cholesterol recommended in the updated "Guidelines for the Management of Blood Lipids in China", where a and b are integers of 1-16, and a≤b, and the amount of statins is c / d of the maximum daily dose of statins for lowering cholesterol recommended in the updated "Guidelines for the Management of Blood Lipids in China", where c and d are integers of 1-16, and c≤d, for example, c≤d / 2. In some embodiments, the medicine box contains a pharmaceutical composition, which contains probucol, a statin, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is an oral unit dosage form. In some embodiments, the pharmaceutical composition is an oral unit dosage form, the oral unit dosage form comprising about 10 mg to about 1000 mg, about 20 mg to about 800 mg, about 20 mg to about 400 mg, about 40 mg to about 400 mg, about 60 mg to about 250 mg, about 31.25 mg, about 62.5 mg, about 125 mg, about 187.5 mg, about 250 mg, about 312.5 mg, or about 375 mg of probucol or a pharmaceutically acceptable salt thereof, and about 1 mg to about 80 mg, about 5 mg to about 80 mg, about 5 mg to about 40 mg, about 10 mg to about 20 mg, or about 1 mg to about 5 mg of a statin. In a preferred embodiment, the oral unit dosage form comprises about 62.5 mg to about 250 mg, or about 125 mg to about 250 mg of probucol or a pharmaceutically acceptable salt thereof; and about 1 mg to about 80 mg, or about 2 mg to about 80 mg of a statin.

[0170] In some embodiments, the pharmaceutical composition is an oral unit dosage form, and the oral unit dosage form is as defined in the second aspect above.

[0171] In a preferred embodiment, the oral unit dosage form comprises about 62.5 mg to about 250 mg, or about 125 mg to about 250 mg of probucol or a pharmaceutically acceptable salt thereof; and about 5 mg to about 40 mg, or about 10 mg to about 20 mg of lovastatin; for example, the oral unit dosage form comprises about 125 mg of probucol or a pharmaceutically acceptable salt thereof; and about 20 mg of lovastatin, or comprises about 250 mg of probucol or a pharmaceutically acceptable salt thereof; and about 10 mg of lovastatin; or The oral unit dosage form comprises about 62.5 mg to about 250 mg, or about 125 mg to about 250 mg of probucol or a pharmaceutically acceptable salt thereof; and about 7.5 mg to about 30 mg, or about 15 mg of pravastatin; for example, the oral unit dosage form comprises about 250 mg of probucol or a pharmaceutically acceptable salt thereof; and about 15 mg of pravastatin; or The oral unit dosage form comprises from about 62.5 mg to about 250 mg, or from about 125 mg to about 250 mg, of probucol or a pharmaceutically acceptable salt thereof; and from about 10 mg to about 80 mg, or from about 20 mg to about 40 mg, of simvastatin; for example, the oral unit dosage form comprises from about 62.5 mg of probucol or a pharmaceutically acceptable salt thereof; and about 40 mg of simvastatin, or comprises from about 125 mg of probucol or a pharmaceutically acceptable salt thereof; and about 40 mg of simvastatin, or comprises from about 250 mg of probucol or a pharmaceutically acceptable salt thereof; and about 20 mg of simvastatin, or comprises from about 250 mg of probucol or a pharmaceutically acceptable salt thereof; and about 40 mg of simvastatin; or The oral unit dosage form comprises from about 62.5 mg to about 250 mg, or from about 125 mg to about 250 mg, of probucol or a pharmaceutically acceptable salt thereof; and from about 20 mg to about 80 mg, or from about 40 mg to about 80 mg, of fluvastatin; for example, the oral unit dosage form comprises about 125 mg of probucol or a pharmaceutically acceptable salt thereof; and about 40 mg of fluvastatin, or comprises about 125 mg of probucol or a pharmaceutically acceptable salt thereof; and about 80 mg of fluvastatin; or The oral unit dosage form comprises from about 62.5 mg to about 250 mg, or from about 125 mg to about 250 mg, of probucol or a pharmaceutically acceptable salt thereof; and from about 5 mg to about 40 mg, or from about 10 mg to about 20 mg, of atorvastatin; for example, the oral unit dosage form comprises from about 62.5 mg of probucol or a pharmaceutically acceptable salt thereof; and about 20 mg of atorvastatin, or comprises from about 125 mg of probucol or a pharmaceutically acceptable salt thereof; and about 20 mg of atorvastatin, or comprises from about 250 mg of probucol or a pharmaceutically acceptable salt thereof; and about 10 mg of atorvastatin, or comprises from about 250 mg of probucol or a pharmaceutically acceptable salt thereof; and about 20 mg of atorvastatin; or The oral unit dosage form comprises about 62.5 mg to about 250 mg, or about 125 mg to about 250 mg of probucol or a pharmaceutically acceptable salt thereof; and about 2.5 mg to about 20 mg, or about 5 mg to about 10 mg of rosuvastatin; for example, the oral unit dosage form comprises about 62.5 mg of probucol or a pharmaceutically acceptable salt thereof; and about 10 mg of rosuvastatin, or comprises about 125 mg of probucol or a pharmaceutically acceptable salt thereof; and about 10 mg of rosuvastatin, or comprises about 250 mg of probucol or a pharmaceutically acceptable salt thereof; and about 5 mg of rosuvastatin, or comprises about 250 mg of probucol or a pharmaceutically acceptable salt thereof; and about 10 mg of rosuvastatin; or The oral unit dosage form comprises about 62.5 mg to about 250 mg, or about 125 mg to about 250 mg of probucol or a pharmaceutically acceptable salt thereof; and about 0.5 mg to about 4 mg, about 1 mg to about 4 mg, or about 2 mg to about 4 mg of pitavastatin; for example, the oral unit dosage form comprises about 250 mg of probucol or a pharmaceutically acceptable salt thereof; and about 2 mg of pitavastatin.

[0172] In some embodiments, the kit optionally includes written material, such as instructions describing the pharmacological activity of the composition, dosage and regimen, side effects, drug interactions, and the like.

[0173] In one embodiment of the third aspect, the amount of probucol and the amount of statin contained in the kit are as described in any one of the above embodiments, and In the medicine kit, probucol and the statin are provided in the form of a single composition in the medicine kit; or the medicine kit comprises one or more identical medicine units isolated from the external environment, each medicine unit comprising a first medicine composition containing probucol and a second medicine composition containing a statin, the first medicine composition and the second medicine composition are each in an oral unit dosage form, wherein opening of each medicine unit exposes the first medicine composition and the second medicine composition to the external environment at the same time.

[0174] In one embodiment of the third aspect, the medicine kit comprises one or more identical medicine units isolated from the external environment, and one, two or three medicine units can be opened simultaneously for each administration, each medicine unit comprising probucol and a statin as described in the present invention, and opening of each medicine unit can expose the first medicine composition and the second medicine composition to the external environment simultaneously.

[0175] The fourth aspect of the present invention provides the use of probucol and statins in the preparation of a drug for treating hyperlipidemia (especially severe hypertriglyceridemia). In particular, the probucol and statins are in the form of probucol and statins (including) in the technical solutions provided in the first, second or third aspects.

[0176] A fifth aspect of the present invention provides a drug combination comprising probucol and a statin, or a pharmaceutical composition comprising probucol, a statin and a pharmaceutically acceptable carrier, or a medicine kit comprising probucol and a statin, which is used to treat hyperlipidemia (especially severe hypertriglyceridemia). In particular, the drug combination comprising probucol and a statin, or a pharmaceutical composition comprising probucol, a statin and a pharmaceutically acceptable carrier, or a medicine kit comprising probucol and a statin corresponds to the drug combination, pharmaceutical composition, and medicine kit provided in the first, second or third aspect, respectively.

[0177] The sixth aspect of the present invention provides a method for treating hyperlipidemia (particularly severe hypertriglyceridemia) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of probucol and a therapeutically effective amount of a statin. In particular, the probucol and the statin are in the form of probucol and statins (including atorvastatin, rosuvastatin, simvastatin, fluvastatin, and lovastatin) in the technical solutions provided in the first, second or third aspects above.

[0178] In some embodiments, the hyperlipidemia is hypertriglyceridemia.

[0179] In some embodiments, the hyperlipidemia is severe hypertriglyceridemia.

[0180] In some embodiments, the hyperlipidemia is hypercholesterolemia.

