Chinese and western medicine composition for treating hyperlipemia

Abstract

The invention relates to a Chinese and western medicine composition for treating hyperlipemia. The invention relates to a probucol and red yeast rice medicinal composition, in particular to a probucol and red yeast rice medicinal composition or a medicine box containing probucol and red yeast rice, and application of the medicinal composition, the medicinal 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 probucol and red yeast rice or the kit containing probucol and red yeast rice contains a small dose of probucol and red yeast rice, and the probucol and red yeast rice are configured in a form of simultaneous administration.

Description

[0001] Citation of Related Applications This application claims priority to Chinese patent application with application number 202410164129.X, application date February 5, 2024, and invention name “Combination of Chinese and Western Medicines for Treating Severe Hypertriglyceridemia”, and Chinese patent application with application number 202411662173.X, application date November 20, 2024, and invention name “Combination of Chinese and Western Medicines for Treating Hyperlipidemia”, and the two Chinese patent applications are incorporated herein in their entirety. Technical Field

[0002] The present invention relates to a pharmaceutical combination of probucol and red yeast rice, a pharmaceutical composition comprising probucol and red yeast rice, and use of the pharmaceutical combination and the pharmaceutical 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, and the benefits of increasing statins are limited, with increased side effects, and they need to be combined with other drugs. According to the 2023 China Blood Lipid Management Guidelines, when LDL-C is not up to standard after statin treatment, cholesterol absorption inhibitors (such as ezetimibe) and / or PCSK9 inhibitors are combined. Statins combined with ezetimibe can further reduce LDL-C levels by 18-20% (China Blood Lipid Management Guidelines, 2023 China Blood Lipid Management Guidelines Revision Joint Expert Committee, Chinese Circulation Journal, March 2023, Vol. 38, No. 3, pp. 237-271). Ezetimibe and statins have the side effect of liver damage, and blood lipids rebound greatly after ezetimibe is discontinued. 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] 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. the regular daily dose is 1000 mg). Literature reports that 1 gram per day can reduce cholesterol by 9-29% and LDL-C by 10-15% (Li Jiatai, ed., 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 in lowering cholesterol, lowering triglycerides, especially lowering triglycerides (TG) in severe hypertriglyceridemia.

[0007] Red yeast rice, also known as red yeast rice, red yeast rice, and red yeast rice, is a traditional Chinese medicine and food with a long history. It is made by the mycelium of the Aspergillus fungus Monascus purpureus Went. parasitizing on japonica rice. Red yeast rice has a history of more than 1,000 years in my country and is widely used in traditional Chinese medicine, brewing, food coloring, etc. Red yeast rice is sweet in taste and warm in nature. It enters the liver, spleen, stomach, and large intestine meridians. It has the effects of digesting food and harmonizing the stomach, promoting blood circulation and relieving pain, and strengthening the spleen and drying the stomach. The lipid-lowering and vascular protective effects of red yeast rice have been recognized. The 2023 Chinese Blood Lipid Management Guidelines list red yeast rice under the entry of other lipid-regulating drugs that mainly lower cholesterol. The European Blood Lipid Guidelines list red yeast rice as a dietary supplement for lowering cholesterol. At present, red yeast rice products can be purchased on the market under the names of red yeast rice (powder / rice), functional red yeast rice (powder / rice), red yeast rice extract, etc. The Chinese patent medicines made using the lipid-lowering effect of red yeast rice mainly include Zhibituo, Zhibitai, and Xuezhikang.

[0008] According to data from the State Food and Drug Administration, there are 7 products of Zhibituo, namely Zhibituo tablets (produced by Chengdu Diao Jiuhong Pharmaceutical Factory, with a specification of 0.35g per tablet; Yunnan Yongan Pharmaceutical Co., Ltd., with a specification of 0.35g per tablet), Zhibituo chewable tablets (Henan Jinhualong Pharmaceutical Co., Ltd., with a specification of 0.45g per tablet), and Zhibituo capsules (Sichuan Luye Pharmaceutical Co., Ltd., with a specification of 0.28g per tablet; Sichuan Xuhua Pharmaceutical Co., Ltd., with a specification of 0.3g per tablet; Tibet Tibetan Medicine Group Co., Ltd., with a specification of 0.32g / tablet; Beijing Huashen Pharmaceutical Co., Ltd., with a specification of 0.35g per tablet). Chengdu Diao Company reported on its website that "Monacolin K is the main lipid-lowering ingredient in Zhibituo Red Yeast. There are two types: open-ring and closed-ring. The open-ring is a hydroxy acid structure and has pharmacological activity; the closed-ring is a lactone structure and has no pharmacological activity. It must be converted to an open-ring structure by carboxylesterase in the body to exert its pharmacological effect. The closed-ring Monacolin K is the same compound as the first statin on the market, lovastatin; the ratio of open-ring and closed-ring Monacolin K in Zhibituo Red Yeast is about 1:1, and each Zhibituo tablet (0.35g) contains more than 0.85mg of lovastatin (i.e., closed-ring Monacolin K); the bioavailability of 6 Zhibituo tablets per day is slightly higher than that of 20mg lovastatin tablets per day." The National Standard for Traditional Chinese Medicines WS-11524 (ZD-1524)-2002 stipulates that each Zhibituo tablet (0.35g) contains no less than 0.85mg of red yeast rice, calculated as lovastatin. Li Yan et al. (HPLC method for simultaneous determination of the contents of three monacolin components in Zhibituo tablets) reported that the lovastatin contents of Zhibituo tablets (specification 0.35g, batch number: 0806045, 0811028, 0812043) were 2.81, 2.84, and 2.77 mg / g, respectively; each Zhibituo tablet contained approximately 0.98 mg of lovastatin. The lovastatin content measured by Li Yan et al. through the conversion method was the total content of acid lovastatin and lactone lovastatin. Hao Shengyuan et al. (Determination of lovastatin and lovastatin acid in red yeast rice and Zhibituo tablets by one-test-multiple-evaluation method) reported that lovastatin acid and lovastatin can be detected simultaneously in Zhibituo tablets. According to the three samples measured (batch numbers 1412030, 1505024, and 1511015), the average mass fractions of lovastatin and lovastatin acid in Zhibituo tablets were 0.340% and 0.030%, respectively. The mass fraction ratio of the two is about 1:10. This is equivalent to Zhibituo tablets (0.35g / tablet) containing 1.19 mg lovastatin and 0.119 mg lovastatin acid, and the total amount of lovastatin and lovastatin acid is 1.31 mg / tablet. The lovastatin and lovastatin acid contents measured by Hao Shengyuan et al. through one-test-multiple-evaluation method are the contents of lactone lovastatin and acid lovastatin, respectively.

[0009] According to the data query of the State Food and Drug Administration, Zhibitai has one product, namely Zhibitai Capsules, with a specification of 0.24g / capsule. Liu Yuan et al. (Determination of lovastatin content in Zhibitai Capsules by HPLC) reported that Zhibitai Capsules contained about 8.3 mg of lovastatin / capsule (produced by Chengdu Diao Jiuhong Pharmaceutical Factory, batch numbers: 080105, 090103, 090204). Wen Zhongming et al. (Determination of red yeast rice content in Zhibitai Capsules) also reported that the lovastatin content in the sample of Zhibitai Capsules (batch number 080105) was 8.3 mg / capsule. It is believed that Liu Yuan et al. and Wen Zhongming et al. did not distinguish between lactone lovastatin and acid lovastatin, and the content they measured should correspond to the content of lactone lovastatin.

[0010] According to the data query of the National Medical Products Administration, Xuezhikang mainly has two products (Beijing Beida Weixin Biotechnology Co., Ltd.), Xuezhikang Tablets (Specification: Each tablet weighs 0.4g) and Xuezhikang Capsules (Specification: Each capsule contains 0.3g). The "Chinese Pharmacopoeia" (Volume 1, 2020 Edition) pages 904-906 record that each tablet / capsule of this product (Xuezhikang Tablets / Xuezhikang Capsules) contains no less than 2.5 mg of red yeast rice in terms of lovastatin. The "Chinese Expert Consensus on the Clinical Application of Xuezhikang (Capsules) (2017 Revised Edition)" reported that the lovastatin content in each Xuezhikang capsule is 2.5 mg. Li Xuemei et al. pointed out in "HPLC Determination of Lovastatin and Lovastatin Acid in Xuezhikang Capsules" that the lovastatin content of 10 batches of Xuezhikang Capsules (Beijing Peking University Weixin Biotechnology Co., Ltd., batch numbers: 20070711, 20070915, 20080112, 20080310, 20100101, 20100102, 20100403, 20110406, 20110407, 20110602) was in the range of 2.95-3.55 mg / capsule (average of about 3.35 mg / capsule), the lovastatin acid content was in the range of 0.19-0.47 mg / capsule (average of about 0.315 mg / capsule), and the total content of lovastatin and lovastatin acid was in the range of 3.17-3.98 mg / capsule (average of about 3.66 In the article “HPLC determination of the content of monacolin components in Xuezhikang capsules”, Wang Lijuan et al. used the same concentration of sodium hydroxide (0.1M) as that used by Li Yan et al. for the ring-opening reaction and measured the content of monacolin K compounds in Xuezhikang capsules with batch numbers 20081117, 20090703, and 20090713 to be 0.33%, 0.29%, and 0.31%, respectively. It is believed that the content of monacolin K compounds reported by Wang Lijuan et al. is wrong, because the lovastatin content of Xuezhikang capsules must not be less than 2.5 mg / 0.3g=0.83%.

[0011] Among the above methods for measuring the active ingredients in red yeast rice, Li Yan et al. and Wang Lijuan et al. used the conversion method; Hao Shengyuan et al. and Li Xuemei et al. used the one-measurement-multiple-evaluation method; while Liu Yuan et al. and Wen Zhongming et al. only determined the content of lactone lovastatin.

[0012] It is reported that Zhibitai can reduce cholesterol by 23.5%, triglycerides by 30.3%, and low-density lipoprotein by 18.9%; Xuezhikang can reduce cholesterol by 18.8%, triglycerides by 30.3%, and low-density lipoprotein by 18.4% (China Heart Alliance, Chinese Expert Consensus on the Clinical Application of Zhibitai Capsules, Chinese Journal of Internal Medicine, August 2017, Vol. 56, No. 8, pp. 628-632). Hundreds of compounds have been isolated from red yeast rice. The active ingredient for lipid regulation is monacolin compounds (monacolins), represented by acid and open-ring monacolin K, which do not require hydroxyl esterase hydrolysis and directly exert their effects. They reduce cholesterol by competitive inhibition of HMG-CoA, and their effects are stronger than statins, with fewer side effects than statins. In terms of lowering triglycerides, red yeast rice is used to treat mild hypertriglyceridemia, and there is no report of its efficacy in lowering triglycerides in severe hypertriglyceridemia.

[0013] CN1618441A discloses a pharmaceutical composition with blood lipid regulating effect, which contains 4 parts of hawthorn, 3 parts of white atractylodes, 3 parts of oriental rhizome, and 2 parts of red yeast rice. CN1919213A, CN1919214A, CN1919215A and CN1969891A disclose red yeast rice pellets, red yeast rice soft capsules and red yeast rice preparations and their preparation methods. It is said that the main ingredients of Zhibitai are hawthorn, oriental rhizome, white atractylodes and red yeast rice, while the main ingredient of Zhibituo is red yeast rice.

[0014] Yuan Xiaodong et al. (Effects of Xuezhikang combined with probucol on MMP-9, CD105 and TIMP-1 in patients with hypertensive carotid atherosclerosis, "Chinese Journal of Gerontology" Vol. 39, July 2019: 3359-3361) aimed to explore the effects of Xuezhikang combined with probucol on carotid intima-media thickness (CIMT), MMP-9, CD105 and TIMP-1 in patients with hypertensive carotid atherosclerosis. The treatment method used was to give Xuezhikang (provided by Peking University Weixin Biotechnology Co., Ltd., national medicine approval number Z10950029, oral, 0.6g / time, 2 times / d, taken after breakfast and dinner) and probucol (provided by Qilu Pharmaceutical Co., Ltd., national medicine approval number H10980054, 0.5g / time, 2 times / d, taken before breakfast and dinner) on the basis of conventional antihypertensive treatment. The treatment method does not use low-dose probucol, nor does it administer red yeast rice and probucol simultaneously, and the indications targeted do not include severe hypertriglyceridemia involved in the present invention.

[0015] Xue Jing (Clinical study on the treatment of hyperlipidemia with Zhibitai capsule combined with probucol, "Modern Drugs and Clinics" Vol. 38, No. 2, February 2023: 346-349) used Zhibitai capsule combined with probucol to treat hyperlipidemia. The treatment method used was oral probucol tablets (0.5g / time, 2 times / d) and Zhibitai capsules (1 capsule / time, 2 times / d). This treatment method does not use low-dose probucol, nor does it explicitly give red yeast rice and probucol at the same time, and the indications targeted do not include severe hypertriglyceridemia involved in this invention. Summary of the invention

[0016] The inventors unexpectedly discovered that as two cholesterol-lowering drugs, probucol and red yeast rice, when combined in small doses, can significantly reduce triglycerides in severe hypertriglyceridemia, and the effect is not inferior to that of fibrates. At the same time, they can further reduce cholesterol and low-density lipoprotein, and the effect is not inferior to that of statins. They can be used to treat (severe) hypertriglyceridemia and / or (severe) hypercholesterolemia. They are broad-spectrum lipid-lowering drugs, and at the same time reduce the risk of ASVCD and drug side effects, thereby meeting the above-mentioned clinical needs.

[0017] In a first aspect of the present invention, a pharmaceutical combination is provided, comprising probucol and red yeast rice.

[0018] In a second aspect of the present invention, a pharmaceutical composition is provided, comprising probucol, red yeast rice and a pharmaceutically acceptable carrier.

[0019] In a third aspect of the present invention, a medicine kit is provided, which comprises a first medicine composition containing probucol and a second medicine composition containing red yeast rice.

[0020] In a fourth aspect of the present invention, there is provided use of probucol and red yeast rice in preparing a medicament for treating hyperlipidemia.

