A pharmaceutical composition of hezemibrane and an HMG-CoA reductase inhibitor

Abstract

This invention provides a pharmaceutical composition containing hezemibrate and an HMG-CoA reductase inhibitor, and may further include one or more excipients selected from calcium carbonate, butylated hydroxyanisole, butylated hydroxytoluene, citric acid, sodium lauryl sulfate, polysorbate, croscarmellose sodium, crospovidone, microcrystalline cellulose, povidone, hydroxypropyl cellulose, lactose, pregelatinized starch, magnesium stearate, and talc. This composition can be formulated into various dosage forms, exhibiting good formulation stability and controllable quality.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 201880073253.8, entitled "A pharmaceutical composition of hezemib and HMG-CoA reductase inhibitor", filed on November 23, 2018. Technical Field

[0002] This invention belongs to the pharmaceutical field, specifically relating to the composition of zebufenib and HMG-CoA reductase inhibitor and their application. Background Technology

[0003] Cardiovascular disease is one of the most common and serious diseases threatening human health, especially among the middle-aged and elderly. Dyslipidemia is a significant risk factor for atherosclerosis, coronary heart disease, and other cardiovascular and cerebrovascular diseases. Lipid-lowering drugs are crucial for the prevention and treatment of cardiovascular diseases.

[0004] Currently, lipid-lowering drugs used clinically and those under development can be classified according to their lipid-lowering mechanism and chemical structure into statins, niacin derivatives, fibrates, bile acid sequestrants, polyene derivatives, as well as novel lipid-lowering drugs and various compound preparations. Different lipid-lowering drugs have their own advantages and disadvantages. Among them, statins are currently the most widely used, most effective, and highly praised by doctors and patients. Commonly used drugs include lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, long-acting fluvastatin sustained-release tablets, rosuvastatin, pitavastatin, etc. Atorvastatin currently has the highest market share. Statins have fewer adverse reactions compared to other lipid-lowering drugs, mainly falling into two categories: one is metabolic disturbance caused by the inhibition of the synthesis of the cholesterol precursor mevalonic acid, and the other is direct toxicity. The most common symptoms include mild gastrointestinal reactions, rhinitis, sinusitis, headache, sore throat, flu syndrome, arthritis, chest pain, and insomnia.

[0005] In recent years, the research and development of new dosage forms and combination therapies has received increasing attention. While continuously developing lipid-lowering drugs with novel mechanisms of action, various new dosage forms and combination preparations that can reduce adverse drug reactions and enhance efficacy have also been applied clinically, achieving good results. These include: Lovastatin controlled-release tablets (Altocor), Niacin sustained-release preparation (Nispan), fenofibrate micronized capsules, Nicostatin (a combination of niacin and lovastatin), ezetimibe / simvastatin combination preparations, and ezetimibe / atorvastatin combination preparations.

[0006] Among numerous studies on compound preparations and combined applications, research on the novel cholesterol absorption inhibitor ezetimibe and statins has attracted the most attention. Pharmacodynamic studies of ezetimibe and statins have found that ezetimibe and statins have a good synergistic effect when used together. However, it has been found that the combined use of ezetimibe and statins has certain hepatotoxicity, especially at synergistic doses, which has an adverse effect on transaminases (especially alanine aminotransferase ALT) (see, for example, NDA 21-445 FDA review: Pharmacology Review(s) 117-129). This may pose a safety risk for the long-term treatment of hyperlipidemia.

[0007] Therefore, there is still a pressing need for drugs that are both effective and safe in lowering blood lipids in the current technology. Summary of the Invention

[0008] The inventors unexpectedly discovered during their research that the combination of zebufenib and an HMG-CoA reductase inhibitor not only has a good synergistic effect in lowering blood lipids but also possesses sufficient safety. Based on this discovery, this invention was completed. Zebufenib, as described in this invention, is a novel intestinal cholesterol absorption inhibitor, disclosed in Chinese Patent CN101993403A. Zebufenib has the following structural formula:

[0009]

[0010] Based on the above findings, one of the technical solutions of the present invention is to provide a pharmaceutical composition containing 0.5-20% by weight of zebufenib and 1-80% by weight of at least one HMG-CoA reductase inhibitor. The composition of the present invention is stable. Preferably, the HMG-CoA reductase inhibitor is a statin or a salt thereof, such as lovastatin, simvastatin, atorvastatin, pravastatin, rosuvastatin, fluvastatin, cerivastatin, pitavastatin, and rosuvastatin or a salt thereof; the salt of the statin is pharmaceutically acceptable, and there are no particular limitations on the salt; preferably, lovastatin, simvastatin, atorvastatin, rosuvastatin, pitavastatin, and rosuvastatin are in calcium salt form; pravastatin, fluvastatin, and cerivastatin are in sodium salt form.

[0011] More preferably, the statin is atorvastatin, rosuvastatin, or simvastatin.

[0012] In one aspect of this invention, the pharmaceutical composition may further contain excipients, which are excipients conventionally used in the art; preferably, the excipients may be one or more of stabilizers, surfactants, fillers, binders, disintegrants and lubricants.

[0013] The stabilizer can be a stabilizer commonly used in the art, such as a carbonate, bicarbonate or phosphate, or an antioxidant such as butylated hydroxyanisole, citric acid or butylated hydroxytoluene. Preferably, the stabilizer is at least one of calcium carbonate, butylated hydroxyanisole, citric acid or butylated hydroxytoluene.

[0014] The surfactant can be a surfactant commonly used in the art, such as anionic surfactant or nonionic surfactant; examples of anionic surfactants include sodium stearate, potassium stearate, sodium oleate, calcium stearate and sodium dodecyl sulfate, etc.; examples of nonionic surfactants include fatty acid sorbitan (Span), polysorbate, myrj, brij, poloxamer, etc.; preferably, the surfactant is at least one of sodium dodecyl sulfate or polysorbate.

[0015] The filler may be a filler conventionally used in the art, such as starch, sugar, cellulose and inorganic salts; preferably, the filler is at least one of lactose, microcrystalline cellulose and pregelatinized starch.

[0016] The adhesive can be an adhesive commonly used in the art, such as hydroxypropyl cellulose, methylcellulose, carboxymethyl cellulose, povidone, gum arabic, sucrose, etc.; preferably, the adhesive is at least one of hydroxypropyl cellulose and povidone.

[0017] The disintegrant can be a disintegrant commonly used in the art, such as croscarmellose sodium, croscarmellose, sodium carboxymethyl starch, sodium alginate, corn starch, or low-substituted hydroxypropyl cellulose; preferably, the disintegrant is at least one of croscarmellose sodium and croscarmellose.

[0018] The lubricant can be a lubricant commonly used in the art, such as magnesium stearate, stearic acid, sodium fumarate, PEG6000, glyceryl behenate, talc, etc.; preferably, the lubricant is at least one of magnesium stearate and talc.

[0019] As a preferred embodiment, the composition of the present invention may contain one or more of the following: 1-25% by weight calcium carbonate, 0.005-0.1% by weight butylated hydroxytoluene, 0.1-10% by weight sodium dodecyl sulfate, 0.05-1.0% by weight polysorbate, 1-10% by weight croscarmellose sodium, 1-10% by weight croscarmellose, 10-50% by weight microcrystalline cellulose, 0.1-5% by weight povidone, 0.1-5% by weight hydroxypropyl cellulose, 10-50% by weight lactose, and 0.1-2% by weight magnesium stearate.

[0020] The second technical solution of the present invention is to provide a pharmaceutical composition containing 0.5-20% by weight of zebufenib and 1-80% by weight of atorvastatin. Preferably, the pharmaceutical composition contains 1-10% by weight of zebufenib and 1-30% by weight of atorvastatin.

[0021] In one aspect of this invention, the composition may optionally include a stabilizer. The stabilizer may be a stabilizer conventionally used in the art; for example, it may be a carbonate, bicarbonate, phosphate, or butylated hydroxytoluene (BHT); preferably, the stabilizer is at least one of calcium carbonate or BHT. The addition of calcium carbonate or BHT to the composition of the present invention is beneficial to the stability of the formulation. More preferably, the pharmaceutical composition may contain 5–25% by weight of calcium carbonate and 0.005%–0.05% by weight of BHT.

[0022] In another aspect of this invention, the pharmaceutical composition may optionally include a surfactant. The surfactant may be a surfactant conventionally used in the art, such as anionic or nonionic surfactants. Examples of anionic surfactants include sodium stearate, potassium stearate, sodium oleate, calcium stearate, and sodium lauryl sulfate; examples of nonionic surfactants include sorbitan (Span), polysorbate, myrj, bryzan, poloxamer, etc.; preferably, the surfactant is at least one of sodium lauryl sulfate or polysorbate. Adding sodium lauryl sulfate or polysorbate to the composition of the present invention can further enhance the efficacy of the pharmaceutical composition. More preferably, the pharmaceutical composition may contain 0.1–5% by weight of sodium lauryl sulfate and 0.05%–0.5% by weight of polysorbate.