[0181] In some embodiments, the hyperlipidemia is fibrate-intolerant or -unresponsive hyperlipidemia, particularly severe hypertriglyceridemia.

[0182] In some embodiments, the hyperlipidemia is hyperlipidemia that is ineffective or ineffective in statin therapy, particularly severe hypertriglyceridemia.

[0183] In some embodiments, the hyperlipidemia is a combination of hypertriglyceridemia and hypercholesterolemia.

[0184] In some embodiments, the hyperlipidemia is a combination of severe hypertriglyceridemia and hypercholesterolemia.

[0185] In some embodiments, probucol and the statin are administered to the subject by an oral route. In some embodiments, probucol and the statin are administered to the subject orally in the form of tablets. In some embodiments, probucol and the statin are administered to the subject orally in the form of capsules.

[0186] In some embodiments, probucol is administered in a daily dose of about 20 mg to about 400 mg.

[0187] In some embodiments, probucol is administered in a daily dose of about 40 mg to about 400 mg.

[0188] In some embodiments, probucol is administered at a daily dose of about 31.25 mg.

[0189] In some embodiments, probucol is administered at a daily dose of about 62.5 mg.

[0190] In some embodiments, probucol is administered at a daily dose of about 125 mg.

[0191] In some embodiments, probucol is administered at a daily dose of about 187.5 mg.

[0192] In some embodiments, probucol is administered at a daily dose of about 250 mg.

[0193] In some embodiments, probucol is administered at a daily dose of about 312.5 mg.

[0194] In some embodiments, probucol is administered at a daily dose of about 375 mg.

[0195] In some embodiments, the statin is administered in a daily dose of about 1 mg to about 80 mg.

[0196] In some embodiments, lovastatin is administered in a daily dose of about 5 mg to about 40 mg, preferably about 10 mg to about 40 mg, more preferably about 10 mg or about 20 mg.

[0197] In some embodiments, pravastatin is administered in a daily dose of about 5 mg to about 40 mg, preferably about 10 mg to about 40 mg, more preferably about 15 mg.

[0198] In some embodiments, simvastatin is administered in a daily dose of about 2.5 mg to about 40 mg, preferably about 10 mg to about 40 mg, more preferably about 20 mg or about 40 mg.

[0199] In some embodiments, fluvastatin is administered in a daily dose of about 10 mg to about 80 mg, preferably about 40 mg to about 80 mg, more preferably about 40 mg or about 80 mg.

[0200] In some embodiments, atorvastatin is administered in a daily dose of about 5 mg to about 80 mg, preferably about 10 mg to about 40 mg, more preferably about 10 mg or about 20 mg.

[0201] In some embodiments, rosuvastatin is administered in a daily dose of about 2.5 mg to about 20 mg, preferably about 5 mg to about 20 mg, more preferably about 5 mg or about 10 mg.

[0202] In some embodiments, pitavastatin is administered in a daily dose of about 0.5 mg to about 4 mg, about 1 mg to about 4 mg, preferably about 2 mg to about 4 mg, more preferably about 2 mg or about 4 mg.

[0203] In a preferred embodiment, probucol is administered at a daily dose of about 62.5 mg to about 250 mg, or about 125 mg to about 250 mg, and the statin is administered at a daily dose of about 1 mg to about 80 mg, or about 2 mg to about 80 mg; for example, lovastatin is administered at a daily dose of about 5 mg to about 40 mg, or about 10 mg to about 20 mg, or pravastatin is administered at a daily dose of about 7.5 mg to about 30 mg, or about 15 mg, or simvastatin is administered at a daily dose of about 10 mg to about 80 mg, or about 20 mg to about 40 mg, or fluvastatin is administered at a daily dose of about 20 mg to about 80 mg, or about 40 mg to about 80 mg, or atorvastatin is administered at a daily dose of about 5 mg to about 40 mg, or about 10 mg to about 20 mg, or rosuvastatin is administered at a daily dose of about 2.5 mg to about 20 mg, or about 5 mg to about 10 mg, or pitavastatin is administered at a daily dose of about 0.5 The invention relates to a daily dosage of about 1 mg to about 4 mg, about 1 mg to about 4 mg, or about 2 mg to about 4 mg.

[0204] In some embodiments, probucol and statins are administered to the subject simultaneously. In some embodiments, probucol and statins are each administered to the subject simultaneously with a separate formulation, with an administration interval of less than 30 minutes, such as less than 15 minutes, less than 10 minutes, less than 5 minutes, or less than 1 minute. In some embodiments, the daily dose of probucol and statins is administered to the subject in a single or multiple doses. In some embodiments, probucol and statins are administered to the subject once a day (QD) simultaneously, preferably simultaneously before going to bed. In some embodiments, probucol and statins are administered to the subject twice a day (BID) simultaneously, preferably twice in the morning and evening after meals. In some embodiments, probucol and statins are administered simultaneously for no less than 7 days. In some embodiments, probucol and statins are administered simultaneously for about 14 days. In some embodiments, probucol and statins are administered simultaneously for about 28 days. In some embodiments, probucol and the statin are administered concurrently for about 56 days. In some embodiments, probucol and the statin are administered chronically.

[0205] Beneficial effects of the present invention The main beneficial effects of the present invention include the following aspects: (1) The present inventors surprisingly found that the combination of probucol and statins can produce a synergistic effect in the treatment of severe hypertriglyceridemia, hyperlipidemia that is intolerant to or unresponsive to fibrates, or hyperlipidemia that is ineffective or ineffective in statin treatment. The use of probucol at an amount lower than its conventional dose can promote the statin to produce a greater therapeutic effect, breaking through the "6% statin efficacy effect", so that even if statins are used at medium or low doses, unexpectedly high therapeutic effects can be achieved. This not only expands the dosage range of statins in disguise, but also discovers a new way to tolerably reduce triglycerides in severe hypertriglyceridemia. (2) The present invention has produced unexpected effects in the treatment of severe hypertriglyceridemia. Probucol alone has no triglyceride-lowering effect, and statins alone do not treat severe hypertriglyceridemia. The present invention uses a low-dose probucol combined with a medium-to-low-dose statin to quickly and effectively reduce triglycerides in severe hypertriglyceridemia, with a reduction of more than 70%, which is not inferior to first-line fibrates (60%). Compared with drugs for treating severe hypertriglyceridemia such as fibrates and high-dose fish oil that increase low-density lipoprotein, the combination can reduce low-density lipoprotein-C, thereby providing a new and more effective treatment option for the treatment of severe hypertriglyceridemia; (3) For patients whose LDL-C levels do not meet the target after statin treatment, the present invention can further reduce cholesterol (32%) and low-density lipoprotein-C (38%), thereby reducing the risk of cardiovascular disease; (4) The present invention can significantly reduce triglycerides in severe hypertriglyceridemia and further reduce cholesterol and low-density lipoprotein-C. It is a broad-spectrum lipid-lowering drug and is suitable for hypertriglyceridemia and / or hypercholesterolemia; (5) In the present invention, probucol is used at an amount lower than its conventional dose (e.g., 12.5% ​​of the conventional dose), and statins are used at medium to low doses, so that the drug combination has better tolerability, lower toxic side effects, and fewer adverse reactions to long-term medication; (6) In the present invention, the drug combination of probucol and statins can take effect quickly and reduce TG, TC and LDL-C to satisfactory levels in a shorter treatment period; (7) The present inventors have found that the simultaneous administration of probucol and statins produces unexpected technical effects. If statins and probucol are taken separately, or if they are taken together but with an increased probucol dose, the effects disappear. Example

[0206] The following examples are intended to specifically illustrate the present invention and should not be construed as limiting the scope of the present invention.

[0207] Example 1: Study on the efficacy of a drug combination of probucol and statins in treating severe hypertriglyceridemia.

[0208] A total of 26 patients with severe hypertriglyceridemia were treated with a combination of probucol and statins, including 21 males and 5 females, aged 27-68 years.

[0209] Before administration, the triglyceride range of patients with severe hypertriglyceridemia was 5.93-21.41 mmol / L, the cholesterol range was 3.46-9.85 mmol / L, and the low-density lipoprotein range was 1.22-4.01 mmol / L.

[0210] Dosage regimen: Probucol and statins are both taken orally in commercially available tablets (which can be taken with water or chewed), once a day, at the same time before bedtime, for an average of 45 days.

