Combination of Chinese and Western medicines for treating hyperlipidemia

Abstract

The present invention relates to a combination of Chinese and Western medicines for treating hyperlipidemia. In particular, the present invention relates to a pharmaceutical combination of probucol and red yeast rice, a pharmaceutical composition or a kit comprising probucol and red yeast rice, and the use of the pharmaceutical combination, pharmaceutical composition or kit in preparing a medicament for treating hyperlipidemia, particularly severe hypertriglyceridemia and severe hypercholesterolemia. The present invention is characterized in that the pharmaceutical combination, pharmaceutical composition or kit comprising probucol and red yeast rice comprises a small dose of probucol and red yeast rice, and the probucol and red yeast rice are configured for simultaneous administration.

Description

[0001] Citation of Related Applications

[0002] This application claims priority to Chinese patent application number 202410164129.X, filed on February 5, 2024, and entitled “Combination of Chinese and Western Medicines for Treating Severe Hypertriglyceridemia”, and Chinese patent application number 202411662173.X, filed on November 20, 2024, and entitled “Combination of Chinese and Western Medicines for Treating Hyperlipidemia”, the two Chinese patent applications are incorporated herein in their entirety. Technical Field

[0003] The present invention relates to a pharmaceutical combination of probucol and red yeast rice, a pharmaceutical composition comprising probucol and red yeast rice, and uses of the pharmaceutical combination and the pharmaceutical composition for treating hyperlipidemia, particularly severe hypertriglyceridemia and severe hypercholesterolemia. Background Art

[0004] Severe hypertriglyceridemia is a specific type of hyperlipidemia. Besides cardiovascular risks, it can also induce pancreatitis. Numerous medications are available for treating hyperlipidemia, but the number of drugs specifically for severe hypertriglyceridemia is relatively limited, with only three oral options: fibrates, high-dose fish oil omega-3, and niacin. In clinical practice, fibrates are the preferred first-line treatment, with fish oil used as an adjunct. They are slow-acting and less effective than fibrates, and niacin is even less effective. Fibrate intolerance is not uncommon, resulting in complications such as myolysis and impaired liver and kidney function. If toxic side effects occur, there are no alternatives, leading to a poor prognosis and a current clinical treatment challenge. Other treatment options include biologics and plasma adsorption, but biologics are difficult to commercialize due to side effects, while plasma adsorption is limited due to its high technical requirements, high cost, and significant side effects. Furthermore, patients with severe hypertriglyceridemia often have concurrent ASCVD risk or hypercholesterolemia, requiring concomitant statin therapy. Combining statins with fibrates can enhance toxicity and side effects. Therefore, there is an urgent clinical need for drugs or drug combinations that can replace fibrates to treat severe hypertriglyceridemia, significantly reduce low-density lipoprotein-C (LDL-C) and cholesterol, and have low side effects and good tolerance.

[0005] 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, requiring combination with other drugs. According to the 2023 Chinese Guidelines for Blood Lipid Management, when LDL-C is not up to standard after statin treatment, cholesterol absorption inhibitors (such as ezetimibe) and / or PCSK9 inhibitors should be used in combination. Statins combined with ezetimibe can further reduce LDL-C levels by 18-20% (Chinese Guidelines for Blood Lipid Management, 2023 Joint Expert Committee for the Revision of the Chinese Guidelines for Blood Lipid Management, Chinese Journal of Circulation, March 2023, Vol. 38, No. 3, pp. 237-271). Ezetimibe and statins have the side effect of liver damage, and blood lipids rebound significantly after discontinuation of ezetimibe. 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.

[0006] Furthermore, some people respond poorly to existing lipid-lowering drugs for both cholesterol and triglyceride levels, requiring a combination of two or more. These drugs are typically used at their original doses, potentially leading to increased toxicity and side effects. Therefore, there is an urgent clinical need for a lipid-lowering drug combination that offers low doses, optimal efficacy, and minimal side effects.

[0007] Probucol (also known as Probucol, Probucol, CAS No.: 23288-49-5) is a bisphenol lipid-lowering compound, and its structure is shown below:

[0008]

[0009] Probucol has minimal effect on triglycerides and is only suitable for hypercholesterolemia with high LDL. The usual dosage is 0.5 g / time, twice a day (i.e., the conventional 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, and especially lowering triglycerides (TG) in severe hypertriglyceridemia.

[0010] 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 parasitizing the mycelium of the Aspergillus fungus Monascus purpureus Went. on japonica rice. Red yeast rice has been used in my country for over 1,000 years and is widely used in traditional Chinese medicine, winemaking, and food coloring. Red yeast rice is sweet and warm in nature, and enters the liver, spleen, stomach, and large intestine meridians. It has the benefits of promoting digestion and soothing the stomach, promoting blood circulation and relieving pain, and strengthening the spleen and stomach. Red yeast rice's lipid-lowering and vascular-protective effects are well-established. The 2023 Chinese Guidelines for Blood Lipid Management list red yeast rice under the category of other lipid-lowering drugs primarily for cholesterol-lowering. The European Guidelines for Blood Lipid Management list red yeast rice as a dietary supplement for cholesterol-lowering. Red yeast rice products are currently available under the names of red yeast rice (powder / rice), functional red yeast rice (powder / rice), and red yeast rice extracts. Traditional Chinese medicines utilizing the lipid-lowering properties of red yeast rice include Zhibituo, Zhibitai, and Xuezhikang.

[0011] 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. It exists in both open-ring and closed-ring forms. The open-ring form has a hydroxy acid structure and is pharmacologically active; the closed-ring form has a lactone structure and is pharmacologically inactive, requiring conversion to the open-ring form by carboxylesterase in the body to exert its pharmacological effect. Closed-ring Monacolin K is the same compound as lovastatin, the first marketed statin. The ratio of open-ring to closed-ring Monacolin K in Zhibituo Red Yeast is approximately 1:1. Each Zhibituo tablet (0.35g) contains at least 0.85mg of lovastatin (i.e., closed-ring Monacolin K). The bioavailability of six Zhibituo tablets taken daily is slightly higher than that of a 20mg lovastatin tablet taken daily." The National Standard for Traditional Chinese Medicines WS-11524 (ZD-1524)-2002 stipulates that each Zhibituo tablet (0.35g) must contain at least 0.85mg of red yeast rice, calculated as lovastatin. Li Yan et al. (simultaneous determination of three monacolin components in Zhibituo tablets by HPLC) reported that the lovastatin contents of Zhibituo tablets (0.35 g, batch numbers 0806045, 0811028, and 0812043) were 2.81, 2.84, and 2.77 mg / g, respectively; each tablet contained approximately 0.98 mg of lovastatin. The lovastatin content determined by Li Yan et al. using a conversion method was the sum of the acid and lactone lovastatin contents. Hao Shengyuan et al. (Determination of lovastatin and lovastatin acid in red yeast rice and Zhibituo tablets using a single-test, multiple-assessment method) reported that lovastatin acid and lovastatin could be detected simultaneously in Zhibituo tablets. Based on the three samples measured (lot 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 lovastatin and lovastatin acid was approximately 1:10. This means that each Zhibituo tablet (0.35 g / tablet) contained 1.19 mg of lovastatin and 0.119 mg of lovastatin acid, for a total of 1.31 mg of lovastatin and lovastatin acid per tablet. The lovastatin and lovastatin acid contents determined by Hao Shengyuan et al. using the single-test, multiple-assessment method represent the contents of lovastatin lactone and lovastatin acid, respectively.

[0012] According to data from the National Medical Products Administration, Zhibitai has one product, Zhibitai Capsules, with a dosage of 0.24g per capsule. Liu Yuan et al. (Determination of lovastatin content in Zhibitai capsules by high-performance liquid chromatography) reported that Zhibitai capsules contained approximately 8.3 mg of lovastatin per capsule (produced by Chengdu Diao Jiuhong Pharmaceutical Factory, batch numbers 080105, 090103, and 090204). Wen Zhongming et al. (Determination of red yeast rice content in Zhibitai capsules) also reported a lovastatin content of 8.3 mg per capsule in a sample of Zhibitai capsules (batch number 080105). It is believed that Liu Yuan et al. and Wen Zhongming et al. did not distinguish between the lactone form of lovastatin and the acid form of lovastatin, and the amounts they measured should correspond to the lactone form.

[0013] According to data from the National Medical Products Administration, Xuezhikang (Beijing Beida Weixin Biotechnology Co., Ltd.) has two main products: Xuezhikang tablets (specification: each tablet weighs 0.4g) and Xuezhikang capsules (specification: each capsule contains 0.3g). The Chinese Pharmacopoeia (2020 edition, Volume 1), pages 904-906, states that each tablet / capsule of this product (Xuezhikang tablets / Xuezhikang capsules) contains at least 2.5mg of red yeast rice, calculated as lovastatin. The "Chinese Expert Consensus on the Clinical Application of Xuezhikang (Capsules) (2017 Revised Edition)" reports that each Xuezhikang capsule contains 2.5mg of lovastatin. Li Xuemei et al. pointed out in "Determination of the Content of Lovastatin and Lovastatin Acid in Xuezhikang Capsules by HPLC" 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 their report "HPLC Determination of Monacolins in Xuezhikang Capsules," Wang Lijuan et al. used the same concentration of sodium hydroxide (0.1M) as Li Yan et al. for the ring-opening reaction and determined that the monacolin K compound content in Xuezhikang Capsules with batch numbers 20081117, 20090703, and 20090713 was 0.33%, 0.29%, and 0.31%, respectively. The monacolin K compound content reported by Wang Lijuan et al. is believed to be incorrect, as the lovastatin content of Xuezhikang Capsules must be at least 2.5 mg / 0.3 g (0.83%).

[0014] 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 measured the content of lactone lovastatin.

[0015] Zhibitai is reported to reduce cholesterol by 23.5%, triglycerides by 30.3%, and low-density lipoprotein by 18.9%, while 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 lipid-regulating components are monacolins, represented by the acidic and open-ring monacolin K. These compounds exert their effects directly, without requiring hydrolysis by hydroxyesterases, by competitively inhibiting HMG-CoA, resulting in cholesterol-lowering effects that are more potent than statins with fewer side effects. Regarding triglyceride lowering, red yeast rice is used to treat mild hypertriglyceridemia, but its efficacy in severe hypertriglyceridemia has not been reported.

[0016] CN1618441A discloses a pharmaceutical composition for regulating blood lipids, comprising 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, as well as their preparation methods. Zhibitai is said to contain hawthorn, oriental rhizome, white atractylodes, and red yeast rice as its main ingredients, while Zhibituo's main ingredient is red yeast rice.