[0023] In another aspect of this invention, the pharmaceutical composition is in oral form, comprising, for example, an oral dosage unit with a total weight of 100-800 mg, and may further contain one or more of the following: a filler, a binder, a disintegrant, and a lubricant. The filler may be a filler conventionally used in the art, such as starch, sugar, cellulose, and inorganic salts; preferably, the filler is at least one of lactose and microcrystalline cellulose. The binder may be a binder conventionally used in the art, such as hydroxypropyl cellulose, methylcellulose, carboxymethyl cellulose, povidone, gum arabic, sucrose, etc.; preferably, the binder is at least one of hydroxypropyl cellulose and povidone. The disintegrant may be a disintegrant conventionally used in the art, such as sodium croscarmellose, croscarmellose, sodium carboxymethyl starch, sodium alginate, corn starch, and low-substituted hydroxypropyl cellulose; preferably, the disintegrant is at least one of sodium croscarmellose and croscarmellose. The lubricant can be a lubricant commonly used in the art, such as magnesium stearate, stearic acid, sodium fumarate, PEG6000, glyceryl behenate, talc, etc.; preferably, the lubricant is magnesium stearate.

[0024] As a more preferred embodiment, the pharmaceutical composition may contain one or more of the following: 1-10% by weight of croscarmellose sodium, 1-10% by weight of croscarmellose, 10-50% by weight of microcrystalline cellulose, 0.1-5% by weight of povidone, 0.1-5% by weight of hydroxypropyl cellulose, 10-50% by weight of lactose, and 0.1-2% by weight of magnesium stearate.

[0025] A third technical solution of the present invention is to provide a pharmaceutical composition containing 0.5-20% by weight of zebufenib and 1-80% by weight of rosuvastatin. Preferably, the pharmaceutical composition contains 1-10% by weight of zebufenib and 1-30% by weight of rosuvastatin.

[0026] In one aspect of this invention, the composition may optionally include a stabilizer. The stabilizer may be a stabilizer conventionally used in the art, such as a carbonate, bicarbonate, or phosphate; preferably, the stabilizer is at least one of calcium carbonate and butylated hydroxytoluene (BHT). Adding calcium carbonate or BHT to the composition of the present invention is beneficial to the stability of the formulation; more preferably, the pharmaceutical composition may contain 1–15% by weight of calcium carbonate and 0.005–0.05% by weight of BHT.

[0027] In another aspect of this invention, the pharmaceutical composition may optionally include a surfactant. The surfactant may be a surfactant conventionally used in the art, such as anionic or nonionic surfactants. Examples of anionic surfactants include sodium stearate, potassium stearate, sodium oleate, calcium stearate, and sodium lauryl sulfate, while examples of nonionic surfactants include sorbitan (Span), polysorbate, myrj, bryzan, and poloxamer. Preferably, the surfactant is sodium lauryl sulfate. Adding sodium lauryl sulfate to the composition of the present invention can further enhance the efficacy of the pharmaceutical composition. More preferably, the pharmaceutical composition may contain 0.1–6% by weight of sodium lauryl sulfate.

[0028] As a more preferred embodiment, the pharmaceutical composition may contain one or more of the following: 1-10% by weight of crospovidone, 10-50% by weight of microcrystalline cellulose, 0.1-5% by weight of povidone, 10-50% by weight of lactose, and 0.1-2% by weight of magnesium stearate.

[0029] The fourth technical solution of the present invention is: a method for preparing a pharmaceutical composition containing zebufenib and an HMG-CoA reductase inhibitor, the method comprising combining the HMG-CoA reductase inhibitor, zebufenib and optional excipients.

[0030] The fifth technical solution of the present invention is: a method for preparing a pharmaceutical composition containing zebufenib and an HMG-CoA reductase inhibitor, comprising the following steps:

[0031] (1) The HMG-CoA reductase inhibitor is granulated with optional excipients to obtain the HMG-CoA reductase inhibitor granule portion;

[0032] (2) Make Haizemab into granules with optional excipients to obtain Haizemab granules;

[0033] (3) Combine the two granular portions prepared in steps (1) and (2) with optional excipients.

[0034] In step (1), the HMG-CoA reductase inhibitor particles can be granulated using water as a solvent, and in step (2), the Haizemab particles can be granulated using water, organic solvents, or mixtures thereof. Preferably, the Haizemab particles in step (2) can be granulated using water, alcohol, chloroform, acetone, acetonitrile, or similar solvents, or mixtures thereof. More preferably, water, alcohol, or mixtures thereof can be used for granulation, more preferably a mixture of alcohol and water can be used for granulation, and most preferably a mixture of ethanol and water can be used for granulation.

[0035] The sixth technical solution of the present invention is: a method for preparing a pharmaceutical composition containing zebufenib and atorvastatin, comprising the following steps:

[0036] (1) Atorvastatin is granulated with optional excipients;

[0037] (2) Grind Haizemab with optional excipients into granules;

[0038] (3) Mix the two granular parts obtained in steps (1) and (2) above with optional excipients evenly.

[0039] Preferably, the preparation method includes the following steps:

[0040] (1) Mix atorvastatin with lactose, microcrystalline cellulose, calcium carbonate and croscarmellose sodium evenly;

[0041] (2) Dissolve hydroxypropyl cellulose in water;

[0042] (3) Add the hydroxypropyl cellulose solution obtained in step (2) to the mixture obtained in step (1) for granulation, drying and granulation;

[0043] (4) Mix Haizemab with lactose, microcrystalline cellulose, sodium lauryl sulfate and croscarmellose sodium evenly;

[0044] (5) Dissolve povidone in water and set aside;

[0045] (6) Add the povidone solution obtained in step (5) to the mixture obtained in step (4) for granulation, drying and granulation;

[0046] (7) The granules after granulation in steps (3) and (6) are optionally mixed with cross-linked sodium carboxymethyl cellulose, and then optionally mixed with magnesium stearate, and then compressed into tablets.

[0047] The seventh technical solution of the present invention is: providing another method for preparing a pharmaceutical composition containing zebufenib and atorvastatin, comprising the following steps:

[0048] (1) Atorvastatin is granulated with optional excipients;

[0049] (2) Grind Haizemab with optional excipients into granules;

[0050] (3) Mix the granules prepared in step (1) with the optional excipients evenly to obtain the first total mixed granules;

[0051] (4) Mix the granules prepared in step (2) above with optional excipients evenly to obtain the second total mixed granules;

[0052] (5) The first and second mixed particles obtained in steps (3) and (4) above are pressed into a double-layer sheet.

[0053] Preferably, the preparation method includes the following steps:

[0054] (1) Mix atorvastatin with lactose, microcrystalline cellulose, calcium carbonate and croscarmellose sodium evenly;

[0055] (2) Dissolve polysorbate and hydroxypropyl cellulose in water;

[0056] (3) Add the solution obtained in step (2) to the mixture obtained in step (1) for granulation, drying and granulation;

[0057] (4) Mix lactose, microcrystalline cellulose, sodium lauryl sulfate and crospovidone evenly;

[0058] (5) Dissolve Hazemab, Butylated Hydroxytoluene, and Povidone in an ethanol solution;

[0059] (6) Add the solution obtained in step (5) to the mixture obtained in step (4) for granulation, drying and granulation;

[0060] (7) The granules after granulation in step (3) are optionally mixed with cross-linked sodium carboxymethyl cellulose, and then optionally mixed with magnesium stearate to obtain the first total mixed granules;

[0061] (8) The granules after granulation in step (6) are optionally mixed with cross-linked sodium carboxymethyl cellulose, and then optionally mixed with magnesium stearate to obtain the second total mixed granules.

[0062] (9) The first and second mixed particles obtained in steps (7) and (8) are pressed into a double-layer sheet.

[0063] The eighth technical solution of the present invention is: a method for preparing a pharmaceutical composition containing zebufenib and rosuvastatin, comprising the following steps:

[0064] (1) Rosuvastatin is granulated with optional excipients;

[0065] (2) Grind Haizemab with optional excipients into granules;

[0066] (3) Mix the granules prepared in steps (1) and (2) with optional excipients until homogeneous.

[0067] Preferably, the preparation method includes the following steps:

[0068] (1) Mix rosuvastatin with lactose, microcrystalline cellulose, calcium carbonate and crospovidone evenly;

[0069] (2) Dissolve povidone in water;

[0070] (3) Add the povidone solution obtained in step (2) to the mixture obtained in step (1) for granulation, drying and granulation;

[0071] (4) Mix lactose, microcrystalline cellulose, sodium lauryl sulfate and crospovidone evenly;

[0072] (5) Dissolve Hazemab and Povidone in an ethanol solution;

[0073] (6) Add the solution obtained in step (5) to the mixture obtained in step (4) for granulation, drying and granulation;

[0074] (7) Mix the granules after granulation in steps (3) and (6), then optionally mix them with cross-linked polyvinyl alcohol, then optionally mix them with magnesium stearate, and compress them into tablets.