[0211] Treatment results: After treatment, the patients' plasma triglycerides dropped significantly, with triglyceride levels dropping by 35-91% and an average drop of 80%; cholesterol dropped by 20-69% and an average drop of 41%; low-density lipoprotein dropped by 8-58% and an average drop of 23%. See Table 1 for specific results.

[0212] Table 1 Treatment outcomes of probucol combined with statins Dosage regimen TG before administration (mmol / L) TG after administration (mmol / L) reduce% TC before administration (mmol / L) TC after administration (mmol / L) reduce% LDL-C before medication (mmol / L) LDL-C after administration (mmol / L) reduce% Number of cases A 10.87 1.01 91 7.32 3.44 53 2.38 1.78 25 1 B 15.94 3.52 78 5.89 2.81 52 2.23 1.13 49 1 C 18.58 2.87 85 8.77 4.15 53 2.61 2.09 20 3 D 6.82 4.97 27 5.38 3.66 32 2.19 1.42 35 3 E 6.09 1.84 41 3.46 2.15 38 1.22 0.8 34 1 F 8.03 3.16 61 5.31 3.89 27 2.53 2.25 11 2 G 10.56 3.58 66 4.98 3.32 33 1.80 1.50 17 3 H 6.01 3.91 35 6.02 3.67 39 3.14 1.7 46 1 I 5.93 1.72 71 7.51 3.66 51 3.42 2.41 30 1 J 9.0 2.30 74 6.05 4.04 33 1.98 1.82 8 2 K 10.86 3.63 67 5.84 3.9 33 1.99 1.82 9 2 L 13.67 4.83 65 7.33 4.14 44 1.81 1.48 18 1 M 8.15 2.93 64 5.17 4.14 20 2.36 2.11 11 1 N 9.78 5.24 46 5.76 4.52 22 2.99 2.41 19 1 O 17.8 2.51 86 7.54 4.08 46 2.98 1.59 47 1 P 6.85 2.34 66 4.13 3.12 24 1.76 1.17 34 2 Q 8.95 4.60 49 4.31 3.04 29 1.75 1.57 10 2 R 21.41 2.09 90 9.85 3.05 69 4.01 1.68 58 1 in: A: Probucol 62.5mg + atorvastatin 20mg, QD; B: Probucol 125mg + atorvastatin 20mg, QD; C: Probucol 250mg + atorvastatin 20mg, QD; D: Probucol 250mg + atorvastatin 10mg, QD; E: Probucol 62.5mg + rosuvastatin 10mg, QD; F: Probucol 125mg + rosuvastatin 10mg, QD; G: Probucol 250mg + rosuvastatin 10mg, QD; H: Probucol 250mg + rosuvastatin 5mg, QD; I: Probucol 62.5mg + simvastatin 40mg mg, QD; J: probucol 125mg + simvastatin 40mg, QD; K: probucol 250mg + simvastatin 40mg, QD; L: probucol 250mg + simvastatin 20mg, QD; M: probucol 250mg + pitavastatin 2mg, QD; N: probucol 125mg + fluvastatin 80mg, QD; O: probucol 125mg + fluvastatin 40mg, QD; P: probucol 125mg + lovastatin 20mg, QD; Q: probucol 250mg + lovastatin 10mg, QD; R: probucol 125mg + pravastatin 15mg, QD.

[0213] The inventor surprisingly found that, at the same dosage of probucol, reducing the dosage of statins can achieve an increase in the degree of LDL-C reduction (probucol 250 mg + atorvastatin 20 mg, QD vs probucol 250 mg + atorvastatin 10 mg, QD; probucol 250 mg + rosuvastatin 10 mg, QD vs probucol 250 mg + rosuvastatin 5 mg, QD; and probucol 125 mg + fluvastatin 80 mg, QD vs probucol 125 mg + fluvastatin 40 mg, QD). Therefore, it is believed that the simultaneous use of probucol and statins produces a synergistic effect.

[0214] Compared with the efficacy of other drugs for treating severe hypertriglyceridemia: the low-dose drug combination of the present invention significantly reduces triglycerides, and the effect is better than fibrates and high-dose fish oil. In addition, unlike fibrates and high-dose fish oil that increase low-density lipoprotein-C, the drug combination of the present invention can also reduce cholesterol and low-density lipoprotein-C at the same time. See Table 2 below.

[0215] Table 2 Comparison of the efficacy of the combination of probucol and statins with other drugs for the treatment of severe hypertriglyceridemia Lipid-lowering drugs Triglycerides cholesterol LDL-C Probucol (125 mg)-Statin Combination Decrease of 46-90% Decrease of 22-69% Decrease of 8-58% Probucol (250 mg)-Statin Combination 35-85% decrease Decrease of 20-53% Decrease of 9-46% <![CDATA[Fenofibrate for 8 weeks (Lipanthyl) a > Decrease: 54.5% Down 13.8% Up 45% <![CDATA[High-dose fish oil for 6 weeks b > Down 31% Up 21% <![CDATA[High-dose fish oil for 16 weeks b > Down 45% Up 31% Data source: a. Liping's instructions; b. Triglyceride Lowering Drugs. Endotext [Internet]. Free Books&Documents. Review.

[0216] Typical case 1: A 39-year-old male patient had long-term severe hypertriglyceridemia, which induced acute severe necrotizing pancreatitis. After improvement, he took fenofibrate regularly (0.2g per day). At 7 months, he developed elevated creatinine and gallstones. Triglycerides could not be ideally controlled, reaching 9.78mmol / l. He tried other treatment options, but still could not achieve good results, and his triglycerides rebounded to 15.94mmol / l. He was treated with a statin-probucol combination: 20mg atorvastatin combined with 125mg probucol every night. After 3 days, his triglycerides dropped to 10.34mmol / l, and after 6 days, they dropped to 7.25mmol / l. At the same time, creatinine returned to normal, and muscle enzymes did not increase significantly, dropping to 4.14mmol / l in 19 days. After 26 days, it dropped to 3.52mmol / l.

[0217] Typical case 2: Female patient, 60 years old, severe hypertriglyceridemia. Probucol 187.5mg + rosuvastatin 10mg, QD, 6 weeks. Triglyceride (TG, mmol / L), total cholesterol (TC, mmol / L) and low-density lipoprotein (LDL-C, mmol) changed from 9.21, 4.65, and 1.70 before treatment to 4.60, 3.49, and 1.32 after treatment, with a decrease of 50%, 25%, and 22%, respectively.

[0218] Typical case 3: A 30-year-old male patient had triglycerides (TG) of 14.62 mmol / L, total cholesterol (TC) of 6.84 mmol / L and low-density lipoprotein (LDL-C) of 2.20 mmol / L. He took atorvastatin 20 mg + probucol 250 mg together before bedtime. After a follow-up examination 2 weeks later, his triglycerides were 2.79 mmol / L, total cholesterol was 4.76 mmol / L and low-density lipoprotein was 1.99 mmol / L. He then took the medicines separately, taking atorvastatin before bedtime and probucol in the afternoon. After 2 weeks, his triglycerides rebounded to 13.30 mmol / L, total cholesterol was 5.97 mmol / L and low-density lipoprotein was 2.02 mmol / L.

[0219] Typical case 4: Male patient, 35 years old, triglycerides: 11.93mmol / L, total cholesterol: 6.58mmol / L and low-density lipoprotein: 1.85mmol / L, rosuvastatin 5mg + probucol 125mg each time, twice a day, re-examination after 6 weeks, triglycerides: 3.72mmol / L, total cholesterol: 3.54mmol / L and low-density lipoprotein: 1.66mmol / L, then increased the dosage on his own (after reading the instructions, he thought his condition was serious and should be increased), rosuvastatin 5mg + probucol 500mg each time, twice a day, after 8 weeks rebound to triglycerides: 8.91mmol / L, total cholesterol: 4.32mmol / L and low-density lipoprotein: 1.75mmol / L.

[0220] Example 2: Study on the efficacy of a drug combination of probucol and statins in treating hypercholesterolemia.