[0017] Yuan Xiaodong et al. (Effects of Xuezhikang combined with probucol on MMP-9, CD105, and TIMP-1 in hypertensive patients with carotid atherosclerosis, Chinese Journal of Gerontology, Vol. 39, July 2019: 3359-3361) aimed to investigate the effects of Xuezhikang combined with probucol on carotid intima-media thickness (CIMT), MMP-9, CD105, and TIMP-1 in hypertensive patients with carotid atherosclerosis. The treatment used was oral administration of Xuezhikang (provided by Peking University Weixin Biotechnology Co., Ltd., National Drug Approval No. Z10950029, 0.6 g / dose, twice daily, taken after breakfast and dinner) and probucol (provided by Qilu Pharmaceutical Co., Ltd., National Drug Approval No. H10980054, 0.5 g / dose, twice daily, taken before breakfast and dinner) in addition to conventional antihypertensive therapy. This 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.

[0018] Xue Jing (Clinical Study of Zhibitai Capsules Combined with Probucol for the Treatment of Hyperlipidemia, Modern Drugs and Clinics, Vol. 38, No. 2, February 2023: 346-349) used Zhibitai Capsules combined with probucol to treat hyperlipidemia. The treatment method used was oral administration of probucol tablets (0.5g / time, twice daily) and Zhibitai Capsules (1 capsule / time, twice daily). This treatment method did not use low-dose probucol, nor did it explicitly specify the simultaneous administration of red yeast rice and probucol. Furthermore, the indications targeted did not include severe hypertriglyceridemia, as discussed in this invention. Summary of the Invention

[0019] The inventors unexpectedly discovered that as two cholesterol-lowering drugs, probucol and red yeast rice, when combined in small doses, can significantly lower triglycerides in severe hypertriglyceridemia, with an effect comparable to that of fibrates, and can further lower cholesterol and low-density lipoprotein, with an effect comparable to that of statins. They can be used to treat (severe) hypertriglyceridemia and / or (severe) hypercholesterolemia, are broad-spectrum lipid-lowering drugs, and simultaneously reduce the risk of ASVCD and drug side effects, thereby meeting the above-mentioned clinical needs.

[0020] In a first aspect of the present invention, a pharmaceutical combination is provided, comprising probucol and red yeast rice.

[0021] In a second aspect of the present invention, a pharmaceutical composition is provided, comprising probucol, red yeast rice and a pharmaceutically acceptable carrier.

[0022] In a third aspect of the present invention, a pharmaceutical kit is provided, comprising a first pharmaceutical composition containing probucol and a second pharmaceutical composition containing red yeast rice.

[0023] 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.

[0024] 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 treating hyperlipidemia.

[0025] 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.

[0026] 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.

[0027] Specifically, the present invention provides the following technical solutions:

[0028] 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 + zetiapine 0.24g BID), (2) red yeast rice + cholesterol absorption inhibitor (zetiapine 0.24g BID + ezetimibe 20mg QD), (3) fish oil + red yeast rice (zetiapine 0.24g BID + fish oil 2g QD); (4) red yeast rice + red yeast rice (zetiapine 0.24g bid + Xuezhikang 0.3-0.6g bid), (5) probucol + ezetimibe (probucol 20-500mg bid + ezetimibe 20mg QD);

[0029] 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;

[0030] More preferably, the simultaneous administration is in the form of an oral unit dosage form, comprising 20-400 mg of probucol and 2-50 mg of red yeast rice, the weight of the red yeast rice being calculated as the active substance monacolin K, wherein the oral unit dosage form is preferably selected from tablets, capsules, granules, dripping pills, and 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; or

[0031] The simultaneous administration is in the form of a kit, which contains probucol and red yeast rice, and the 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

[0032] 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 containing a first pharmaceutical composition containing probucol and a second pharmaceutical composition containing red yeast rice, the first pharmaceutical composition contains 20-400 mg of probucol, and the second pharmaceutical composition contains 2-50 mg of red yeast rice, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, and opening each medicine unit exposes the first pharmaceutical composition and the second pharmaceutical 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, 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.

[0033] 2. The pharmaceutical 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.

[0034] 3. The pharmaceutical 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 pharmaceutical excipients,

[0035] 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);

[0036] Preferably, in the composition containing red yeast rice, the weight ratio of the active ingredient to the pharmaceutical excipient is (5-95):(95-5); the active ingredient includes the traditional Chinese medicine 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 Alisma or its extract.

[0037] 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

[0038] The composition containing red yeast rice 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).

[0039] 5. The pharmaceutical 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.

[0040] 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.

[0041] 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 the monacolin compounds is calculated as the total amount of monacolin K, monacolin L and / or dehydrated lovastatin.

[0042] 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, 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). 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 as 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.

[0043] 9. The pharmaceutical combination of technical solution 1, wherein each dosage unit of the pharmaceutical combination contains 20-400 mg of probucol, and each dosage unit of the pharmaceutical combination contains 2-55 mg of a monacolin compound, wherein the content of the monacolin compound is calculated as the total amount of monacolin K, monacolin L and / or dehydrated lovastatin; wherein each dosage unit refers to the oral unit dosage form, the single composition, the first pharmaceutical composition, or the second pharmaceutical composition.

[0044] 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.

[0045] 11. The use of technical solution 10, wherein the hyperlipidemia is hypertriglyceridemia, hypercholesterolemia, or mixed hyperlipidemia (i.e., a combination of hypertriglyceridemia and hypercholesterolemia).

[0046] 12. The use of technical solution 10, wherein the hyperlipidemia meets one of the following requirements (1)-(5):

[0047] (1) The subject's TG level is: TG ≥ 5.6 mmol / L;

[0048] (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;

[0049] (3) The subject is an extremely high-risk patient for ASCVD and meets one of the following conditions:

[0050] (3.1) LDL-C level greater than 1.8 mmol / L;

[0051] (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;

[0052] (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

[0053] The subject's LDL-C level after treatment is reduced by <50% compared to baseline; or

[0054] Patients with significant statin side effects who require dose reduction; or

[0055] Patients who have severe side effects from cholesterol absorption inhibitors or PCSK9 monoclonal antibodies and need to stop taking statins in combination with cholesterol absorption inhibitors or statins in combination with PCSK9 monoclonal antibodies, or statins in combination with cholesterol absorption inhibitors and PCSK9 monoclonal antibodies;

[0056] (4) The subject is an ultra-high-risk ASCVD patient and meets one of the following conditions:

[0057] (4.1) LDL-C level greater than 1.4 mmol / L;

[0058] (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;

[0059] (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

[0060] The subject's LDL-C level after treatment is reduced by <50% compared to baseline; or

[0061] Patients with significant statin side effects who require dose reduction; or

[0062] Patients who have severe side effects from cholesterol absorption inhibitors or PCSK9 monoclonal antibodies and need to stop taking statins in combination with cholesterol absorption inhibitors or statins in combination with PCSK9 monoclonal antibodies, or statins in combination with cholesterol absorption inhibitors and PCSK9 monoclonal antibodies;

[0063] (5) The subject is a high-risk ASCVD patient and meets one of the following conditions:

[0064] (5.1) LDL-C level greater than 2.6 mmol / L;

[0065] (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;

[0066] (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

[0067] The subject's LDL-C level after treatment is reduced by <50% compared to baseline; or

[0068] Patients with significant statin side effects who require dose reduction; or

[0069] Patients who have severe side effects from cholesterol absorption inhibitors or PCSK9 monoclonal antibodies and need to stop taking statins in combination with cholesterol absorption inhibitors or statins in combination with PCSK9 monoclonal antibodies, or statins in combination with cholesterol absorption inhibitors and PCSK9 monoclonal antibodies;

[0070] The ASCVD extremely high-risk patients, ASCVD ultra-high-risk patients, and ASCVD high-risk patients mentioned therein are divided according to the standards of the "Guidelines for Blood Lipid Management in China (2023)".

[0071] 13. The use of technical solution 10, wherein the hyperlipidemia is

[0072] Severe hypertriglyceridemia,

[0073] Severe hypercholesterolemia,

[0074] Hyperlipidemia that is ineffective or ineffective with statins and / or red yeast rice, or

[0075] Hyperlipidemia that is intolerant to or unresponsive to fibrates.

[0076] 14. The use of technical solution 10, wherein the hyperlipidemia is

[0077] Combination of (severe) hypertriglyceridemia and (severe) hypercholesterolemia,

[0078] (Severe) hypercholesterolemia that is ineffective or ineffective with statins and / or red yeast rice,

[0079] (Severe) hypertriglyceridemia that is ineffective or ineffective with statins and / or red yeast rice, or

[0080] (Severe) hypertriglyceridemia intolerant of or unresponsive to fibrates.

[0081] 15. The use according to any one of technical solutions 10-14, wherein

[0082] 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;

[0083] 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;

[0084] Probucol and red yeast rice were administered orally at the same time.

[0085] 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;

[0086] Preferably, the red yeast rice is provided in the form of a composition containing red yeast rice, which comprises an active ingredient and pharmaceutical excipients.

[0087] The composition containing red yeast rice 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),

[0088] In the composition containing red yeast rice, the weight ratio of the active ingredient to the pharmaceutical excipient is (5-95):(95-5); the active ingredient includes the traditional Chinese medicine red yeast rice, functional red yeast rice or its extract, and optionally any one or more of hawthorn or its extract, white atractylodes or its extract, and oriental rhizome or its extract.

[0089] 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 as the active substance monacolin K.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 21. A pharmaceutical composition comprising probucol and a red yeast rice active ingredient, wherein the red yeast rice active ingredient is prepared as follows:

[0094] 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 twice, filter, combine the filtrate, recover the ethanol, concentrate to an appropriate amount, and spray it into the red yeast rice powder to obtain the product.

[0095] 22. A pharmaceutical composition comprising probucol and monacolin K.

[0096] 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.

[0097] 24. The pharmaceutical composition of technical solution 22 or 23, which 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, monacolinic acid A, dehydromonacolin J, dehydromonacolin K, dehydromonacolin L, dehydromonacolin N, dihydromonacolin K, dihydromonacolin L, dihydromonacolin MV, dehydromonacolin MV2 and monacolin K ethyl ester.

[0098] 25. A pharmaceutical 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;

[0099] Preferably, the medicine kit comprises one or more identical medicine units isolated from the external environment, each medicine unit comprising a first medicine composition containing probucol and a second medicine composition containing 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.

[0100] 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 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.

[0101] 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.

[0102] 28. The pharmaceutical kit according to any one of technical solutions 25-27, wherein the first pharmaceutical composition and the second pharmaceutical composition are provided in separate dosage forms.

[0103] 29. The medicine box according to 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, capsule, granule, dripping pill, 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.

