Application of pharmaceutical composition in preparation of cholesterol-lowering drugs

Abstract

The present invention provides an application of a pharmaceutical composition in preparation of a cholesterol lowering drug, and particularly provides a product composition, which comprises: (i) a first pharmaceutical composition, which contains (a) a first active component, which is diol-type ginsenoside and a pharmaceutically acceptable carrier; and (ii) a second pharmaceutical composition, the second pharmaceutical composition containing (b) a second active ingredient, the second active ingredient being a statin drug, and a pharmaceutically acceptable carrier; wherein the first pharmaceutical composition and the second pharmaceutical composition are different pharmaceutical compositions or the same pharmaceutical composition. The product composition disclosed by the invention can be used for synergistically preventing and / or treating high cholesterol related diseases.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, and more specifically, to the use of a pharmaceutical composition in the preparation of cholesterol-lowering drugs. Background Technology

[0002] The main lipid components in blood plasma include total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c). LDL-c is the main culprit behind blood vessel blockage, coronary heart disease, and stroke, hence it's called "bad cholesterol." HDL-c transports LDL-c from the blood back to the liver, lowering LDL-c levels and preventing its deposition on blood vessel walls. HDL-c can also carry 1 / 4 to 3 / 4 of the cholesterol in the blood. Furthermore, HDL-c may remove excess cholesterol from atherosclerotic plaques, thus it's called "good cholesterol."

[0003] Hypercholesterolemia is a common and prevalent metabolic disease, mainly caused by abnormalities in the metabolism or transport of adipose tissue, resulting in elevated levels of one or more lipids in the serum, primarily characterized by elevated total cholesterol (TC) and triglycerides (TG). Systemic atherosclerosis and renal failure are closely related to hyperlipidemia. Numerous studies have shown that hyperlipidemia is a significant risk factor for stroke, coronary heart disease, and myocardial infarction. Furthermore, hyperlipidemia is also a major risk factor for hypertension, impaired glucose tolerance, and diabetes. Hyperlipidemia can also lead to fatty liver, cirrhosis, gallstones, pancreatitis, retinal hemorrhage and even blindness, peripheral vascular disease, and hyperuricemia. Fatty liver, caused by excessive fat accumulation in liver cells, is seriously threatening the health of the Chinese population, becoming the second most common liver disease after viral hepatitis, and is widely recognized as a common cause of occult cirrhosis. Fatty liver is a common clinical phenomenon, not an independent disease. Its clinical manifestations range from asymptomatic in mild cases to rapidly progressing in severe cases. Generally, fatty liver is a reversible disease; early diagnosis and timely treatment often lead to recovery. Nonalcoholic fatty liver disease (NAFLD) is a clinical and pathological syndrome characterized by fat accumulation in hepatocytes due to various causes without a history of excessive alcohol consumption. It is a common clinical condition.

[0004] HMG-CoA reductase (HMGCR) is a rate-limiting enzyme in cholesterol synthesis, primarily located on the endoplasmic reticulum (ER) membrane of hepatocytes. It catalyzes the production of mevalonate from the substrate HMG-CoA, a necessary precursor for cholesterol synthesis. HMGCR inhibitors (statins) reduce cholesterol synthesis by competitively inhibiting HMGCR, thereby lowering the level of low-density lipoprotein cholesterol (LDL-C) in the blood.

[0005] The safety of statins is receiving increasing attention. The most serious and common side effects are liver damage and muscle toxicity (myalgia, myositis, and rhabdomyolysis, etc.). Other manifestations include gastrointestinal discomfort, headache, sleep disturbances, and peripheral neuropathy. In particular, long-term use of statins leads to a compensatory increase in HMGCR protein, forcing patients to increase the dosage to suppress the increased intracellular HMGCR. This effect severely weakens the efficacy of statins and increases side effects. Although this drawback of statins was recognized from the beginning of their clinical use, there is still no way to prevent statin-induced HMGCR accumulation and its side effects.