[0221] Treatment targets: Patients who have taken statins for more than half a year and whose cholesterol levels do not meet the target (including patients who have received statin treatment, patients who have received statins combined with cholesterol absorption inhibitors, patients who have received statins combined with PCSK9 monoclonal antibodies, and patients who have received statins combined with cholesterol absorption inhibitors and PCSK9 monoclonal antibodies) are switched to probucol and statin combination treatment. A total of 11 patients with hypercholesterolemia received probucol and statin combination treatment, including 3 males and 8 females, aged 28-78 years. Before administration, the triglyceride range of hypercholesterolemia patients was 1.3-4.51 mmol / L, the cholesterol range was 4.5-7.56 mmol / L, and the low-density lipoprotein range was 2.77-4.64 mmol / L.

[0222] Dosage regimen: Probucol and statins are both taken orally in commercially available tablets (which can be taken with water or chewed), once a day, at the same time before bedtime, for an average of 3 weeks.

[0223] Treatment results: After treatment, the patient's plasma cholesterol level dropped by 25-36%; the low-density lipoprotein level dropped by 25-40%. The specific results are shown in Table 3 below.

[0224] Table 3 Treatment results of probucol combined with statins in the treatment of hypercholesterolemia Dosage regimen TC before administration (mmol / L) TC after administration (mmol / L) reduce% TG before administration (mmol / L) TG after administration (mmol / L) reduce% LDL-C before medication (mmol / L) LDL-C after administration (mmol / L) reduce% Number of cases AA 6.71 5.06 25 2.69 1.82 32 3.61 2.64 27 2 BB 7.56 4.85 36 3.01 2.38 21 4.12 2.49 40 4 CC 5.41 4.07 25 4.51 2.22 51 2.77 1.83 34 1 DD 6.87 4.52 34 1.57 1.22 22 4.64 2.67 42 1 EE 5.63 3.87 31 1.81 1.64 9 3.37 2.22 34 3 FF 4.5 2.82 37 1.3 1.11 15 2.84 1.42 50 1 in: AA: probucol 62.5 mg + atorvastatin 20 mg; BB: probucol 125 mg + atorvastatin 20 mg; CC: probucol 250 mg + simvastatin 40 mg; DD: probucol 250 mg + atorvastatin 20 mg; EE: probucol 250 mg + rosuvastatin 10 mg; FF: probucol 125 mg + rosuvastatin 10 mg.

[0225] Comparison of efficacy with other drugs for treating hypercholesterolemia: According to the 2023 China Blood Lipid Management Guidelines, when LDL-C is not up to standard after statin treatment, statin combined with ezetimibe can further reduce LDL-C levels by 18-20%. The drug combination of the present invention can further reduce LDL-C by 25-40%, and further reduce it by 38% on average, which is better than statin combined with ezetimibe. In addition, probucol is used in small doses, has low side effects, and has greater benefits.

[0226] Typical case 1: Male patient, 68 years old, myocardial infarction, post-stent surgery. Rosuvastatin 10mg before bedtime treatment for 12 weeks, cholesterol 8.86mmol / L; triglycerides 2.61mmol / L; LDL-C 5.54mmol / L, combined with 140mg of eloumab subcutaneously injected every 2 weeks for 1 year: cholesterol 6.45mmol / L; triglycerides 3.05mmol / L; LDL-C 3.61mmol / L. After taking probucol 125mg and rosuvastatin 10mg before bedtime for 3 weeks: cholesterol 4.62mmol / L; triglycerides 1.39mmol / L; LDL-C 2.31mmol / L, taking separately for 6 weeks: cholesterol 6.97mmol / L; triglycerides 3.11mmol / L; LDL-C 3.55mmol / L.

[0227] Typical case 2: Female patient, 67 years old, ASCVD patient, cholesterol 13.1mmol / L, LDL-C 8.13mmol / L, triglycerides 3.60mmol / L; advised to take probucol 125mg and atorvastatin 20mg daily before bedtime, in fact, the patient took it according to the instructions, atorvastatin 20mg daily before bedtime, probucol 500mg each time, 2 times / day, 12 weeks later, cholesterol 9.32mmol / L, LDL-C 5.18mmol / L, triglycerides 4.04mmol / L; resumed low dose, 14 weeks later, cholesterol 4.66mmol / L, LDL-C 2.25mmol / L, triglycerides 2.79mmol / L.

[0228] Typical case 3: Male patient, 66 years old, ASCVD patient, myocardial infarction, post-stent surgery, probucol 187.5mg + rosuvastatin 10mg, 3 weeks, QD. The results are as follows: before administration, low-density lipoprotein (LDL-C): 3.19mmol / L, cholesterol: 5.51mmol / L, triglycerides: 2.49mmol / L; after administration: low-density lipoprotein (LDL-C): 1.00mmol / L, cholesterol: 2.52mmol / L, triglycerides: 1.28mmol / L; reduced by 69%, 54% and 49% respectively.

[0229] The results of the trial showed that in the treatment of severe hypertriglyceridemia, the combination of probucol and statins (such as atorvastatin, rosuvastatin, simvastatin, fluvastatin, and lovastatin) can achieve a comparable or even greater TG reduction at a lower probucol dose; and when the statin dose is doubled, the LDL-C reduction can be significantly more than 6%, or when the statin dose is maintained unchanged and a lower dose of probucol is used, a greater reduction in LDL-C is achieved, or when the probucol dose is maintained unchanged and a lower dose of statin is used, a greater reduction in LDL-C is achieved. Therefore, the combination of a low dose of probucol and a statin can not only significantly reduce TG levels, but also expand the therapeutic window of statins.

[0230] Increasing the dose of probucol will eliminate the effect of lowering severe hypertriglyceridemia, and the effect will also disappear if the same dose is taken in divided doses; especially for lowering LDL-C, this goes against common sense in medicine. In addition to being ineffective when taken separately, the incremental effect of two cholesterol-lowering drugs is poor. Probucol was launched in 1977, and many studies on its combined use at home and abroad have found no effect on treating severe hypertriglyceridemia or lowering LDL-C. This is related to the above-mentioned characteristics of the combination and the habit of taking statins and probucol (statins are taken before bedtime, and probucol is taken twice a day, morning and evening).

[0231] Example 3: Study on the efficacy of a drug combination of probucol and statins in treating hypercholesterolemia at double the dose.

[0232] Treatment subjects: Four patients with hypercholesterolemia were treated with a combination of probucol and statins, including 2 males and 2 females, aged 50-70 years.

[0233] Dosage regimen: Probucol and statins are both administered orally in the form of commercially available tablets (which can be taken with water or chewed), once a day, and administered simultaneously before bedtime. First, administer the low dose shown in Table 4 for a period of time (more than 6 weeks), and then administer the doubled dose shown in Table 4 (the doubled dose is 1.5 or 2 times the original dose) for another period of time (5-12 weeks).

[0234] Results: As shown in Table 4, the results of the trial showed that in the treatment of hyperlipidemia, by co-administering probucol with statins, when the dose of statins was doubled at low doses of probucol, a significantly greater than 6% reduction in LDL-C could be achieved. This is contrary to the common view that doubling the dose of statins can only bring an additional 6% reduction in LDL-C levels. It is believed that this unexpected result may be due to the co-administration of probucol and statins.

[0235] Table 4 Efficacy of probucol combined with statins at doubled doses Statins Dosage (mg / day) Probucol (mg / day) LDL-C before medication (mmol / L) LDL-C after administration (mmol / L) TC before administration (mmol / L) TC after administration (mmol / L) TG before administration (mmol / L) TG after administration (mmol / L) Simva 40 125 4.11 2.89 8.33 5.67 3.31 2.23 Simva 60 187.5 4.11 1.79 8.33 3.85 3.31 1.08 Atova 20 125 5.93 3.35 10.4 7.53 1.74 1.53 Atova 30 187.5 5.93 2.23 10.4 5.25 1.74 1.16 Atova 10 62.5 4.89 2.84 7.92 5.76 2.11 1.86 Atova 20 125 4.89 1.76 7.92 3.92 2.11 1.23 Atova 20 125 7.59 5.18 12.04 7.72 2.92 2.36 Atova 40 250 7.59 3.76 12.04 5.73 2.92 1.84 Example 4: Study on the efficacy of a drug combination of probucol and statins in treating severe hypercholesterolemia.

[0236] The treatment subjects and the dosing regimen are shown in Table 5, wherein both probucol and statins are administered orally in the form of commercially available tablets (which can be taken with water or chewed), once a day, and are administered simultaneously before bedtime.