[0021] In a fifth aspect of the present invention, a pharmaceutical combination comprising probucol and red yeast rice or a pharmaceutical composition comprising probucol, red yeast rice and a pharmaceutically acceptable carrier is provided for use in treating hyperlipidemia.

[0022] 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 red yeast rice to a subject in need thereof.

[0023] In the fourth, fifth and sixth aspects above, the hyperlipidemia is familial or non-familial (severe) hypertriglyceridemia and / or familial or non-familial (severe) hypercholesterolemia.

[0024] Specifically, the present invention provides the following technical solutions: 1. A drug combination, wherein the drug combination comprises probucol and red yeast rice; or the drug combination is selected from (1) fibrate + red yeast rice (such as fenofibrate 0.2g QD + zebitai 0.24g BID), (2) red yeast rice + cholesterol absorption inhibitor (zebitai 0.24g BID + ezetimibe 20mg QD), (3) fish oil + red yeast rice (zebitai 0.24g BID + fish oil 2g QD); (4) red yeast rice + red yeast rice (zebitai 0.24g bid + Xuezhikang 0.3-0.6g bid), (5) probucol + ezetimibe (probucol 20-500mg bid + ezetimibe 20mg QD); Preferably, probucol and red yeast rice are configured to be administered simultaneously, or the components of the above-mentioned drug combination (1)-(5) are configured to be administered simultaneously in the drug combination, or some of the drugs are configured to be administered simultaneously; More preferably, the simultaneous administration is in the form of an oral unit dosage form, which contains 20-400 mg of probucol and 2-50 mg of red yeast rice, the weight of which is based on the active substance monacolin K, wherein the oral unit dosage form is preferably selected from tablets, capsules, granules, pellets, and micropills, and more preferably, 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 red yeast rice and a pharmaceutically acceptable carrier thereof; or The simultaneous administration is in the form of a kit, which contains probucol and red yeast rice, and probucol and red yeast rice are provided in the form of a single composition in the kit, wherein the single composition contains 20-400 mg of probucol and 2-50 mg of red yeast rice, or The simultaneous administration is in the form of a medicine kit, which includes 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 red yeast rice, the first medicine composition comprising 20-400 mg of probucol, the second medicine composition comprising 2-50 mg of red yeast rice, the first medicine composition and the second medicine composition are each in an oral unit dosage form, and opening of each medicine unit exposes the first medicine composition and the second medicine composition to the external environment at the same time, wherein the oral unit dosage form is preferably selected from tablets, capsules, granules, pills, and micropills, and more preferably, 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 red yeast rice and a pharmaceutically acceptable carrier thereof.

[0025] 2. The drug combination of technical solution 1, wherein red yeast rice is provided in one or more of the following forms: natural red yeast rice, traditional Chinese medicine red yeast rice, functional red yeast rice, red yeast rice extract and a composition containing red yeast rice.

[0026] 3. The drug combination of technical solution 1, wherein the red yeast rice is provided in the form of a composition containing red yeast rice, the composition comprising an active ingredient and a pharmaceutical excipient, The red yeast rice composition contains closed-ring monacolin K and open-ring monacolin K, the total content of the two is 0.2-5 wt%, based on the weight of the composition being 100 wt%, and the weight ratio of closed-ring monacolin K to open-ring monacolin K is (100:1) to (1:100); Preferably, in the composition containing red yeast rice, the weight ratio of active ingredients to pharmaceutical excipients is (5-95):(95-5); the active ingredients include Chinese medicinal red yeast rice, functional red yeast rice or its extract, and optionally any one or more of hawthorn or its extract, atractylodes or its extract and orientalis or its extract.

[0027] 4. The drug combination of technical solution 2, wherein the red yeast rice extract or the composition containing red yeast rice is selected from Zhibituo, Zhibitai or Xuezhikang; or The red yeast rice-containing composition contains closed-ring monacolin K and open-ring monacolin K, the total content of which is 0.2-5 wt%, based on 100 wt% of the weight of the composition, and the weight ratio of closed-ring monacolin K to open-ring monacolin K is (100:1) to (1:100).

[0028] 5. The drug combination of technical solution 1, wherein the red yeast rice contains monacolin compounds, the monacolin compounds contain monacolin K, and optionally, monacolin L and dehydrated lovastatin.

[0029] 6. The drug combination of technical solution 5, wherein the weight ratio of probucol to red yeast rice is (1-100):1, and the weight of the red yeast rice is calculated based on the active substance monacolin K.

[0030] 7. The drug combination of technical solution 5, wherein the weight ratio of probucol to the total amount of monacolin compounds in red yeast rice is (0.8-57):1, and the total amount of monacolin compounds is calculated as the total amount of monacolin K, monacolin L and / or dehydrated lovastatin.

[0031] 8. The drug combination of technical solution 1, wherein each dosage unit of the drug combination comprises 20-400 mg (for example, 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, 225 375 mg, 380 mg, 385 mg, 390 mg, 395 mg or 400 mg of probucol, and each dosage unit of the drug combination contains 2-50 mg (e.g., 3-40 mg, 5-35 mg, 7-30 mg, or 7-20 mg) of probucol (for example, a therapeutically effective amount of red yeast rice is about 2 mg, 2.5 mg, 3.5 mg, 3.5 mg, 3.5 mg, 3.5 mg, 3.5 mg, 3.5 mg, 3.5 mg, 3.5 mg, 3.5 mg, 3.5 mg, 3.5 mg, 3.5 mg, 3.5 mg, 3.5 mg, 3.5 mg, 3.5 mg, mg, 3 mg, 3.5 mg, 4 mg, 5 mg, 6 mg, 7 mg, 7.5 mg, 8 mg, 8.3 mg, 9 mg, 10 mg, 10 .5 mg, 11 mg, 12 mg, 12.5 mg, 13 mg, 14 mg, 15 mg, 16 mg, 16 .6 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 24.9 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 33.2 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg or 50 mg) of red yeast rice, the weight of which is calculated based on the active substance monacolin K; wherein each dosage unit refers to the oral unit dosage form, the single composition, the first pharmaceutical composition, or the second pharmaceutical composition.

[0032] 9. The drug combination of technical solution 1, wherein each dosage unit of the drug combination contains 20-400 mg of probucol, and each dosage unit of the drug combination contains 2-55 mg of monacolin compounds, wherein the content of the monacolin compounds is calculated as the total amount of monacolin K, monacolin L and / or dehydrated lovastatin; wherein each dosage unit refers to the oral unit dosage form, the single composition, the first drug composition, or the second drug composition.

[0033] 10. Use of the drug combination of any one of technical solutions 1-9 in the preparation of a drug for treating hyperlipidemia, treating atherosclerotic vascular lesions, reducing ischemic stroke, reducing lower limb arteriosclerosis occlusion, reducing ischemic kidney lesions, or reducing cardiovascular events.

[0034] 11. The use of technical solution 10, wherein the hyperlipidemia is hypertriglyceridemia, hypercholesterolemia, or mixed hyperlipidemia (i.e., a combination of hypertriglyceridemia and hypercholesterolemia).

[0035] 12. The use of technical solution 10, wherein the hyperlipidemia meets one of the following requirements (1)-(5): (1) The TG level of the subject is: TG ≥ 5.6 mmol / L; (2) 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; (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; 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)".

[0036] 13. The use of technical solution 10, wherein the hyperlipidemia is Severe hypertriglyceridemia, Severe hypercholesterolemia, Hyperlipidemia that is ineffective or ineffective with statins and / or red yeast rice, or Hyperlipidemia that is intolerant or unresponsive to fibrate drugs.

[0037] 14. The use of technical solution 10, wherein the hyperlipidemia is Combination of (severe) hypertriglyceridemia and (severe) hypercholesterolemia, (Severe) hypercholesterolemia that is ineffective or ineffective with statins and / or red yeast rice, (Severe) hypertriglyceridemia that is ineffective or ineffective with statins and / or red yeast rice, or (Severe) hypertriglyceridemia in patients who are intolerant or unresponsive to fibrates.

[0038] 15. The use according to any one of technical solutions 10-14, wherein The therapeutically effective amount of probucol is 20-800 mg per day, preferably 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, 305mg, 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; The therapeutically effective amount of red yeast rice is 2-100 mg per day, preferably 3-40 mg, 5-35 mg, 7-30 mg, or 7-20 mg, calculated as the active substance monacolin K; Probucol and red yeast rice were administered orally at the same time.

[0039] 16. A pharmaceutical composition comprising probucol and red yeast rice, and a pharmaceutically acceptable carrier; wherein the probucol and red yeast rice are configured to be administered simultaneously; Preferably, the red yeast rice is provided in the form of a composition containing red yeast rice, wherein the composition comprises an active ingredient and a pharmaceutical excipient. The red yeast rice composition contains closed-ring monacolin K and open-ring monacolin K, the total content of the two is 0.2-5 wt%, based on the weight of the composition as 100 wt%, and the weight ratio of closed-ring monacolin K to open-ring monacolin K is (100:1) to (1:100), In the composition containing red yeast rice, the weight ratio of active ingredients to pharmaceutical excipients is (5-95):(95-5); the active ingredients include Chinese medicinal red yeast rice, functional red yeast rice or its extract, and optionally any one or more of hawthorn or its extract, atractylodes or its extract, and orientalis or its extract.

[0040] 17. The pharmaceutical composition of technical solution 16, wherein the weight ratio of probucol to red yeast rice is (1-100):1, and the weight of the red yeast rice is calculated based on the active substance monacolin K.

[0041] 18. The pharmaceutical composition of technical solution 16 or 17 is in the form of an oral unit dosage form, preferably in the form of tablets, capsules, granules, pellets, or micropills; more preferably, 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 red yeast rice and a pharmaceutically acceptable carrier thereof.

[0042] 19. The pharmaceutical composition of technical solution 18, wherein the oral unit dosage form comprises 20-400 mg of probucol, preferably 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, 325mg, 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.

[0043] 20. The pharmaceutical composition of technical solution 18 or 19, wherein the oral unit dosage form contains 2-50 mg of red yeast rice, preferably 3-40 mg, more preferably 5-35 mg, even more preferably 7-30 mg, even more preferably 7-20 mg, and the weight of the red yeast rice is calculated as the active substance monacolin K.

[0044] 21. A pharmaceutical composition comprising probucol and red yeast rice active ingredients, wherein the red yeast rice active ingredients are prepared as follows: Take part of the red yeast rice and crush it into fine powder; add a certain concentration of ethanol to the remaining red yeast rice and reflux extract it twice, filter it, combine the filtrate, recover the ethanol, concentrate it to a suitable amount, and spray it into the red yeast rice fine powder to obtain the product.

[0045] 22. A pharmaceutical composition comprising probucol and monacolin K.

[0046] 23. The pharmaceutical composition of technical solution 22, wherein the weight ratio of probucol to monacolin K is (1-100):1, wherein the weight of monacolin K is the total weight of acid monacolin K and lactone monacolin K, and the ratio of lactone monacolin K to acid monacolin K is 1:10 to 10:1.

[0047] 24. The pharmaceutical composition of technical solution 22 or 23 further comprises one or more compounds selected from the following: monacolin L, dehydrated lovastatin, monacolin M, monacolin N1, monacolin N2, monacolin N3, monacolin N4, monacolin N5, monacolin N6, monacolin Q, monacolin R, monacolin S, monacolin T, monacolin U, monacolin X, monacolin acid A, dehydromonacolin J, dehydromonacolin K, dehydromonacolin L, dehydromonacolin N, dihydromonacolin K, dihydromonacolin L, dihydromonacolin MV, dehydromonacolin MV2 and monacolin K ethyl ester.

[0048] 25. A kit comprising a first pharmaceutical composition containing probucol and a second pharmaceutical composition containing red yeast rice, wherein the first pharmaceutical composition and the second pharmaceutical composition are configured for simultaneous administration; Preferably, the medicine kit comprises one or more identical medicine units isolated from the external environment, each medicine unit comprises a first medicine composition containing probucol and a second medicine composition containing red yeast rice, 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.

[0049] 26. The kit of technical solution 25, wherein the first pharmaceutical composition comprises 20-400 mg of probucol, preferably comprises 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 of probucol.

[0050] 27. The medicine kit of technical solution 25 or 26, wherein the second pharmaceutical composition comprises 2-50 mg of red yeast rice, preferably 3-40 mg, more preferably 5-35 mg, even more preferably 7-30 mg, even more preferably 7-20 mg, and the weight of the red yeast rice is calculated as the active substance monacolin K.

[0051] 28. The pharmaceutical kit described in any one of technical solutions 25-27, wherein the first pharmaceutical composition and the second pharmaceutical composition are provided in separate dosage forms.

[0052] 29. The medicine box described in any one of technical solutions 25-27, wherein the first pharmaceutical composition and the second pharmaceutical composition are provided in a single dosage form, preferably, the single dosage form is provided in a tablet, a capsule, a granule, a pellet, and a micropill; more preferably, 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 red yeast rice and a pharmaceutically acceptable carrier thereof.

[0053] 30. A medicine box comprising probucol and red yeast rice as active ingredients, preferably, probucol and red yeast rice are configured in the medicine box in a form that can be administered simultaneously; more preferably, the medicine box 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 red yeast rice of the present invention, and the opening of each medicine unit can expose the probucol and red yeast rice of the present invention to the external environment at the same time.

[0054] 31. The medicine box of technical solution 30, wherein the amount of probucol and red yeast rice as active ingredients contained in each drug unit is: Probucol: 20-400 mg, preferably 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, 120 125 mg 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; Red yeast rice: 2-50 mg, for example 3-40 mg, 5-35 mg, 7-30 mg, 7-20 mg, the weight of the red yeast rice is calculated based on the active substance monacolin K.

[0055] 32. A medicine kit, characterized in that the medicine kit comprises a drug combination according to any one of technical solutions 1 to 9, comprising a first pharmaceutical composition containing probucol and a second pharmaceutical composition containing red yeast rice, wherein the first pharmaceutical composition and the second pharmaceutical composition are configured for simultaneous administration; wherein the first pharmaceutical composition comprises 20-400 mg of probucol; and the second pharmaceutical composition comprises 2-50 mg of red yeast rice, and the weight of the red yeast rice is calculated as the active substance monacolin K.