[0006] Natural products play a crucial role in the discovery of lead compounds for novel drugs. As a significant source of natural products, plant secondary metabolites not only boast diverse structural types but also exhibit numerous compounds with remarkable biological activities. For example, ginseng, a traditional and precious Chinese herbal medicine with a long history, is primarily used for strengthening the body and prolonging life. Studies have shown that ginsenosides are the main active components of ginseng. Ginsenosides are triterpenoid glycosides, which can be classified into diol and triol types based on the number of hydroxyl groups in the aglycone. Currently, various pharmacologically active ginsenosides have been applied, such as the antitumor drug ginsenoside Rg3 and the antiarrhythmic drug ginsenoside Re. However, existing reports do not mention the use of ginsenosides for degrading HMGCR protein.

[0007] Therefore, there is an urgent need in this field to develop a method that can effectively treat high cholesterol-related diseases, reduce the dosage of statins, and thus reduce side effects. Summary of the Invention

[0008] The purpose of this invention is to develop a method that can effectively treat high cholesterol-related diseases and reduce the side effects caused by long-term, high-dose use of statins.

[0009] This application addresses the aforementioned technical problems by providing a pharmaceutical composition of diol-type ginsenosides and statin molecules, and the application of the pharmaceutical preparation in lowering cholesterol, including reducing blood cholesterol and liver cholesterol, thereby treating hypercholesterolemia, and combating atherosclerosis and non-alcoholic steatohepatitis.

[0010] The first aspect of the present invention provides a product portfolio comprising:

[0011] (i) a first pharmaceutical composition comprising (a) a first active ingredient, wherein the first active ingredient is a diol-type ginsenoside, and a pharmaceutically acceptable carrier; and

[0012] (ii) a second pharmaceutical composition comprising (b) a second active ingredient, the second active ingredient being a statin, and a pharmaceutically acceptable carrier;

[0013] The first pharmaceutical composition and the second pharmaceutical composition may be different pharmaceutical compositions or the same pharmaceutical composition.

[0014] In another preferred embodiment, the diol-type ginsenoside is selected from the group consisting of: protopanaxadiol, ginsenoside CK, ginsenoside Rh2, 25-hydroxyprotopanaxadiol, 25-hydroxymethylprotopanaxadiol, or combinations thereof.

[0015] In another preferred embodiment, the statin is selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, or combinations thereof.

[0016] In another preferred embodiment, the weight ratio of component (i) to component (ii) is 1:1-20, more preferably, 1:1-10, more preferably, 1:1-4, and even more preferably, 1:1-2.

[0017] In another preferred embodiment, the content of the diol-type ginsenoside in the product combination is 1%-99%, more preferably 1%-60%, and even more preferably 1%-30%.

[0018] In another preferred embodiment, the statin drug content in the product combination is 1%-99%, more preferably 10%-90%, and even more preferably 50%-90%.

[0019] In another preferred embodiment, the components (i) and (ii) account for 0.01-99.99 wt% of the total weight of the product combination, more preferably 0.1-80 wt%, and even more preferably 1-50 wt%.

[0020] In another preferred embodiment, the dosage form of the pharmaceutical composition includes injectable dosage forms and oral dosage forms.

[0021] In another preferred embodiment, the oral dosage form includes tablets, capsules, films, and granules.

[0022] In another preferred embodiment, the dosage form of the pharmaceutical composition includes a sustained-release dosage form and a non-sustained-release dosage form.

[0023] A second aspect of the present invention provides a composition comprising:

[0024] (i) Diol-type ginsenosides;

[0025] (ii) statins; and

[0026] (iii) Pharmaceutically acceptable carriers.

[0027] In another preferred embodiment, the weight ratio of component (i) to component (ii) is 1:1-20, more preferably, 1:1-10, more preferably, 1:1-4, and even more preferably, 1:1-2.

[0028] In another preferred embodiment, the components (i) and (ii) in the composition account for 0.01-99.99 wt% of the total weight of the medicine box, more preferably 0.1-80 wt%, and even more preferably 1-50 wt%.

[0029] In another preferred embodiment, the composition further includes other medications for treating high cholesterol-related diseases.

[0030] In another preferred embodiment, the high cholesterol-related diseases include hypercholesterolemia, anti-atherosclerosis, and anti-nonalcoholic steatohepatitis.