[0237] Table 5: Treatment results of probucol combined with statins in the treatment of severe hypercholesterolemia Dosage regimen Subjects Time of administration TC before administration (mmol / L) TC after administration (mmol / L) reduce% TG before administration (mmol / L) TG after administration (mmol / L) reduce% LDL-C before medication (mmol / L) LDL-C after administration (mmol / L) reduce% GG Female / 21 years old 12 weeks 10.11 3.49 66 1.38 1.11 20 7.34 1.98 73 HH Male / 44 years old 8 weeks 7.98 3.21 60 1.8 1.11 38 5.39 1.89 65 II Male / 54 years old 7 weeks 10.41 4.88 53 3.7 1.94 50 6.72 2.94 56 JJ Male / 61 years old 6 weeks 12.16 5.44 55 2.43 1.82 25 7.65 3.6 53 in: GG: probucol 125 mg + simvastatin 40 mg; HH: probucol 250 mg + atorvastatin 20 mg; II: probucol 250 mg + rosuvastatin 10 mg; JJ: probucol 125 mg + rosuvastatin 10 mg.

[0238] Treatment results: After treatment, the patients' plasma cholesterol levels dropped by 53-66%; low-density lipoprotein levels dropped by 53-73%. See Table 5 for specific results.

[0239] Example 5: Other therapeutic cases of drug combinations of probucol and statins.

[0240] Case A1: Female, 62 years old, severe hypertriglyceridemia, ASCVD, probucol 312.5 mg + simvastatin 40 mg, QD, 2 weeks, probucol and statins taken together before bedtime.

[0241] Case A2: Male, 50 years old, ASCVD patient, probucol 312.5 mg + atorvastatin 20 mg, QD, 4 weeks, probucol and statins were taken together before bedtime.

[0242] Case A3: A 27-year-old male with a family history of severe hypertriglyceridemia was treated with probucol 125 mg and rosuvastatin 10 mg at bedtime for 3 weeks.

[0243] Case A4: Male, 42 years old, with a family history of severe hypercholesterolemia, coronary heart disease, myocardial infarction, and post-stent surgery. Before lipid-lowering treatment: LDL-C was 6.09mmol / L, cholesterol was 8.95mmol / L, and triglycerides were 2.56mmol / L; rosuvastatin 10mg combined with evolocumab 140mg subcutaneously injected every 2 weeks for more than 4 months, LDL-C was 2.84mmol / L; cholesterol was 4.50mmol / L; triglycerides were 1.3mmol / L; if the target was still not reached, probucol 125mg was added and taken together with rosuvastatin 10mg before bedtime. After 5 weeks, LDL-C was 1.42mmol / L; cholesterol was 2.82mmol / L; triglycerides were 1.11mmol / L.

[0244] The treatment results of the above cases A1-A4 are shown in Table 6.

[0245] Table 6: Efficacy of combined use of probucol in specific cases Case TG before administration (mmol / L) TG after administration (mmol / L) reduce% TC before administration (mmol / L) TC after administration (mmol / L) reduce% LDL-C before medication (mmol / L) LDL-C after drug administration (mmol / L) reduce% A1 5.82 3.68 37 4.68 4.39 6 1.96 1.52 22 A2 2.22 1.85 17 4.85 3.71 24 3.10 1.96 37 A3 9.12 2.51 72 6.53 4.39 33 3.41 2.55 25 A4 1.30 1.11 14.6 4.50 2.82 37 2.84 1.42 50 Example 6: Other cases.

[0246] A 62-year-old female patient with ASCVD had cholesterol 6.24mmol / L, triglycerides 3.22mmol / L, and LDL-C 4.51mmol / L before treatment. Rosuvastatin 10mg before bedtime, cholesterol 5.28mmol / L, triglycerides 2.58mmol / L, and LDL-C 3.73mmol / L after 8 weeks. Adding ezetimibe 20mg QD, cholesterol 3.98mol / L, triglycerides 2.01mmol / L, and LDL-C 2.66mmol / L after 6 weeks.

[0247] In this article, the three indicators of blood lipids, TC, TG and LDL-C, refer to total cholesterol (sometimes also referred to as "cholesterol"), triglycerides, and low-density lipoprotein-cholesterol (sometimes also referred to as "LDL"), respectively.

[0248] The above embodiments are only used to illustrate the present invention and are not intended to limit the technical solutions described in the present invention. The present invention is not limited to the above specific implementations. All technical solutions and improvements that do not depart from the spirit and scope of the invention should be considered to fall within the protection scope of the present invention.

Claims

1. Use of a drug combination in the preparation of a medicament for treating hyperlipidemia in a subject in need thereof, characterized in that: The drug combination comprises probucol and a statin, and the probucol and the statin are configured to be administered simultaneously.

2. The use according to claim 1, characterized in that The statin is selected from atorvastatin, rosuvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, and simvastatin.

3. The use according to claim 2, characterized in that The amount of probucol is a / 2b of the maximum daily dose of probucol for lowering cholesterol, wherein a and b are integers from 1 to 16, and a≤b, and the amount of statin is c / d of the maximum daily dose of statin for lowering cholesterol, wherein c and d are integers from 1 to 16, and c≤d / 2; or the amount of probucol is 5a / 16b of the maximum daily dose of probucol for lowering cholesterol, wherein a and b are integers from 1 to 16 and a≤b, and the amount of statin is c / d of the maximum daily dose of statin for lowering cholesterol, wherein c and d are integers from 1 to 16 and c≤d / 2; or The amount of probucol is 3a / 4b of the maximum daily dose of probucol for lowering cholesterol, wherein a and b are integers from 1 to 16, and a≤b, and the amount of statin is c / d of the maximum daily dose of statin for lowering cholesterol, wherein c and d are integers from 1 to 16, and c≤d / 2; Among them, the maximum daily dose of probucol for lowering cholesterol is 1000 mg; and the maximum daily doses of statins for lowering cholesterol are: pravastatin: 40 mg, simvastatin: 40 mg, fluvastatin: 80 mg, atorvastatin: 80 mg, rosuvastatin: 20 mg, and pitavastatin: 4 mg.