[0056] 33. The medicine box of technical solution 32, wherein the first pharmaceutical composition comprises 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, 240 375 mg, 380 mg, 385 mg, 390 mg, 395 mg or 400 mg of probucol; and the second pharmaceutical composition comprises 3-40 mg, 5-35 mg, 7-30 mg or 7-20 mg of red yeast rice, the weight of which is calculated as the active substance monacolin K.

[0057] 34. The pharmaceutical kit of technical solution 32, wherein the first pharmaceutical composition and the second pharmaceutical composition are provided in separate dosage forms; or wherein the first pharmaceutical composition and the second pharmaceutical composition are provided in a single dosage form.

[0058] 35. The medicine box described in technical solution 34, wherein the dosage form is selected from tablets, capsules, granules, pellets, and micropills.

[0059] 36. The medicine box described in technical solution 35, wherein the tablet is a two-layer or multi-layer tablet, 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.

[0060] 37. A medicine box as described in any one of technical solutions 32-36, wherein the medicine box comprises one or more identical drug units isolated from the external environment, each drug unit comprises a first drug composition containing probucol and a second drug composition containing red yeast rice, wherein opening of each drug unit exposes probucol and red yeast rice to the external environment at the same time.

[0061] 38. Use of the pharmaceutical composition of any one of Technical Solutions 16-24, or the medicine kit of any one of Technical Solutions 25-36 in the preparation of medicine for treating hyperlipidemia, preferably, the use is the use of any one of Technical Solutions 1-15. DETAILED DESCRIPTION

[0062] 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.

[0063] 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, in the absence of a prescribed frequency of administration, the term "effective amount" or "therapeutically effective amount" is based on daily.

[0064] 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.

[0065] As used herein, the term "treat" refers to at least partially alleviating, controlling and / or ameliorating a disease or its symptoms.

[0066] 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.

[0067] As used herein, the term "QD" means once daily.

[0068] As used herein, the term "BID" means twice daily.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] The term "hypercholesterolemia" as used herein refers to hyperlipidemia with TC>6.22 mmol / L or 240 mg / dL, LDL-C>4.14 mmol / L or 160 mg / dL, including familial (severe) hypercholesterolemia.

[0074] The term "severe hypercholesterolemia" as used herein refers to hyperlipidemia with LDL-C>4.9mmol / L.

[0075] The term "hypertriglyceridemia" as used herein refers to hyperlipidemia with TG>1.7 mmol / L or>150 mg / dL.

[0076] The term "severe hypertriglyceridemia" as used herein refers to hyperlipidemia with TG ≥ 5.6 mmol / L (500 mg / dL).

[0077] The term "fibrate-intolerant or -unresponsive hyperlipidemia" as used herein refers to hyperlipidemia in which fibrate therapy causes liver and kidney damage, elevated muscle enzymes, or TG remains greater than 5.6 mmol / L after fibrate therapy.

[0078] The term "hyperlipidemia that is ineffective or ineffective in treatment with statins and / or red yeast rice" as used in this article refers to hyperlipidemia that does not reach the target recommended by lipid management guidelines after treatment with statins and / or red yeast rice.

[0079] Hypercholesterolemia, severe hypercholesterolemia, hypertriglyceridemia, severe hypertriglyceridemia, fibrate-intolerant or non-responsive hyperlipidemia, and hyperlipidemia that is ineffective or ineffective with statins and / or red yeast rice are defined as above. A similar definition can be used for the following terms: combination of hypertriglyceridemia and hypercholesterolemia, hypercholesterolemia that is ineffective or ineffective with statins and / or red yeast rice treatment, hypertriglyceridemia that is ineffective or ineffective with statins and / or red yeast rice treatment, 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 and / or red yeast rice treatment, severe hypertriglyceridemia that is intolerant or unresponsive to fibrates, severe hypercholesterolemia that is ineffective or ineffective with statins and / or red yeast rice treatment.

[0080] The "probucol" mentioned herein includes probucol and pharmaceutically acceptable salts or esters thereof, such as probucol disuccinate and the like.

[0081] Herein, unless otherwise specified, the effective amount, therapeutically effective amount and content of probucol or its pharmaceutically acceptable salt or ester are all calculated based on probucol free phenol.

[0082] The "red yeast rice" described herein can be provided by natural red yeast rice, traditional Chinese medicine red yeast rice, functional red yeast rice, red yeast rice extract or a composition containing red yeast rice.

[0083] Natural red yeast rice refers to a product that is naturally formed by fermenting rice (or crushed rice) with Monascus sp. Depending on the type of Monascus sp. used, natural red yeast rice can be subdivided into red yeast rice pigment, functional red yeast rice and brewing red yeast rice. Monascus fungi that can be used include, but are not limited to, Monascus albidulus, Monascus anka, Monascus argentinensis, Monascus aurantiacus, Monascus barkeri, Monascus eremophilus, Monascus floridanus, Monascus fuliginosus, Monascus fumeus, Monascus kaoliang, Monascus lunisporas, Monascus pallens, Monascus paxii, Monascus pilosus, Monascus purpureus, Monascus ruber, Monascus rust rubiginosus), Monascus rutilus, Monascus sanguineus, Monascus pubigerus, Monascus sp. A commercially available natural red yeast rice or red yeast powder containing ≥0.2 wt% of moracolin K on an absolute dry basis.

[0084] The Chinese medicine red yeast rice or red yeast rice powder is a Chinese medicine or intermediate formed by processing the mycelium of the Aspergillus fungus such as Monascus purpureus Went. parasitizing on rice or polished rice by traditional Chinese medicine processing means such as processing. In one embodiment, the Chinese medicine red yeast rice contains 3-6 mg / g of unsaturated fatty acids and 15-30 mg / g of lovastatin, wherein the percentage of open-ring structure lovastatin in the total lovastatin is 10-90%.

[0085] Functional red yeast rice refers to a product containing monacolin K and other bioactive substances produced by fermentation of rice (or crushed rice) with Monascus sp., and is divided into red yeast rice and red yeast powder according to its form. In particular, functional red yeast rice contains ≥0.4wt% of monacolin K on an absolute dry basis [refer to QB / T 2847-2023 Functional red yeast rice (powder)]. The Monascus sp. used to prepare the functional Monascus may include, but is not limited to, Monascus albidulus, Monascus fuliginosus, Monascus paxii, Monascus pilosus, Monascus purpureus, and Monascus ruber; in particular, the Monascus is Monascus purpureus with a strain number of CICC®5046 or Monascus ruber with a strain number of CICC®41649.

[0086] Red yeast rice extract refers to the product obtained in the process of extracting active substances from natural red yeast rice or functional red yeast rice. The specific extraction method is known, for example, reference can be made to the methods disclosed in literature methods such as CN1618441A (Di'ao), CN103417601A (Weixin), CN103372040A (Weixin), and CN1174037A (Weixin). Red yeast rice extract can be prepared by a person skilled in the art using conventional extraction methods, for example, reflux extraction of red yeast rice 2-3 times with 50-90% methanol, ethanol or ethyl acetate, and combining the extracts. The extract can also be post-processed. The post-processing method is well known to those of ordinary skill in the pharmaceutical field, for example, including filtering and recovering the solvent, concentrating, and drying (such as spray drying) to obtain the final red yeast rice extract.

[0087] Natural red yeast rice, Chinese herbal red yeast rice, functional red yeast rice and red yeast rice extracts are all commercially available. The Notice on the Application and Review of Health Food Products Using Red Yeast Rice as Raw Materials (No. 2 of the State Food and Drug Administration

[2010] ) issued by the State Food and Drug Administration stipulates that for health foods, "the recommended daily intake of red yeast rice is temporarily set at no more than 2g. The lovastatin in the product should be derived from red yeast rice, and the total recommended daily intake of lovastatin is temporarily set at no more than 10mg. If the above limit is exceeded, sufficient evidence of food safety should be provided." The Red Yeast Rice Health Food Specification Standard issued by the Health and Welfare Administration of Taiwan Province stipulates that for red yeast rice products, the product's specification ingredients should meet the requirement of "the daily intake of monacolin K should be at least 4.8 mg, but not more than 15 mg".

[0088] The composition containing red yeast rice is a composition containing active ingredients and pharmaceutical excipients, wherein the active ingredients include Chinese medicine red yeast rice or functional red yeast rice or red yeast rice extract. The composition containing red yeast rice contains closed-loop monacolin K and open-loop monacolin K, the total content of the two is 0.2-5 wt%, based on the weight of the composition as 100 wt%, and the weight ratio of closed-loop monacolin K to open-loop monacolin K can be (100:1) to (1:100), for example, (50:1) to (1:50), or (15:1) to (1:15), or (1:1) to (1:15).

[0089] In the composition containing red yeast rice, the weight ratio of the active ingredient to the pharmaceutical excipient can be (5-95):(95-5), or (10-90):(90-10), or (20-80):(80-20), or (30-70):(70-30), or (40-60):(60-40), or (45-55):(55-45).

[0090] The pharmaceutical excipients are conventional and are not particularly limited in the present invention. For example, the pharmaceutical excipients may be selected from disintegrants (selected from one or more of sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose), fillers (selected from one or more of lactose, microcrystalline cellulose, sucrose, sorbitol, mannitol, pregelatinized starch, starch), binders (the binder is selected from one or more of ethanol, water, ethanol-water solution, syrup, starch slurry, sodium carboxymethyl cellulose solution, polyvinylpyrrolidone solution, or a mixture of several thereof), flavoring agents (selected from Orange flavor, mint flavor, grape flavor, cherry flavor, banana flavor, pineapple flavor, vanilla flavor, lemon flavor, aspartame, saccharin sodium, stevioside, a mixture of one or more thereof), a lubricant (selected from micro powder silica gel, magnesium stearate, calcium stearate, stearic acid, talcum powder, silicon dioxide, magnesium dodecyl sulfate, PEG4000, PEG6000, a mixture of one or more thereof), a coating agent (acrylic resin, hydroxypropyl methylcellulose, polyethylene glycol, a mixture of one or more thereof), etc. The pharmaceutical excipients may also include one or more of donkey-hide gelatin, salad oil, soybean lecithin, vitamin E, beeswax, safflower seed oil, low-substituted hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, polyethylene glycol, sodium carboxymethyl cellulose, microcrystalline cellulose, micro powder silica gel, talcum powder, polyvinyl pyrrolidone.

[0091] The active ingredient may consist of only the Chinese herbal medicine red yeast rice or the functional red yeast rice or the red yeast rice extract, or may consist of the Chinese herbal medicine red yeast rice or the functional red yeast rice or the red yeast rice extract and a second active substance.

[0092] The second active substance may be one or more other Chinese medicinal materials or extracts thereof. Other Chinese medicinal materials are relative to Chinese medicinal red yeast rice or functional red yeast rice. Extracts of one or more other Chinese medicinal materials may be obtained by methods known to those skilled in the art. When extracting a variety of Chinese medicinal materials (including Chinese medicinal red yeast rice or functional red yeast rice), one Chinese medicinal material may be extracted alone, and / or two or more Chinese medicinal materials may be mixed together for extraction, and / or all Chinese medicinal materials may be mixed together for extraction.

[0093] In one embodiment of the present invention, the composition containing red yeast rice is a red yeast rice micro-pill, which is obtained by adding a wetting agent to the raw materials and auxiliary materials in the following weight ratio to make pills: 8-12 parts of red yeast rice, 3-5 parts of auxiliary materials, wherein the auxiliary materials are starch or dextrin, and the wetting agent is 60%-80% ethanol. The preparation method of the red yeast rice micro-pill comprises the following steps: a. weighing red yeast rice, drying, crushing, and passing through a 60-200 mesh sieve; b. adding starch or dextrin, using 60-80% ethanol as a wetting agent, making a soft material, and using a micro-pill machine to make pills, that is, the pill making is divided into three stages, wherein the first and second stages of pill making adopt a static drying method, and the third stage of pill making adopts a high temperature drying expansion method to make pills; the first stage drying temperature is 30-40°C, and the drying time is 1 hour; the second stage drying temperature is 50-60°C, and the drying time is 1 hour; the third stage drying temperature is 70-80°C, and the drying time is 8 hours. For the specific preparation method, reference may be made to Chinese patent application CN200510021520.1 with publication number CN1919213A.

[0094] In one embodiment of the present invention, the composition containing red yeast rice is a red yeast rice soft capsule, which is a soft capsule prepared from raw materials and matrix excipients in the following weight ratio: the weight ratio of red yeast rice to matrix excipients is 1: (0.8-1.2), and the matrix excipients are soybean oil and beeswax. The preparation method of the red yeast rice soft capsule comprises the following steps: a. Preparation of capsule material glue: weighing raw materials containing the following weight ratio to prepare capsule material: the weight ratio of dry plasticizer to dry gelatin is (0.3-0.6): 1.0, and the weight ratio of water to dry gelatin is 1: 1; b. weighing red yeast rice, drying, crushing, and passing through a 60-200 mesh sieve; c. adding red yeast rice to soybean oil and beeswax, mixing, and preparing soft capsules by compression. The specific preparation method can refer to the Chinese patent application CN200510021521.6 with publication number CN1919214A.

[0095] In one embodiment of the present invention, the composition containing red yeast rice is a red yeast rice preparation, which is prepared by adding a coating agent to prepare coated red yeast rice, and then adding excipients commonly used in pharmacy to prepare the preparation, wherein the weight ratio of the red yeast rice or its extract to the coating agent is 50-500 parts of red yeast rice or its extract and 20-200 parts of the coating agent; the coating agent is one or a mixture of acrylic resin, hydroxypropyl methylcellulose, and polyethylene glycol; wherein the raw material of the red yeast rice or its extract can pass through a 60-300 mesh sieve. In particular, the red yeast rice preparation is a tablet, and its preparation method includes: a. Weigh the following weight ratio of red yeast rice or its extract and auxiliary materials: 50-500 parts of red yeast rice or its extract, pass through the No. 4 pharmacopoeia sieve; the rest are pharmaceutical excipients including 20-200 parts of coating agent, 0-200 parts of filler, 10-200 parts of disintegrant, 0-10 parts of flavoring agent, 0-50 parts of lubricant, 0-10 parts of glidant, pass through the No. 3 pharmacopoeia sieve respectively, and set aside; b. Use the coating agent to coat the original powder of red yeast rice or its extract, and pass through the No. 3 pharmacopoeia sieve, and set aside; c. Mix the original powder of red yeast rice after coating with auxiliary materials, and directly compress the tablets to obtain. The specific preparation method can refer to the Chinese patent application CN200510022143.3 with the publication number CN1969891A.