[0031] A third aspect of the present invention provides a medicine box, comprising:

[0032] (a1) A first container, and a diol-type ginsenoside or a drug containing a diol-type ginsenoside located in the first container;

[0033] (b1) A second container, and a statin drug or a drug containing a statin drug located in the second container.

[0034] In another preferred embodiment, the weight ratio of the diol-type ginsenoside to statins is 1:1-20, more preferably, 1:1-10, even more preferably, 1:1-4, and still more preferably, 1:1-2.

[0035] In another preferred embodiment, the first container and the second container may be the same or different containers.

[0036] In another preferred embodiment, the drug in the first container is a single-ingredient preparation containing diol-type ginsenosides.

[0037] In another preferred embodiment, the drug in the second container is a single-drug formulation containing a statin.

[0038] In another preferred embodiment, the dosage form of the drug is an oral dosage form or an injectable dosage form.

[0039] In another preferred embodiment, the kit also includes instructions for use.

[0040] In another preferred embodiment, the specification includes the following description:

[0041] (a) A method for synergistic treatment of high cholesterol-related diseases by combining diol-type ginsenosides with statins;

[0042] (b) A method of synergistically promoting the degradation of HMGCR protein and reducing endogenous cholesterol levels by combining diol-type ginsenosides and statins.

[0043] A fourth aspect of the present invention provides a combination of ginsenoside diol and statin drugs for the preparation of a pharmaceutical composition or kit for the prevention and / or treatment of high cholesterol-related diseases.

[0044] In another preferred embodiment, the weight ratio of the diol-type ginsenoside to statins is 1:1-20, more preferably, 1:1-10, even more preferably, 1:1-4, and still more preferably, 1:1-2.

[0045] In another preferred embodiment, the high cholesterol-related diseases include hypercholesterolemia, anti-atherosclerosis, and anti-nonalcoholic steatohepatitis.

[0046] In another preferred embodiment, the pharmaceutical composition or cassette promotes the degradation of HMGCR protein while inhibiting HMGCR activity, thereby reducing endogenous cholesterol levels.

[0047] In another preferred embodiment, the effective concentration of the diol-type ginsenoside is 0.1 μM-50 μM, more preferably 1-20 μM, even more preferably 2-10 μM, and still more preferably 2-6 μM.

[0048] In another preferred embodiment, the pharmaceutical composition or kit comprises (a) a diol-type ginsenoside; and (b) a statin; and (c) a pharmaceutically acceptable carrier.

[0049] In another preferred embodiment, the diol-type ginsenosides and statins account for 0.01-99.99 wt% of the total weight of the pharmaceutical composition or cassette, more preferably 0.1-80 wt%, and even more preferably 1-50 wt%.

[0050] In another preferred embodiment, the pharmaceutical composition or kit may also include other medications for treating high cholesterol-related diseases.

[0051] The fifth aspect of the present invention provides a method for treating high cholesterol-related diseases, comprising:

[0052] The product combination described in the first aspect of the present invention, the composition described in the second aspect of the present invention, or the medicine box described in the third aspect of the present invention may be applied to the recipient.

[0053] In another preferred embodiment, the object includes a person or non-human mammal suffering from a high cholesterol-related disease.

[0054] In another preferred embodiment, the non-human mammals include rodents and primates, preferably mice, rats, rabbits, and monkeys.

[0055] In another preferred embodiment, the weight ratio of the diol-type ginsenoside to statins is 1:1-20, more preferably, 1:1-10, even more preferably, 1:1-4, and still more preferably, 1:1-2.

[0056] In another preferred embodiment, the dosage of the diol-type ginsenoside is 0.1-100 mg / kg, more preferably 1-60 mg / kg, and even more preferably 5-30 mg / kg.

[0057] In another preferred embodiment, the dosage of the statin is 0.1-200 mg / kg, more preferably 1-100 mg / kg, and even more preferably 10-60 mg / kg.

[0058] In another preferred embodiment, the diol-type ginsenoside is applied 1-6 times daily, more preferably 2-4 times daily, and most preferably once daily.

[0059] In another preferred embodiment, the diol-type ginsenoside is applied for 1-4000 days, more preferably 1-1000 days, and most preferably 1-365 days.