[0104] 30. A medicine kit comprising probucol and red yeast rice as active ingredients. Preferably, probucol and red yeast rice are configured in the medicine kit so as to be administered simultaneously. More preferably, the medicine kit comprises one or more identical medicine units isolated from the external environment. For each administration, one, two, or three, preferably one or two, medicine units can be opened simultaneously. Each medicine unit comprises the probucol and red yeast rice of the present invention. Opening each medicine unit can expose the probucol and red yeast rice of the present invention to the external environment simultaneously.

[0105] 31. The medicine box of technical solution 30, wherein the amount of probucol and red yeast rice contained as active ingredients in each drug unit is:

[0106] 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;

[0107] 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.

[0108] 32. A medicine kit, characterized in that the medicine kit contains the drug combination according to any one of technical solutions 1-9, which comprises 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 contains 20-400 mg of probucol; and the second pharmaceutical composition contains 2-50 mg of red yeast rice, and the weight of the red yeast rice is calculated as the active substance monacolin K.

[0109] 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 The invention relates to a pharmaceutical composition comprising: a first ...

[0110] 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.

[0111] 35. The medicine box described in technical solution 34, wherein the dosage form is selected from tablets, capsules, granules, pills, and micropills.

[0112] 36. The medicine box according to technical solution 35, wherein the tablet is a two-layer or multi-layer tablet, wherein at least one layer contains probucol and a pharmaceutically acceptable carrier thereof, and at least another layer contains a statin and a pharmaceutically acceptable carrier thereof.

[0113] 37. The medicine box according to any one of technical solutions 32-36, wherein the medicine box 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, wherein opening of each medicine unit exposes probucol and red yeast rice to the external environment at the same time.

[0114] 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 a drug for treating hyperlipidemia. Preferably, the use is the use as described in any one of technical solutions 1-15. DETAILED DESCRIPTION

[0115] 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.

[0116] As used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of a compound or combination of compounds that provides an expected clinical or therapeutic benefit in the subject being treated. A 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 conventional practice. As used herein, in the absence of a prescribed frequency of administration, the term "effective amount" or "therapeutically effective amount" is based on daily use.

[0117] As used herein, the term "about" can allow for a 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.

[0118] As used herein, the term "treat" refers to at least partially alleviating, controlling and / or ameliorating a disease or its symptoms.

[0119] As used herein, the term "subject" refers to a human subject to whom the pharmaceutical combination or pharmaceutical composition of the present invention is intended to be administered.

[0120] The term "QD" as used herein means once daily.

[0121] As used herein, the term "BID" means twice daily.

[0122] The term "pharmaceutically acceptable" as used herein refers to those substances or materials that 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.

[0123] 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.

[0124] As used herein, the term "pharmaceutically acceptable carrier" refers to a carrier (or excipient) that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. Any commonly used pharmaceutically acceptable carrier may be used, the selection of which 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 skill 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.

[0125] The term "hyperlipidemia" as used herein refers to abnormal blood lipids with elevated levels of total cholesterol (TC) and / or triglyceride (TG) in serum.

[0126] The term "hypercholesterolemia" as used herein refers to hyperlipidemia with TC>6.22 mmol / L or 240 mg / dL and LDL-C>4.14 mmol / L or 160 mg / dL, including familial (severe) hypercholesterolemia.

[0127] The term "severe hypercholesterolemia" as used herein refers to hyperlipidemia with LDL-C>4.9 mmol / L.

[0128] The term "hypertriglyceridemia" as used herein refers to hyperlipidemia with TG > 1.7 mmol / L or > 150 mg / dL.

[0129] The term "severe hypertriglyceridemia" as used herein refers to hyperlipidemia with TG ≥ 5.6 mmol / L (500 mg / dL).

[0130] The term "fibrate-intolerant or non-responsive hyperlipidemia" as used herein refers to hyperlipidemia in which fibrate treatment causes liver and kidney damage, elevated muscle enzymes, or TG remains greater than 5.6 mmol / L after fibrate treatment.

[0131] 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.

[0132] 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. Similar definitions 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.

[0133] The "probucol" mentioned herein includes probucol and pharmaceutically acceptable salts or esters thereof, such as probucol disuccinate.

[0134] 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.

[0135] 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.

[0136] Natural red yeast rice refers to a product formed naturally by fermenting rice (or crushed rice) with the fungus Monascus sp. Depending on the type of Monascus used, natural red yeast rice can be further categorized as red yeast rice pigment, functional red yeast rice, and brewing red yeast rice. Monascus 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, and Monascus sp. A commercially available natural red yeast rice is red yeast rice or red yeast powder containing ≥0.2 wt% of moracolin K on an absolute dry basis.

[0137] Red yeast rice (Red Yeast Rice) refers to a Chinese medicinal product or intermediate made by processing the mycelium of the Aspergillus fungus, such as Monascus purpureus Went., on rice or japonica rice using traditional Chinese medicine processing methods, such as rinsing. In one embodiment, the Red Yeast Rice contains 3-6 mg / g of unsaturated fatty acids and 15-30 mg / g of lovastatin, with the percentage of open-ring lovastatin in the total lovastatin being 10-90%.

[0138] Functional red yeast rice (Red Yeast Rice) is a product made from rice (or crushed rice) fermented with Monascus sp. to produce bioactive substances such as monacolin K. It is categorized by form as red yeast rice and red yeast rice powder. Specifically, functional red yeast rice should contain ≥0.4wt% monacolin K on an absolute dry basis [see QB / T 2847-2023, Functional Red Yeast Rice (Powder)]. The Monascus sp. used to prepare the functional red yeast rice 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.

[0139] 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 those skilled in the art using conventional extraction methods, for example, by refluxing red yeast rice with 50-90% methanol, ethanol or ethyl acetate for 2-3 times, 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.

[0140] Natural red yeast rice, traditional Chinese medicine red yeast rice, functional red yeast rice, and red yeast rice extracts are all commercially available. The "Notice on Matters Related to the Application and Review of Health Food Products Using Red Yeast Rice as Ingredients" (State Food and Drug Administration

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

[0141] The composition containing red yeast rice is a composition containing an active ingredient and a pharmaceutical excipient, wherein the active ingredient includes red yeast rice of traditional Chinese medicine, functional red yeast rice, or red yeast rice extract. The composition containing red yeast rice 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 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).

[0142] 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).

[0143] 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 (selected from one or more of ethanol, water, ethanol-water solution, syrup, starch slurry, sodium carboxymethyl cellulose solution, polyvinylpyrrolidone solution, or a mixture thereof), flavoring agents (selected from one or more of The pharmaceutical excipients may further include one or more of the following: orange flavor, mint flavor, grape flavor, cherry flavor, banana flavor, pineapple flavor, vanilla flavor, lemon flavor, aspartame, saccharin sodium, and stevioside; a lubricant (selected from one or more of the following: micropowdered silica gel, magnesium stearate, calcium stearate, stearic acid, talc, silicon dioxide, magnesium lauryl sulfate, PEG4000, and PEG6000); and a coating agent (selected from one or more of the following: acrylic resin, hydroxypropyl methylcellulose, and polyethylene glycol). The pharmaceutical excipients may also include one or more of the following: donkey-hide gelatin, salad oil, soybean lecithin, vitamin E, beeswax, safflower seed oil, low-substituted hydroxypropyl cellulose, methylcellulose, ethylcellulose, polyethylene glycol, sodium carboxymethylcellulose, microcrystalline cellulose, micropowdered silica gel, talc, and polyvinyl pyrrolidone.

[0144] The active ingredient may consist of only the Chinese herbal medicine red yeast rice or functional red yeast rice or red yeast rice extract, or may consist of the Chinese herbal medicine red yeast rice or functional red yeast rice or red yeast rice extract and a second active substance.

[0145] The second active substance can 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. The extracts of one or more other Chinese medicinal materials can be obtained by methods known to those skilled in the art. When extracting multiple Chinese medicinal materials (including Chinese medicinal red yeast rice or functional red yeast rice), one Chinese medicinal material can be extracted alone, and / or two or more Chinese medicinal materials can be mixed together for extraction, and / or all Chinese medicinal materials can be mixed together for extraction.

[0146] In one embodiment of the present invention, the composition containing red yeast rice is a red yeast rice micropill, which is obtained by adding a wetting agent to the following raw materials and auxiliary materials in the following weight ratio and making pills: 8-12 parts of red yeast rice and 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 micropill 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 to make a soft material, and using a micropill machine to make pills; the pill making process is divided into three stages, wherein the first and second stages adopt a static drying method, and the third stage adopts a high-temperature drying expansion method to form pills; the drying temperature of the first stage is 30-40°C and the drying time is 1 hour; the drying temperature of the second stage is 50-60°C and the drying time is 1 hour; the drying temperature of the third stage 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.

[0147] 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 excipient is 1: (0.8-1.2), and the matrix excipient is soybean oil and beeswax. The preparation method of the red yeast rice soft capsule comprises the following steps: a, preparing 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 Chinese patent application CN200510021521.6 with publication number CN1919214A.

[0148] 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 a 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 the red yeast rice or its extract and 20-200 parts of the coating agent; the coating agent is one or more of acrylic resin, hydroxypropyl methylcellulose, and polyethylene glycol; 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. Weighing the following weight ratios of red yeast rice or its extract and excipients: 50-500 parts of red yeast rice or its extract, and passing through a No. 4 pharmacopoeia sieve; the remaining pharmaceutical excipients include 20-200 parts of a coating agent, 0-200 parts of a filler, 10-200 parts of a disintegrant, 0-10 parts of a flavoring agent, 0-50 parts of a lubricant, and 0-10 parts of a glidant, and passing through a No. 3 pharmacopoeia sieve for later use; b. Coating the sieved red yeast rice powder or its extract with a coating agent to form an isolation coat, and passing through a No. 3 pharmacopoeia sieve for later use; c. Mixing the coated red yeast rice powder with the excipients and directly compressing the tablets to obtain the tablets. The specific preparation method can be referred to Chinese patent application CN200510022143.3 with publication number CN1969891A.

[0149] In one embodiment of the present invention, the composition containing red yeast rice is a pill made of red yeast rice, wherein the raw materials used to prepare the pills include or consist of the following: a red yeast rice extract and polyethylene glycol in a weight ratio of 1:(1-3), and the preparation method includes: 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 the 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 of the aforementioned red yeast rice. / 6 weight of red yeast rice is crushed into fine powder; the concentrated solution is continuously sprayed into the red yeast rice fine powder, and boiling dried to obtain a dry extract; the dry extract is crushed into fine powder to obtain the red yeast rice extract; the boiling drying conditions are: material temperature of 60-80°C, spraying speed of 25-35 liters / hour; after heating and melting polyethylene glycol, the red yeast rice extract is added, mixed evenly, and kept warm at 75±2°C; using a pill dropping machine, the coolant is dropped into the coolant, wherein the temperature of the coolant is 20±2°C, and after forming, the pills are taken out, the coolant on the surface is removed, and the pills are packaged. The specific preparation method can be referred to Chinese patent application CN200510123460.4 with publication number CN1899317A.