[0096] In one embodiment of the present invention, the composition containing red yeast rice is a dripping pill made of red yeast rice, wherein the raw material for preparing the dripping pill comprises or consists of the following: a red yeast rice extract and polyethylene glycol in a weight ratio of 1:(1-3), and the preparation method comprises: taking red yeast rice, extracting it 1-3 times with 75% ethanol, adding 2-3 times the amount of ethanol each time, extracting it for 2-3 hours each time, filtering, combining the filtrate, recovering ethanol, and concentrating it to a concentrate with a relative density of 0.9-1.1 measured at a temperature of 55-60°C; taking another 1 / 10-1 / 6 weight of red yeast rice, crushed into fine powder; the concentrated solution is continuously sprayed into the red yeast rice fine powder, boiling and drying to obtain a dry extract; the dry extract is crushed into fine powder to obtain a red yeast rice extract; the boiling and drying conditions are: the material temperature is 60-80°C, the spraying speed is 25-35 liters / hour; after the polyethylene glycol is heated and melted, the red yeast rice extract is added, mixed evenly, and kept warm at 75±2°C; the coolant is dripped into the coolant with a pill machine, wherein the temperature of the coolant is 20±2°C, the pills are taken out after forming, the coolant on the surface is removed, and the pills are packaged. The specific preparation method can refer to the Chinese patent application CN200510123460.4 with the publication number CN1899317A.

[0097] In one embodiment of the present invention, the composition containing red yeast rice is a Chinese medicine red yeast rice preparation, wherein the raw material of the Chinese medicine red yeast rice preparation includes or consists of the following: 273 parts of red yeast rice, 5-10 parts of micro powder silica gel. The preparation method of the Chinese medicine red yeast rice preparation includes the following steps: a. weighing red yeast rice, drying, crushing, and sieving; b. adding auxiliary materials, granulating, and adding auxiliary materials commonly used in pharmacy to prepare a preparation commonly used in pharmacy. The specific preparation method can refer to the Chinese patent application CN200510129372.5 with publication number CN1919215A.

[0098] In one embodiment of the present invention, the composition containing red yeast rice is a pharmaceutical composition drop pill for treating cardiovascular diseases, wherein the raw materials of the pharmaceutical composition include or consist of the following: red yeast rice extract: matrix = 1: (0.5-2.0), the matrix refers to one of polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 10000, glycerol, gelatin, poloxamer; or a mixture of polyethylene glycol 4000: polyethylene glycol 6000 = 1:1; the red yeast rice extract contains more than 33 mg / g of lovastatin as determined by HPLC. The preparation method of the red yeast rice extract comprises: taking 1 part by weight of red yeast rice medicinal material, adding 1-4 parts by volume of 60-90% ethanol to reflux and extract for 1-4 hours, filtering the extract, adding 1-3 parts by volume of 60-90% ethanol to the filter residue for reflux and extract for 1-3 hours, filtering the extract, combining the filtrate, decompressing and recovering ethanol, and concentrating the extract into a thick paste after evaporating the ethanol; adding 0.5-1.25 parts by volume of deionized water to the thick paste for precipitation, placing it at room temperature or under refrigeration for 2-16 hours, siphoning off the supernatant, or collecting the precipitate by centrifugation; adding 2-5% of the weight of the medicinal material to the precipitate, one of the excipients selected from red yeast rice medicinal material powder, microcrystalline cellulose, starch, sodium carboxymethyl starch or pregelatinized starch, mixing well, and drying at 60-90°C for 6-10 hours to make the moisture content less than 5%, thereby obtaining the red yeast rice extract. The specific preparation method can refer to the Chinese patent application CN200710099767.4 with the publication number CN101313918A.

[0099] In one embodiment of the present invention, the composition containing red yeast rice is a pharmaceutical composition having the effect of regulating blood lipids, wherein the raw materials of the pharmaceutical composition include or consist of the following: 1-5 parts by weight of red yeast rice, 1-5 parts by weight of kudzu root; the pharmaceutical composition is prepared by the following method: Step 1: Preparation of Red Yeast Extract I Red yeast rice extract I is prepared by any of the following methods: A, 1 weight part of red yeast rice, add 2-10 volume parts of 50-90% ethanol, methanol or ethyl acetate each time, heat and reflux for 1-3 hours, extract 2-3 times; filter the extract, combine the filtrate, recover the solvent, and concentrate it into a thick paste with a relative density of 0.95-1.06 measured at 55-60°C to obtain Extract I; B. 1 weight part of red yeast rice, add 2-10 volume parts of 50-90% ethanol, methanol or ethyl acetate each time, heat and reflux for 1-3 hours, extract 2-3 times; filter the extract, combine the filtrate, recover the solvent, concentrate to 55-60°C to measure the relative density of 0.95-1.06, add 0.5-2.0 times of deionized water to the concentrate, mix well, place at room temperature or refrigerate for 2-12 hours, centrifuge, collect the precipitate, and dry to obtain extract I; Step 2: Preparation of Pueraria Extract II 1 weight part of Pueraria root medicinal material, add 4-20 volume parts of water or ethanol each time, heat and reflux for 1-3 hours, extract 2-4 times, filter the extract, combine the filtrate, recover the solvent, and concentrate into a thick paste to obtain Extract II; Step 3: Preparation Extracts I and II are prepared into clinically acceptable pills, powders, tablets, granules, capsules or oral liquid preparations by conventional methods and adding conventional excipients.

[0100] For the specific preparation method, reference may be made to Chinese patent application CN201210118280.7 with publication number CN103372051A.

[0101] In one embodiment of the present invention, the composition containing red yeast rice is a pharmaceutical composition having the effect of regulating blood lipids, wherein the raw materials of the pharmaceutical composition include or consist of the following: 1-5 parts by weight of red yeast rice, 1-5 parts by weight of orientalis; The pharmaceutical composition is prepared by the following method: Step 1: Preparation of Red Yeast Extract I Red yeast rice extract I is prepared by any of the following methods: A, 1 weight part of red yeast rice, add 2-10 volume parts of 50-90% ethanol, methanol or ethyl acetate each time, heat and reflux for 1-3 hours, extract 2-3 times; filter the extract, combine the filtrate, recover the solvent, and concentrate it into a thick paste with a relative density of 0.95-1.06 measured at 55-60°C to obtain Extract I; B. 1 weight part of red yeast rice, add 2-10 volume parts of 50-90% ethanol, methanol or ethyl acetate each time, heat and reflux for 1-3 hours, extract 2-3 times; filter the extract, combine the filtrate, recover the solvent, concentrate to 55-60°C to measure the relative density of 0.95-1.06, add 0.5-2.0 times of deionized water to the concentrate, mix well, place at room temperature or refrigerate for 2-12 hours, centrifuge, collect the precipitate, and dry to obtain extract I; Step 2: Preparation of Alisma Orientalis Extract II 1 weight part of oriental medicine material, add 4-20 volume parts of water or ethanol each time, heat and reflux to extract for 1-3 hours, extract 2-4 times, filter the extract, combine the filtrate, recover the solvent, and concentrate to a thick paste to obtain extract II; Step 3: Preparation Extracts I and II are prepared into clinically acceptable pills, powders, tablets, granules, capsules or oral liquid preparations by conventional methods and adding conventional excipients.

[0102] For the specific preparation method, reference may be made to Chinese patent application CN201210118859.3 with publication number CN103372114A.

[0103] In one embodiment of the present invention, the composition containing red yeast rice is a pharmaceutical composition having the effect of regulating blood lipids, and the raw materials of the pharmaceutical composition include or consist of the following: 1-5 parts by weight of red yeast rice and 1-5 parts by weight of hawthorn.

[0104] The pharmaceutical composition is prepared by the following method: Step 1: Preparation of Red Yeast Extract I Red yeast rice extract I is prepared by any of the following methods: A, 1 weight part of red yeast rice, add 2-10 volume parts of 50-90% ethanol, methanol or ethyl acetate each time, heat and reflux for 1-3 hours, extract 2-3 times; filter the extract, combine the filtrate, recover the solvent, and concentrate it into a thick paste with a relative density of 0.95-1.06 measured at 55-60°C to obtain extract I; B. 1 weight part of red yeast rice, add 2-10 volume parts of 50-90% ethanol, methanol or ethyl acetate each time, heat and reflux for 1-3 hours, and extract 2-3 times; filter the extract, combine the filtrate, recover the solvent, concentrate to 55-60°C, measure the relative density of 0.95-1.06, add 0.5-2.0 times of deionized water to the concentrate, mix well, place at room temperature or refrigerate for 2-12 hours, centrifuge, collect the precipitate, and dry to obtain extract I; Step 2: Preparation of Hawthorn Extract II 1 part by weight of hawthorn medicinal material, add 4-20 parts by volume of water or ethanol each time, heat and reflux for extraction for 1-3 hours, extract 2-4 times, filter the extract, combine the filtrate, recover the solvent, and concentrate into a thick paste to obtain extract II; Step 3: Preparation Extract I and Extract II are prepared into clinically acceptable pills, powders, tablets, granules, capsules or oral liquid preparations by conventional methods and adding conventional excipients.

[0105] For the specific preparation method, reference may be made to Chinese patent application CN201210119095.X with publication number CN103372073A.

[0106] In one embodiment of the present invention, the composition containing red yeast rice is a pharmaceutical composition having the effect of regulating blood lipids, wherein the raw materials of the pharmaceutical composition include or consist of the following: 1-5 parts by weight of red yeast rice, 1-5 parts by weight of chuanxiong; The pharmaceutical composition is prepared by the following method: Step 1: Preparation of Red Yeast Extract I Red yeast rice extract I is prepared by any of the following methods: A, 1 weight part of red yeast rice, add 2-10 volume parts of 50-90% ethanol, methanol or ethyl acetate each time, heat and reflux for 1-3 hours, extract 2-3 times; filter the extract, combine the filtrate, recover the solvent, and concentrate it into a thick paste with a relative density of 0.95-1.06 measured at 55-60°C to obtain Extract I; B. 1 weight part of red yeast rice, add 2-10 volume parts of 50-90% ethanol, methanol or ethyl acetate each time, heat and reflux for 1-3 hours, extract 2-3 times; filter the extract, combine the filtrate, recover the solvent, concentrate to 55-60°C to measure the relative density of 0.95-1.06, add 0.5-2.0 times of deionized water to the concentrate, mix well, place at room temperature or refrigerate for 2-12 hours, centrifuge, collect the precipitate, and dry to obtain extract I; Step 2: Preparation of Chuanxiong Extract II 1 weight part of Chuanxiong medicinal material, add 4-20 volume parts of water or ethanol each time, heat and reflux for extraction for 1-3 hours, extract 2-4 times, filter the extract, combine the filtrate, recover the solvent, and concentrate into a thick paste to obtain Extract II; Step 3: Preparation Extracts I and II are prepared into clinically acceptable pills, powders, tablets, granules, capsules or oral liquid preparations by conventional methods and adding conventional excipients.

[0107] For the specific preparation method, reference may be made to Chinese patent application CN201210119116.8 with publication number CN103372040A.

[0108] In one embodiment of the present invention, the composition containing red yeast rice is a pharmaceutical composition for regulating blood lipids, which is composed of red yeast rice extract and gynostemma pentaphyllum extract; the weight ratio of red yeast rice to gynostemma pentaphyllum medicinal materials is 1:10 to 10:1; the weight percentage of total saponins in the gynostemma pentaphyllum extract is ≥8%; Wherein, the Gynostemma pentaphyllum extract is prepared by the following method: Take 1 weight part of Gynostemma pentaphyllum medicinal material, add 4-20 volume parts of water or ethanol or ethanol solution each time, heat and extract for 1-3 hours, extract 2-4 times, filter the extract, combine the filtrate, recover the solvent, and concentrate into a thick paste; The red yeast rice extract is prepared by method Ⅰ or method Ⅱ: Method I: 1) Take 1 part by weight of red yeast rice, add 2-10 parts by volume of 50-90% ethanol, methanol or ethyl acetate each time, heat and reflux for 1-3 hours, and extract 2-3 times; 2) filtering the extract and combining the filtrates; 3) concentrating the filtrate obtained in step 2) into a thick paste; Method II: (1) Take 1 part by weight of red yeast rice, add 3 parts by volume of 75% ethanol each time, heat and reflux for 2-3 hours, and extract twice; (2) filtering the extract and combining the filtrates; (3) Concentrating the filtrate obtained in step (2) to a concentrated solution having a relative density of 0.95-1.06 at 55-60°C.

[0109] For the specific preparation method, reference may be made to Chinese patent application CN201210155323.9 with publication number CN103417601A.

[0110] In one embodiment of the present invention, the composition containing red yeast rice is a medicament, wherein the raw material composition for preparing the active ingredient of the medicament includes or consists of the following: 6 parts of red yeast rice, 9 parts of atractylodes macrocephala, and 12 parts of hawthorn; or 3-6 parts of red yeast rice, 9-12 parts of white atractylodes, 12 parts of hawthorn; or 3-15 parts of red yeast rice, 3-15 parts of atractylodes macrocephala, 3-15 parts of hawthorn; or 6 parts of red yeast rice, 9 parts of oriental rhizome, 9 parts of atractylodes macrocephala, 12 parts of hawthorn fruit; or 3-6 parts of red yeast rice, 6-9 parts of oriental rhizome, 9-12 parts of atractylodes macrocephala, 12 parts of hawthorn; 3-15 parts of red yeast rice, 3-15 parts of oriental rhizome, 3-15 parts of atractylodes macrocephala, 3-15 parts of hawthorn; The preparation method of the drug comprises the following steps: a. Weigh Chinese medicinal materials as raw materials; b. Extract the above medicinal materials with alcohol or aqueous ethanol, filter, and obtain filtrate A; c. Recover ethanol from filtrate A, and concentrate under reduced pressure to obtain extract B; d. Add appropriate amount of water to extract B, let stand, centrifuge, obtain supernatant C and precipitate D, and dry precipitate D as active ingredient I; e. Pass supernatant C through a pretreated resin column, wash with water until colorless, and then wash with ethanol until colorless, collect eluate, recover ethanol, concentrate and dry to obtain thick paste E as active ingredient II; f. Active ingredients I and II are mixed with pharmaceutically acceptable excipients to prepare a pharmaceutical preparation. The specific preparation method can refer to Chinese patent application CN200310110995.9 with publication number CN1618441A.