4. The use according to claim 2, characterized in that The drug combination comprises 20-400 mg of probucol; and 1-80 mg of a statin; Or the drug combination comprises Probucol and lovastatin in a weight ratio of (3-40):1; or Probucol and pravastatin in a weight ratio of (6-10):1; or Probucol and simvastatin in a weight ratio of (1-15):1; or Probucol and fluvastatin in a weight ratio of (1-4):1; or Probucol and atorvastatin in a weight ratio of (3-25):1; or Probucol and rosuvastatin in a weight ratio of (5-60):1; or Probucol and pitavastatin in a weight ratio of (80-150):1; Or the pharmaceutical combination comprises 20-400 mg of probucol; and 10-80 mg of lovastatin, or 10-80 mg of pravastatin, or 5-80 mg of simvastatin, or 20-80 mg of fluvastatin, or 10-80 mg of atorvastatin, or 5-40 mg of rosuvastatin, or 1-4 mg of pitavastatin; Or the pharmaceutical combination comprises 20-400 mg of probucol; and 10-40 mg of lovastatin, or 20-80 mg of pravastatin, or 20-80 mg of simvastatin, or 20-80 mg of fluvastatin, or 5-40 mg of atorvastatin, or 10-40 mg of rosuvastatin, or 2-4 mg of pitavastatin; Or the pharmaceutical combination comprises 20-400 mg of probucol; and 20-40 mg of lovastatin, or 20-400 mg of pravastatin, or 20-40 mg of simvastatin, or 40-80 mg of fluvastatin, or 10-20 mg of atorvastatin, or 5-10 mg of rosuvastatin, or 2-3 mg of pitavastatin; Or the pharmaceutical combination comprises 20-400 mg of probucol; and 10-40 mg of lovastatin, or 10-40 mg of pravastatin, or 10-40 mg of simvastatin, or 20-80 mg of fluvastatin, or 10-40 mg of atorvastatin, or 5-20 mg of rosuvastatin, or 1-4 mg of pitavastatin; Or the pharmaceutical combination comprises 20-400 mg of probucol; and 10-20 mg of lovastatin, or 10-20 mg of pravastatin, or 20-40 mg of simvastatin, or 40-80 mg of fluvastatin, or 10-20 mg of atorvastatin, or 5-10 mg of rosuvastatin, or 2-4 mg of pitavastatin; or in the drug combination The weight ratio of probucol to lovastatin is not greater than 50 / 2; or The weight ratio of probucol to pravastatin is not greater than 50 / 4; or The weight ratio of probucol to simvastatin is not greater than 50 / 2; or The weight ratio of probucol to fluvastatin is not greater than 50 / 8; or The weight ratio of probucol to atorvastatin is not greater than 50 / 1; or The weight ratio of probucol to rosuvastatin is not greater than 50 / 1; or The weight ratio of probucol to pitavastatin is no greater than 500 / 2; or in the drug combination The weight ratio of probucol to lovastatin is not greater than 37.5 / 2; or The weight ratio of probucol to pravastatin is not greater than 37.5 / 4; or The weight ratio of probucol to simvastatin is not greater than 37.5 / 2; or The weight ratio of probucol to fluvastatin is not greater than 37.5 / 8; or The weight ratio of probucol to atorvastatin is not greater than 37.5 / 1; or The weight ratio of probucol to rosuvastatin is not greater than 37.5 / 1; or The weight ratio of probucol to pitavastatin is no greater than 375 / 2; or in the drug combination The weight ratio of probucol to lovastatin is not greater than 37.5 / 1; or The weight ratio of probucol to pravastatin is not greater than 37.5 / 2; or The weight ratio of probucol to simvastatin is not greater than 37.5 / 1; or The weight ratio of probucol to fluvastatin is not greater than 37.5 / 4; or The weight ratio of probucol to atorvastatin is not greater than 75 / 1; or The weight ratio of probucol to rosuvastatin is not greater than 75 / 1; or The weight ratio of probucol to pitavastatin is no greater than 375 / 1; or in the drug combination The weight ratio of probucol to lovastatin is not greater than 31.25 / 2; or The weight ratio of probucol to pravastatin is not greater than 31.25 / 4; or The weight ratio of probucol to simvastatin is not greater than 31.25 / 2; or The weight ratio of probucol to fluvastatin is not greater than 31.25 / 8; or The weight ratio of probucol to atorvastatin is not greater than 31.25 / 1; or The weight ratio of probucol to rosuvastatin is not greater than 31.25 / 1; or The weight ratio of probucol to pitavastatin is no greater than 312.5 / 2; or in the drug combination The weight ratio of probucol to lovastatin is not greater than 31.25 / 1; or The weight ratio of probucol to pravastatin is not greater than 31.25 / 2; or The weight ratio of probucol to simvastatin is not greater than 31.25 / 1; or The weight ratio of probucol to fluvastatin is not greater than 31.25 / 4; or The weight ratio of probucol to atorvastatin is not greater than 62.5 / 1; or The weight ratio of probucol to rosuvastatin is not greater than 62.5 / 1; or The weight ratio of probucol to pitavastatin is no greater than 625 / 2; or in the drug combination The weight ratio of probucol to lovastatin is not greater than 25 / 2; or The weight ratio of probucol to pravastatin is not greater than 25 / 4; or The weight ratio of probucol to simvastatin is not greater than 25 / 2; or The weight ratio of probucol to fluvastatin is not greater than 25 / 8; or The weight ratio of probucol to atorvastatin is not greater than 25 / 1; or The weight ratio of probucol to rosuvastatin is not greater than 25 / 1; or The weight ratio of probucol to pitavastatin is no greater than 125 / 1; or in the drug combination The weight ratio of probucol to lovastatin is not greater than 20 / 2; or The weight ratio of probucol to pravastatin is not greater than 20 / 4; or The weight ratio of probucol to simvastatin is not greater than 20 / 2; or The weight ratio of probucol to fluvastatin is not greater than 20 / 8; or The weight ratio of probucol to atorvastatin is not greater than 20 / 1; or The weight ratio of probucol to rosuvastatin is not greater than 20 / 1; or The weight ratio of probucol to pitavastatin is no greater than 200 / 2; or in the drug combination The weight ratio of probucol to lovastatin is not greater than 25 / 4; or The weight ratio of probucol to pravastatin is not greater than 25 / 8; or The weight ratio of probucol to simvastatin is not greater than 25 / 4; or The weight ratio of probucol to fluvastatin is not greater than 25 / 16; or The weight ratio of probucol to atorvastatin is not greater than 25 / 2; or The weight ratio of probucol to rosuvastatin is not greater than 25 / 2; or The weight ratio of probucol to pitavastatin is no greater than 125 / 2; Or the drug combination comprises Probucol and lovastatin in a weight ratio not greater than 25 / 1; or Probucol and pravastatin in a weight ratio not greater than 25 / 3; or Probucol and simvastatin in a weight ratio not greater than 25 / 2; or Probucol and fluvastatin in a weight ratio not greater than 25 / 8; or Probucol and atorvastatin in a weight ratio not greater than 25 / 1; or Probucol and rosuvastatin in a weight ratio not greater than 50 / 1; or Probucol and pitavastatin in a weight ratio no greater than 125 / 1.

5. The use according to claim 4, characterized in that In the drug combination The weight ratio of probucol to lovastatin is not less than 2 / 2; or The weight ratio of probucol to pravastatin is not less than 2 / 4; or The weight ratio of probucol to simvastatin is not less than 2 / 2; or The weight ratio of probucol to fluvastatin is not less than 2 / 8; or The weight ratio of probucol to atorvastatin is not less than 2 / 1; or The weight ratio of probucol to rosuvastatin is not less than 2 / 1; or The weight ratio of probucol to pitavastatin is not less than 20 / 2; or in the drug combination The weight ratio of probucol to lovastatin is not less than 5 / 2; or The weight ratio of probucol to pravastatin is not less than 5 / 4; or The weight ratio of probucol to simvastatin is not less than 5 / 2; or The weight ratio of probucol to fluvastatin is not less than 5 / 8; or The weight ratio of probucol to atorvastatin is not less than 5 / 1; or The weight ratio of probucol to rosuvastatin is not less than 5 / 1; or The weight ratio of probucol to pitavastatin is not less than 50 / 2; or in the drug combination The weight ratio of probucol to lovastatin is not less than 10 / 2; or The weight ratio of probucol to pravastatin is not less than 10 / 4; or The weight ratio of probucol to simvastatin is not less than 10 / 2; or The weight ratio of probucol to fluvastatin is not less than 10 / 8; or The weight ratio of probucol to atorvastatin is not less than 10 / 1; or The weight ratio of probucol to rosuvastatin is not less than 10 / 1; or The weight ratio of probucol to pitavastatin is not less than 100 / 2.

6. The use according to claim 1, characterized in that The amount of probucol as the active ingredient is 20 mg, 25 mg, 30 mg, 31.25 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 62.5 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 187.5 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 312.5 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg or 400 mg.

7. The use according to claim 1, characterized in that The amount of probucol as the active ingredient is 20-400 mg, excluding 20 mg, 25 mg, 30 mg, 31.25 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 62.5 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 187.5 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 312.5 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg and / or 400 mg.