[0150] In one embodiment of the present invention, the composition containing red yeast rice is a traditional Chinese medicine red yeast rice preparation, wherein the raw material of the traditional Chinese medicine red yeast rice preparation comprises or consists of the following: 273 parts of red yeast rice and 5-10 parts of micronized silica gel. The preparation method of the traditional Chinese medicine red yeast rice preparation comprises the following steps: a. weighing the red yeast rice, drying, crushing, and sieving; b. adding excipients, granulating, and adding commonly used pharmaceutical excipients to prepare a commonly used pharmaceutical preparation. The specific preparation method can be found in Chinese patent application CN200510129372.5, published as CN1919215A.

[0151] In one embodiment of the present invention, the composition containing red yeast rice is a pharmaceutical composition 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, and 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 and refluxing and extracting for 1-4 hours, filtering the extract, adding 1-3 parts by volume of 60-90% ethanol to the residue and refluxing and extracting for 1-3 hours, filtering the extract, combining the filtrate, recovering ethanol under reduced pressure, 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, leaving it at room temperature or under refrigeration for 2-16 hours, siphoning off the supernatant, or collecting the precipitate by centrifugation; adding 2-5% by weight of the medicinal material to the precipitate, one of the auxiliary materials 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 reduce the moisture content to less than 5%, thereby obtaining the red yeast rice extract. The specific preparation method can be referred to Chinese patent application CN200710099767.4 with publication number CN101313918A.

[0152] In one embodiment of the present invention, the composition containing red yeast rice is a pharmaceutical composition having a lipid-regulating effect, wherein 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 kudzu root; the pharmaceutical composition is prepared by the following method:

[0153] Step 1: Preparation of Red Yeast Extract I

[0154] Red yeast rice extract I is prepared by any of the following methods:

[0155] To 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 under reflux for 1-3 hours, and extract 2-3 times; filter the extract, combine the filtrates, recover the solvent, and concentrate to a thick paste with a relative density of 0.95-1.06 measured at 55-60°C to obtain Extract I;

[0156] B. To 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 under reflux for 1-3 hours, and extract 2-3 times; filter the extract, combine the filtrates, recover the solvent, and concentrate to a relative density of 0.95-1.06 measured at 55-60°C. Add 0.5-2.0 times the amount of deionized water to the concentrate and mix well. Place at room temperature or refrigerate for 2-12 hours, centrifuge, collect the precipitate, and dry to obtain Extract I;

[0157] Step 2: Preparation of Pueraria Extract II

[0158] 1 part by weight of Pueraria root is added with 4-20 parts by volume of water or ethanol each time, heated under reflux for 1-3 hours, extracted 2-4 times, filtered, the filtrate is combined, the solvent is recovered, and concentrated into a thick paste to obtain Extract II;

[0159] Step 3: Preparation

[0160] 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.

[0161] For the specific preparation method, reference can be made to Chinese patent application CN201210118280.7 with publication number CN103372051A.

[0162] 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 oriental rhizome;

[0163] The pharmaceutical composition is prepared by the following method:

[0164] Step 1: Preparation of Red Yeast Extract I

[0165] Red yeast rice extract I is prepared by any of the following methods:

[0166] To 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 under reflux for 1-3 hours, and extract 2-3 times; filter the extract, combine the filtrates, recover the solvent, and concentrate to a thick paste with a relative density of 0.95-1.06 measured at 55-60°C to obtain Extract I;

[0167] B. To 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 under reflux for 1-3 hours, and extract 2-3 times; filter the extract, combine the filtrates, recover the solvent, and concentrate to a relative density of 0.95-1.06 measured at 55-60°C. Add 0.5-2.0 times the amount of deionized water to the concentrate and mix well. Place at room temperature or refrigerate for 2-12 hours, centrifuge, collect the precipitate, and dry to obtain Extract I;

[0168] Step 2: Preparation of Alisma Orientalis Extract II

[0169] 1 part by weight of Alisma orientalis is added with 4-20 parts by volume of water or ethanol each time, heated under reflux for 1-3 hours, extracted 2-4 times, filtered, the filtrate is combined, the solvent is recovered, and concentrated into a thick paste to obtain Extract II;

[0170] Step 3: Preparation

[0171] 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.

[0172] For the specific preparation method, reference may be made to Chinese patent application CN201210118859.3 with publication number CN103372114A.

[0173] 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.

[0174] The pharmaceutical composition is prepared by the following method:

[0175] Step 1: Preparation of Red Yeast Extract I

[0176] Red yeast rice extract I was prepared by any of the following methods:

[0177] To 1 part by weight of red yeast rice (A), add 2-10 parts by volume of 50-90% ethanol, methanol, or ethyl acetate each time, heat under reflux for 1-3 hours, and extract 2-3 times; filter the extract, combine the filtrates, recover the solvent, and concentrate to a thick paste with a relative density of 0.95-1.06 measured at 55-60°C to obtain Extract I;

[0178] B. To 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 under reflux for 1-3 hours, and extract 2-3 times; filter the extract, combine the filtrates, recover the solvent, and concentrate to a relative density of 0.95-1.06 measured at 55-60°C. Add 0.5-2.0 times the amount of deionized water to the concentrate, mix well, store at room temperature or refrigerate for 2-12 hours, centrifuge, collect the precipitate, and dry to obtain Extract I;

[0179] Step 2: Preparation of Hawthorn Extract II

[0180] 1 part by weight of hawthorn medicinal material is added with 4-20 parts by volume of water or ethanol each time, heated under reflux for 1-3 hours, extracted 2-4 times, filtered, the filtrate is combined, the solvent is recovered, and concentrated into a thick paste to obtain Extract II;

[0181] Step 3: Preparation

[0182] 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.

[0183] For the specific preparation method, please refer to Chinese patent application CN201210119095.X with publication number CN103372073A.

[0184] 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;

[0185] The pharmaceutical composition is prepared by the following method:

[0186] Step 1: Preparation of Red Yeast Extract I

[0187] Red yeast rice extract I is prepared by any of the following methods:

[0188] To 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 under reflux for 1-3 hours, and extract 2-3 times; filter the extract, combine the filtrates, recover the solvent, and concentrate to a thick paste with a relative density of 0.95-1.06 measured at 55-60°C to obtain Extract I;

[0189] B. To 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 under reflux for 1-3 hours, and extract 2-3 times; filter the extract, combine the filtrates, recover the solvent, and concentrate to a relative density of 0.95-1.06 measured at 55-60°C. Add 0.5-2.0 times the amount of deionized water to the concentrate and mix well. Place at room temperature or refrigerate for 2-12 hours, centrifuge, collect the precipitate, and dry to obtain Extract I;

[0190] Step 2: Preparation of Chuanxiong Extract II

[0191] 1 part by weight of Chuanxiong is added with 4-20 parts by volume of water or ethanol each time, and the mixture is heated under reflux for 1-3 hours, and extracted 2-4 times. The extract is filtered, the filtrate is combined, the solvent is recovered, and the mixture is concentrated into a thick paste to obtain Extract II.

[0192] Step 3: Preparation

[0193] 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.

[0194] For the specific preparation method, reference may be made to Chinese patent application CN201210119116.8 with publication number CN103372040A.

[0195] In one embodiment of the present invention, the composition containing red yeast rice is a pharmaceutical composition for regulating blood lipids, comprising a red yeast rice extract and a gynostemma pentaphyllum extract; the weight ratio of the red yeast rice to the gynostemma pentaphyllum medicinal materials is 1:10 to 10:1; the weight percentage of total saponins in the gynostemma pentaphyllum extract is ≥8%;

[0196] Wherein, the Gynostemma pentaphyllum extract is prepared by the following method:

[0197] Take 1 part by weight of Gynostemma pentaphyllum, add 4-20 parts by volume 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;

[0198] The red yeast rice extract is prepared by method I or method II:

[0199] Method I:

[0200] 1) Take 1 part by weight of red yeast rice, add 2-10 parts by volume of 50-90% ethanol, methanol or ethyl acetate, heat under reflux for 1-3 hours, and extract 2-3 times;

[0201] 2) filtering the extract and combining the filtrates;

[0202] 3) concentrating the filtrate obtained in step 2) into a thick paste;

[0203] Method II:

[0204] (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;

[0205] (2) filtering the extract and combining the filtrates;

[0206] (3) Concentrating the filtrate obtained in step (2) to a concentrate having a relative density of 0.95-1.06 at 55-60°C.

[0207] For the specific preparation method, reference may be made to Chinese patent application CN201210155323.9 with publication number CN103417601A.

[0208] 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:

[0209] 6 parts of red yeast rice, 9 parts of white atractylodes, and 12 parts of hawthorn; or

[0210] 3-6 parts red yeast rice, 9-12 parts white atractylodes, 12 parts hawthorn; or

[0211] 3-15 parts of red yeast rice, 3-15 parts of white atractylodes, and 3-15 parts of hawthorn; or

[0212] 6 parts of red yeast rice, 9 parts of rhizome of Alisma orientalis, 9 parts of atractylodes macrocephala, and 12 parts of hawthorn; or

[0213] 3-6 parts of red yeast rice, 6-9 parts of rhizome of Alisma orientalis, 9-12 parts of atractylodes macrocephala, and 12 parts of hawthorn;

[0214] 3-15 parts of red yeast rice, 3-15 parts of rhizome of Alisma orientalis, 3-15 parts of atractylodes macrocephala, and 3-15 parts of hawthorn;

[0215] The preparation method of the drug comprises the following steps: a. Weighing Chinese medicinal materials as raw materials; b. Extracting the above medicinal materials with alcohol or aqueous ethanol, filtering to obtain filtrate A; c. Recovering ethanol from filtrate A and concentrating under reduced pressure to obtain extract B; d. Adding an appropriate amount of water to extract B, allowing it to stand, and centrifuging to obtain supernatant C and precipitate D, drying precipitate D to obtain active ingredient I; e. Passing supernatant C through a pretreated resin column, washing with water until colorless, then washing with ethanol until colorless, collecting the eluate, recovering ethanol, concentrating and drying to obtain a thick paste E as active ingredient II; f. Mixing active ingredients I and II with pharmaceutically acceptable excipients to prepare a pharmaceutical preparation. For the specific preparation method, reference can be made to Chinese patent application CN200310110995.9, publication number CN1618441A.

[0216] For example, the composition containing red yeast rice can be a Chinese patent medicine made from red yeast rice, which can be commercially obtained under the trade names of Zhibitai, Zhibituo, Xuezhikang, etc.