[0111] For example, the composition containing red yeast rice can be a Chinese patent medicine made from red yeast rice, which can be commercially available under the trade names of Zhibitai, Zhibituo, Xuezhikang, etc.

[0112] The above-mentioned Chinese medicine red yeast rice, functional red yeast rice, red yeast rice extract and red yeast rice containing composition all contain a certain amount of effective ingredient monacolin compounds, wherein the monacolin compounds contain monacolin K, and optionally, monacolin L and dehydrated lovastatin, and further optionally, contain one or more compounds selected from the following: monacolin L, dehydrated lovastatin, monacolin M, monacolin N1, monacolin N2, monacolin L, dehydrated lovastatin, monacolin M, monacolin N2, monacolin N3, monacolin N4, monacolin N5, monacolin N6, monacolin N7, monacolin N8, monacolin N9, monacolin N10, monacolin N112, monacolin N123, monacolin N13, monacolin N14, monacolin N15, monacolin N16 Monacolin N3, monacolin N4, monacolin N5, monacolin N6, monacolin Q, monacolin R, monacolin S, monacolin T, monacolin U, monacolin X, monacolin acid A, dehydromonacolin J, dehydromonacolin K, dehydromonacolin L, dehydromonacolin N, dihydromonacolin K, dihydromonacolin L, dihydromonacolin MV, dehydromonacolin MV2 and monacolin K ethyl ester.

[0113] In this article, unless otherwise specified, the effective amount, therapeutically effective amount and content of red yeast rice are all calculated based on the active ingredient monacolin K. Monacolin compounds have two structures: open ring and closed ring. In the present invention, the content of each monacolin compound refers to the sum of the open ring structure and the closed ring structure. The method for determining the content of monacolin K in red yeast rice is known in the prior art, for example, see: Light Industry Standard of the People's Republic of China QB / T 2847-2023 Functional Red Yeast Rice (Powder); Hao Shengyuan et al. Determination of lovastatin and lovastatin acid in red yeast rice and Zhibituo tablets by one test and multiple evaluations [J]. Chinese Journal of Experimental Traditional Chinese Medicine, 2017, 23(5):74-78; Li Xuemei et al. Determination of lovastatin and lovastatin acid in Xuezhikang Capsules by HPLC [J]. Chinese Pharmacist, 2012, 15(2): 164-166; Li Yan et al., Simultaneous determination of the contents of three monacolin components in Zhibituo tablets by HPLC, Journal of Drug Analysis, 2011, 31(2), pp. 270-273; Wang Lijuan et al., Determination of the contents of monacolin components in Xuezhikang capsules by HPLC, Chinese Journal of Convalescent Medicine, 2015, 24(5), pp. 479-481; Wen Zhongming et al., Determination of the content of red yeast rice in Zhibitai capsules, Drug Identification, 2011, 20(13), pp. 21-23. When it is clearly stated that the content of monacolin compounds is measured, the content of monacolin compounds refers to the total amount of monacolin K, monacolin L and / or dehydrated lovastatin, for example, the total amount of monacolin K and monacolin L and / or dehydrated lovastatin, more particularly the total amount of monacolin K, monacolin L and dehydrated lovastatin, which can be measured, for example, by referring to the method reported in the literature (Li Yan et al., Simultaneous determination of the contents of three monacolin components in Zhibituo tablets by HPLC, Journal of Drug Analysis, 2011, 31(2), pp. 270-273; Wang Lijuan et al., Determination of the content of monacolin components in Xuezhikang capsules by HPLC, Chinese Journal of Convalescent Medicine, 2015, 24(5), pp. 479-481). It should also be understood that the various embodiments of red yeast rice measured in monacolin K in the following text can also be replaced by measuring in monacolin compounds without affecting the technical effects of the present invention.

[0114] Monacolin K synthesized by microbial fermentation is an open-ring structure, but in the subsequent drying and storage process, the open-ring structure of monacolin K will be converted into a closed-ring structure. The efficacy of the open-ring structure of monacolin K is twice that of the closed-ring structure. As early as 2003, Zhu Hua et al. (Zhu Hua, Xu Ganrong, Chen Yun. Determination of acid and lactone monacolin K in red yeast rice by HPLC [J]. Journal of Wuxi University of Light Industry, 2003, 22(3): 46-52.) published a paper using high performance liquid chromatography (HPLC) to simultaneously detect open-ring and closed-ring monacolin K. The monacolin K detection method in the "Functional Red Yeast Rice (Powder)" standard issued by the light industry also detects two structures at the same time.

[0115] A first aspect of the present invention provides a pharmaceutical combination comprising probucol and red yeast rice.

[0116] In some embodiments, the drug combination comprises a therapeutically effective amount of probucol and a therapeutically effective amount of red yeast rice. In some embodiments, the therapeutically effective amount of probucol is from about 10 mg to about 1000 mg. In some embodiments, the therapeutically effective amount of probucol is from about 20 mg to about 800 mg. In some embodiments, the therapeutically effective amount of probucol is from about 20 mg to about 400 mg. In some embodiments, the therapeutically effective amount of probucol is from about 40 mg to about 400 mg. In some embodiments, the therapeutically effective amount of probucol is from about 62.5 mg to about 375 mg. In some embodiments, the therapeutically effective amount of probucol is from about 62.5 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 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275mg, 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.

[0117] In some embodiments, the pharmaceutical combination comprises a therapeutically effective amount of red yeast rice. In some embodiments, the therapeutically effective amount of red yeast rice is about 2 mg to about 50 mg. In some embodiments, the therapeutically effective amount of red yeast rice is about 3 mg to about 40 mg. In some embodiments, the therapeutically effective amount of red yeast rice is about 5 mg to about 35 mg. In some embodiments, the therapeutically effective amount of red yeast rice is about 7 to about 30 mg. In some embodiments, the therapeutically effective amount of red yeast rice is about 7 to about 20 mg. In some embodiments, the therapeutically effective amount of red yeast rice is, for example, about 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 5 mg, 6 mg, 7 mg, 7.5 mg, 8 mg, 8.3 mg, 9 mg, 10 mg, 10 .5 mg, 11 mg, 12 mg, 12.5 mg, 13 mg, 14 mg, 15 mg, 16 mg, 16 .6 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 24.9 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 33.2 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg or 50 mg.

[0118] Any weight of the therapeutically effective amount of probucol within the above range and any weight of the therapeutically effective amount of red yeast rice within the above range may constitute the pharmaceutical composition mentioned in the present invention.

[0119] In some embodiments, the pharmaceutical combination comprises a therapeutically effective amount of probucol and a therapeutically effective amount of red yeast rice, wherein the therapeutically effective amount ratio of probucol to red yeast rice is about (1-100): 1. In some embodiments, the therapeutically effective amount ratio of probucol to red yeast rice is about (1.5-75): 1. In some embodiments, the therapeutically effective amount ratio of probucol to red yeast rice is about (5-40): 1. In some embodiments, the therapeutically effective amount ratio of probucol to red yeast rice is about (6-20): 1. In some embodiments, the therapeutically effective amount ratio of probucol to red yeast rice is about (7-15): 1. In some embodiments, the therapeutically effective amount ratio of probucol to red yeast rice is about 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 25:1, 30:1, 35:1, or 40:1.

[0120] In some embodiments, the pharmaceutical combination comprises about 20 to about 800 mg of probucol and about 2 to about 50 mg of red yeast rice. In some embodiments, the pharmaceutical combination comprises about 20 to about 400 mg of probucol and about 2 to about 50 mg of red yeast rice. In some embodiments, the pharmaceutical combination comprises about 20 to about 400 mg of probucol and about 3 to about 40 mg of red yeast rice. In some embodiments, the pharmaceutical combination comprises about 40 to about 400 mg of probucol and about 5 to about 35 mg of red yeast rice. In some embodiments, the pharmaceutical combination comprises about 62.5 to about 375 mg of probucol and about 5 to about 35 mg of red yeast rice. In some embodiments, the pharmaceutical combination comprises about 62.5 to about 250 mg of probucol and about 7 to about 30 mg of red yeast rice. In some embodiments, the pharmaceutical combination comprises about 62.5 mg of probucol and about 7 mg of red yeast rice. In some embodiments, the pharmaceutical combination comprises about 62.5 mg of probucol and about 8 mg of red yeast rice. In some embodiments, the pharmaceutical combination comprises about 62.5 mg of probucol and about 10 mg of red yeast rice. In some embodiments, the pharmaceutical combination comprises about 62.5 mg of probucol and about 12 mg of red yeast rice. In some embodiments, the pharmaceutical combination comprises about 62.5 mg of probucol and about 17 mg of red yeast rice. In some embodiments, the pharmaceutical combination comprises about 62.5 mg of probucol and about 20 mg of red yeast rice. In some embodiments, the pharmaceutical combination comprises about 125 mg of probucol and about 7 mg of red yeast rice. In some embodiments, the pharmaceutical combination comprises about 125 mg of probucol and about 8 mg of red yeast rice. In some embodiments, the pharmaceutical combination comprises about 125 mg of probucol and about 10 mg of red yeast rice. In some embodiments, the pharmaceutical combination comprises about 125 mg of probucol and about 12 mg of red yeast rice. In some embodiments, the pharmaceutical combination comprises about 125 mg of probucol and about 17 mg of red yeast rice. In some embodiments, the pharmaceutical combination comprises about 125 mg of probucol and about 20 mg of red yeast rice. In some embodiments, the pharmaceutical combination comprises about 250 mg of probucol and about 7 mg of red yeast rice. In some embodiments, the pharmaceutical combination comprises about 250 mg of probucol and about 8 mg of red yeast rice. In some embodiments, the pharmaceutical combination comprises about 250 mg of probucol and about 10 mg of red yeast rice. In some embodiments, the pharmaceutical combination comprises about 250 mg of probucol and about 12 mg of red yeast rice. In some embodiments, the pharmaceutical combination comprises about 250 mg of probucol and about 17 mg of red yeast rice.In some embodiments, the pharmaceutical combination comprises about 250 mg of probucol and about 20 mg of red yeast rice.

[0121] In some embodiments, probucol and red yeast rice are provided in separate preparations, respectively. In some embodiments, probucol is provided in the form of probucol tablets. In some embodiments, red yeast rice is provided in the form of tablets (including dispersible tablets), granules, capsules or pills, preferably tablets or capsules. The tablets, granules, capsules or pills contain a certain amount of red yeast rice, so that the tablets or capsules contain 0.2-5 wt% of monacolin K, wherein the weight ratio of closed-loop monacolin K to open-loop monacolin K can be (100: 1) to (1: 100), for example (50: 1) to (1: 50), or (15: 1) to (1: 15), or (1: 1) to (1: 15). The tablets or capsules can be provided in the form of Chinese patent medicine Zhibitai capsules, Zhibituo capsules, Zhibitai tablets, Xuezhikang capsules, and Xuezhikang tablets.

[0122] In some embodiments, probucol and red yeast rice are provided in a single composition, for example, in a single tablet, capsule, granule, pellet, or micropellet.

[0123] The second aspect of the present invention provides a pharmaceutical composition comprising probucol, red yeast rice and a pharmaceutically acceptable carrier.

[0124] In some embodiments, the pharmaceutical composition comprises about 0.1 wt %-99.5 wt % of the active ingredient (i.e., probucol and red yeast rice), preferably about 0.5 wt %-99.5 wt %, more preferably about 1 wt %-50 wt %, for example, about 1 wt %, about 1.5 wt %, about 2 wt %, about 5 wt %, about 10 wt %, about 15 wt %, about 20 wt %, about 25 wt %, about 30 wt % or about 50 wt % of the active ingredient. In some embodiments, the weight ratio of probucol to red yeast rice in the pharmaceutical composition is about (1-100): 1, for example, about (1.5-75): 1, (5-40): 1, (6-20): 1, (7-15): 1, 5: 1, 6: 1, 7: 1, 8: 1, 9: 1, 10: 1, 11: 1, 12: 1, 13: 1, 14: 1, 15: 1, 16: 1, 17: 1, 18: 1, 19: 1, 20: 1, 25: 1, 30: 1, 35: 1 or 40: 1. 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, excipients, fillers, binders, wetting agents, disintegrants, lubricants, colorants, fragrances, absorption promoters, surfactants, adsorption carriers, etc. in the pharmaceutical field.

[0125] In some embodiments, the pharmaceutical composition is prepared into a pharmaceutically acceptable dosage form. For example, in some embodiments, probucol and red yeast rice (e.g., red yeast rice extract) 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 (e.g., 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, suspended granules, enteric-coated granules, sustained-release granules, controlled-release granules, effervescent granules, etc.), pills, micropills, etc.), liquid dosage forms (e.g., but not limited to solutions, syrups, suspensions, emulsions, etc.), etc.

[0126] In some embodiments, the pharmaceutical composition is presented as a unit dosage form suitable for oral administration. For example, tablets, capsules or granules, 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 red yeast rice and a pharmaceutically acceptable carrier.