[0060] In another preferred embodiment, the statin is administered 1-6 times daily, more preferably 2-4 times daily, and most preferably once daily.

[0061] In another preferred embodiment, the duration of administration of the statin is 1-4000 days, more preferably 1-1000 days, and most preferably 1-365 days.

[0062] In another preferred embodiment, the diol-type ginsenosides are administered simultaneously or sequentially with statins.

[0063] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0064] Figure 1 The HMGCR degradation activity of protopanaxadiol in HepG2 cells

[0065] Figures 2-4 For animal testing. Among them, Figure 2 For changes in mouse body weight, Figure 3 For the detection of serum and liver cholesterol levels, Figure 4 For the detection of HMGCR protein levels in the liver. Detailed Implementation

[0066] Through extensive and in-depth research, the inventors unexpectedly discovered for the first time that the combined use of the diol-type ginsenosides of this invention and statins can effectively treat high cholesterol-related diseases and has a synergistic effect. Based on this, the inventors completed this invention.

[0067] Ginsenoside diol (formerly ginsenoside diol)

[0068] Protopanaxadiol-type saponins, as the main saponin components of ginseng, have a wide range of pharmacological effects in cardiovascular diseases, anti-tumor, immune regulation, diabetes and inflammation. To date, more than 20 types of protopanaxadiol-type saponins have been discovered, including ginsenosides Rbl, Rb2, Rc, Rd, Rh2, RS3, CK, protopanaxadiol and its derivatives.

[0069] statins

[0070] Statins, or 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors, not only effectively lower total cholesterol (TC) and low-density lipoprotein (LDL), but also reduce triglycerides (TG) to some extent and increase high-density lipoprotein (HDL). Therefore, statins can be considered a relatively comprehensive lipid-regulating drug. The mechanism of action of statins is through competitive inhibition of HMG-CoA reductase, the rate-limiting enzyme in endogenous cholesterol synthesis, blocking the intracellular hydroxymethylvalerate metabolic pathway, thus reducing intracellular cholesterol synthesis. This, in turn, provides feedback stimulation to increase the number and activity of LDL receptors on the cell membrane, leading to increased serum cholesterol clearance and a decrease in serum cholesterol levels. Clinically, they are mainly used to lower cholesterol, especially LDL-C, and to treat atherosclerosis. They have now become the most effective drugs for the prevention and treatment of coronary heart disease.

[0071] The research of this invention shows that the diol-type ginsenosides of this invention, when used in combination with statins such as lovastatin for the prevention and / or treatment of high cholesterol-related diseases, can exert a synergistic effect, effectively improving the efficacy of prevention and / or treatment of high cholesterol-related diseases. Furthermore, this invention also finds that combining diol-type ginsenosides (such as protopanaxadiol) with statins such as lovastatin in specific ratios, such as 1:1-20, preferably 1:1-10, more preferably 1:1-4, and even more preferably 1:1-2, yields even better results.

[0072] Composition and method of application

[0073] As used herein, the term "composition" includes (a1) a first active ingredient, wherein the first active ingredient is a diol-type ginsenoside; and (a2) a second active ingredient, wherein the second active ingredient is a statin; and (b) a pharmaceutically acceptable carrier. Furthermore, the compositions include pharmaceutical compositions.

[0074] Typically, the active ingredients of this invention can be formulated into a non-toxic, inert, and pharmaceutically acceptable carrier medium. The formulated pharmaceutical compositions can be administered via conventional routes, including (but not limited to): oral, intramuscular, intraperitoneal, intravenous, subcutaneous, intradermal, or local administration.