[0075] Preferably, the preparation method includes the following steps:

[0076] (1) Mix rosuvastatin with lactose, microcrystalline cellulose, calcium carbonate and crospovidone evenly;

[0077] (2) Dissolve povidone in water;

[0078] (3) Add the povidone solution obtained in step (2) to the mixture in step (1) for granulation, drying and granulation;

[0079] (4) Mix lactose, microcrystalline cellulose, sodium lauryl sulfate and crospovidone evenly;

[0080] (5) Dissolve Hazemab, Butylated Hydroxytoluene, and Povidone in an ethanol solution;

[0081] (6) Add the solution obtained in step (5) to the mixture obtained in step (4) for granulation, drying and granulation;

[0082] (7) Mix the granules after granulation in steps (3) and (6), then optionally mix them with cross-linked polyvinyl alcohol, then optionally mix them with magnesium stearate, and compress them into tablets.

[0083] The ninth technical solution of the present invention is: a method for preparing a pharmaceutical composition containing zebufenib and rosuvastatin, comprising the following steps:

[0084] (1) Rosuvastatin is granulated with optional excipients;

[0085] (2) Grind Haizemab with optional excipients into granules;

[0086] (3) Mix the granules prepared in step (1) with the optional excipients evenly to obtain the first total mixed granules;

[0087] (4) Mix the granules prepared in step (2) above with optional excipients evenly to obtain the second total mixed granules;

[0088] (5) The first and second mixed particles obtained in steps (3) and (4) above are pressed into a double-layer sheet.

[0089] Preferably, the preparation method includes the following steps:

[0090] (1) Mix rosuvastatin with lactose, microcrystalline cellulose, calcium carbonate and crospovidone evenly;

[0091] (2) Dissolve povidone in water;

[0092] (3) Add the povidone solution obtained in step (2) to the mixture obtained in step (1) for granulation, drying and granulation;

[0093] (4) Mix lactose, microcrystalline cellulose, sodium lauryl sulfate and crospovidone evenly;

[0094] (5) Dissolve Hazemab, Butylated Hydroxytoluene, and Povidone in an ethanol solution;

[0095] (6) Add the solution obtained in step (5) to the mixture obtained in step (4) for granulation, drying and granulation;

[0096] (7) The granules after granulation in step (3) are optionally mixed with cross-linked polyvinyl ketone and then optionally mixed with magnesium stearate to obtain the first total mixed granules.

[0097] (8) The granules after granulation in step (6) are optionally mixed with cross-linked polyvinyl ketone and then optionally mixed with magnesium stearate to obtain the second total mixed granules.

[0098] (9) The first and second mixed particles obtained in steps (7) and (8) are pressed into a double-layer sheet.

[0099] The tenth technical solution of the present invention is: providing a drug dosage unit containing 5-20 mg of zebufenib and 5-80 mg of atorvastatin. Preferably, the dosage of zebufenib is 5 mg, 10 mg, or 20 mg; and the dosage of atorvastatin is 5 mg, 10 mg, 20 mg, 40 mg, or 80 mg. Preferably, this drug dosage unit is an oral dosage unit.

[0100] In one aspect of this solution, the dosing unit may optionally contain calcium carbonate as a component. Preferably, the dosing unit may contain 5 to 100 mg of calcium carbonate.

[0101] In another aspect of this solution, the dosage unit may optionally contain calcium carbonate and butylated hydroxytoluene (BHT) as components. Preferably, the dosage unit may contain 5–100 mg of calcium carbonate and 0.01–0.2 mg of BHT.

[0102] In one aspect of this solution, the dosing unit may optionally contain sodium dodecyl sulfate as a component. Preferably, the dosing unit may contain 0.5 to 5 mg of sodium dodecyl sulfate.

[0103] In another aspect of this solution, the dosing unit may optionally contain sodium dodecyl sulfate and polysorbate as components. Preferably, the dosing unit may contain 0.5–5 mg of sodium dodecyl sulfate and 0.1–5 mg of polysorbate.

[0104] In another aspect of this scheme, the dosage unit may also contain 1–50 mg of croscarmellose sodium, 20–250 mg of microcrystalline cellulose, 0.5–10 mg of povidone, 0.5–10 mg of hydroxypropyl cellulose, 10–250 mg of lactose, and 0.1–10 mg of magnesium stearate.

[0105] In another aspect of this scheme, the dosage unit may also contain 1–50 mg of croscarmellose sodium, 1–30 mg of croscarmellose, 20–250 mg of microcrystalline cellulose, 0.5–10 mg of povidone, 0.5–10 mg of hydroxypropyl cellulose, 10–250 mg of lactose, and 0.1–10 mg of magnesium stearate.

[0106] The eleventh technical solution of the present invention is: providing a drug dosage unit containing 5-20 mg of hezemib and 5-80 mg of rosuvastatin, preferably, the dosage of hezemib is 5 mg, 10 mg, or 20 mg; and the dosage of rosuvastatin is 5 mg, 10 mg, 20 mg, or 40 mg. Preferably, the drug dosage unit is an oral dosage unit.

[0107] In one aspect of this solution, the dosing unit may optionally contain calcium carbonate as a component. Preferably, the dosing unit may contain 1 to 50 mg of calcium carbonate.

[0108] In one aspect of this solution, the dosage unit may optionally contain calcium carbonate and butylated hydroxytoluene (BHT) as components. Preferably, the dosage unit may contain 1–50 mg of calcium carbonate and 0.01–0.2 mg of BHT.

[0109] In another aspect of this scheme, the dosing unit may optionally contain sodium dodecyl sulfate as a component. Preferably, the dosing unit may contain 0.5 to 10 mg of sodium dodecyl sulfate.

[0110] In another aspect of this scheme, the dosage unit may also contain 5–40 mg of crospovidone, 20–250 mg of microcrystalline cellulose, 1–20 mg of povidone, 20–250 mg of lactose, and 0.1–5 mg of magnesium stearate.

[0111] In this invention, povidone is preferably povidone K30.

[0112] The pharmaceutical composition or dosage unit described in this invention can be in various dosage forms such as capsules, tablets, granules, powders, solutions, or lozenges.

[0113] The combination of zebufen and HMG-CoA reductase inhibitor described in this invention can be in various forms, such as tablets. The formulation design of this invention is reasonable, easy to prepare into suitable formulations, and the formulations have good stability and controllable quality.

[0114] Compared with the prior art, the pharmaceutical composition containing zebufenozide and HMG-CoA reductase inhibitor involved in this invention has the following advantages:

[0115] (1) This invention combines zebufenib with an HMG-CoA reductase inhibitor, especially when the HMG-CoA reductase inhibitor is a statin, resulting in a good synergistic effect. This can reduce the incidence of cardiotoxicity and cardiovascular events by lowering the dosage of statins, demonstrating significant clinical benefits.

[0116] (2) The pharmaceutical composition provided by the present invention not only reduces adverse reactions by synergistically reducing the dosage of statin drugs, but also has higher safety and fewer clinical adverse reactions compared with drugs of the same mechanism and statin drugs, and patients have better medication compliance.

[0117] (3) The pharmaceutical composition provided by the present invention is stable and the prepared formulation can be stored stably using ordinary packaging.

[0118] (4) The pharmaceutical composition of the present invention can use a small number of excipients, and the excipients can all be commonly used excipients, so the quality of the preparation is controllable and the stability is good.

[0119] (5) The preparation method of the pharmaceutical composition of the present invention is simple, easy to operate, and suitable for large-scale industrial production.

[0120] In preclinical evaluations, ezetimibe combined with statins was equivalent in efficacy to ezetimibe combined with statins, but ezetimibe combined with statins had a significantly better safety profile than ezetimibe combined with statins, and may have greater advantages in clinical application. Detailed Implementation

[0121] The present invention will be described in detail below with reference to the embodiments. It should be noted that the following embodiments are for illustrative purposes only and are not intended to limit the invention. Experimental methods in the following embodiments that do not specify specific conditions are performed according to conventional methods and conditions, or as selected according to the product instructions.

[0122] The hezetimibe (HS-25), ezetimibe, atorvastatin, rosuvastatin, and simvastatin used in the following examples were obtained from Zhejiang Hisun Pharmaceutical Co., Ltd., or were prepared by referring to existing methods.

[0123] It should be noted that the atorvastatin, rosuvastatin, and simvastatin used in the following examples are all in calcium salt form, and their content refers to the content of atorvastatin, rosuvastatin, and simvastatin. For example, in Example 1, the specification is 5mg / 10mg acetaminophen atorvastatin tablets, where 10mg refers to the weight of atorvastatin. If the weight of atorvastatin in the prescription is converted to the weight of atorvastatin calcium, it is 10.83mg. In Example 6, the specification is 20mg / 20mg acetaminophen rosuvastatin tablets, where 20mg refers to the weight of rosuvastatin. If the weight of rosuvastatin in the prescription is converted to the weight of rosuvastatin calcium, it is 20.83mg.

[0124] Example 1: Haizemabuatorvastatin tablets, specifications: 5mg / 10mg, each tablet weighs 92.25mg, the formula is shown in Table 1.

[0125] Table 1. Formulation composition of Example 1 (unit: g)

[0126]

[0127] Preparation method:

[0128] (1) Mix the prescribed amount of atorvastatin and the lactose, microcrystalline cellulose, calcium carbonate and croscarmellose sodium of the atorvastatin granule portion evenly;

[0129] (2) Dissolve the prescribed amount of hydroxypropyl cellulose in purified water and set aside;

[0130] (3) The hydroxypropyl cellulose solution obtained in step (2) is added to the mixture obtained in step (1) for granulation, drying, and granulation to obtain atorvastatin granules.