[0127] In some embodiments, the pharmaceutical composition is an oral unit dosage form containing a therapeutically effective amount of probucol and red yeast rice. 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 62.5 mg to about 375 mg, about 62.5 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 red yeast rice in the oral unit dosage form can vary in the range of about 2 mg to about 50 mg, such as about 3 mg to about 40 mg, about 5 mg to about 35 mg, about 7 mg to about 30 mg, or about 7 mg to about 20 mg. In some embodiments, the oral unit dosage form contains about 20 mg to about 800 mg of probucol and about 2 mg to about 50 mg of red yeast rice. In some embodiments, the oral unit dosage form contains about 20 mg to about 400 mg of probucol and about 2 mg to about 50 mg of red yeast rice. In some embodiments, the oral unit dosage form contains about 20 mg to about 400 mg of probucol and about 3 mg to about 40 mg of red yeast rice. In some embodiments, the oral unit dosage form contains about 40 mg to about 400 mg of probucol and about 5 mg to about 35 mg of red yeast rice. 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 35 mg of red yeast rice. In some embodiments, the oral unit dosage form contains about 62.5 mg to about 250 mg of probucol and about 7 mg to about 30 mg of red yeast rice. In some embodiments, the oral unit dosage form contains 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 and about 2.5 mg, about 3.5 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 10 mg, about 12 mg, about 16 mg, or about 20 mg of red yeast rice.

[0128] The third aspect of the present invention provides a drug kit comprising a first pharmaceutical composition containing probucol and a second pharmaceutical composition containing red yeast rice.

[0129] 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 red yeast rice in an amount of about 2 mg to about 50 mg. 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 800 mg, and the second pharmaceutical composition comprises red yeast rice in an amount of about 2 mg to about 50 mg. 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 red yeast rice in an amount of about 2 mg to about 50 mg. 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 red yeast rice in an amount of about 3 mg to about 40 mg. 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 red yeast rice in an amount of about 5 mg to about 35 mg. 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 62.5 mg to about 375 mg, and the second pharmaceutical composition comprises red yeast rice in an amount of about 5 mg to about 35 mg. 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 62.5 mg to about 250 mg, and the second pharmaceutical composition comprises red yeast rice in an amount of about 7 mg to about 30 mg. 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 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, and the second pharmaceutical composition comprises red yeast rice in an amount of about 2.5 mg, about 3.5 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 10 mg, about 12 mg, about 16 mg, or about 20 mg.

[0130] In some embodiments, probucol and red yeast rice are provided as a single composition in a medicine box. In some embodiments, the medicine box comprises a pharmaceutical composition comprising probucol, red yeast rice 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, and the oral unit dosage form comprises 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 62.5 mg to about 375 mg or about 62.5 mg to about 250 mg of probucol, and about 2 mg to about 50 mg, about 3 mg to about 40 mg, about 5 mg to about 35 mg, about 7 mg to about 30 mg or about 7 mg to about 20 mg of red yeast rice. In some embodiments, the pharmaceutical composition is an oral unit dosage form, and the oral unit dosage form is as defined in the aforementioned second aspect.

[0131] 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.

[0132] The fourth aspect of the present invention provides the use of probucol and red yeast rice in preparing a medicament for treating hyperlipidemia.

[0133] A fifth aspect of the present invention provides a pharmaceutical combination comprising probucol and red yeast rice or a pharmaceutical composition comprising probucol, red yeast rice and a pharmaceutically acceptable carrier for use in treating hyperlipidemia.

[0134] A sixth aspect of the present invention provides a method for treating hyperlipidemia 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 red yeast rice.

[0135] In some embodiments, the hyperlipidemia is hypertriglyceridemia.

[0136] In some embodiments, the hyperlipidemia is severe hypertriglyceridemia.

[0137] In some embodiments, the hyperlipidemia is (severe) hypercholesterolemia.

[0138] In some embodiments, the hyperlipidemia is fibrate-intolerant or non-responsive hyperlipidemia.

[0139] In some embodiments, the hyperlipidemia is hyperlipidemia that is ineffective or ineffectively treated with statins and / or red yeast rice.

[0140] In some embodiments, probucol and red yeast rice are administered to a subject by an oral route. In some embodiments, probucol and red yeast rice are administered to a subject orally in the form of tablets. In some embodiments, probucol and red yeast rice are administered to a subject orally in the form of capsules. In some embodiments, probucol is administered to a subject orally in the form of tablets and red yeast rice is administered to a subject orally in the form of capsules. In some embodiments, probucol is administered to a subject orally in the form of capsules and red yeast rice is administered to a subject orally in the form of tablets. In some embodiments, probucol is administered to a subject orally in the form of granules and red yeast rice is administered to a subject orally in the form of tablets.

[0141] In some embodiments, probucol is administered at a daily dose of about 20 mg to about 400 mg. In some embodiments, probucol is administered at a daily dose of about 31.25 mg to about 375 mg. In some embodiments, probucol is administered at a daily dose of about 31.25 mg to about 375 mg. In some embodiments, probucol is administered at a daily dose of about 62.5 mg to about 250 mg. In some embodiments, probucol is administered at a daily dose of 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.

[0142] In some embodiments, red yeast rice is administered at a daily dose of about 2 mg to about 50 mg. In some embodiments, red yeast rice is administered at a daily dose of about 3 mg to about 40 mg. In some embodiments, red yeast rice is administered at a daily dose of about 5 mg to about 35 mg. In some embodiments, red yeast rice is administered at a daily dose of about 7 mg to about 30 mg. In some embodiments, red yeast rice is administered at a daily dose of about 7 mg to about 20 mg. In some embodiments, red yeast rice is administered at a daily dose of about 2.5 mg, about 3.5 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 10 mg, about 12 mg, about 17 mg, or about 20 mg.

[0143] In some embodiments, probucol and red yeast rice are administered to the subject simultaneously. In some embodiments, probucol and red yeast rice are each administered to the subject simultaneously with a separate preparation, and the dosing interval is 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 red yeast rice is administered to the subject in a single or multiple doses. In some embodiments, probucol and red yeast rice are administered to the subject once a day (QD) simultaneously. In some embodiments, probucol and red yeast rice are administered to the subject twice a day (BID) simultaneously. In some embodiments, probucol and red yeast rice are administered simultaneously for no less than 7 days. In some embodiments, probucol and red yeast rice are administered simultaneously for about 14 days. In some embodiments, probucol and red yeast rice are administered simultaneously for about 28 days. In some embodiments, probucol and red yeast rice are administered simultaneously for about 56 days. In some embodiments, probucol and red yeast rice are administered for a long time.

[0144] Beneficial Effects of the Invention The main beneficial effects of the present invention include the following aspects: (1) The drug combination of the present invention has an unexpected effect in treating severe hypertriglyceridemia. Probucol alone has no effect on lowering triglycerides, and red yeast rice alone has no efficacy in treating severe hypertriglyceridemia. The present invention uses a small dose of probucol (e.g., 12.5%-25% of the conventional dose) in combination with red yeast rice to quickly and effectively lower triglycerides in severe hypertriglyceridemia, with a reduction of about 70%, which is as effective as first-line fibrates, thereby solving the problem of no alternative effective drugs when myolysis and liver and kidney dysfunction occur after fibrate treatment in clinical practice, and provides a new treatment option for treating severe hypertriglyceridemia; (2) For patients whose LDL-C levels do not meet the target after treatment with red yeast rice / statins, the drug combination of the present invention can further reduce cholesterol (26%) and low-density lipoprotein-C (28%), which is better than the statin combined with ezetimibe recommended by the lipid management guidelines, thereby reducing the risk of cardiovascular disease; (3) The current drugs for treating severe hypertriglyceridemia, fibrates and high-dose fish oil, increase low-density lipoprotein. If severe hypertriglyceridemia is combined with cardiovascular risk, fibrates need to be combined with statins for treatment, and the combination of the two has great side effects. The drug combination of the present invention can not only significantly reduce triglycerides in severe hypertriglyceridemia, but also further reduce cholesterol and low-density lipoprotein-C. It is a broad-spectrum lipid-lowering drug that is suitable for hypertriglyceridemia and / or hypercholesterolemia, and can reduce cardiovascular risk, thus solving clinical problems; (4) In the drug combination of the present invention, probucol is used in an amount lower than its conventional dose (e.g., 25% of the conventional dose), and red yeast rice contains natural statins with less muscle toxicity and liver and kidney damage, so that the drug combination has better tolerability, lower toxic side effects, and fewer adverse reactions to long-term medication; (5) The present inventors have found that the simultaneous administration of probucol and red yeast rice produces unexpected technical effects. If taken separately, the effects of lowering severe hypertriglyceridemia and / or lowering LDL-C disappear.

[0145] The present invention also includes the following embodiments: Embodiment 1. A pharmaceutical combination comprising probucol and red yeast rice.

[0146] Embodiment 2. The pharmaceutical combination of embodiment 1, wherein red yeast rice is provided in one or more of the following forms: red yeast rice powder, functional red yeast rice powder, red yeast rice extract, and a composition containing red yeast rice.

[0147] Embodiment 3. The pharmaceutical combination of embodiment 2, wherein the red yeast rice extract or the composition containing red yeast rice is selected from Zhibituo, Zhibitai or Xuezhikang.

[0148] Embodiment 4. The pharmaceutical combination according to any one of embodiments 1 to 3, wherein the weight ratio of probucol to red yeast rice is 1:100 to 4:1, based on the weight of red yeast rice, and the content of monacolin K in red yeast rice is 0.5-5%.

[0149] Embodiment 5. The pharmaceutical combination according to any one of Embodiments 1 to 4, wherein the red yeast rice comprises monacolin compounds, the monacolin compounds including monacolin K, and optionally, monacolin L and dehydrated lovastatin.

[0150] Embodiment 6. The drug combination of Embodiment 5 is characterized in that the weight ratio of probucol to monacolin K in red yeast rice is (1-80):1.

[0151] Embodiment 7. The drug combination of Embodiment 5 is characterized in that the weight ratio of probucol to monacolin K in red yeast rice is (1-67):1.

[0152] Embodiment 8. The drug combination of Embodiment 5 is characterized in that the weight ratio of probucol to the total amount of monacolin compounds in red yeast rice is (0.8-57):1, wherein the total amount of monacolin compounds is calculated as the total amount of monacolin K, monacolin L and / or dehydrated lovastatin.

[0153] Embodiment 9. The pharmaceutical combination of embodiment 5, wherein each dosage unit comprises probucol 40-400 mg.

[0154] Embodiment 10. The pharmaceutical combination of embodiment 5, wherein each dosage unit comprises 100-3500 mg of red yeast rice in terms of weight of red yeast rice.

[0155] Embodiment 11. The pharmaceutical combination of embodiment 5, wherein each dosage unit comprises 2-55 mg of a monacolin compound, wherein the content of the monacolin compound is calculated based on the total amount of monacolin K, monacolin L and / or dehydrated lovastatin.

[0156] Embodiment 12. The pharmaceutical combination of embodiment 5, wherein each dosage unit comprises 7-55 mg of a monacolin compound, wherein the content of the monacolin compound is calculated as the total amount of monacolin K, monacolin L and dehydrated lovastatin.

[0157] Embodiment 13. A pharmaceutical composition comprising probucol and a red yeast rice active ingredient, wherein the red yeast rice active ingredient is prepared as follows: Take part of the red yeast rice and crush it into fine powder; add a certain concentration of ethanol to the remaining red yeast rice and reflux extract it twice, filter it, combine the filtrate, recover the ethanol, concentrate it to a suitable amount, and spray it into the red yeast rice fine powder to obtain the product.

[0158] Embodiment 14. A pharmaceutical composition comprising probucol and monacolin K.

[0159] Embodiment 15. The pharmaceutical composition of Embodiment 14, wherein the weight ratio of probucol to monacolin K is (1-67):1, wherein the content of monacolin K is the total weight of acid monacolin K and lactone monacolin K, and the ratio of lactone monacolin K to acid monacolin K is 1:10 to 10:1.

[0160] Embodiment 16. The pharmaceutical composition of embodiment 14 or 15, further comprising one or more compounds selected from the group consisting of monacolin L, dehydrated lovastatin, monacolin M, monacolin N1, monacolin N2, monacolin N3, monacolin N4, monacolin N5, monacolin N6, monacolin Q, monacolin R, monacolin S, monacolin T, monacolin U, monacolin X, monacolin acid A, dehydromonacolin J, dehydromonacolin K, dehydromonacolin L, dehydromonacolin N, dihydromonacolin K, dihydromonacolin L, dihydromonacolin MV, dehydromonacolin MV2 and monacolin K ethyl ester. Example

[0161] The following examples are intended to specifically illustrate the present invention and should not be construed as limiting the scope of the present invention.

[0162] Example 1: Study on the efficacy of a drug combination of probucol and red yeast rice in treating severe hypertriglyceridemia.

[0163] Treatment subjects: A total of 32 patients with severe hypertriglyceridemia received probucol and red yeast rice combination treatment, including 23 males and 9 females, aged 26-72 years. Before treatment, the patients' triglyceride levels were 5.75-22.02mmol / l, cholesterol levels were 3.43-14.08mmol / l, and low-density lipoprotein levels were 1.02-7.89mmol / l.

[0164] Dosage regimen: Probucol is administered orally with commercially available probucol tablets (125 mg / tablet) (can be taken with water or chewed), with a dosage of 62.5-312.5 mg / time, once or twice a day; red yeast rice is administered orally with the following commercially available products (can be taken with water or chewed): Zhibitai capsules (240 mg / tablet, containing approximately 9.1 mg / tablet of monacolin K), with a dosage of 240-480 mg / time, once or twice a day; Zhibituo tablets (350 mg / tablet, containing approximately 1.3 mg / tablet of monacolin K), with a dosage of 700-1050 mg / time, once or twice a day; Xuezhikang capsules (300 mg / tablet, containing approximately 3.7 mg / tablet of monacolin K), with a dosage of 300-600 mg / time, once or twice a day; natural red yeast rice (containing 0.2% monacolin K), with a dosage of 6 g / time, twice a day. Probucol and red yeast rice were administered simultaneously for an average of 4 weeks.

[0165] Treatment results: After patients were treated with different doses of probucol and red yeast rice, plasma triglycerides decreased by 34-75% (calculated as the average value of each dosing group, the same below), and the average decreased by 69% (calculated as the average value of all patients, the same below); cholesterol decreased by 12-55%, and the average decreased by 43%; low-density lipoprotein decreased by 18-47%, and the average decreased by 29%. The specific results are shown in Table 1 below.