[0217] The above-mentioned Chinese medicine red yeast rice, functional red yeast rice, red yeast rice extract and composition containing red yeast rice all contain a certain amount of active ingredient monacolin compounds, and the monacolin compounds include 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 N1, monacolin N2, monacolin K, and monacolin L, dehydrated lovastatin, monacolin 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.

[0218] 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-multiple-evaluation method [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 Pharmaceutical 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 determined, for example, by referring to the methods reported in the literature (Li Yan et al., Simultaneous determination of the content of three monacolin components in Zhibituo tablets by HPLC, Journal of Pharmaceutical 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 terms of monacolin K in the following text can also be replaced by measuring in terms of monacolin compounds without affecting the technical effects of the present invention.

[0219] Monacolin K synthesized by microbial fermentation is all open-ring structure, but during the subsequent drying and storage process, the open-ring structure of monacolin K will partially convert to 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-type and lactone-type 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 simultaneously detects both structures.

[0220] A first aspect of the present invention provides a pharmaceutical combination comprising probucol and red yeast rice.

[0221] In some embodiments, the pharmaceutical 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.

[0222] 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 from about 2 mg to about 50 mg. In some embodiments, the therapeutically effective amount of red yeast rice is from about 3 mg to about 40 mg. In some embodiments, the therapeutically effective amount of red yeast rice is from about 5 mg to about 35 mg. In some embodiments, the therapeutically effective amount of red yeast rice is from about 7 to about 30 mg. In some embodiments, the therapeutically effective amount of red yeast rice is from about 7 to about 20 mg. In some embodiments, a 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.

[0223] 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.

[0224] 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.

[0225] 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.

[0226] 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, Xuezhikang tablets.

[0227] In some embodiments, probucol and red yeast rice are provided in a single composition, for example, in a single tablet, capsule, granule, pellet, or micropill.

[0228] The second aspect of the present invention provides a pharmaceutical composition comprising probucol, red yeast rice and a pharmaceutically acceptable carrier.

[0229] 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 enhancers, surfactants, adsorption carriers, etc. in the pharmaceutical field.

[0230] 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 (such as, but not limited to, tablets (including ordinary tablets, coated tablets, chewable tablets, enteric-coated tablets, sustained-release tablets, controlled-release tablets, orally disintegrating tablets, dispersible tablets, effervescent tablets, etc.), capsules (including hard capsules, soft capsules, enteric-coated capsules, sustained-release capsules, controlled-release capsules, etc.), granules (including soluble granules, suspension granules, enteric-coated granules, sustained-release granules, controlled-release granules, effervescent granules, etc.), pills, micropills, etc.), liquid dosage forms (such as, but not limited to, solutions, syrups, suspensions, emulsions, etc.), etc.

[0231] In some embodiments, the pharmaceutical composition is in a unit dosage form suitable for oral administration. For example, a tablet, capsule, or granule, each containing 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 multi-layer tablet, such as a bi-layer 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.

[0232] 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, for example, 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, for example, 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.

[0233] A third aspect of the present invention provides a pharmaceutical kit comprising a first pharmaceutical composition containing probucol and a second pharmaceutical composition containing red yeast rice.

[0234] 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.

[0235] In some embodiments, probucol and red yeast rice are provided as a single composition in a medicine kit. In some embodiments, the medicine kit 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 comprising about 10 mg to about 1000 mg, about 20 mg to about 800 mg, about 20 mg to about 400 mg, about 40 mg to about 400 mg, about 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.

[0236] 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.

[0237] A fourth aspect of the present invention provides use of probucol and red yeast rice in preparing a medicament for treating hyperlipidemia.

[0238] 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.

[0239] 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.

[0240] In some embodiments, the hyperlipidemia is hypertriglyceridemia.

[0241] In some embodiments, the hyperlipidemia is severe hypertriglyceridemia.

[0242] In some embodiments, the hyperlipidemia is (severe) hypercholesterolemia.

[0243] In some embodiments, the hyperlipidemia is fibrate-intolerant or non-responsive hyperlipidemia.

[0244] In some embodiments, the hyperlipidemia is hyperlipidemia that is ineffective or ineffectively treated with statins and / or red yeast rice.

[0245] In some embodiments, probucol and red yeast rice are administered to a subject orally. In some embodiments, probucol and red yeast rice are administered orally to a subject in the form of tablets. In some embodiments, probucol and red yeast rice are administered orally to a subject in the form of capsules. In some embodiments, probucol is administered orally to a subject in the form of tablets and red yeast rice is administered orally to a subject in the form of capsules. In some embodiments, probucol is administered orally to a subject in the form of capsules and red yeast rice is administered orally to a subject in the form of tablets. In some embodiments, probucol is administered orally to a subject in the form of granules and red yeast rice is administered orally to a subject in the form of tablets.

[0246] 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.

[0247] 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.

[0248] 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 formulation, with an administration interval of less than 30 minutes, such as less than 15 minutes, less than 10 minutes, less than 5 minutes, or less than 1 minute. In some embodiments, the daily dose of probucol and 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 term.

[0249] Beneficial effects of the present invention

[0250] The main beneficial effects of the present invention include the following aspects:

[0251] (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 no less effective than first-line fibrates. This solves the clinical problem of having no alternative effective drug when myolysis and liver and kidney dysfunction occur after fibrate treatment, and provides a new treatment option for treating severe hypertriglyceridemia.

[0252] (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 superior to the statin combined with ezetimibe recommended by the lipid management guidelines, thereby reducing the risk of cardiovascular disease;

[0253] (3) Current treatments for severe hypertriglyceridemia, such as fibrates and high-dose fish oil, increase low-density lipoprotein (LDL). If severe hypertriglyceridemia is complicated by cardiovascular risk, fibrates must be combined with statins for treatment, but the combined treatment has significant side effects. The drug combination of the present invention can significantly reduce triglycerides in severe hypertriglyceridemia and further reduce cholesterol and LDL-C. It is a broad-spectrum lipid-lowering drug that is suitable for both hypertriglyceridemia and / or hypercholesterolemia and can reduce cardiovascular risk, thus resolving a clinical problem.

[0254] (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, which makes the drug combination better tolerated, has lower toxic side effects, and has fewer adverse reactions after long-term medication;

[0255] (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 LDL-C disappear.

[0256] The present invention also includes the following embodiments:

[0257] Embodiment 1. A pharmaceutical combination comprising probucol and red yeast rice.

[0258] Embodiment 2. The pharmaceutical combination of embodiment 1, wherein the 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.

[0259] 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.

[0260] Embodiment 4. The pharmaceutical combination according to any one of embodiments 1-3, 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 the red yeast rice is 0.5-5%.

[0261] 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 anhydrolovastatin.

[0262] Embodiment 6. The pharmaceutical combination of Embodiment 5, characterized in that the weight ratio of probucol to monacolin K in red yeast rice is (1-80):1.

[0263] Embodiment 7. The pharmaceutical combination of Embodiment 5, characterized in that the weight ratio of probucol to monacolin K in red yeast rice is (1-67):1.

[0264] Embodiment 8. The pharmaceutical combination of Embodiment 5, 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 the monacolin compounds is calculated as the total amount of monacolin K, monacolin L and / or dehydrated lovastatin.

[0265] Embodiment 9. The pharmaceutical combination of embodiment 5, wherein each dosage unit comprises probucol 40-400 mg.

[0266] Embodiment 10. The pharmaceutical combination of embodiment 5, wherein each dosage unit comprises 100-3500 mg of red yeast rice based on the weight of red yeast rice.

[0267] 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 anhydrolovastatin.

[0268] 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 anhydrolovastatin.

[0269] 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:

[0270] 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 twice, filter, combine the filtrate, recover the ethanol, concentrate to an appropriate amount, and spray it into the red yeast rice powder to obtain the product.

[0271] Embodiment 14. A pharmaceutical composition comprising probucol and monacolin K.

[0272] 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.

[0273] Embodiment 16. The pharmaceutical composition of embodiment 14 or 15, further comprising one or more compounds selected from the group consisting of monacolin L, dehydrolovastatin, 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, monacolinic acid A, dehydromonacolin J, dehydromonacolin K, dehydromonacolin L, dehydromonacolin N, dihydromonacolin K, dihydromonacolin L, dihydromonacolin MV, dehydromonacolin MV2, and monacolin K ethyl ester. Example

[0274] The following examples are intended to illustrate the present invention in detail and should not be construed as limiting the scope of the present invention.

[0275] Example 1: Study on the efficacy of a drug combination of probucol and red yeast rice in treating severe hypertriglyceridemia.

[0276] Patients: A total of 32 patients with severe hypertriglyceridemia (23 males and 9 females, aged 26-72 years) received probucol and red yeast rice combination therapy. Their pre-treatment triglyceride levels ranged from 5.75 to 22.02 mmol / l, cholesterol levels ranged from 3.43 to 14.08 mmol / l, and low-density lipoprotein levels ranged from 1.02 to 7.89 mmol / l.

[0277] Dosage regimen: Probucol is administered orally as 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 as the following commercially available products (can be taken with water or chewed): Zhibitai capsules (240 mg / tablet, containing approximately 9.1 mg of monacolin K / tablet), with a dosage of 240-480 mg / time, once or twice a day; Zhibituo tablets (350 mg / tablet, containing approximately 1.3 mg of monacolin K / tablet), with a dosage of 700-1050 mg / time, once or twice a day; Xuezhikang capsules (300 mg / tablet, containing approximately 3.7 mg of monacolin K / tablet), 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, and the average treatment period was 4 weeks.

[0278] Treatment Results: After patients were treated with different doses of probucol and red yeast rice, plasma triglycerides decreased by 34-75% (average values ​​for each treatment group, the same below), with an average decrease of 69% (average values ​​for all patients, the same below); cholesterol decreased by 12-55%, with an average decrease of 43%; and low-density lipoprotein decreased by 18-47%, with an average decrease of 29%. Specific results are shown in Table 1 below.

[0279] Table 1 Treatment results of probucol combined with red yeast rice

[0280] 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 312.5 mg + Zhibitai 240 mg, 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 62.5 mg + Dibucil 700 mg, BID 16.01 5.21 67 6.51 3.32 49 1.83 1.19 35 1 Probucol 125mg + Dibucol 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 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

[0281] 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.

[0282] Compared to other drugs for treating severe hypertriglyceridemia, the low-dose drug combination of the present invention significantly lowered triglycerides, outperforming fibrates and high-dose fish oil. Furthermore, unlike fibrates and high-dose fish oil, which increase LDL, the drug combination of the present invention also simultaneously lowered cholesterol and LDL-C. See Table 2 below.