[0075] This invention also provides a pharmaceutical composition containing a safe and effective amount of the active ingredient of this invention and a pharmaceutically acceptable carrier or excipient. Such carriers include (but are not limited to): saline, buffer solutions, glucose, water, glycerol, ethanol, and combinations thereof. The pharmaceutical formulation should be matched to the route of administration. The pharmaceutical compositions of this invention can be formulated into injectable forms, for example, prepared by conventional methods using physiological saline or an aqueous solution containing glucose and other excipients. Pharmaceutical compositions such as tablets and capsules can be prepared by conventional methods. Pharmaceutical compositions such as injections, solutions, tablets, and capsules are preferably manufactured under sterile conditions. The dosage of the active ingredient is a therapeutically effective amount, for example, about 1 microgram to 10 milligrams per kilogram of body weight per day. Preferably, the dosage of an EP4 receptor antagonist can be: 0.1 to 2000 mg daily for adults, preferably 1 to 300 mg / day. The dosage of a PD-1 inhibitor can be: 0.1 to 2000 mg every two weeks for adults, preferably 1 to 300 mg / two weeks. As a drug for adjuvant therapy against tumors, it can be formulated into oral and non-oral formulations. Oral administration can be formulated into common dosage forms such as tablets, powders, granules, and capsules. The excipients used can be one or more of starch, lactose, sucrose, mannose, and hydroxymethyl cellulose. Disintegrants can be one or more of potato starch and hydroxymethyl cellulose. Binders can be one or more of gum arabic, corn starch, gelatin, and dextrin. In addition to the above dosage forms, oral preparations can also be formulated into emulsions and syrups.

[0076] Non-oral preparations can be formulated into injectable forms, which can be prepared with water for injection, physiological saline, or glucose solution, or with the addition of certain proportions of ethanol, propanol, ethylene glycol, etc. They can also be formulated into commonly used dosage forms such as nasal drops, sprays, rectal suppositories, and rectal retention enemas.

[0077] Furthermore, the active ingredients of this invention are particularly suitable for use in combination with other drugs for treating tumors (such as immune checkpoint inhibitors and immune agonists) to more effectively prevent and / or treat high cholesterol-related diseases.

[0078] medicine box

[0079] The present invention also provides a medicine box, the medicine box comprising:

[0080] (a1) A first container, and a diol-type ginsenoside or a drug containing a diol-type ginsenoside located in the first container;

[0081] (b1) A second container, and a statin drug or a drug containing a statin drug located in the second container.

[0082] In a preferred embodiment, the first container and the second container may be the same or different containers.

[0083] The preparation containing diol-type ginsenosides can be a single dosage form containing diol-type ginsenosides, and the preparation containing statins can be a single dosage form containing statins.

[0084] As used herein, the term "unit dosage form" refers to a dosage form in which a composition is prepared for a single dose for ease of administration, including but not limited to various solid dosage forms (such as tablets), liquid dosage forms, capsules, and sustained-release formulations.

[0085] In another preferred embodiment, the instruction manual describes the following method of use:

[0086] (I) Simultaneously administer to the desired subject a preparation containing diol-type ginsenosides and a preparation containing statins; and optionally (II) repeat steps (I)-(II).

[0087] The formulation of this invention can be taken three times a day to once every twenty days, or in a sustained-release manner once every ten days. The preferred method is once daily, as this facilitates patient adherence and significantly improves patient compliance.

[0088] When taking this medication, in most cases the total daily dose should be lower than (or in a few cases equal to or slightly greater than) the usual daily dose of each individual drug. Of course, the effective dose of the active ingredient may vary depending on the administration method and the severity of the disease being treated.

[0089] The main advantages of this invention include:

[0090] (1) This invention is the first to discover that the combined use of the diol-type ginsenosides of this invention and statin drugs can effectively prevent and / or treat high cholesterol-related diseases and has a synergistic effect.

[0091] (2) This invention confirms that diol-type ginsenosides have cholesterol-lowering effects, including lowering blood cholesterol and liver cholesterol, and the effect is better when used in combination with lovastatin, with a synergistic effect. It can be used to treat hypercholesterolemia, atherosclerosis and non-alcoholic fatty liver.

[0092] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0093] Unless otherwise specified, all materials and reagents described in this invention specification are commercially available products.

[0094] Example 1: Assay of HMGCR protein activity in HepG2 cells degraded by protopanaxadiol

[0095] The specific method is as follows:

[0096] (1) Cell seeding and drug administration. The specific method is as follows: HepG2 cells in good growth condition (purchased from ATCC) were seeded in 60 mm cell culture dishes. The culture medium was DMEM (containing 10% FBS, 100 units / mL Penicil lin-Streptomycin), and the cell density was 3 × 10⁶ cells per dish. 5 Cells were cultured in a 37°C, 5% CO2 incubator for 24 hours. The culture medium was then aspirated, and the cells were washed twice with PBS buffer. DMEM culture medium containing different concentrations of the compound (protopanaxadiol, purchased from Medchemexpress) was then added, and the cells were cultured for another 16 hours in a 37°C, 5% CO2 incubator.