[0166] Table 1 Treatment results of probucol combined with red yeast rice Dosage regimen Triglyceride before treatment (mmol / L) Triglyceride after treatment (mmol / L) reduce% Cholesterol before treatment (mmol / L) Cholesterol after treatment (mmol / L) reduce% Low-density lipoprotein before treatment (mmol / L) Low-density lipoprotein after treatment (mmol / L) reduce% Number of cases Probucol 62.5mg + Zhibitai 240mg, BID 6.58 3.17 52 5.13 3.92 24 2.62 2.16 18 1 Probucol 125mg + Zhibitai 240mg, BID 12.91 3.32 74 7.08 3.87 45 2.69 2.14 20 7 Probucol 125mg + Zhibitai 480mg, QD 6.20 2.21 64 4.98 3.58 28 2.52 1.79 29 2 Probucol 312.5mg + Zhibitai 240mg, BID 6.32 4.15 34 4.31 3.78 12 2.23 1.54 31 2 Probucol 62.5mg + Zhibitai 480mg, BID 7.73 4.30 44 7.39 4.73 36 3.85 2.52 35 2 Probucol 125mg + Zhibitai 480mg, BID 11.27 2.80 75 9.52 5.24 45 5.32 3.14 41 3 Probucol 250mg + Zhibitai 480mg, BID 8.13 3.28 60 6.97 3.63 48 3.41 1.80 47 3 Probucol 62.5mg + Diprotocol 700mg, BID 16.01 5.21 67 6.51 3.32 49 1.83 1.19 35 1 Probucol 125mg + Diprotocol 1050mg, BID 13.16 3.27 75 7.88 3.56 55 2.38 1.84 23 5 Probucol 125mg + Xuezhikang 600mg, BID 10.77 2.70 75 5.25 3.66 30 2.23 1.82 18 3 Probucol 125mg + natural red yeast rice 6g, BID 8.55 3.3 61 5.66 3.37 40 2.45 1.68 31 3 total 10.48 3.30 69 6.75 3.88 43 2.89 2.06 29 32 Side effect evaluation: No side effects such as increased muscle enzymes, abnormal liver function, and increased creatinine were observed in all treated patients during the treatment period.

[0167] Compared with 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, compared with fibrates and high-dose fish oil that increase low-density lipoprotein, the drug combination of the present invention can also reduce cholesterol and low-density lipoprotein-C at the same time. See Table 2 below.

[0168] Table 2 Comparison of the efficacy of the combination of probucol and red yeast rice with other drugs for the treatment of severe hypertriglyceridemia Lipid-lowering drugs Triglycerides cholesterol LDL-C Probucol-Red Yeast Combination 4 Weeks Down 69% Down 43% Down 29% <![CDATA[Fenofibrate for 8 weeks (Lipanthyl) a > Down 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% <![CDATA[(China) High-dose fish oil for 12 weeks c > Down 29.5% Down 6.9% Up 12.7% <![CDATA[(Abroad) High-dose fish oil for 16 weeks c > Down 44.9% Down 9.7% Up 44.5% Data sources: a. Liping instructions; b. TriglycerideLoweringDrugs. (https: / / pubmed.ncbi.nlm.nih.gov / 28402615 / ). c. ω3 fatty acid ethyl ester 90 soft capsule instructions.

[0169] Typical case 1: The patient is a 62-year-old female with hypertension, diabetes, hyperlipidemia, and a family history of severe hypertriglyceridemia. Ten years ago, severe hypertriglyceridemia induced pancreatitis, leaving behind complications of diabetes. Because triglycerides reached 22.68mmol / L, cholesterol was 9.75mmol / L, and low-density lipoprotein cholesterol was 5.7mmol / L, fenofibrate was taken at 0.2 grams per day. After 3, 6, and 8 weeks, triglycerides dropped to 6.57mmol / L, 8.35mmol / L, and 6.12mmol / L, respectively. During the period, liver function and muscle enzyme monitoring were basically stable. After 14 weeks of treatment, creatine kinase was 4402U / L, myoglobin was greater than 3000ng / ml, triglycerides were 13.14mmol / L, aspartate aminotransferase and alanine aminotransferase were elevated, and renal function did not change. After discontinuation of fenofibrate, myoenzyme returned to normal, but triglycerides were still high at 16.58mmol / L. Statin treatment was tried, but triglycerides did not decrease and myoenzyme increased again. Statin treatment was stopped. Because cholesterol was 10.32mmol / l and probucol had low side effects of liver and kidney damage, probucol was given 0.5 grams each time, twice a day. Liver function and myoenzyme were stable, but triglycerides continued to increase. However, fibrate and statin treatment could not be continued. During this period, intermittent pain and claudication in both lower limbs gradually developed into continuous pain and inability to walk. The skin of both lower limbs gradually turned cyanotic, the skin temperature increased, and heparin anticoagulation treatment could not relieve it. B-ultrasound of the lower limb arteries showed multiple plaques, complete occlusion of most blood vessels, and severe stenosis in a small part. Therefore, he received a low-dose red yeast rice and probucol combination treatment, 0.125 grams of probucol and 0.24 grams of Zhibitai each time, twice a day. After 14 days of treatment, triglycerides dropped from 22.02mmol / L to 4.57mmol / L, lower limb pain and cyanosis quickly relieved and disappeared, and he gradually recovered after 1 month. After 4 months of treatment, B-ultrasound was rechecked, and only one artery was completely occluded, and the remaining stenosis was significantly relieved. During the treatment, the monitoring of muscle enzymes and liver function indicators was stable. Blood lipids are stable at a low level. In the following years, the patient has been receiving red yeast rice and probucol combination treatment, liver function gradually returned to normal, muscle enzymes were normal, triglyceride levels fluctuated between 1.5-4mmol / L, no cardiovascular and cerebrovascular events occurred, no pain in both lower limbs, normal lower limb activity, and normal electrocardiogram QT interval.

[0170] Surprisingly, it was found that the combination of probucol and red yeast rice had an excellent therapeutic effect on severe hypertriglyceridemia, particularly when the daily dose of 480 mg of Zhibitai was used, the therapeutic effect of a daily dose of 125 mg of probucol (2 groups: 62.5 mg of probucol + 240 mg of Zhibitai, BID, and 125 mg of probucol + 480 mg of Zhibitai, QD) was significantly higher than the therapeutic effect of a daily dose of 625 mg of probucol (312.5 mg of probucol + 240 mg of Zhibitai, BID).

[0171] Example 2: Study on the efficacy of a drug combination of probucol and red yeast rice in treating hypercholesterolemia.

[0172] Treatment subjects: A total of 28 patients with hypercholesterolemia received probucol and red yeast rice combination therapy, including 16 males and 12 females, aged 27-78 years, with an average age of 56.54±11.74 years. These cases included patients who had received statin therapy, patients who had received statin therapy combined with cholesterol absorption inhibitors, patients who had received statin therapy combined with PCSK9 monoclonal antibody therapy, and patients who had received statin therapy combined with cholesterol absorption inhibitors and PCSK9 monoclonal antibody therapy. These cases also included patients with familial hypercholesterolemia and patients with familial severe hypercholesterolemia.

[0173] Dosage regimen: Probucol is administered orally in the form of commercially available probucol tablets (125 mg / tablet) (which can be taken with water or chewed), with a dosage of 62.5-250 mg / time, once or twice a day; red yeast rice is administered orally in the form of the following commercially available Chinese patent medicines (which can be taken with water or chewed): Zhibitai capsules (240 mg / tablet, containing approximately 9.1 mg / tablet of monacolin K), with a dosage of 240-480 mg / time, once or twice a day; Xuezhikang tablets (400 mg / tablet, containing approximately 3.7 mg / tablet of monacolin K), with a dosage of 1200-2400 mg / time, once or twice a day; probucol and red yeast rice are administered simultaneously for 7-97 days.

[0174] Treatment results: After patients were treated with different doses of probucol and red yeast rice, their plasma cholesterol levels dropped by 40-45%, low-density lipoprotein dropped by 45-55%, and plasma triglycerides dropped by 22-49%. See Table 3 for specific results.

[0175] Table 3 Treatment results of probucol combined with red yeast rice Dosage regimen Cholesterol before treatment (mmol / L) Cholesterol after treatment (mmol / L) reduce% Triglyceride before treatment (mmol / L) Triglyceride after treatment (mmol / L) reduce% Low-density lipoprotein before treatment (mmol / L) Low-density lipoprotein after treatment (mmol / L) reduce% Number of cases Probucol 125mg + Zhibitai 240mg, BID 7.29 4.27 41 2.33 1.69 28 4.84 2.36 51 9 Probucol 250mg + Zhibitai 480mg, BID 8.34 4.62 45 2.85 2.22 22 5.58 2.50 55 7 Probucol 250mg + Zhibitai 480mg, QD 6.92 4.18 40 2.32 1.82 22 4.09 2.25 45 2 Probucol 62.5mg + Zhibitai 240mg, BID 6.28 3.73 41 4.43 2.25 49 3.56 1.8 49 1 Probucol 125mg + Xuezhikang 600mg, BID 7.75 4.48 42 2.25 1.57 30 4.77 2.55 47 9 total 7.64 4.4 42 2.51 1.82 27 4.90 2.43 50 28 Side effect evaluation: No side effects such as increased muscle enzymes, abnormal liver function, and increased creatinine were observed in all treated patients during the treatment period.

[0176] Compared with other drugs for treating hypercholesterolemia: Compared with probucol alone and red yeast rice alone at normal doses, the low-dose drug combination of the present invention can reduce cholesterol and low-density lipoprotein-C to a greater extent. Long-term use can reduce cholesterol by 40-45% (calculated as the average value of the values ​​of each dosing group, the same below), an average of 42% (calculated as the average value of all patients, the same below); low-density lipoprotein-C is reduced by 45-55% (calculated as the average value of the values ​​of each dosing group, the same below), an average of 50% (calculated as the average value of all patients, the same below), and plasma triglycerides are reduced by 22-49%, an average of 27%, which is significantly greater than the single sufficient dose of probucol, Zhibitai and Xuezhikang, and the effect is better than statins. See Table 4 below.

[0177] Table 4 Comparison of the efficacy of the combination of probucol and red yeast rice with other drugs for the treatment of hypercholesterolemia drug Triglycerides cholesterol LDL-C Probucol-Red Yeast Rice Combination Down 27% Down 42% 50% decrease <![CDATA[Probucol a > - Decrease of 9-29% 10-15% decrease <![CDATA[Zhibitai b > Down 30.3% Down 23.5% Down 18.9% <![CDATA[Xuezhikang b > Down 30.3% Down 18.8% Down 18.4% <![CDATA[20 mg atorvastatin (Lipitor) for 6 weeks c > Down 26% Down 33% Down 43% <![CDATA[10 mg Rosuvastatin (Crestor) for 12 weeks d > 10% decrease Down 36% Down 52% Data sources: a. Li Jiatai, Clinical Pharmacology (3rd Edition), People's Medical Publishing House, pp. 1530-1531; b. China Heart Alliance, Chinese Expert Consensus on the Clinical Application of Zhibitai Capsules, Chinese Journal of Internal Medicine, 2017, Vol. 56, No. 8, pp. 628-631; c. Lipitor instructions; d. Keding instructions.

[0178] Example 3: Study on the changes in blood lipids after changing the combination therapy (i.e., combining with a low-dose of probucol) based on the original red yeast rice treatment.

[0179] Treatment subjects: 23 patients with hyperlipidemia who had taken red yeast rice for more than 8 weeks, 11 males and 12 females, aged 29-77 years old, continued treatment with low-dose probucol because their low-density lipoprotein and / or triglycerides were not up to standard.

[0180] Dosage regimen: Probucol is administered orally with commercially available probucol tablets (125 mg / tablet) (can be taken with water or chewed), with a dosage of 62.5-250 mg / time, once or twice a day; red yeast rice is administered with Zhibitai capsules (240 mg / capsule, containing approximately 9.1 mg / capsule of monacolin K), with a dosage of 240 mg / time, once or twice a day. Probucol and red yeast rice are taken at the same time, and the treatment duration is 7 weeks.

[0181] Treatment results: After patients were treated with different doses of probucol combined with red yeast rice, plasma cholesterol levels dropped by 22-25%, with an average of 24%; low-density lipoprotein levels dropped by 27-34%, with an average of 27%; the extent of further reduction in LDL-C was better than that of statins combined with ezetimibe (18%-20%). See Table 5 below for specific results.

[0182] Table 5 Changes in blood lipids after the original red yeast rice treatment combined with probucol Dosage regimen Cholesterol before treatment (mmol / L) Cholesterol after treatment (mmol / L) reduce% Triglyceride before treatment (mmol / L) Triglyceride after treatment (mmol / L) reduce% Low-density lipoprotein before treatment (mmol / L) Low-density lipoprotein after treatment (mmol / L) reduce% Number of cases Probucol 125mg + Zhibitai 240mg, BID 6.05 4.55 25 2.62 2.05 22 3.62 2.66 27 20 Probucol 62.5mg + Zhibitai 240mg, BID 4.8 3.76 22 2.21 1.81 18 2.98 1.97 34 3 total 5.88 4.45 24 2.57 2.02 21 3.54 2.57 27 Example 4: Study on the efficacy of a drug combination of probucol and red yeast rice in treating hypercholesterolemia at double the dose.

[0183] Treatment subjects: Two patients with hypercholesterolemia were treated with a combination of probucol and red yeast rice, including one male and one female, aged 55-60 years.

[0184] Dosage scheme: Probucol was orally administered in the form of commercially available probucol tablets (125 mg / tablet), with a dosage of 125 or 250 mg / time, twice a day; red yeast rice was administered in the form of Zhibitai capsules (240 mg / tablet, containing approximately 9.1 mg / tablet of monacolin K), with a dosage of 240 or 480 mg / time, twice a day; probucol and red yeast rice were administered simultaneously. First, the low dose shown in Table 6 was administered for a period of time (more than 6 weeks), and then the doubled dose in Table 6 (the doubled dose was twice the original dose) was administered for a period of time (5-12 weeks).