[0131] (4) Mix the prescribed amount of Hezemab and the lactose, microcrystalline cellulose, sodium dodecyl sulfate and croscarmellose sodium in the granular portion of Hezemab evenly;

[0132] (5) Dissolve the prescribed amount of povidone K30 in purified water and set aside;

[0133] (6) Add the polyvinylpyrrolidone K30 solution obtained in step (5) to the mixture obtained in step (4) for granulation, drying, and granulation to obtain Haizemab granules.

[0134] (7) Mix the granules after granulation in steps (3) and (6) with the added cross-linked sodium carboxymethyl cellulose evenly, then add the prescribed amount of magnesium stearate and mix evenly, then compress into tablets.

[0135] Example 2: Haizemabuatorvastatin tablets, specifications: 5mg / 20mg, each tablet weighs 143.50mg, the formula is shown in Table 2.

[0136] Table 2. Formulation composition of Example 2 (unit: g)

[0137]

[0138] Preparation method: Same as in Example 1.

[0139] Example 3: Haizemabuatorvastatin tablets, specification: 10mg / 10mg, each tablet weighs 133.25mg, the formula is shown in Table 3.

[0140] Table 3. Formulation composition of Example 3 (unit: g)

[0141]

[0142] Preparation method: Same as in Example 1.

[0143] Example 4: Haizemabuatorvastatin tablets, specifications: 10mg / 20mg, each tablet weighs 184.50mg, the formula is shown in Table 4.

[0144] Table 4. Formulation composition of Example 4 (unit: g)

[0145]

[0146] Preparation method: Same as in Example 1.

[0147] Example 5: Haizemabuatorvastatin tablets, specifications: 10mg / 80mg, each tablet weighs 492.00mg, the formula is shown in Table 5.

[0148] Table 5. Formulation composition of Example 5 (unit: g)

[0149]

[0150] Preparation method: Same as in Example 1.

[0151] Example 6: Haizemabupresuvastatin tablets, specification: 20mg / 20mg, each tablet weighs 460.00mg, the formula is shown in Table 6.

[0152] Table 6. Formulation composition of Example 6 (unit: g)

[0153]

[0154] Preparation method:

[0155] (1) Mix the prescribed amount of rosuvastatin and the lactose, microcrystalline cellulose, calcium carbonate and crospovidone of the rosuvastatin granules evenly;

[0156] (2) Dissolve the povidone K30 in the rosuvastatin granule fraction in purified water;

[0157] (3) The povidone K30 solution obtained in step (2) is added to the mixture obtained in step (1) for granulation, drying, and granulation to obtain rosuvastatin granules.

[0158] (4) Mix the lactose, microcrystalline cellulose, sodium lauryl sulfate and crospovidone in the granular part of Haizemaibu evenly;

[0159] (5) Dissolve the prescribed amount of Hazemabu and the povidone K30 of Hazemabu granules in an ethanol solution;

[0160] (6) Add the solution obtained in step (5) to the mixture obtained in step (4) for granulation, drying, and granulation to obtain Haizemaibu granules.

[0161] (7) Mix the granules after granulation in step (3) with the granules after granulation in step (6), then mix them evenly with the added cross-linked polyvinyl alcohol, then add the prescribed amount of magnesium stearate and mix evenly, then compress into tablets.

[0162] Example 7: Haizemabupresuvastatin tablets, specifications: 10mg / 20mg, each tablet weighs 297.00mg, the formula is shown in Table 7.

[0163] Table 7. Formulation composition of Example 7 (unit: g)

[0164]

[0165] Preparation method: Same as in Example 6.

[0166] Example 8: Haizemabupresuvastatin tablets, specifications: 20mg / 10mg, each tablet weighs 393.00mg, the formula is shown in Table 8.

[0167] Table 8. Formulation composition of Example 8 (unit: g)

[0168]

[0169] Preparation method: Same as in Example 6.

[0170] Example 9: Haizemabupresuvastatin tablets, specification: 10mg / 10mg, each tablet weighs 230.00mg, the formula is shown in Table 9.

[0171] Table 9. Formulation composition of Example 9 (unit: g)

[0172]

[0173] Preparation method: Same as in Example 6.

[0174] Example 10: Haizemabusimvastatin tablets, specifications: 6mg / 20mg, each tablet weighs 100.00mg, the formula is shown in Table 10.

[0175] Table 10. Formulation composition of Example 10 (unit: g)

[0176] Haizemabu 6 Simvastatin 20 lactose 48.54 microcrystalline cellulose 16.185 Cross-linked polyvinylpyrrolidone 3 Povidone K30 5 Butylated anisole 0.025 Citric acid 0.25 magnesium stearate 1 30% ethanol solution Appropriate amount total 1000 pieces

[0177] Preparation method:

[0178] (1) Dissolve butylated hydroxyanisole and citric acid in an appropriate amount of 30% ethanol solution;

[0179] (2) Weigh out the following ingredients according to the prescription: Hazemaibu, Simvastatin, Microcrystalline cellulose, Lactose, Povidone K30, and Cross-linked Povidone. Pass them through a 40-mesh sieve and mix the sieved raw and auxiliary materials evenly.

[0180] (3) Add the solution obtained in step (1) to the mixture obtained in step (2) and granulate it;

[0181] (4) Dry and granulate the wet granules;

[0182] (5) Add magnesium stearate to it and mix, then compress into tablets.

[0183] Example 11: Stability Study of Hazemib Atorvastatin Tablets (5mg / 10mg strength)

[0184] Method 1: The tablets prepared in Example 1 were packaged in high-density polyethylene bottles (containing 2g of desiccant) and placed under conditions of 40℃±2℃ and 75%±5% RH for stability studies. The test results are shown in Table 11.

[0185] Table 11. Stability data of atorvastatin tablets (5mg / 10mg strength)

[0186]

[0187]

[0188] The results showed that after 6 months of storage at 40℃±2℃ and RH75%±5%, the content and dissolution of Haizemabuatorvastatin tablets (5mg / 10mg) did not change significantly, and the impurities only increased slightly, indicating that the sample was relatively stable.

[0189] Method 2: The tablets prepared in Example 1 were packaged in high-density polyethylene bottles (containing 2g of desiccant) and placed under conditions of 25℃±2℃ and 60%±5% humidity for stability studies. The test results are shown in Table 12.

[0190] Table 12. Stability data of atorvastatin tablets (5mg / 10mg strength)

[0191]

[0192] The results showed that after 24 months of storage at 25℃±2℃ and RH60%±5%, the content and dissolution of Haizemabuatorvastatin tablets (5mg / 10mg) did not change significantly, and the impurities only increased slightly, indicating that the sample was relatively stable.

[0193] Example 12: Stability Study of Haizemabuatorvastatin Tablets (5mg / 20mg strength)

[0194] Method 1: The tablets prepared in Example 2 were packaged in high-density polyethylene bottles (containing 2g of desiccant) and placed under conditions of 40℃±2℃ and 75%±5% humidity for stability studies. The test results are shown in Table 13.

[0195] Table 13. Stability data of atorvastatin tablets (5mg / 20mg strength)

[0196]

[0197] The results showed that after 6 months of storage at 40℃±2℃ and RH75%±5%, the various test indicators of Haizemabuatorvastatin tablets (5mg / 20mg) did not change significantly, indicating that the sample was relatively stable.

[0198] Method 2: The tablets prepared in Example 2 were packaged in high-density polyethylene bottles (containing 2g of desiccant) and placed under conditions of 25℃±2℃ and 60%±5% humidity for stability studies. The test results are shown in Table 14.

[0199] Table 14. Stability data of atorvastatin tablets (5mg / 20mg strength)

[0200]

[0201]

[0202] The results showed that after 24 months of storage at 25℃±2℃ and RH60%±5%, the content and dissolution of Haizemabuatorvastatin tablets (5mg / 20mg) did not change significantly, and the impurities only increased slightly, indicating that the sample was relatively stable.

[0203] Example 13: Stability Study of Hazemib Atorvastatin Tablets (10mg / 10mg strength)

[0204] Method 1: The tablets prepared in Example 3 were packaged in high-density polyethylene bottles (containing 2g of desiccant) and placed at 40℃±2℃ and RH75%±5% for stability studies. The test results are shown in Table 15.

[0205] Table 15. Stability data of atorvastatin tablets (10mg / 10mg strength)

[0206]

[0207] The results showed that after 6 months of storage at 40℃±2℃ and RH75%±5%, the various test indicators of Haizemabuatorvastatin tablets (10mg / 10mg) did not change significantly, indicating that the sample was relatively stable.

[0208] Method 2: The tablets prepared in Example 3 were packaged in high-density polyethylene bottles (containing 2g of desiccant) and placed at 25℃±2℃ and 60%±5% humidity for stability studies. The test results are shown in Table 16.

[0209] Table 16. Stability data of atorvastatin tablets (10mg / 10mg strength)

[0210]

[0211] The results showed that after 24 months of storage at 25℃±2℃ and RH60%±5%, the content and dissolution of Haizemabuatorvastatin tablets (10mg / 10mg) did not change significantly, and the impurities only increased slightly, indicating that the sample was relatively stable.