8. The use according to any one of claims 1 to 7, characterized in that The hyperlipidemia is a hyperlipidemia that meets any of the following requirements (1)-(5): (1) The TG level of the subject is: TG ≥ 5.6 mmol / L; (2) The subject is an extremely high-risk patient for ASCVD and meets one of the following conditions: (2.1) LDL-C level greater than 1.8 mmol / L; (2.2) The subject has received statin therapy, and / or has received statin combined with cholesterol absorption inhibitor, statin combined with PCSK9 monoclonal antibody, or statin combined with cholesterol absorption inhibitor and PCSK9 monoclonal antibody, and the LDL-C level is greater than 1.8 mmol / L; (2.3) The subject has received statin therapy, and / or has received statin combined with cholesterol absorption inhibitor, statin combined with PCSK9 monoclonal antibody, or statin combined with cholesterol absorption inhibitor and PCSK9 monoclonal antibody, and The subjects have a reduction in LDL-C of less than 50% after treatment compared with the baseline; or patients with severe side effects of statins who need to reduce the dosage; or patients with severe side effects of cholesterol absorption inhibitors or PCSK9 monoclonal antibodies when statins are combined with cholesterol absorption inhibitors or statins are combined with PCSK9 monoclonal antibodies or statins are combined with cholesterol absorption inhibitors and PCSK9 monoclonal antibodies and need to stop the medication; (3) The subject is an ASCVD ultra-high-risk patient and meets one of the following conditions: (3.1) LDL-C level greater than 1.4 mmol / L; (3.2) The subject has received statin therapy, and / or has received statin combined with cholesterol absorption inhibitor, statin combined with PCSK9 monoclonal antibody, or statin combined with cholesterol absorption inhibitor and PCSK9 monoclonal antibody, and the LDL-C level is greater than 1.4 mmol / L; (3.3) The subject has received statin therapy, and / or has received statin combined with cholesterol absorption inhibitor, statin combined with PCSK9 monoclonal antibody, or statin combined with cholesterol absorption inhibitor and PCSK9 monoclonal antibody, and The subjects have a reduction in LDL-C of less than 50% after treatment compared with the baseline; or patients with severe side effects of statins who need to reduce the dosage; or patients with severe side effects of cholesterol absorption inhibitors or PCSK9 monoclonal antibodies when statins are combined with cholesterol absorption inhibitors or statins are combined with PCSK9 monoclonal antibodies or statins are combined with cholesterol absorption inhibitors and PCSK9 monoclonal antibodies and need to stop the medication; (4) The subject is a high-risk ASCVD patient and meets one of the following conditions: (4.1) LDL-C level greater than 2.6 mmol / L; (4.2) The subject has received statin therapy, and / or has received statin combined with cholesterol absorption inhibitor, statin combined with PCSK9 monoclonal antibody, or statin combined with cholesterol absorption inhibitor and PCSK9 monoclonal antibody, and the LDL-C level is greater than 2.6 mmol / L; (4.3) The subject has received statin therapy, and / or has received statin combined with cholesterol absorption inhibitor, statin combined with PCSK9 monoclonal antibody, or statin combined with cholesterol absorption inhibitor and PCSK9 monoclonal antibody, and The subjects have a reduction in LDL-C of less than 50% after treatment compared with the baseline; or patients with severe side effects of statins who need to reduce the dosage; or patients with severe side effects of cholesterol absorption inhibitors or PCSK9 monoclonal antibodies when statins are combined with cholesterol absorption inhibitors or statins are combined with PCSK9 monoclonal antibodies or statins are combined with cholesterol absorption inhibitors and PCSK9 monoclonal antibodies and need to stop the medication; (5) The subject's TC > 6.22 mmol / L and / or LDL-C > 4.14 mmol / L, and / or the subject's TG > 1.7 mmol / L.

9. The use according to any one of claims 1 to 7, characterized in that The hyperlipidemia is familial or non-familial hypertriglyceridemia, or familial or non-familial hypercholesterolemia, or a combination thereof.

10. The use according to any one of claims 1 to 7, characterized in that The hyperlipidemia is a combination of hypertriglyceridemia and severe hypercholesterolemia, or a combination of severe hypertriglyceridemia and hypercholesterolemia.

11. The use according to any one of claims 1 to 7, characterized in that The hyperlipidemia is hyperlipidemia that is ineffective or ineffective in statin treatment, or hyperlipidemia that is intolerant to or unresponsive to fibrate drugs.

12. The use according to any one of claims 1 to 7, characterized in that The hyperlipidemia is hypercholesterolemia that is ineffective or ineffective in statin therapy, or hypercholesterolemia that is intolerant or unresponsive to fibrate therapy.

13. The use according to any one of claims 1 to 7, characterized in that The hyperlipidemia is hypertriglyceridemia that is ineffective or ineffective in statin therapy, or hypertriglyceridemia that is intolerant or unresponsive to fibrate therapy.

14. The use according to any one of claims 1 to 7, characterized in that The hyperlipidemia is familial or non-familial severe hypertriglyceridemia, familial or non-familial severe hypercholesterolemia, or a combination thereof.

15. The use according to any one of claims 1 to 7, characterized in that The hyperlipidemia is severe hypertriglyceridemia that is ineffective or ineffective with statins, severe hypertriglyceridemia that is intolerant or unresponsive to fibrates, severe hypercholesterolemia that is ineffective or ineffective with statins, or severe hypercholesterolemia that is intolerant or unresponsive to fibrates.

16. A drug combination, characterized in that The drug combination comprises probucol and a statin, and the statin is selected from atorvastatin, rosuvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, and simvastatin, wherein the drug combination does not include the following combinations 1-69: The probucol and the statin are formulated for simultaneous administration.

17. A drug combination, characterized in that The drug combination comprises probucol and a statin, and the statin is selected from atorvastatin, rosuvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, and simvastatin, wherein the probucol and the statin are configured for simultaneous administration.

18. The pharmaceutical combination according to claim 16, characterized in that Besides probucol and the statin, the drug combination comprises no other active ingredients.

19. The pharmaceutical combination according to claim 17, characterized in that Besides probucol and the statin, the drug combination comprises no other active ingredients.

20. The pharmaceutical combination according to any one of claims 16 to 19, characterized in that The amount of probucol is a / 2b of the maximum daily dose of probucol for lowering cholesterol, wherein a and b are integers from 1 to 16, and a≤b, and the amount of statin is c / d of the maximum daily dose of statin for lowering cholesterol, wherein c and d are integers from 1 to 16, and c≤d / 2; or the amount of probucol is 5a / 16b of the maximum daily dose of probucol for lowering cholesterol, wherein a and b are integers from 1 to 16 and a≤b, and the amount of statin is c / d of the maximum daily dose of statin for lowering cholesterol, wherein c and d are integers from 1 to 16 and c≤d / 2; or The amount of probucol is 3a / 4b of the maximum daily dose of probucol for lowering cholesterol, wherein a and b are integers from 1 to 16, and a≤b, and the amount of statin is c / d of the maximum daily dose of statin for lowering cholesterol, wherein c and d are integers from 1 to 16, and c≤d / 2; Among them, the maximum daily dose of probucol for lowering cholesterol is 1000 mg; and the maximum daily doses of statins for lowering cholesterol are: pravastatin: 40 mg, simvastatin: 40 mg, fluvastatin: 80 mg, atorvastatin: 80 mg, rosuvastatin: 20 mg, and pitavastatin: 4 mg.