[0185] Table 6 Efficacy of the combination of probucol and red yeast rice at double the dose Zhibitai (g / time, bid) Probucol (mg / time, bid) LDL-C before treatment (mmol / L) LDL-C after treatment (mmol / L) Decline TC before treatment (mmol / L) TC after treatment (mmol / L) TG before treatment (mmol / L) TG after treatment (mmol / L) 0.24 125 2.45 1.66 5.07 3.91 8.22 7.07 0.48 250 0.87 Down 32% 2.65 4.19 0.24 125 5.57 4.17 7.82 6.99 2.05 1.96 0.48 250 2.28 Down 34% 4.05 1.85 Results: The results showed that in the treatment of hyperlipidemia, by administering probucol and red yeast rice simultaneously, at a low dose of probucol, when the dose of red yeast rice was doubled, a significant reduction in LDL-C of more than 6% could be achieved.

[0186] Example 5: Study on the difference between small and large doses of probucol and red yeast rice, taken separately and taken simultaneously.

[0187] Typical case 1: Female, 64 years old, ASCVD patient, cholesterol 5.79mmol / L; LDL-C 3.93mmol / L; triglycerides 2.07mmol / L. The doctor ordered to take 125mg of probucol and 0.24g of Zhibitai together, twice a day, and the patient took it according to the dosage instructions, 500mg of probucol and 0.24g of Zhibitai together each time, after 10 weeks, the cholesterol was 4.81mmol / L; LDL-C 2.92mmol / L, triglycerides 2.63mmol / L, resumed the original dosage, after 8 weeks, the cholesterol was 4.19mmol / L; LDL-C 1.99mmol / L; triglycerides 1.87mmol / L. Results: Comparing the results of the three tests, increasing the dose of probucol in the combination and taking them simultaneously decreased the extent of LDL-C reduction, which is contrary to the common sense that the incremental effect of combining two cholesterol-lowering drugs should be enhanced. The therapeutic response of the combination to cholesterol is consistent with its response to severe hypertriglyceridemia.

[0188] Typical case 2: Female, 75 years old, ASCVD patient, cholesterol 5.73mmol / L; triglycerides 1.55mmol / L; LDL-C 3.22mmol / L. Treatment: The doctor ordered 125mg of probucol and 0.24g of Zhibitai to be taken together, twice a day, but in fact the patient thought that Chinese and Western medicines should be taken separately. After 5 weeks, the cholesterol was 5.74mmol / L; triglycerides 1.66mmol / L; LDL-C 3.47mmol / L. After 8 weeks of taking the medicine together, the cholesterol was 3.69mmol / L; triglycerides 1.24mmol / L; LDL-C 2.13mmol / L.

[0189] Results: The same dose of probucol and Zhibitai was used to observe the difference between taking them separately and taking them at the same time. Separating them was ineffective. Increasing the dose of probucol, although still taking them together, had poor effects on reducing severe hypertriglyceridemia and LDL-C. Although red yeast rice and probucol are commonly used drugs for lowering blood lipids, there has been no unexpected effect of taking them at low doses together. There are two reasons for this. First, it is customary to take Chinese and Western medicines separately. Second, if cholesterol is to be lowered, it is common sense to increase the dose.

[0190] Example 6: Other treatment cases of the drug combination of probucol and red yeast rice.

[0191] Case B1: male, 36 years old, severe hypertriglyceridemia, probucol 312.5 mg + Zhibitai 0.24 g (taken together), BID, 3 weeks. Case B2: female, 67 years old, ASCVD, probucol 312.5 mg + Zhibitai 0.24 g, BID (taken together), 2 weeks. The treatment results of the above cases B1-B2 are shown in Table 7.

[0192] Table 7: Efficacy of combined use of probucol in specific cases Case Triglyceride before administration (mmol / L) Triglyceride after administration (mmol / L) reduce% Cholesterol before administration (mmol / L) Cholesterol after administration (mmol / L) reduce% Low-density lipoprotein before administration (mmol / L) Low-density lipoprotein after administration (mmol / L) reduce% B1 5.6 4.09 27 4.54 4.20 8 2.36 2.21 6 B2 4.03 2.27 44 5.70 4.63 19 3.32 2.49 25 Example 7: Examples of other administration routes.

[0193] Other case 1: male patient, 72 years old, ASCVD patient, history of elevated creatinine enzymes with statin therapy, cholesterol 5.94mmol / L, triglycerides 1.25mmol / L, LDL-C 2.98mmol / L, medication: probucol 0.5g BID, ezetimibe 20mg QD, 6 weeks later, cholesterol 4.21mol / L, triglycerides 1.22mmol / L, LDL-C 1.76mmol / L; and Other case 2: Female patient, 66 years old, ASCVD patient, history of elevated transaminases while taking statins, cholesterol was 7.21mmol / L; triglycerides were 3.11mmol / L; LDL-C was 4.85mmol / L, she took 0.24g BID of statin and 1g BID of fish oil, after 8 weeks, cholesterol was 5.33mol / L; triglycerides were 1.96mmol / L; LDL-C was 2.99mmol / L.

[0194] 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.

[0195] 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. A drug combination, characterized in that The drug combination comprises probucol and red yeast rice; probucol and red yeast rice are configured to be administered simultaneously.

2. The drug combination according to claim 1, characterized in that The form of simultaneous administration is in the form of an oral unit dosage form, which contains 20-400 mg of probucol and 2-50 mg of red yeast rice, wherein the weight of the red yeast rice is calculated as the active substance monacolin K.

3. The drug combination according to claim 2, characterized in that The oral unit dosage form is selected from tablets, capsules, granules, pellets, and micropills.

4. The drug combination according to claim 2, characterized in that The oral unit dosage forms include 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, 130 135 mg mg, 245 mg, 250 375 mg, 380 mg, 385 mg, 390 mg, 395 mg or 400 mg of probucol and 3-40 mg, 5-35 mg, 7-30 mg or 7-20 mg of red yeast rice, the weight of which is calculated as the active ingredient monacolin K.

5. The drug combination according to claim 2, characterized in that The oral unit dosage form comprises: Probucol as an active ingredient in an amount of 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, and 3-40 mg, 5-35 mg, 7-30 mg, or 7-20 mg of red yeast rice, wherein the weight of the red yeast rice is calculated as the active substance monacolin K.

6. The pharmaceutical combination according to claim 3, 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 red yeast rice and a pharmaceutically acceptable carrier thereof.

7. The pharmaceutical combination according to claim 1, characterized in that The form of simultaneous administration is in the form of a medicine kit, which contains probucol and red yeast rice, and probucol and red yeast rice are provided in the form of a single composition in the medicine kit, wherein the single composition contains 20-400 mg of probucol and 2-50 mg of red yeast rice, and the weight of the red yeast rice is calculated as the active substance monacolin K.

8. The pharmaceutical combination according to claim 7, characterized in that The single composition contains 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, 130 135 mg mg, 240mg, 245 mg, 250 mg, 255 390 mg, 395 mg or 400 mg of probucol and 3-40 mg, 5-35 mg, 7-30 mg or 7-20 mg of red yeast rice, the weight of which is calculated as the active ingredient monacolin K.

9. The pharmaceutical combination according to claim 1, characterized in that The simultaneous administration is in the form of a medicine kit, which includes 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 red yeast rice, the first medicine composition comprising 20-400 mg of probucol, the second medicine composition comprising 2-50 mg of red yeast rice, the weight of the red yeast rice being calculated based on the active substance monacolin K, 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.

10. The pharmaceutical combination according to claim 9, characterized in that The oral unit dosage form is selected from tablets, capsules, granules, pellets, and micropills.

11. The pharmaceutical combination according to claim 9, characterized in that The first pharmaceutical composition comprises 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, 250 375 mg, 380 mg, 385 mg, 390 mg, 395 mg or 400 mg of probucol, and the second pharmaceutical composition comprises 3-40 mg, 5-35 mg, 7-30 mg, or 7-20 mg of red yeast rice, and the weight of the red yeast rice is calculated as the active substance monacolin K.

12. The pharmaceutical combination according to claim 10, 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 red yeast rice and a pharmaceutically acceptable carrier thereof.

13. The pharmaceutical combination according to any one of claims 1 to 12, characterized in that Red yeast rice is provided in one or more of the following forms: natural red yeast rice, traditional Chinese medicine red yeast rice, functional red yeast rice, red yeast rice extract and a composition containing red yeast rice.

14. The pharmaceutical combination according to claim 13, characterized in that The red yeast rice extract or the composition containing red yeast rice is selected from Zhibituo, Zhibitai or Xuezhikang.

15. The pharmaceutical combination according to claim 13, characterized in that The red yeast rice composition contains closed-ring monacolin K and open-ring monacolin K, and the total content of the two is 0.2-5 wt%.

16. The pharmaceutical combination according to claim 15, characterized in that The weight of the composition is 100 wt %, and the weight ratio of the closed-ring monacolin K to the open-ring monacolin K is (100:1) to (1:100).

17. The pharmaceutical combination according to any one of claims 1 to 12, characterized in that The red yeast rice contains monacolin compounds, and the monacolin compounds contain monacolin K, and optionally, monacolin L and dehydrated lovastatin.

18. The pharmaceutical combination according to claim 17, characterized in that The weight ratio of probucol to red yeast rice is (1-100):1, and the weight of the red yeast rice is calculated based on the active substance monacolin K.

19. Use of the pharmaceutical combination according to any one of claims 1 to 18 in the preparation of a medicament for treating hyperlipidemia in a subject in need thereof.

20. The use according to claim 19, characterized in that The hyperlipidemia is familial or non-familial hypertriglyceridemia, familial or non-familial hypercholesterolemia, or a combination.

21. The use according to claim 19, characterized in that The hyperlipidemia is a combination of hypertriglyceridemia and severe hypercholesterolemia, or a combination of severe hypertriglyceridemia and hypercholesterolemia.

22. The use according to claim 19, characterized in that The hyperlipidemia is hyperlipidemia that is ineffective or ineffective in treatment with statins and / or red yeast rice, or hyperlipidemia that is intolerant to or unresponsive to fibrates.

23. The use according to claim 19, characterized in that The hyperlipidemia is hypercholesterolemia that is ineffective or ineffectively treated with statins and / or red yeast rice, or hypercholesterolemia that is intolerant to or unresponsive to fibrates.

24. The use according to claim 19, characterized in that The hyperlipidemia is hypertriglyceridemia for which statins and / or red yeast rice are ineffective or ineffective, or hypertriglyceridemia for which fibrate drugs are intolerant or unresponsive.

25. The use according to claim 19, characterized in that The hyperlipidemia is familial or non-familial severe hypertriglyceridemia, or familial or non-familial severe hypercholesterolemia, or a combination.

26. The use according to claim 19, characterized in that The hyperlipidemia is severe hypertriglyceridemia for which statins and / or red yeast rice are ineffective or ineffective, or severe hypertriglyceridemia for which fibrates are intolerant or unresponsive.

27. The use according to claim 19, characterized in that The hyperlipidemia meets one of the following requirements (1)-(5): (1) The TG level of the subject is: TG ≥ 5.6 mmol / L; (2) 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; (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; 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)".

28. A pharmaceutical composition characterized in that The pharmaceutical composition comprises the drug combination according to any one of claims 1 and 13-18, and a pharmaceutically acceptable carrier.

29. The pharmaceutical composition according to claim 28, characterized in that The pharmaceutical composition is in the form of an oral unit dosage form, which contains 20-400 mg of probucol and 2-50 mg of red yeast rice, and the weight of the red yeast rice is calculated based on the active substance monacolin K.

30. The pharmaceutical composition according to claim 29, characterized in that The oral unit dosage form is selected from tablets, capsules, granules, pellets, and micropills.

31. The pharmaceutical composition according to claim 30, 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 red yeast rice and a pharmaceutically acceptable carrier thereof.

32. The pharmaceutical composition according to claim 29, characterized in that The oral unit dosage forms include 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, 130 135 mg mg, 245 mg, 250 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg or 400 mg g of probucol and 3-40 mg, 5-35 mg, 7-30 mg, or 7-20 mg of red yeast rice.

33. A medicine box, characterized in that The kit comprises the drug combination according to any one of claims 1 and 13-18, wherein the kit comprises probucol and red yeast rice, and probucol and red yeast rice are provided in the form of a single composition in the kit, wherein the single composition comprises 20-400 mg of probucol and 2-50 mg of red yeast rice.

34. The kit according to claim 33, characterized in that The single composition contains 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, 130 135 mg mg, 240mg, 245 mg, 250 mg, 255 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg or 400 mg of probucol and 3-40 mg, 5-35 mg, 7-30 mg, or 7-20 mg of red yeast rice.

35. A medicine box, characterized in that The medicine kit comprises the drug combination according to any one of claims 1 and 13-18, wherein the medicine kit includes one or more identical drug units isolated from the external environment, each drug unit comprises a first drug composition containing probucol and a second drug composition containing red yeast rice, the first drug composition comprises 20-400 mg of probucol, the second drug composition comprises 2-50 mg of red yeast rice, the first drug composition and the second drug composition are each in an oral unit dosage form, wherein opening each drug unit exposes the first drug composition and the second drug composition to the external environment at the same time.

36. The kit according to claim 35, characterized in that The oral unit dosage form is selected from tablets, capsules, granules, pellets, and micropills.

37. The kit according to claim 36, 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 red yeast rice and a pharmaceutically acceptable carrier thereof.

38. The kit according to claim 35, characterized in that The first pharmaceutical composition includes 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, 130 135 mg mg, 245 mg, 250 375 mg, 380 mg, 385 mg, 390 mg, 395 mg or 400 mg of probucol, and the second pharmaceutical composition comprises 3-40 mg, 5-35 mg, 7-30 mg, or 7-20 mg of red yeast rice.

39. A medicine box, characterized in that The medicine kit comprises a pharmaceutical combination according to any one of claims 1 and 13-18, comprising a first pharmaceutical composition containing probucol and a second pharmaceutical composition containing red yeast rice, wherein the first pharmaceutical composition and the second pharmaceutical composition are configured for simultaneous administration; wherein the first pharmaceutical composition comprises 20-400 mg of probucol; and the second pharmaceutical composition comprises 2-50 mg of red yeast rice, the weight of the red yeast rice being calculated as the active substance monacolin K.

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