[0283] Table 2 Comparison of the efficacy of the combination of probucol and red yeast rice with other drugs for the treatment of severe hypertriglyceridemia

[0284] lipid-lowering drugs triglycerides cholesterol LDL-C Probucol-Red Yeast Rice 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%

[0285] Data sources: a. Liping package insert; b. TriglycerideLoweringDrugs (https: / / pubmed.ncbi.nlm.nih.gov / 28402615 / ). c. Omega-3 fatty acid ethyl ester 90 soft capsules package insert.

[0286] Typical case 1:

[0287] The patient was a 62-year-old female with hypertension, diabetes, hyperlipidemia, and a family history of severe hypertriglyceridemia. Ten years prior, severe hypertriglyceridemia induced pancreatitis, leaving behind diabetic complications. With triglycerides reaching 22.68 mmol / L, cholesterol 9.75 mmol / L, and low-density lipoprotein cholesterol 5.7 mmol / L, she took fenofibrate 0.2 g daily. After 3, 6, and 8 weeks, triglycerides dropped to 6.57 mmol / L, 8.35 mmol / L, and 6.12 mmol / L, respectively. Liver function and muscle enzymes remained stable during this period. After 14 weeks of treatment, creatine kinase was 4402 U / L, myoglobin was greater than 3000 ng / mL, triglycerides were 13.14 mmol / L, aspartate aminotransferase and alanine aminotransferase were elevated, and renal function remained unchanged. After discontinuation of fenofibrate, muscle enzymes returned to normal, but triglycerides remained elevated at 16.58 mmol / L. A trial of statin therapy failed to reduce triglycerides, and muscle enzymes rose again. The statin therapy was discontinued. Because cholesterol was 10.32 mmol / L and probucol had minimal side effects on liver and kidney damage, probucol 0.5 g twice daily was administered. Liver function and muscle enzymes stabilized, but triglycerides remained elevated. However, fibrate and statin therapy could not be continued. During this period, intermittent pain and claudication in both lower limbs gradually progressed to persistent pain and inability to walk. The skin on both lower limbs gradually turned bluish-purple, and the skin temperature increased. Heparin anticoagulation was ineffective. Ultrasound of the lower limb arteries revealed multiple plaques, complete occlusion of most vessels, and severe stenosis in a small number of vessels. 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 to walk after 1 month. After 4 months of treatment, a B-ultrasound was repeated, and only one artery was completely occluded, and the remaining stenosis was significantly relieved. During the treatment, muscle enzyme and liver function indicators were monitored and stable. Blood lipids were stable at a low level. In the following years, the patient has been receiving red yeast rice and probucol combination treatment, and his liver function gradually returned to normal, muscle enzymes were normal, triglyceride levels fluctuated between 1.5-4mmol / L, no cardiovascular and cerebrovascular events occurred, there was no pain in both lower limbs, both lower limbs had normal activities, and the electrocardiogram QT interval was normal.

[0288] Surprisingly, it was found that the combination of probucol and red yeast rice had an excellent therapeutic effect on severe hypertriglyceridemia. In particular, when the daily dose of Zhibitai was 480 mg, the therapeutic effect of a daily dose of 125 mg of probucol (2 groups: probucol 62.5 mg + Zhibitai 240 mg, BID, and probucol 125 mg + Zhibitai 480 mg, QD) was significantly higher than the therapeutic effect of a daily dose of 625 mg of probucol (probucol 312.5 mg + Zhibitai 240 mg, BID).

[0289] Example 2: Study on the efficacy of a combination of probucol and red yeast rice in treating hypercholesterolemia.

[0290] Patients: A total of 28 patients with hypercholesterolemia received probucol and red yeast rice combination therapy. These patients included 16 males and 12 females, aged 27 to 78 years (mean, 56.54 ± 11.74 years). These patients included those who had previously received statins, statins combined with cholesterol absorption inhibitors, statins combined with PCSK9 monoclonal antibodies, and statins combined with both cholesterol absorption inhibitors and PCSK9 monoclonal antibodies. These patients also included patients with familial hypercholesterolemia and familial severe hypercholesterolemia.

[0291] Dosage regimen: Probucol is administered orally as 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 orally as the following commercially available Chinese patent medicines (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.

[0292] Treatment Results: After treatment with varying doses of probucol and red yeast rice, patients experienced a 40-45% decrease in plasma cholesterol, a 45-55% decrease in low-density lipoprotein cholesterol, and a 22-49% decrease in plasma triglycerides. See Table 3 below for detailed results.

[0293] Table 3 Treatment results of probucol and red yeast rice combination

[0294] 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

[0295] 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.

[0296] Compared with other drugs for treating hypercholesterolemia: Compared with probucol alone or red yeast rice alone at normal doses, the low-dose drug combination of the present invention can significantly reduce cholesterol and low-density lipoprotein-C. Long-term use can reduce cholesterol by 40-45% (calculated as the average value of the values ​​of each dosing group, the same below), and an average of 42% (calculated as the average value of the values ​​of all patients, the same below); low-density lipoprotein-C can be reduced by 45-55% (calculated as the average value of the values ​​of each dosing group, the same below), and an average of 50% (calculated as the average value of the values ​​of all patients, the same below). Plasma triglycerides decreased by 22-49%, an average of 27%, which is significantly greater than the effect of sufficient probucol, Zhibitai and Xuezhikang alone, and the effect is better than statins. See Table 4 below.

[0297] Table 4 Comparison of the efficacy of the combination of probucol and red yeast rice with other drugs for the treatment of hypercholesterolemia

[0298] drug triglycerides cholesterol LDL-C Probucol-Red Yeast Rice Combination down 27% down 42% 50% decrease <![CDATA[Probucol a > - Decrease of 9-29% Decrease of 10-15% <![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%

[0299] Data sources: a. Li Jiatai, Clinical Pharmacology (3rd ed.), 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.

[0300] Example 3: Study on changes in blood lipids after changing to combination therapy (i.e., combining with a low-dose of probucol) based on the original red yeast rice treatment.

[0301] Treatment subjects: 23 patients with hyperlipidemia who had been taking red yeast rice for more than 8 weeks, 11 males and 12 females, aged 29-77 years. Because their low-density lipoprotein and / or triglyceride levels were not up to standard, they continued treatment with low-dose probucol.

[0302] Dosing regimen: Probucol is administered orally as commercially available probucol tablets (125 mg / tablet) (which can be taken with water or chewed) at a dose of 62.5-250 mg once or twice daily. Red yeast rice is administered as Zhibitai capsules (240 mg / capsule, containing approximately 9.1 mg of monacolin K / capsule) at a dose of 240 mg once or twice daily. Probucol and red yeast rice are taken simultaneously for 7 weeks.

[0303] Treatment Results: After treatment with varying doses of probucol plus red yeast rice, patients' plasma cholesterol levels decreased by 22-25%, with an average of 24%. Low-density lipoprotein cholesterol levels decreased by 27-34%, with an average of 27%. This further reduction in LDL-C was superior to that achieved with a statin combined with ezetimibe (18%-20%). Specific results are shown in Table 5 below.

[0304] Table 5 Changes in blood lipids after treatment with original red yeast rice combined with probucol

[0305] 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

[0306] Example 4: Study on the efficacy of a drug combination of probucol and red yeast rice in treating hypercholesterolemia at double the dose.

[0307] Treatment subjects: Two patients with hypercholesterolemia received probucol and red yeast rice combination therapy, including one male and one female, aged 55-60 years.

[0308] Dosage regimen: Probucol was administered orally using commercially available probucol tablets (125 mg / tablet) at a dose of 125 or 250 mg twice daily. Red yeast rice was administered using Zhibitai capsules (240 mg / pill, containing approximately 9.1 mg of monacolin K / pill) at a dose of 240 or 480 mg twice daily. Probucol and red yeast rice were administered simultaneously. Initially, the low dose shown in Table 6 was administered for a period of more than 6 weeks, followed by a doubled dose (2 times the original dose) as shown in Table 6 for a period of 5-12 weeks.

[0309] Table 6 Efficacy of the combination of probucol and red yeast rice at double the dose

[0310] 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

[0311] 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 of LDL-C of more than 6% could be achieved.

[0312] Example 5: Study on the difference between low-dose and high-dose probucol and red yeast rice, taken separately and taken simultaneously.

[0313] Case 1: A 64-year-old female ASCVD patient had cholesterol levels of 5.79 mmol / L, LDL-C of 3.93 mmol / L, and triglycerides of 2.07 mmol / L. The doctor prescribed probucol 125 mg and valproate 0.24 g twice daily. The patient took the prescribed dosage according to the instructions, probucol 500 mg and valproate 0.24 g. Ten weeks later, a follow-up examination revealed cholesterol levels of 4.81 mmol / L, LDL-C of 2.92 mmol / L, and triglycerides of 2.63 mmol / L. The original dosage was resumed, and eight weeks later, the following results were obtained: cholesterol 4.19 mmol / L, LDL-C of 1.99 mmol / L, and triglycerides of 1.87 mmol / L. Results: Comparing the results of the three tests, increasing the dose of probucol in the combination and taking them simultaneously actually reduced 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 for cholesterol is consistent with its response for severe hypertriglyceridemia.

[0314] Case 2: A 75-year-old female ASCVD patient had cholesterol levels of 5.73 mmol / L, triglycerides of 1.55 mmol / L, and LDL-C of 3.22 mmol / L. Treatment: The doctor ordered a combined dose of 125 mg of probucol and 0.24 g of ciprofloxacin twice daily. However, the patient insisted that the Chinese and Western medications should be taken separately. After five weeks, a follow-up examination revealed cholesterol levels of 5.74 mmol / L, triglycerides of 1.66 mmol / L, and LDL-C of 3.47 mmol / L. After eight weeks of combined therapy, the results were 3.69 mmol / L, triglycerides of 1.24 mmol / L, and LDL-C of 2.13 mmol / L.

[0315] Results: Using the same dose of probucol and lipopolysaccharide, we observed differences between separate and simultaneous administration. Separation was ineffective. Increasing the probucol dose, even when taken together, was less effective in lowering severe hypertriglyceridemia and LDL-C. Despite being commonly used lipid-lowering medications, combined use of red yeast rice and probucol at low doses has not been associated with unexpected benefits. This is due to two factors: first, the traditional practice of taking traditional Chinese and Western medicine separately; second, the common sense principle of increasing the dose for enhanced cholesterol-lowering is to increase cholesterol levels.

[0316] Example 6: Other treatment cases of the drug combination of probucol and red yeast rice.

[0317] Case B1: A 36-year-old male with severe hypertriglyceridemia received probucol 312.5 mg plus 0.24 g of valproate twice daily for three weeks. Case B2: A 67-year-old female with ASCVD received probucol 312.5 mg plus 0.24 g of valproate twice daily for two weeks. The treatment outcomes for Cases B1 and B2 are shown in Table 7.