[0212] Example 14: Stability Study of Hazemib Atorvastatin Tablets (10mg / 20mg strength)

[0213] Method 1: The tablets prepared in Example 4 were packaged in high-density polyethylene bottles (containing 2g of desiccant) and placed at 40℃±2℃ and RH75%±5% for stability studies. The results are shown in Table 17.

[0214] Table 17. Stability data of atorvastatin tablets (10mg / 20mg strength)

[0215]

[0216]

[0217] The results showed that after 6 months of storage at 40℃±2℃ and RH75%±5%, the content and dissolution of Haizemabuatorvastatin tablets (10mg / 20mg) did not change significantly, and the impurities only increased slightly, indicating that the sample was relatively stable.

[0218] Method 2: The tablets prepared in Example 4 were packaged in high-density polyethylene bottles (containing 2g of desiccant) and placed at 25℃±2℃ and 60%±5% humidity for stability studies. The results are shown in Table 18.

[0219] Table 18. Stability data of atorvastatin tablets (10mg / 20mg strength)

[0220]

[0221] The results showed that after 24 months of storage at 25℃±2℃ and RH60%±5%, the content and dissolution of Haizemabuatorvastatin tablets (10mg / 20mg) did not change significantly, and the impurities only increased slightly, indicating that the sample was relatively stable.

[0222] Example 15: Stability Study of Hazemib Atorvastatin Tablets (10mg / 80mg strength)

[0223] The tablets prepared in Example 5 were packaged in high-density polyethylene bottles (containing 2g of desiccant) and placed under temperature (40℃±2℃) and humidity (RH75%±5%) conditions for stability studies. The results are shown in Table 19.

[0224] Table 19. Stability data of atorvastatin tablets (10mg / 80mg strength)

[0225]

[0226] The results showed that after 3 months of storage at 40℃±2℃ and RH75%±5%, the various test indicators of Haizemabuatorvastatin tablets (10mg / 80mg) did not change significantly, indicating that the sample was relatively stable.

[0227] Example 16: Stability Study of Haizemabupresuvastatin Tablets (20 / 20mg)

[0228] The tablets prepared in Example 6 were placed at 50°C and 75% humidity for stability studies. The results are shown in Table 20.

[0229] Table 20. Stability data of Haizemabrurisuvastatin tablets (20mg / 20mg strength)

[0230]

[0231]

[0232] The results showed that after being placed at 50℃ and 75% humidity for 10 days, the content, related substances and dissolution of Haizemabupresuvastatin tablets remained basically unchanged, indicating that the sample was stable and the quality was controllable.

[0233] Example 17: Stability Study of Haizemabsimvastatin Tablets (6mg / 20mg strength)

[0234] The tablets prepared in Example 10, without packaging, were placed under high temperature (60°C), high humidity (92.5% humidity, 25°C), and strong light (4500 Lx ± 500 Lx) conditions for stability studies. The measured stability data are shown in Table 21.

[0235] Table 21. Stability data of Haizemibsimvastatin tablets (6mg / 20mg strength)

[0236]

[0237] The results showed that after 20 days of storage under various conditions, the content of Haizemabusimvastatin tablets remained basically unchanged, while the content of related substances increased slightly, indicating that the sample was stable and the quality was controllable.

[0238] Example 18: Pharmacodynamic Study of the Combined Use of Hazemib and Simvastatin

[0239] Rhesus monkeys with primary hyperlipidemia (lipidemia indicators: TC>6.22mmol / L, LDL>4.91mmol / L, HDL<1.55mmol / L, TG>1.0mmol / L) were selected. After inducing stable lipid levels for at least 2 weeks using a high-fat diet (see pre-drug data), they were orally induced to take zezemid (HS-25) or zezemid in combination with simvastatin, with ezetimibe as a control. Oral administration was continued for 4 weeks to observe the effects of single-drug and combined simvastatin treatments on lipid levels. Experimental groups and detection indicators are shown in Table 22.

[0240] Table 22. Pharmacodynamic Regimen of HS-25 / ezetimibe in Combination with Simvastatin

[0241]

[0242]

[0243] The test results show that:

[0244] HS-25 and ezetimibe, alone or in combination with simvastatin, did not significantly affect the body weight, blood biochemistry, complete blood count, or blood glucose in hyperlipidemic rhesus monkeys, and no abnormal clinical manifestations were observed.

[0245] The improvement in lipid parameters in all treatment groups was mainly reflected in TC and LDL, while other parameters such as TG, HDL, and APoA1 showed no significant improvement. The efficacy of HS-25 combined with simvastatin was essentially the same as that of ezetimibe combined with simvastatin. Experimental data are shown in Tables 23 and 24.

[0246] Impact on TC (see Table 23):

[0247] Simvastatin alone reduced total TC, and compared with the model group, P<0.05, indicating a statistically significant difference.

[0248] The HS-25 monotherapy group and the ezetimibe monotherapy group showed significant TC-reducing effects, which were superior to the simvastatin monotherapy group. Compared with the model group, P<0.01, indicating a statistically significant difference. The efficacy gradually increased with the duration of administration, suggesting that the TC-reducing effect of HS-25 and ezetimibe has a certain degree of persistence.

[0249] When HS-25 and ezetimibe were used in combination with simvastatin, their effects on reducing total cholesterol (TC) were superior to those of HS-25 alone, ezetimibe alone, and simvastatin alone. This was mainly reflected in the fact that the reduction in TC was faster at 1 week after administration than with either drug alone, and the maximum percentage reduction in TC (at 4 weeks after administration) was also greater.

[0250] The impact on LDL (see Table 24):

[0251] The effects of HS-25 and ezetimibe alone or in combination with atorvastatin on LDL were consistent with those of TC.

[0252] Table 23. Effects of HS-25 and ezetimibe alone or in combination with simvastatin on total TC (mmol / L and %) in model animals

[0253]

[0254]

[0255] Table 24. Effects of HS-25 and ezetimibe alone or in combination with simvastatin on LDL levels in model animals (mmol / L and %).

[0256]

[0257]

[0258] Example 19: Pharmacodynamics of the combination of zebufenib and atorvastatin

[0259] A primary hyperlipidemic rhesus monkey model was used (lipidemia indicators: TC>6.22mmol / L, LDL>4.91mmol / L, HDL<1.55mmol / L, TG>1.0mmol / L). A high-fat diet was added to induce hyperlipidemia. After the hyperlipidemia level stabilized, animals were orally administered atorvastatin or its combination with ezetimibe (HS-25) or ezetimibe for 3 consecutive months. The effects of HS-25 and ezetimibe combined with atorvastatin on blood lipids were observed. Experimental groups and detection indicators are shown in Table 25.

[0260] Table 25. Pharmacodynamic Regimen of HS-25 / Ezetimibe Combined with Atorvastatin

[0261]

[0262] The test results show that:

[0263] Atorvastatin alone or in combination with HS-25 or ezetimibe did not significantly affect the body weight, blood biochemistry, complete blood count, or blood glucose of rhesus monkeys, and no abnormal clinical manifestations were observed.

[0264] The improvement in lipid profiles in all treatment groups was mainly observed in TC and LDL, while other indicators such as TG, HDL, APoA1, and APoB showed no significant changes. Experimental data are shown in Tables 26 and 27.

[0265] Impact on TC (Table 26):

[0266] In each treatment group, the efficacy reached a plateau after 30 days of administration, and no further reduction in TC was observed with continued administration. Due to the small number of animals, the TC levels in the model group fluctuated to some extent. Therefore, overall, the TC reduction effect of atorvastatin monotherapy was approximately 25%, while the TC reduction percentage in the two combined therapy groups was around 50%, which was significantly better than that of atorvastatin monotherapy.

[0267] The TC content in the model group remained relatively stable during the experiment, with no significant fluctuations, proving that the model is relatively stable.

[0268] Impact on LDL (Table 27)

[0269] The trend of atorvastatin alone or in combination with HS-25 or ezetimibe for LDL is consistent with TC.

[0270] Table 26. Effects of atorvastatin alone or in combination with HS-25 and ezetimibe on serum total cholesterol (TC) in hyperlipidemic rhesus monkeys after 90 days of administration (mmol / L, %).

[0271]

[0272] Table 27. Effects of atorvastatin alone or in combination with HS-25 and ezetimibe on serum LDL in hyperlipidemic rhesus monkeys after 90 days of administration (mmol / L, %)

[0273]

[0274] Example 20: Repeat-dose toxicity study of azetiem combined with atorvastatin in beagle dogs

[0275] SPF-grade normal beagle dogs aged 6-9 months, with equal numbers of males and females, were divided into a solvent group, an atorvastatin monotherapy group, and an HS-25 combined with atorvastatin group. Administered the drugs continuously for 2 weeks. The toxicity of atorvastatin monotherapy or HS-25 combination was observed. Grouping and administration are shown in Table 28.

[0276] Table 28. Toxicity Study Protocol for Repeated Dosing of HS-25 in Beagle Dogs

[0277]

[0278] The experimental results show that:

[0279] The drooling observed in a few beagle dogs was related to atorvastatin. Other indicators such as weight, food intake, electrocardiogram, complete blood count, gross anatomy, and pathology were normal; the decrease in blood lipids showed a dose-related correlation with atorvastatin.