[0097] (2) Total cell protein extraction. The specific method is as follows: After collecting cells, add 120 μL of lysis buffer (50 mM Tris-HCl, pH 8.0, 150 mM NaCl, 2 mM MgCl2, 1.5% NP-40, 0.1% SDS) and homogenize. After completion, centrifuge at 14000g for 10 minutes at 4℃, add 4×SDS Loading Buffer (150 mM Tris-HCl, pH 6.8, 12% SDS, 30% glycerol, 0.02% bromophenol blue, 6% β-mercaptoethanol) and incubate at 37℃ for 30 minutes.

[0098] (3) Western blotting was used to detect the degradation of HMGCR protein. The specific method is as follows:

[0099] Load 20 μL of each protein sample into the wells of an 8% SDS-PAGE gel. Set the voltage to 85 V and electrophoresis for 40 minutes to allow the protein to enter the stacking gel. Then adjust the voltage to 120 V and electrophoresis for 1 hour to allow the protein to enter the separating gel for separation. After electrophoresis, remove the gel and place it into the transfer apparatus in the following order: filter paper, nitrocellulose membrane, gel, filter paper, taking care to remove air bubbles. Transfer at a constant voltage of 110 V for 1.5 hours.

[0100] After transfer, the nitrocellulose membrane containing the protein was immersed in TBST buffer (20 mM Tris-HCl (pH 7.4)) and rinsed once with 150 mM NaCl and 0.05% Tween-20. The membrane was then immersed in TBST buffer containing 5% skim milk powder and incubated on a shaker at room temperature for 30 minutes. After blocking, the membrane was washed three times with TBST buffer. HMGCR antibody (Abcam) diluted 1:4000 was added, and the membrane was incubated overnight on a shaker at 4°C. The membrane was washed five times with TBST for 5 minutes each time. Then, goat anti-rabbit HRP-conjugated secondary antibody (purchased from Shanghai Sangon Biotech Co., Ltd.) diluted 1:5000 was added, and the membrane was incubated at room temperature for 3 hours. The membrane was washed five times with TBST for 5 minutes each time.

[0101] The ECL luminescent substrate was coated onto a nitrocellulose membrane, sealed with plastic wrap, and images were captured using a Tanon SF4600 gel imaging analyzer. HMGCR protein was quantified using grayscale values. The obtained grayscale images were then analyzed using ImageJ software, with the untreated group set as 100%. A bar chart of HMGCR protein degradation was plotted using GraphPad Prism 7 software.

[0102] The results are as follows Figure 1As shown, protopanaxadiol dose-dependently reduced HMGCR protein levels in HepG2 cells. The DCEC50 value of protopanaxadiol in degrading HMGCR was 4.5 μM.

[0103] Example 2: Detection of the effect of combined use of protopanaxadiol and lovastatin to reduce blood and liver cholesterol in mice.

[0104] After confirming the HMGCR degradation effect of protopanaxadiol, the inventors continued to study whether protopanaxadiol had a synergistic effect with lovastatin, a commonly used cholesterol-lowering drug in clinical practice.

[0105] C57BL / 6J mice (purchased from Nanjing Jicui), SPF grade, male, weighing (20±2) g, were randomly divided into two groups. The first group (n=7) served as the normal control group, fed a normal diet (D12450B, purchased from Research Diets). The remaining mice (n=22) were used to establish the model group, fed a medium-fat diet (MFD, normal diet supplemented with 20% lard and 0.5% sodium cholate). All mice had free access to food and water. After 8 weeks of continuous feeding, two mice from each of the normal control and model groups were sacrificed. Serum and liver cholesterol levels were compared between the two groups to determine if the model was successfully established. Twenty successfully modeled mice were randomly divided into four groups: a model group (n=5), a ginsenoside diol group (n=5), a lovastatin group (n=5), and a ginsenoside diol + lovastatin group (n=5). All mice were administered the drugs by gavage for 6 weeks. During the drug administration period, except for the normal control group which was fed standard feed, all other groups continued to be fed an MFD diet until the end of the experiment. The original dose of ginsenoside diol was 30 mg / kg / day, and the dose of lovastatin was 60 mg / kg / day.