[0318] Table 7: Efficacy of combined use of probucol in specific cases

[0319] 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

[0320] Example 7: Examples of other administration routes.

[0321] Other case 1: A 72-year-old male patient with ASCVD had a history of elevated creatinine levels while taking statins, with cholesterol levels of 5.94 mmol / L, triglycerides of 1.25 mmol / L, and LDL-C levels of 2.98 mmol / L. He was given probucol 0.5 g BID and ezetimibe 20 mg QD. After 6 weeks, cholesterol levels were 4.21 mol / L, triglycerides of 1.22 mmol / L, and LDL-C levels of 1.76 mmol / L.

[0322] Other case 2: The patient was a 66-year-old female ASCVD patient with a history of elevated transaminases while taking statins. The cholesterol level was 7.21mmol / L, triglycerides were 3.11mmol / L, and LDL-C was 4.85mmol / L. She took 0.24g of statin BID and 1g of fish oil BID. After 8 weeks, the cholesterol level was 5.33mol / L, triglycerides were 1.96mmol / L, and LDL-C was 2.99mmol / L.

[0323] 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.

[0324] 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 embodiments. All technical solutions and improvements that do not depart from the spirit and scope of the invention should be considered to fall within the scope of protection of the present invention.

Claims

1. A pharmaceutical combination product, characterized in that The pharmaceutical combination product comprises probucol and red yeast rice; probucol and red yeast rice are configured for simultaneous administration, and the simultaneous administration form is in the form of an oral unit dosage form, 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.

2. The pharmaceutical combination product according to claim 1, characterized in that The weight ratio of probucol to red yeast rice is (1.5-75):1, and the weight of the red yeast rice is calculated based on the active substance monacolin K.

3. The pharmaceutical combination product according to claim 1, characterized in that The weight ratio of probucol to red yeast rice is (5-40):1, and the weight of the red yeast rice is calculated based on the active substance monacolin K.

4. The pharmaceutical combination product according to claim 1, characterized in that The weight ratio of probucol to red yeast rice is (6-20):1, and the weight of the red yeast rice is calculated based on the active substance monacolin K.

5. The pharmaceutical combination product according to claim 1, characterized in that The weight ratio of probucol to red yeast rice is (7-15):1, and the weight of the red yeast rice is calculated based on the active substance monacolin K.

6. The pharmaceutical combination product according to claim 1, characterized in that The weight ratio of probucol to red yeast rice is (1.5-40):1, and the weight of the red yeast rice is calculated based on the active substance monacolin K.

7. The pharmaceutical combination product according to claim 1, characterized in that The weight ratio of probucol to red yeast rice is (1.5-20):1, and the weight of the red yeast rice is calculated based on the active substance monacolin K.

8. The pharmaceutical combination product according to claim 1, characterized in that The weight ratio of probucol to red yeast rice is (1.5-15):1, and the weight of the red yeast rice is calculated based on the active substance monacolin K.

9. The pharmaceutical combination product according to claim 1, characterized in that The weight ratio of probucol to red yeast rice is (1-40):1, and the weight of the red yeast rice is calculated based on the active substance monacolin K.

10. The pharmaceutical combination product according to claim 1, characterized in that The weight ratio of probucol to red yeast rice is (1-75):1, and the weight of the red yeast rice is calculated based on the active substance monacolin K.

11. The pharmaceutical combination product according to claim 1, characterized in that The oral unit dosage form contains 20-800 mg of probucol.

12. The pharmaceutical combination product according to claim 2, characterized in that The oral unit dosage form contains 20-800 mg of probucol.

13. The pharmaceutical combination product according to claim 3, characterized in that The oral unit dosage form contains 20-800 mg of probucol.

14. The pharmaceutical combination product according to claim 4, characterized in that The oral unit dosage form contains 20-800 mg of probucol.

15. The pharmaceutical combination product according to claim 5, characterized in that The oral unit dosage form contains 20-800 mg of probucol.

16. The pharmaceutical combination product according to claim 6, characterized in that The oral unit dosage form contains 20-800 mg of probucol.

17. The pharmaceutical combination product according to claim 7, characterized in that The oral unit dosage form contains 20-800 mg of probucol.

18. The pharmaceutical combination product according to claim 8, characterized in that The oral unit dosage form contains 20-800 mg of probucol.

19. The pharmaceutical combination product according to claim 9, characterized in that The oral unit dosage form contains 20-800 mg of probucol.

20. The pharmaceutical combination product according to claim 10, characterized in that The oral unit dosage form contains 20-800 mg of probucol.

21. The pharmaceutical combination product according to claim 1, characterized in that The oral unit dosage form is selected from tablets, capsules, granules, pellets, and micropills.

22. The pharmaceutical combination product according to claim 21, 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.

23. A pharmaceutical combination product characterized in that The pharmaceutical combination product comprises probucol and red yeast rice; probucol and red yeast rice are configured for simultaneous administration, and the simultaneous administration form is in the form of an oral unit dosage form, wherein the oral unit dosage form comprises 20-800 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.

24. The pharmaceutical combination product according to claim 23, characterized in that The oral unit dosage form 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.

25. The pharmaceutical combination product according to claim 23, characterized in that The oral unit dosage form is selected from tablets, capsules, granules, pellets, and micropills.

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

27. The pharmaceutical combination product according to claim 23, 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, 125 130 mg mg, 240 mg, 245 mg, 250 or 400 mg of probucol and 2-50 mg of red yeast rice, the weight of which is calculated as the active ingredient monacolin K.

28. The pharmaceutical combination product according to claim 27, characterized in that The oral unit dosage form contains 2-40 mg of red yeast rice, and the weight of the red yeast rice is calculated as the active substance monacolin K.

29. The pharmaceutical combination product according to claim 27, characterized in that The oral unit dosage form contains 2-35 mg of red yeast rice, the weight of which is calculated as the active substance monacolin K.

30. The pharmaceutical combination product according to claim 27, characterized in that The oral unit dosage form contains 2-30 mg of red yeast rice, the weight of which is calculated as the active substance monacolin K.

31. The pharmaceutical combination product according to claim 27, characterized in that The oral unit dosage form contains 2-20 mg of red yeast rice, and the weight of the red yeast rice is calculated as the active substance monacolin K.

32. The pharmaceutical combination product according to claim 27, characterized in that The oral unit dosage form contains 3-40 mg of red yeast rice, where the weight of the red yeast rice is calculated as the active substance monacolin K.

33. The pharmaceutical combination product according to claim 27, characterized in that The oral unit dosage form contains 5-35 mg of red yeast rice, the weight of which is calculated as the active substance monacolin K.

34. The pharmaceutical combination product according to claim 27, characterized in that The oral unit dosage form contains 7-30 mg of red yeast rice, the weight of which is calculated as the active substance monacolin K.

35. The pharmaceutical combination product according to claim 27, characterized in that The oral unit dosage form contains 7-20 mg of red yeast rice, the weight of which is calculated as the active substance monacolin K.

36. A pharmaceutical combination product characterized in that The pharmaceutical combination product comprises probucol and red yeast rice; probucol and red yeast rice are configured for simultaneous administration in the form of an oral unit dosage form, wherein the oral unit dosage form comprises: Probucol as the active ingredient in an amount of 20-800 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 2-50 mg of red yeast rice, wherein the weight of the red yeast rice is calculated as the active substance monacolin K.

37. The pharmaceutical combination product according to claim 36, characterized in that The oral unit dosage form contains 2-40 mg of red yeast rice, and the weight of the red yeast rice is calculated as the active substance monacolin K.

38. The pharmaceutical combination product according to claim 36, characterized in that The oral unit dosage form contains 2-35 mg of red yeast rice, the weight of which is calculated as the active substance monacolin K.

39. The pharmaceutical combination product according to claim 36, characterized in that The oral unit dosage form contains 2-30 mg of red yeast rice, the weight of which is calculated as the active substance monacolin K.

40. The pharmaceutical combination product according to claim 36, characterized in that The oral unit dosage form contains 2-20 mg of red yeast rice, and the weight of the red yeast rice is calculated as the active substance monacolin K.

41. The pharmaceutical combination product according to claim 36, characterized in that The oral unit dosage form contains 3-40 mg of red yeast rice, where the weight of the red yeast rice is calculated as the active substance monacolin K.

42. The pharmaceutical combination product according to claim 36, characterized in that The oral unit dosage form contains 5-35 mg of red yeast rice, the weight of which is calculated as the active substance monacolin K.

43. The pharmaceutical combination product according to claim 36, characterized in that The oral unit dosage form contains 7-30 mg of red yeast rice, the weight of which is calculated as the active substance monacolin K.

44. The pharmaceutical combination product according to claim 36, characterized in that The oral unit dosage form contains 7-20 mg of red yeast rice, the weight of which is calculated as the active substance monacolin K.

45. The pharmaceutical combination product according to claim 36, characterized in that The oral unit dosage form comprises, as an active ingredient, probucol 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 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 and / or 400 mg, and 2-50 mg of red yeast rice, wherein the weight of the red yeast rice is calculated as the active substance monacolin K.

46. ​​The pharmaceutical combination product according to claim 36, characterized in that The oral unit dosage form is selected from tablets, capsules, granules, pellets, and micropills.

47. The pharmaceutical combination product according to claim 46, 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.

48. A pharmaceutical combination product, characterized in that The pharmaceutical combination product comprises probucol and red yeast rice; probucol and red yeast rice are configured for simultaneous administration, wherein the simultaneous administration is in the form of a medicine kit, wherein the medicine kit comprises 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 comprises probucol and red yeast rice in a weight ratio of (1-100):1, and the weight of the red yeast rice is calculated as the active substance monacolin K.

49. The pharmaceutical combination product according to claim 48, characterized in that The weight ratio of probucol to red yeast rice is (1.5-75):1, and the weight of the red yeast rice is calculated based on the active substance monacolin K.

50. The pharmaceutical combination product according to claim 48, characterized in that The weight ratio of probucol to red yeast rice is (5-40):1, and the weight of the red yeast rice is calculated based on the active substance monacolin K.

51. The pharmaceutical combination product according to claim 48, characterized in that The weight ratio of probucol to red yeast rice is (6-20):1, and the weight of the red yeast rice is calculated based on the active substance monacolin K.

52. The pharmaceutical combination product according to claim 48, characterized in that The weight ratio of probucol to red yeast rice is (7-15):1, and the weight of the red yeast rice is calculated based on the active substance monacolin K.

53. The pharmaceutical combination product according to claim 48, characterized in that The weight ratio of probucol to red yeast rice is (1.5-40):1, and the weight of the red yeast rice is calculated based on the active substance monacolin K.