[0280] The toxicity of this experiment was mainly reflected in liver function tests in blood biochemistry: alanine aminotransferase (ALT) and aspartate aminotransferase (AST). ALT was more sensitive than AST. The results of the two-week experiment are shown in Table 29.

[0281] Table 29. Toxicity test results of atorvastatin alone or HS-25 in combination with repeated atorvastatin in beagle dogs.

[0282]

[0283] Literature on ezetimibe (see NDA 21-445 FDA review: Pharmacology Review(s) 117-129) shows that ezetimibe, in combination with atorvastatin, caused hepatotoxicity at a dose of 0.3 / 1 mg / kg, and the toxicity increased with increasing atorvastatin dose; blood lipid levels and liver enzyme levels were basically consistent. Data from the 3-week experiment are shown in Table 30.

[0284] Table 30. Toxicity test results of atorvastatin monotherapy or repeated administration of atorvastatin in Zetia in beagle dogs.

[0285]

[0286] The comparative analysis of the above data shows that the liver function levels in the two experiments were consistent in both the blank group and the atorvastatin 10mg / kg dose, indicating that the data are comparable.

[0287] The results showed that no significant toxicity was observed in the atorvastatin monotherapy group at 10 mg / kg; a slight increase in ALT was observed in the atorvastatin monotherapy group at 30 mg / kg.

[0288] The toxicity of HS-25 combined with atorvastatin was only manifested as an increase in ALT, with no abnormalities in AST; the toxicity of Zetia combined with atorvastatin was observed at 3 / 10 and 30 / 10 mg / kg, with both ALT and AST increasing.

[0289] The toxicity of HS-25 combined with atorvastatin (30 / 10 mg / kg) was ALT: 112.8; the toxicity of Zetia combined with atorvastatin (0.3 / 1 mg / kg) was ALT: 112.8; suggesting that the safety of HS-25 combined with atorvastatin is at least 10 times that of Zetia combined with atorvastatin.

[0290] Furthermore, the toxicity of HS-25 combined with atorvastatin at 30 / 10, 100 / 10, and 100 / 30 mg / kg showed ALT levels of 112.8, 188.3, ​​and 242.8, respectively, indicating a relatively small increase in ALT. In contrast, the toxicity of Zetia combined with atorvastatin at 0.3 / 1, 3 / 1, 3 / 10, and 30 / 10 mg / kg showed ALT levels of 112.8, 156.3, 990.3, and 657.0 in females and 88.8, 106.3, 391.5, and 1133.5 in males, respectively, indicating a significantly greater increase in ALT with increasing dose, suggesting more pronounced hepatotoxicity.

[0291] In summary, the combination of HS-25 and atorvastatin is significantly safer than the combination of Zetia and atorvastatin, with a safety multiple of approximately 10 times in beagles.

[0292] Example 21: Haizemabuatorvastatin tablets, specification: 20mg / 20mg, each tablet weighs 480mg, the formula is shown in Table 31.

[0293] Table 31. Formulation composition of Example 21 (unit: g)

[0294]

[0295] Preparation method:

[0296] (1) Mix the prescribed amount of atorvastatin and the lactose, microcrystalline cellulose, calcium carbonate and croscarmellose sodium of the atorvastatin granule portion evenly;

[0297] (2) Dissolve the prescribed amounts of polysorbate and hydroxypropyl cellulose in purified water;

[0298] (3) The solution obtained in step (2) is added to the mixture obtained in step (1) for granulation, drying, and granulation to obtain atorvastatin granules.

[0299] (4) Mix the lactose, microcrystalline cellulose, sodium lauryl sulfate and crospovidone in the granular part of Haizemaibu evenly;

[0300] (5) Dissolve the prescribed amounts of Hazemab, Butylated Hydroxytoluene, and Povidone K30 in an ethanol solution;

[0301] (6) Add the solution obtained in step (5) to the mixture obtained in step (4) for granulation, drying, and granulation to obtain Haizemaibu granules.

[0302] (7) Mix the granules after granulation in step (3) with the cross-linked sodium carboxymethyl cellulose added to the atorvastatin granules evenly, and then add magnesium stearate and mix evenly.

[0303] (8) Mix the granules after granulation in step (6) with the cross-linked sodium carboxymethyl cellulose added to the Haizemaibu granules evenly, and then add magnesium stearate and mix evenly.

[0304] (9) Press the particles obtained in steps (7) and (8) into a double-layer sheet.

[0305] Example 22: Haizemabuatorvastatin tablets, specifications: 20mg / 10mg, each tablet weighs 480mg, the formula is shown in Table 32.

[0306] Table 32. Formulation composition of Example 22 (unit: g)

[0307]

[0308] Preparation method: Same as in Example 21.

[0309] Example 23: Haizemabuatorvastatin tablets, specifications: 10mg / 20mg, each tablet weighs 315mg, the formula is shown in Table 33.

[0310] Table 33. Formulation composition of Example 23 (unit: g)

[0311]

[0312]

[0313] Preparation method: Same as in Example 21.

[0314] Example 24: Haizemabuatorvastatin tablets, specification: 10mg / 10mg, each tablet weighs 315mg, the formula is shown in Table 34.

[0315] Table 34. Formulation composition of Example 24 (unit: g)

[0316]

[0317] Preparation method: Same as in Example 21.

[0318] Example 25: Haizemabupresuvastatin tablets, specification: 20mg / 20mg, each tablet weighs 460mg, the formula is shown in Table 35.

[0319] Table 35. Formulation composition of Example 25 (unit: g)

[0320]

[0321]

[0322] Preparation method:

[0323] (1) Mix the prescribed amount of rosuvastatin and the lactose, microcrystalline cellulose, calcium carbonate and crospovidone of the rosuvastatin granules evenly;

[0324] (2) Dissolve the povidone K30 in the rosuvastatin granule fraction in purified water;

[0325] (3) The povidone K30 solution obtained in step (2) is added to the mixture obtained in step (1) for granulation, drying, and granulation to obtain rosuvastatin granules.

[0326] (4) Mix the lactose, microcrystalline cellulose, sodium lauryl sulfate and crospovidone in the granular part of Haizemaibu evenly;

[0327] (5) Dissolve the prescribed amount of Hazemabu, Butylated Hydroxytoluene, and the povidone K30 of Hazemabu granules in an ethanol solution;

[0328] (6) Add the solution obtained in step (5) to the mixture obtained in step (4) for granulation, drying, and granulation to obtain Haizemaibu granules.

[0329] (7) Mix the granules after granulation in step (3) with the cross-linked polyvinyl chloride added to the rosuvastatin granules evenly, and then add magnesium stearate and mix evenly.

[0330] (8) Mix the granules after granulation in step (6) with the cross-linked polyvinyl ketone added to the Haizemaibu granules evenly, and then add magnesium stearate and mix evenly.

[0331] (9) Press the particles obtained in steps (7) and (8) into a double-layer sheet.

[0332] Example 26: Haizemabupresuvastatin tablets, specifications: 20mg / 10mg, each tablet weighs 460mg, the formula is shown in Table 36.

[0333] Table 36. Formulation composition of Example 26 (unit: g)

[0334]

[0335]

[0336] Preparation method: Same as in Example 25.

[0337] Example 27: Haizemabupresuvastatin tablets, specifications: 10mg / 20mg, each tablet weighs 295mg, the formula is shown in Table 37.

[0338] Table 37. Formulation composition of Example 27 (unit: g)

[0339]

[0340] Preparation method: Same as in Example 25.

[0341] Example 28: Haizemabupresuvastatin tablets, specification: 10mg / 10mg, each tablet weighs 295mg, the formula is shown in Table 38.

[0342] Table 38. Formulation composition of Example 28 (unit: g)

[0343]

[0344]

[0345] Preparation method: Same as in Example 25.

[0346] Example 29: Haizemabupresuvastatin tablets, specification: 20mg / 20mg, each tablet weighs 460mg, the formula is shown in Table 39.

[0347] Table 39. Formulation composition of Example 29 (unit: g)

[0348]

[0349] (1) Mix the prescribed amount of rosuvastatin and the lactose, microcrystalline cellulose, calcium carbonate and crospovidone of the rosuvastatin granules evenly;

[0350] (2) Dissolve the povidone K30 in the rosuvastatin granule fraction in purified water;

[0351] (3) The povidone K30 solution obtained in step (2) is added to the mixture obtained in step (1) for granulation, drying, and granulation to obtain rosuvastatin granules.

[0352] (4) Mix the lactose, microcrystalline cellulose, sodium lauryl sulfate and crospovidone in the granular part of Haizemaibu evenly;

[0353] (5) Dissolve the prescribed amount of Hazemabu and the butylated hydroxytoluene and povidone K30 of the Hazemabu granules in an ethanol solution;

[0354] (6) Add the solution obtained in step (5) to the mixture obtained in step (4) for granulation, drying, and granulation to obtain Haizemaibu granules.

[0355] (7) Mix the granules after granulation in step (3) and the granules after granulation in step (6), then mix them evenly with the added cross-linked polyvinyl alcohol, then add the prescribed amount of magnesium stearate and mix evenly, then compress into tablets.