21. The pharmaceutical combination according to any one of claims 16 to 19, characterized in that The drug combination comprises 20-400 mg of probucol; and 1-80 mg of a statin; Or the drug combination comprises Probucol and lovastatin in a weight ratio of (3-40):1; or Probucol and pravastatin in a weight ratio of (6-10):1; or Probucol and simvastatin in a weight ratio of (1-15):1; or Probucol and fluvastatin in a weight ratio of (1-4):1; or Probucol and atorvastatin in a weight ratio of (3-25):1; or Probucol and rosuvastatin in a weight ratio of (5-60):1; or Probucol and pitavastatin in a weight ratio of (80-150):1; Or the pharmaceutical combination comprises 20-400 mg of probucol; and 10-80 mg of lovastatin, or 10-80 mg of pravastatin, or 5-80 mg of simvastatin, or 20-80 mg of fluvastatin, or 10-80 mg of atorvastatin, or 5-40 mg of rosuvastatin, or 1-4 mg of pitavastatin; Or the pharmaceutical combination comprises 20-400 mg of probucol; and 10-40 mg of lovastatin, or 20-80 mg of pravastatin, or 20-80 mg of simvastatin, or 20-80 mg of fluvastatin, or 5-40 mg of atorvastatin, or 10-40 mg of rosuvastatin, or 2-4 mg of pitavastatin; Or the pharmaceutical combination comprises 20-400 mg of probucol; and 20-40 mg of lovastatin, or 20-400 mg of pravastatin, or 20-40 mg of simvastatin, or 40-80 mg of fluvastatin, or 10-20 mg of atorvastatin, or 5-10 mg of rosuvastatin, or 2-3 mg of pitavastatin; Or the pharmaceutical combination comprises 20-400 mg of probucol; and 10-40 mg of lovastatin, or 10-40 mg of pravastatin, or 10-40 mg of simvastatin, or 20-80 mg of fluvastatin, or 10-40 mg of atorvastatin, or 5-20 mg of rosuvastatin, or 1-4 mg of pitavastatin; Or the pharmaceutical combination comprises 20-400 mg of probucol; and 10-20 mg of lovastatin, or 10-20 mg of pravastatin, or 20-40 mg of simvastatin, or 40-80 mg of fluvastatin, or 10-20 mg of atorvastatin, or 5-10 mg of rosuvastatin, or 2-4 mg of pitavastatin; or in the drug combination The weight ratio of probucol to lovastatin is not greater than 50 / 2; or The weight ratio of probucol to pravastatin is not greater than 50 / 4; or The weight ratio of probucol to simvastatin is not greater than 50 / 2; or The weight ratio of probucol to fluvastatin is not greater than 50 / 8; or The weight ratio of probucol to atorvastatin is not greater than 50 / 1; or The weight ratio of probucol to rosuvastatin is not greater than 50 / 1; or The weight ratio of probucol to pitavastatin is no greater than 500 / 2; or in the drug combination The weight ratio of probucol to lovastatin is not greater than 37.5 / 2; or The weight ratio of probucol to pravastatin is not greater than 37.5 / 4; or The weight ratio of probucol to simvastatin is not greater than 37.5 / 2; or The weight ratio of probucol to fluvastatin is not greater than 37.5 / 8; or The weight ratio of probucol to atorvastatin is not greater than 37.5 / 1; or The weight ratio of probucol to rosuvastatin is not greater than 37.5 / 1; or The weight ratio of probucol to pitavastatin is no greater than 375 / 2; or in the drug combination The weight ratio of probucol to lovastatin is not greater than 37.5 / 1; or The weight ratio of probucol to pravastatin is not greater than 37.5 / 2; or The weight ratio of probucol to simvastatin is not greater than 37.5 / 1; or The weight ratio of probucol to fluvastatin is not greater than 37.5 / 4; or The weight ratio of probucol to atorvastatin is not greater than 75 / 1; or The weight ratio of probucol to rosuvastatin is not greater than 75 / 1; or The weight ratio of probucol to pitavastatin is no greater than 375 / 1; or in the drug combination The weight ratio of probucol to lovastatin is not greater than 31.25 / 2; or The weight ratio of probucol to pravastatin is not greater than 31.25 / 4; or The weight ratio of probucol to simvastatin is not greater than 31.25 / 2; or The weight ratio of probucol to fluvastatin is not greater than 31.25 / 8; or The weight ratio of probucol to atorvastatin is not greater than 31.25 / 1; or The weight ratio of probucol to rosuvastatin is not greater than 31.25 / 1; or The weight ratio of probucol to pitavastatin is no greater than 312.5 / 2; or in the drug combination The weight ratio of probucol to lovastatin is not greater than 31.25 / 1; or The weight ratio of probucol to pravastatin is not greater than 31.25 / 2; or The weight ratio of probucol to simvastatin is not greater than 31.25 / 1; or The weight ratio of probucol to fluvastatin is not greater than 31.25 / 4; or The weight ratio of probucol to atorvastatin is not greater than 62.5 / 1; or The weight ratio of probucol to rosuvastatin is not greater than 62.5 / 1; or The weight ratio of probucol to pitavastatin is no greater than 625 / 2; or in the drug combination The weight ratio of probucol to lovastatin is not greater than 25 / 2; or The weight ratio of probucol to pravastatin is not greater than 25 / 4; or The weight ratio of probucol to simvastatin is not greater than 25 / 2; or The weight ratio of probucol to fluvastatin is not greater than 25 / 8; or The weight ratio of probucol to atorvastatin is not greater than 25 / 1; or The weight ratio of probucol to rosuvastatin is not greater than 25 / 1; or The weight ratio of probucol to pitavastatin is no greater than 125 / 1; or in the drug combination The weight ratio of probucol to lovastatin is not greater than 20 / 2; or The weight ratio of probucol to pravastatin is not greater than 20 / 4; or The weight ratio of probucol to simvastatin is not greater than 20 / 2; or The weight ratio of probucol to fluvastatin is not greater than 20 / 8; or The weight ratio of probucol to atorvastatin is not greater than 20 / 1; or The weight ratio of probucol to rosuvastatin is not greater than 20 / 1; or The weight ratio of probucol to pitavastatin is no greater than 200 / 2; or in the drug combination The weight ratio of probucol to lovastatin is not greater than 25 / 4; or The weight ratio of probucol to pravastatin is not greater than 25 / 8; or The weight ratio of probucol to simvastatin is not greater than 25 / 4; or The weight ratio of probucol to fluvastatin is not greater than 25 / 16; or The weight ratio of probucol to atorvastatin is not greater than 25 / 2; or The weight ratio of probucol to rosuvastatin is not greater than 25 / 2; or The weight ratio of probucol to pitavastatin is no greater than 125 / 2; Or the drug combination comprises Probucol and lovastatin in a weight ratio not greater than 25 / 1; or Probucol and pravastatin in a weight ratio not greater than 25 / 3; or Probucol and simvastatin in a weight ratio not greater than 25 / 2; or Probucol and fluvastatin in a weight ratio not greater than 25 / 8; or Probucol and atorvastatin in a weight ratio not greater than 25 / 1; or Probucol and rosuvastatin in a weight ratio not greater than 50 / 1; or Probucol and pitavastatin in a weight ratio no greater than 125 / 1.

22. The pharmaceutical combination according to claim 21, characterized in that In the drug combination The weight ratio of probucol to lovastatin is not less than 2 / 2; or The weight ratio of probucol to pravastatin is not less than 2 / 4; or The weight ratio of probucol to simvastatin is not less than 2 / 2; or The weight ratio of probucol to fluvastatin is not less than 2 / 8; or The weight ratio of probucol to atorvastatin is not less than 2 / 1; or The weight ratio of probucol to rosuvastatin is not less than 2 / 1; or The weight ratio of probucol to pitavastatin is not less than 20 / 2; or in the drug combination The weight ratio of probucol to lovastatin is not less than 5 / 2; or The weight ratio of probucol to pravastatin is not less than 5 / 4; or The weight ratio of probucol to simvastatin is not less than 5 / 2; or The weight ratio of probucol to fluvastatin is not less than 5 / 8; or The weight ratio of probucol to atorvastatin is not less than 5 / 1; or The weight ratio of probucol to rosuvastatin is not less than 5 / 1; or The weight ratio of probucol to pitavastatin is not less than 50 / 2; or in the drug combination The weight ratio of probucol to lovastatin is not less than 10 / 2; or The weight ratio of probucol to pravastatin is not less than 10 / 4; or The weight ratio of probucol to simvastatin is not less than 10 / 2; or The weight ratio of probucol to fluvastatin is not less than 10 / 8; or The weight ratio of probucol to atorvastatin is not less than 10 / 1; or The weight ratio of probucol to rosuvastatin is not less than 10 / 1; or The weight ratio of probucol to pitavastatin is not less than 100 / 2.

23. The pharmaceutical combination according to claim 21, characterized in that The amount of probucol as the active ingredient is selected from 20 mg, 25 mg, 30 mg, 31.25 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 62.5 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 187.5 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 312.5 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg or 400 mg.

24. The pharmaceutical combination according to claim 21, characterized in that The amount of probucol as the active ingredient is 20-400 mg, excluding 20 mg, 25 mg, 30 mg, 31.25 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 62.5 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 187.5 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 312.5 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg and / or 400 mg.

25. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises a drug combination according to any one of claims 16 to 24 and a pharmaceutically acceptable carrier, characterized in that the form of simultaneous administration is in the form of an oral unit dosage form selected from tablets, capsules, granules, pellets, and micropills, and the oral unit dosage form comprises probucol and a statin.

26. The pharmaceutical composition according to claim 25, characterized in that The tablet is a two-layer or multi-layer tablet, wherein at least one layer contains probucol and a pharmaceutically acceptable carrier thereof, and at least another layer contains a statin and a pharmaceutically acceptable carrier thereof.

27. A medicine box, characterized in that The kit has the drug combination according to any one of claims 16 to 19, the amount of probucol and the amount of statin contained in the kit are according to any one of claims 20 to 24, and probucol and statin are provided in the form of a single composition in the kit.

28. A medicine box, characterized in that The medicine kit has a drug combination according to any one of claims 16-19, the medicine kit includes one or more identical drug units isolated from the external environment, each drug unit contains a first drug composition containing probucol and a second drug composition containing a statin, the amount of probucol in the first drug composition and the amount of statin in the second drug composition are according to any one of claims 20-24, the first drug composition and the second drug composition are each in an oral unit dosage form, The opening of each pharmaceutical unit exposes the first pharmaceutical composition and the second pharmaceutical composition to the external environment simultaneously.

Images