54. The pharmaceutical combination product according to claim 48, characterized in that The weight ratio of probucol to red yeast rice is (1.5-20):1, and the weight of the red yeast rice is calculated based on the active substance monacolin K.

55. The pharmaceutical combination product according to claim 48, characterized in that The weight ratio of probucol to red yeast rice is (1.5-15):1, and the weight of the red yeast rice is calculated based on the active substance monacolin K.

56. The pharmaceutical combination product according to claim 48, characterized in that The weight ratio of probucol to red yeast rice is (1-75):1, and the weight of the red yeast rice is calculated based on the active substance monacolin K.

57. The pharmaceutical combination product according to claim 48, characterized in that The weight ratio of probucol to red yeast rice is (1-40):1, and the weight of the red yeast rice is calculated based on the active substance monacolin K.

58. The pharmaceutical combination product according to claim 48, characterized in that The single composition comprises 20-800 mg of probucol.

59. The pharmaceutical combination product according to claim 49, characterized in that The single composition comprises 20-800 mg of probucol.

60. The pharmaceutical combination product according to claim 50, characterized in that The single composition comprises 20-800 mg of probucol.

61. The pharmaceutical combination product according to claim 51, characterized in that The single composition comprises 20-800 mg of probucol.

62. The pharmaceutical combination product according to claim 52, characterized in that The single composition comprises 20-800 mg of probucol.

63. The pharmaceutical combination product according to claim 53, characterized in that The single composition comprises 20-800 mg of probucol.

64. The pharmaceutical combination product according to claim 54, characterized in that The single composition comprises 20-800 mg of probucol.

65. The pharmaceutical combination product according to claim 55, characterized in that The single composition comprises 20-800 mg of probucol.

66. The pharmaceutical combination product according to claim 56, characterized in that The single composition comprises 20-800 mg of probucol.

67. The pharmaceutical combination product according to claim 57, characterized in that The single composition comprises 20-800 mg of probucol.

68. A pharmaceutical combination product characterized by The pharmaceutical combination product comprises probucol and red yeast rice; probucol and red yeast rice are configured for simultaneous administration, wherein the simultaneous administration is in the form of a medicine kit, wherein the medicine kit comprises 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 comprises 20-800 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.

69. The pharmaceutical combination product according to claim 68, characterized in that The single composition comprises: Probucol as the active ingredient in an amount of 20-800 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 2-50 mg of red yeast rice, wherein the weight of the red yeast rice is calculated as the active substance monacolin K.

70. The pharmaceutical combination product according to claim 68, characterized in that The single composition comprises 20-400 mg of probucol and 2-50 mg of red yeast rice, the weight of which is calculated as the active substance monacolin K.

71. The pharmaceutical combination product according to claim 68, 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, 245 mg, 250 mg, 255 , 375 mg, 380 mg, 385 mg, 390 mg, 395 mg or 400 mg of probucol and 2-50 mg of red yeast rice, the weight of which is calculated as the active ingredient monacolin K.

72. The pharmaceutical combination product according to claim 71, characterized in that The single composition comprises 2-40 mg of red yeast rice, the weight of which is calculated as the active substance monacolin K.

73. The pharmaceutical combination product according to claim 71, characterized in that The single composition contains 2-35 mg of red yeast rice, the weight of which is calculated as the active substance monacolin K.

74. The pharmaceutical combination product according to claim 71, characterized in that The single composition contains 2-30 mg of red yeast rice, the weight of which is calculated as the active substance monacolin K.

75. The pharmaceutical combination product according to claim 71, characterized in that The single composition contains 2-20 mg of red yeast rice, the weight of which is calculated as the active substance monacolin K.

76. The pharmaceutical combination product according to claim 71, characterized in that The single composition contains 3-40 mg of red yeast rice, the weight of which is calculated as the active substance monacolin K.

77. The pharmaceutical combination product according to claim 71, characterized in that The single composition contains 5-35 mg of red yeast rice, the weight of which is calculated as the active substance monacolin K.

78. The pharmaceutical combination product according to claim 71, characterized in that The single composition contains 7-30 mg of red yeast rice, the weight of which is calculated as the active substance monacolin K.

79. The pharmaceutical combination product according to claim 71, characterized in that The single composition contains 7-20 mg of red yeast rice, the weight of which is calculated as the active substance monacolin K.

80. The pharmaceutical combination according to any one of claims 1 to 79, characterized in that Red Yeast Rice is provided as natural red yeast rice.

81. The pharmaceutical combination according to any one of claims 1 to 79, characterized in that Red yeast rice is available as the traditional Chinese medicine red yeast rice.

82. The pharmaceutical combination according to any one of claims 1 to 79, characterized in that Red yeast rice is provided in the form of functional red yeast rice.

83. The pharmaceutical combination according to any one of claims 1 to 79, characterized in that The red yeast rice is provided in the form of a red yeast rice extract or a composition containing the red yeast rice.

84. The pharmaceutical combination product according to claim 83, characterized in that The red yeast rice extract or the composition containing red yeast rice is selected from Zhibituo, Zhibitai and Xuezhikang.

85. Use of a pharmaceutical combination according to any one of claims 1 to 84 in the preparation of a medicament for treating hyperlipidemia in a subject in need thereof.

86. The use according to claim 85, characterized in that The hyperlipidemia is familial or non-familial hypertriglyceridemia, familial or non-familial hypercholesterolemia, or a combination.

87. The use according to claim 85, characterized in that The hyperlipidemia is a combination of hypertriglyceridemia and severe hypercholesterolemia.

88. The use according to claim 85, characterized in that The hyperlipidemia is a combination of severe hypertriglyceridemia and hypercholesterolemia.

89. The use according to claim 85, characterized in that The hyperlipidemia is hyperlipidemia that is ineffective or ineffectively treated with statins and / or red yeast rice.

90. The use according to claim 85, characterized in that The hyperlipidemia is fibrate-intolerant or fibrate-unresponsive hyperlipidemia.

91. The use according to claim 85, characterized in that The hyperlipidemia is hypercholesterolemia that is ineffective or ineffectively treated with statins and / or red yeast rice.

92. The use according to claim 85, characterized in that The hyperlipidemia is hypertriglyceridemia for which statins and / or red yeast rice are ineffective or ineffective to treat.

93. The use according to claim 85, characterized in that The hyperlipidemia is hypertriglyceridemia that is intolerant to or unresponsive to fibrate drugs.

94. The use according to claim 85, characterized in that The hyperlipidemia is familial or non-familial severe hypertriglyceridemia, or familial or non-familial severe hypercholesterolemia, or a combination.

95. The use according to claim 85, characterized in that The hyperlipidemia is severe hypercholesterolemia that is ineffective or ineffectively treated with statins and / or red yeast rice.

96. The use according to claim 85, characterized in that The hyperlipidemia is severe hypertriglyceridemia for which statins and / or red yeast rice are ineffective or ineffective in treatment.

97. The use according to claim 85, characterized in that The hyperlipidemia is severe hypertriglyceridemia that is intolerant to or unresponsive to fibrate drugs.

98. The method according to any one of claims 86, 88 and 91, characterized in that Hypercholesterolemia refers to TC > 6.22 mmol / L and / or LDL-C > 4.14 mmol / L.

99. The method according to any one of claims 86, 87, 92 and 93, characterized in that Hypertriglyceridemia refers to TG > 1.7 mmol / L.

100. The use according to any one of claims 88, 94, 96, and 97, characterized in that Severe hypertriglyceridemia refers to a TG level of TG ≥ 5.6 mmol / L.

101. The use according to any one of claims 87, 94, and 95, characterized in that Severe hypercholesterolemia refers to LDL-C>4.9 mmol / L.

102. Use of a pharmaceutical combination according to any one of claims 1 to 84 for the preparation of a medicament for treating hyperlipidemia in a subject in need thereof, characterized in that The hyperlipidemia meets the following requirements: The subject is an extremely high-risk ASCVD patient and meets one of the following requirements: (1) LDL-C level greater than 1.8 mmol / L; (2) The subject has received statin treatment, 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) 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 is reduced by <50% compared to baseline; or Patients with significant statin side effects who require dose reduction; or Patients who have severe side effects from cholesterol absorption inhibitors or PCSK9 monoclonal antibodies and need to stop taking statins in combination with cholesterol absorption inhibitors or statins in combination with PCSK9 monoclonal antibodies, or statins in combination with cholesterol absorption inhibitors and PCSK9 monoclonal antibodies; The extremely high-risk ASCVD patients mentioned here are divided according to the standards of the "Guidelines for Chinese Blood Lipid Management (2023)".

103. Use of a pharmaceutical combination according to any one of claims 1 to 84 for the preparation of a medicament for treating hyperlipidemia in a subject in need thereof, characterized in that The hyperlipidemia meets the following requirements: The subject is an ASCVD ultra-high-risk patient and meets one of the following requirements: (1) LDL-C level greater than 1.4 mmol / L; (2) The subject has received statin treatment, and / or has received statin combined with cholesterol absorption inhibitor, statin combined with PCSK9 monoclonal antibody, or statin combined with cholesterol absorption inhibitor and PCSK9 monoclonal antibody, and the LDL-C level is greater than 1.4 mmol / L; (3) 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 is reduced by <50% compared to baseline; or Patients with significant statin side effects who require dose reduction; or Patients who have severe side effects from cholesterol absorption inhibitors or PCSK9 monoclonal antibodies and need to stop taking statins in combination with cholesterol absorption inhibitors or statins in combination with PCSK9 monoclonal antibodies, or statins in combination with cholesterol absorption inhibitors and PCSK9 monoclonal antibodies; The ultra-high-risk ASCVD patients mentioned here are divided according to the standards of the "Guidelines for Chinese Blood Lipid Management (2023)".

104. Use of a pharmaceutical combination according to any one of claims 1 to 84 for the preparation of a medicament for treating hyperlipidemia in a subject in need thereof, characterized in that The hyperlipidemia meets the following requirements: The subject is a high-risk ASCVD patient and meets one of the following requirements: (1) LDL-C level greater than 2.6 mmol / L; (2) The subject has received statin treatment, 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; (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 is reduced by <50% compared to baseline; or Patients with significant statin side effects who require dose reduction; or Patients who have severe side effects from cholesterol absorption inhibitors or PCSK9 monoclonal antibodies and need to stop taking statins in combination with cholesterol absorption inhibitors or statins in combination with PCSK9 monoclonal antibodies, or statins in combination with cholesterol absorption inhibitors and PCSK9 monoclonal antibodies; The high-risk ASCVD patients mentioned here are divided according to the standards of the "Guidelines for Chinese Blood Lipid Management (2023)".

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