[0356] Example 30: Stability Study of Hazemibuatorvastatin Calcium Tablets (20mg / 10mg strength)

[0357] The tablets prepared in Example 22 were bottle-packaged and placed under accelerated conditions (40°C / 75% RH) for stability studies. The stability data are shown in Table 40.

[0358] Table 40. Stability data of atorvastatin tablets (20mg / 10mg strength)

[0359]

[0360] The results showed that after 3 months of storage at 40℃±2℃ and RH75%±5%, the various test indicators of Haizemabuatorvastatin tablets (20mg / 10mg) did not change significantly, indicating that the sample was relatively stable.

[0361] Example 31: Haizemabuatorvastatin tablets, specifications: 20mg / 10mg, each tablet weighs 480mg, the formula is shown in Table 41.

[0362] Table 41. Formulation composition of Example 31 (unit: g)

[0363]

[0364]

[0365] Preparation method:

[0366] (1) Mix the prescribed amount of atorvastatin and the lactose, microcrystalline cellulose, calcium carbonate and croscarmellose sodium of the atorvastatin granule portion evenly;

[0367] (2) Dissolve the prescribed amounts of polysorbate and hydroxypropyl cellulose in purified water;

[0368] (3) The solution obtained in step (2) is added to the mixture obtained in step (1) for granulation, drying, and granulation to obtain atorvastatin granules.

[0369] (4) Mix the lactose, microcrystalline cellulose, sodium lauryl sulfate and crospovidone in the granular part of Haizemaibu evenly;

[0370] (5) Dissolve the prescribed amounts of Hazemab, Butylated Hydroxytoluene, and Povidone K30 in isopropanol solution;

[0371] (6) Add the solution obtained in step (5) to the mixture obtained in step (4) for granulation, drying, and granulation to obtain Haizemaibu granules.

[0372] (7) Mix the granules after granulation in step (3) with the cross-linked sodium carboxymethyl cellulose added to the atorvastatin granules evenly, and then add magnesium stearate and mix evenly.

[0373] (8) Mix the granules after granulation in step (6) with the cross-linked sodium carboxymethyl cellulose added to the Haizemaibu granules evenly, and then add magnesium stearate and mix evenly.

[0374] (9) Press the particles obtained in steps (7) and (8) into a double-layer sheet.

[0375] Example 32: Haizemabuatorvastatin tablets, specification: 20mg / 20mg, each tablet weighs 630mg, the formula is shown in Table 42.

[0376] Table 42. Formulation composition of Example 32 (unit: g)

[0377]

[0378] Preparation method: Same as in Example 31.

[0379] Example 33: Haizemabuatorvastatin tablets, specifications: 10mg / 20mg, each tablet weighs 465mg, the formula is shown in Table 43.

[0380] Table 43. Formulation composition of Example 33 (unit: g)

[0381]

[0382]

[0383] Preparation method: Same as in Example 31.

[0384] Example 34: Stability study of Hazemib Atorvastatin Tablets (20mg / 20mg strength)

[0385] Method 1: The tablets prepared in Example 21 were packaged in double aluminum foil and placed at 40℃±2℃ and RH75%±5% for stability studies. The results are shown in Table 44.

[0386] Table 44. Stability data of atorvastatin tablets (20mg / 20mg strength)

[0387]

[0388] The results showed that after 3 months of storage at 40℃±2℃ and RH75%±5%, the content and dissolution of Haizemabuatorvastatin tablets (20mg / 10mg) did not change significantly, and the impurities only increased slightly, indicating that the sample was relatively stable.

[0389] Method 2: The tablets prepared in Example 21 were packaged in double aluminum foil and placed at 25℃±2℃ and 60%±5% humidity for stability studies. The results are shown in Table 45.

[0390] Table 45. Stability data of atorvastatin tablets (20mg / 20mg strength)

[0391]

[0392]

[0393] The results showed that after 9 months of storage at 25℃±2℃ and RH60%±5%, the content and dissolution of Haizemabuatorvastatin tablets (20mg / 20mg) did not change significantly, and the impurities only increased slightly, indicating that the sample was relatively stable.

[0394] Example 35: Stability Study of Hazemib Atorvastatin Tablets (20mg / 10mg strength)

[0395] Method 1: The tablets prepared in Example 22 were packaged in double aluminum foil and placed at 40℃±2℃ and RH75%±5% for stability studies. The results are shown in Table 46.

[0396] Table 46. Stability data of atorvastatin tablets (20mg / 10mg strength)

[0397]

[0398] The results showed that after 3 months of storage at 40℃±2℃ and RH75%±5%, the content and dissolution of Haizemabuatorvastatin tablets (20mg / 10mg) did not change significantly, and the impurities only increased slightly, indicating that the sample was relatively stable.

[0399] Method 2: The tablets prepared in Example 22 were packaged in double aluminum foil and placed at 25℃±2℃ and 60%±5% humidity for stability studies. The results are shown in Table 47.

[0400] Table 47. Stability data of atorvastatin tablets (20mg / 10mg strength)

[0401]

[0402]

[0403] The results showed that after 9 months of storage at 25℃±2℃ and RH60%±5%, the content and dissolution of Haizemabuatorvastatin tablets (20mg / 10mg) did not change significantly, and the impurities only increased slightly, indicating that the sample was relatively stable.

[0404] Example 36: Stability Study of Haizemabuatorvastatin Tablets (10mg / 20mg strength)

[0405] Method 1: The tablets prepared in Example 23 were packaged in double aluminum foil and placed at 40℃±2℃ and RH75%±5% for stability studies. The results are shown in Table 48.

[0406] Table 48. Stability data of atorvastatin tablets (10mg / 20mg strength)

[0407]

[0408] The results showed that after 3 months of storage at 40℃±2℃ and RH75%±5%, the content and dissolution of Haizemabuatorvastatin tablets (10mg / 20mg) did not change significantly, and the impurities only increased slightly, indicating that the sample was relatively stable.

[0409] Method 2: The tablets prepared in Example 23 were packaged in double aluminum foil and placed at 25℃±2℃ and 60%±5% humidity for stability studies. The results are shown in Table 49.

[0410] Table 49. Stability data of atorvastatin tablets (10mg / 20mg strength)

[0411]

[0412]

[0413] The results showed that after 9 months of storage at 25℃±2℃ and RH60%±5%, the content and dissolution of Haizemabuatorvastatin tablets (10mg / 20mg) did not change significantly, and the impurities only increased slightly, indicating that the sample was relatively stable.

[0414] Example 37: Stability Study of Hazemib Atorvastatin Tablets (10mg / 10mg strength)

[0415] Method 1: The tablets prepared in Example 24 were packaged in double aluminum foil and placed at 40℃±2℃ and RH75%±5% for stability studies. The results are shown in Table 50.

[0416] Table 50 Stability data for Hazemib Atorvastatin Tablets (10mg / 10mg strength)

[0417]

[0418] The results showed that after 3 months of storage at 40℃±2℃ and RH75%±5%, the content and dissolution of Haizemabuatorvastatin tablets (10mg / 10mg) did not change significantly, and the impurities only increased slightly, indicating that the sample was relatively stable.

[0419] Method 2: The tablets prepared in Example 24 were packaged in double aluminum foil and placed at 25℃±2℃ and 60%±5% humidity for stability studies. The results are shown in Table 51.

[0420] Table 51. Stability data of atorvastatin tablets (10mg / 10mg strength)

[0421]

[0422]

[0423] The results showed that after 9 months of storage at 25℃±2℃ and RH60%±5%, the content and dissolution of Haizemabuatorvastatin tablets (10mg / 10mg) did not change significantly, and the impurities only increased slightly, indicating that the sample was relatively stable.

[0424] Example 38: Haizemabupresuvastatin tablets, specifications: 20mg / 10mg, each tablet weighs 320mg, the formula is shown in Table 52.

[0425] Table 52. Formulation composition of Example 38 (unit: g)

[0426]

[0427] (1) Mix the prescribed amount of rosuvastatin and the lactose, microcrystalline cellulose, calcium carbonate and crospovidone of the rosuvastatin granules evenly;

[0428] (2) Dissolve the povidone K30 in the rosuvastatin granule fraction in purified water;

[0429] (3) The povidone K30 solution obtained in step (2) is added to the mixture obtained in step (1) for granulation, drying, and granulation to obtain rosuvastatin granules.

[0430] (4) Mix the lactose, microcrystalline cellulose, sodium lauryl sulfate and crospovidone in the granular part of Haizemaibu evenly;

[0431] (5) Dissolve the prescribed amount of Hazemabu and the butylated hydroxytoluene and povidone K30 of the Hazemabu granules in an ethanol solution;

[0432] (6) Add the solution obtained in step (5) to the mixture obtained in step (4) for granulation, drying, and granulation to obtain Haizemaibu granules.

[0433] (7) Mix the granules after granulation in step (3) and the granules after granulation in step (6), then add the prescribed amount of magnesium stearate and mix evenly, then compress into tablets.

[0434] Example 39: Haizemabupresuvastatin tablets, specifications: 20mg / 5mg, each tablet weighs 270mg, the formula is shown in Table 53.