[0106] In the examples, the weight ratio of protopanaxadiol to lovastatin was 1:2.

[0107] Observation indicators

[0108] 1. Mouse body weight.

[0109] 2. Blood and liver cholesterol levels

[0110] 3. HMGCR protein level in liver tissue.

[0111] Experimental results

[0112] like Figure 2 As shown, the mouse weight was largely unaffected by the drug administration.

[0113] like Figure 3 As shown, compared with the normal control group, the blood and liver cholesterol levels in the model group were significantly lower, indicating that the high cholesterol model was successfully established. Compared with the model group, both the lovastatin group and the protopanaxadiol group showed reduced cholesterol levels, while the combined lovastatin and protopanaxadiol group showed a more significant reduction.

[0114] like Figure 4 As shown, compared with the control group, the HMGCR level in the model group was upregulated. The lovastatin group showed significant HMGCR accumulation, while the original ginsenoside diol-lovastatin combination group showed a significant decrease in HMGCR level.

[0115] These results indicate that the combination of protopanaxadiol and lovastatin can significantly reduce cholesterol levels and can be used to treat diseases such as hypercholesterolemia, atherosclerosis, and non-alcoholic steatohepatitis.

[0116] By using them in combination, the accumulation of HMGCR caused by statins can be significantly alleviated, thereby avoiding the need to increase the dosage of statins and reducing side effects.

[0117] This invention adjusted the weight ratio of ginsenoside diol and lovastatin to 1:1, 1:3, 1:4, 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, and 1:20. The results showed that all of these ratios exhibited similar synergistic effects as when the weight ratio was 1:2.

[0118] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A product portfolio, characterized in that, include: (i) a first pharmaceutical composition comprising (a) a first active ingredient, the first active ingredient being a diol-type ginsenoside, and a pharmaceutically acceptable carrier; and (ii) a second pharmaceutical composition comprising (b) a second active ingredient, the second active ingredient being a statin, and a pharmaceutically acceptable carrier; The first pharmaceutical composition and the second pharmaceutical composition may be different pharmaceutical compositions or the same pharmaceutical composition.

2. The product portfolio as described in claim 1, characterized in that, The diol-type ginsenosides are selected from the following group: protopanaxadiol, ginsenoside CK, ginsenoside Rh2, 25-hydroxyprotopanaxadiol, 25-hydroxymethylprotopanaxadiol, or combinations thereof.

3. The product portfolio as described in claim 1, characterized in that, The statins are selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, or combinations thereof.

4. The product portfolio as described in claim 1, characterized in that, The weight ratio of component (i) to component (ii) is 1:1-20, preferably 1:1-10, more preferably 1:1-4, and even more preferably 1:1-2.

5. A composition, characterized in that, The composition comprises: (i) Diol-type ginsenosides; (ii) statins; and (iii) Pharmaceutically acceptable carriers.

6. The composition according to claim 5, characterized in that, The composition also includes other medications for treating high cholesterol-related diseases.

7. The composition according to claim 6, characterized in that, The high cholesterol-related diseases mentioned include hypercholesterolemia, anti-atherosclerosis, and anti-non-alcoholic steatohepatitis.

8. A medicine box, characterized in that, include: (a1) A first container, and a diol-type ginsenoside or a drug containing a diol-type ginsenoside located in the first container; (b1) A second container, and a statin drug or a drug containing a statin drug located in the second container.

9. An application of a combination, characterized in that, The combination comprises diol-type ginsenosides and statins, used to prepare a pharmaceutical composition or kit for the prevention and / or treatment of high cholesterol-related diseases.

10. The use as described in claim 9, characterized in that, The high cholesterol-related diseases mentioned include hypercholesterolemia, anti-atherosclerosis, and anti-non-alcoholic steatohepatitis.

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