[0435] Table 53. Formulation composition of Example 38 (unit: g)

[0436]

[0437] Preparation method: Same as in Example 38.

Claims

1. A pharmaceutical composition comprising: (a) 0.5-20% by weight of Hezemab; (b) 1 to 80% by weight of at least one HMG-CoA reductase inhibitor, wherein the HMG-CoA reductase inhibitor is a statin or a salt thereof, wherein the statin is selected from rosuvastatin and simvastatin.

2. The pharmaceutical composition according to claim 1, further comprising one or more excipients selected from stabilizers, surfactants, fillers, binders, disintegrants, and lubricants.

3. The pharmaceutical composition according to claim 2, wherein the stabilizer is at least one of calcium carbonate, butylated hydroxyanisole, citric acid, and butylated hydroxytoluene; the surfactant is at least one of sodium dodecyl sulfate and polysorbate; the filler is at least one of lactose, microcrystalline cellulose, and pregelatinized starch; the binder is at least one of hydroxypropyl cellulose and povidone; the disintegrant is at least one of croscarmellose sodium and croscarmellose; and the lubricant is at least one of magnesium stearate and talc.

4. The pharmaceutical composition according to claim 2, wherein the composition contains one or more of the following: 1-25% by weight calcium carbonate, 0.005-0.1% by weight butylated hydroxytoluene, 0.1-10% by weight sodium dodecyl sulfate, 0.05-1.0% by weight polysorbate, 1-10% by weight croscarmellose sodium, 1-10% by weight croscarmellose, 10-50% by weight microcrystalline cellulose, 0.1-5% by weight povidone, 0.1-5% by weight hydroxypropyl cellulose, 10-50% by weight lactose, and 0.1-2% by weight magnesium stearate.

5. The pharmaceutical composition according to claim 1, wherein it contains 1-10% by weight of zebufenib and 1-30% by weight of rosuvastatin.

6. The pharmaceutical composition according to claim 1 or 5, further comprising a stabilizer.

7. The pharmaceutical composition according to claim 6, wherein the stabilizer is at least one of calcium carbonate and butylated hydroxytoluene.

8. The pharmaceutical composition according to claim 6, wherein the stabilizer is at least one of 1-15% by weight calcium carbonate and 0.005-0.05% by weight butylated hydroxytoluene.

9. The pharmaceutical composition according to claim 1 or 5, further comprising a surfactant.

10. The pharmaceutical composition according to claim 9, wherein the surfactant is sodium dodecyl sulfate.

11. The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition contains 0.1 to 6% by weight of sodium dodecyl sulfate.

12. The pharmaceutical composition according to claim 1 or 5, further comprising one or more of a filler, a binder, a disintegrant, and a lubricant.

13. The pharmaceutical composition according to claim 12, wherein the filler is at least one of lactose and microcrystalline cellulose, the binder is at least one of hydroxypropyl cellulose and povidone, the disintegrant is at least one of croscarmellose sodium and croscarmellose, and the lubricant is magnesium stearate.

14. The pharmaceutical composition according to claim 12, wherein the pharmaceutical composition contains one or more of the following: 1-10% by weight of crospovidone, 10-50% by weight of microcrystalline cellulose, 0.1-5% by weight of povidone, 10-50% by weight of lactose, and 0.1-2% by weight of magnesium stearate.

15. A method for preparing a pharmaceutical composition according to any one of claims 1 to 14, comprising combining an HMG-CoA reductase inhibitor, zebufenib, and optional excipients.

16. The preparation method of claim 15, comprising: (1) The HMG-CoA reductase inhibitor is granulated with optional excipients to obtain the HMG-CoA reductase inhibitor granule portion; (2) Make Haizemab into granules with optional excipients to obtain Haizemab granules; (3) Combine the granules prepared in steps (1) and (2) with optional excipients.

17. The production method according to claim 16, wherein The HMG-CoA reductase inhibitor granules in step (1) were obtained by granulation using water as a solvent; the Haizemab granules in step (2) were obtained by granulation using water, organic solvents, or mixtures thereof.

18. The production method according to claim 17, wherein The Haizemab granules in step (2) are obtained by granulation with water, alcohol, chloroform, acetone, acetonitrile or similar solvents, and mixtures thereof.

19. The production method according to claim 18, wherein The Haizemab granules in step (2) are obtained by granulation with water, alcohol and mixtures thereof.

20. The production method according to claim 18, wherein The Haizemab granules in step (2) are obtained by granulation of a mixture of alcohol and water.

21. The production method according to claim 18, wherein The Haizemab granules in step (2) were obtained by granulation using a mixture of ethanol and water.

22. A method for preparing the pharmaceutical composition according to any one of claims 15 to 21, comprising: (1) Rosuvastatin is granulated with optional excipients; (2) Grind Haizemab with optional excipients into granules; (3) Mix the granules prepared in steps (1) and (2) above with optional excipients evenly.

23. The method for preparing the pharmaceutical composition according to claim 22, comprising: (1) Mix rosuvastatin with lactose, microcrystalline cellulose, calcium carbonate and crospovidone evenly; (2) Dissolve povidone in water; (3) Add the povidone solution obtained in step (2) to the mixture obtained in step (1) for granulation, drying and granulation; (4) Mix lactose, microcrystalline cellulose, sodium lauryl sulfate and crospovidone evenly; (5) Dissolve Hazemab and Povidone in an ethanol solution; (6) Add the solution obtained in step (5) to the mixture obtained in step (4) for granulation, drying and granulation; (7) Mix the granules after granulation in steps (3) and (6), then optionally mix them with cross-linked polyvinyl alcohol, then optionally mix them with magnesium stearate, and compress them into tablets.

24. A method for preparing the pharmaceutical composition according to claim 22, comprising: (1) Mix rosuvastatin with lactose, microcrystalline cellulose, calcium carbonate and crospovidone evenly; (2) Dissolve povidone in water; (3) Add the povidone solution obtained in step (2) to the mixture obtained in step (1) for granulation, drying and granulation; (4) Mix lactose, microcrystalline cellulose, sodium lauryl sulfate and crospovidone evenly; (5) Dissolve Haizemab, Butylated Hydroxytoluene, and Povidone in an ethanol solution; (6) Add the solution obtained in step (5) to the mixture obtained in step (4) for granulation, drying and granulation; (7) Mix the granules after granulation in steps (3) and (6), then optionally mix them with cross-linked polyvinyl alcohol, then optionally mix them with magnesium stearate, and compress them into tablets.

25. A method for preparing the pharmaceutical composition according to any one of claims 15 to 21, comprising: (1) Rosuvastatin is granulated with optional excipients; (2) Grind Haizemab with optional excipients into granules; (3) Mix the granules prepared in step (1) with the optional excipients evenly to obtain the first total mixed granules; (4) Mix the granules prepared in step (2) above with the optional excipients evenly to obtain the second total mixed granules; (5) The first and second mixed particles obtained in steps (3) and (4) above are pressed into a double-layer sheet.

26. A method for preparing the pharmaceutical composition according to claim 25, comprising: (1) Mix rosuvastatin with lactose, microcrystalline cellulose, calcium carbonate and crospovidone evenly; (2) Dissolve povidone in water; (3) Add the povidone solution obtained in step (2) to the mixture obtained in step (1) for granulation, drying and granulation; (4) Mix lactose, microcrystalline cellulose, sodium lauryl sulfate and crospovidone evenly; (5) Dissolve Haizemab, Butylated Hydroxytoluene, and Povidone in an ethanol solution; (6) Add the solution obtained in step (5) to the mixture obtained in step (4) for granulation, drying and granulation; (7) The granules after granulation in step (3) are optionally mixed with cross-linked polyvinyl ketone and then optionally mixed with magnesium stearate to obtain the first total mixed granules; (8) The granules after granulation in step (6) are optionally mixed with cross-linked polyvinyl ketone and then optionally mixed with magnesium stearate to obtain the second total mixed granules; (9) The first and second mixed particles obtained in steps (7) and (8) are pressed into a double-layer sheet.

27. A drug dosage unit comprising 5-20 mg of zebufenib and 5-80 mg of rosuvastatin.

28. The drug dosing unit according to claim 27, wherein, The dosage of the hazemib is 5 mg, 10 mg or 20 mg; the dosage of the rosuvastatin is 5 mg, 10 mg, 20 mg or 40 mg.

29. The drug dosage unit according to claim 27 or 28, further comprising 1 to 50 mg of calcium carbonate.

30. The drug dosage unit according to claim 27 or 28, further comprising 1 to 50 mg of calcium carbonate and 0.01 to 0.2 mg of butylated hydroxytoluene.

31. The drug dosage unit according to claim 27 or 28, further comprising 0.5 to 10 mg of sodium dodecyl sulfate.

32. The drug dosage unit according to claim 27 or 28, further comprising 5-40 mg of crospovidone, 20-250 mg of microcrystalline cellulose, 1-20 mg of povidone, 20-250 mg of lactose, and 0.1-5 mg of magnesium stearate.

33. The pharmaceutical composition of any one of claims 1 to 5 or the pharmaceutical dosage unit of any one of claims 27 to 28, wherein the pharmaceutical composition or pharmaceutical dosage unit is a capsule, tablet, granule, powder, solution or lozenge.

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