CN111836620B - A pharmaceutical composition of Hezumab and HMG-CoA reductase inhibitor - Google Patents

Abstract

The invention provides a pharmaceutical composition, which contains Hezumab and HMG-CoA reductase inhibitor, and may also include calcium carbonate, butylated hydroxyanisole, butylated hydroxytoluene, citric acid, sodium lauryl sulfate, In polysorbate, croscarmellose sodium, crospovidone, microcrystalline cellulose, povidone, hydroxypropyl cellulose, lactose, pregelatinized starch, magnesium stearate and talc One or more excipients. The composition can be made into various dosage forms, and the preparation has good stability and controllable quality.

Description

A pharmaceutical composition of hezemib and HMG-CoA reductase inhibitor

Cross-references

This application claims the priority of Chinese patent application No. 201711183715.5, entitled “A pharmaceutical composition of hezemib and HMG-CoA reductase inhibitor”, filed with the Patent Office of China on November 23, 2017, the contents of which are incorporated herein by reference in their entirety.

Technical Field

The invention belongs to the field of medicine, and specifically relates to a composition of hezemib and an HMG-CoA reductase inhibitor and application thereof.

Background Art

Cardiovascular disease is one of the most common and serious diseases that endangers human health (especially the middle-aged and elderly). Dyslipidemia is an important risk factor for atherosclerosis, coronary heart disease and other cardiovascular and cerebrovascular diseases. Lipid-lowering drugs are very important for the prevention and treatment of cardiovascular diseases.

At present, the lipid-lowering chemical drugs in clinical application and in the research and development stage can be divided into statins, niacin, fibrates, bile acid chelators, polyenes, new lipid-lowering drugs and various compound preparations according to their lipid-lowering mechanism and chemical structure. Different lipid-lowering drugs have their own advantages and disadvantages. Among them, statins are the most widely used, most effective and well-received lipid-lowering drugs in clinical practice. Commonly used drugs in clinical practice include: lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, long-acting fluvastatin sustained-release tablets, rosuvastatin, pitavastatin, etc. At present, atorvastatin has the highest market share. The adverse reactions of statins are less than other lipid-lowering drugs. There are two main categories: one is the metabolic disorder in the body caused by the inhibition of the synthesis of mevalonic acid, a cholesterol precursor, and the other is direct toxic effects. The most common symptoms are mild gastrointestinal reactions, rhinitis, sinusitis, headache, sore throat, influenza syndrome, arthritis, chest pain, insomnia, etc.

In recent years, the research and development of new dosage forms and compound combination drugs has attracted more and more attention. While continuously developing lipid-lowering drugs with new mechanisms of action, various new dosage forms and compound preparations that can reduce adverse drug reactions and enhance efficacy have also been applied in clinical practice, achieving good results. Among them are: Altocor, lovastatin controlled-release tablets, Nispan, niacin sustained-release preparations, fenofibrate micronized capsules, Nicostatin, a compound preparation of niacin and lovastatin, ezetimibe/simvastatin compound preparations, ezetimibe/atorvastatin compound preparations, etc.

Among the many compound preparations and combined application studies, the research on the new cholesterol absorption inhibitor Ezetimibe and statins has attracted the most attention. The pharmacodynamic study of Ezetimibe and statins found that the combination of Ezetimibe and statins has good pharmacodynamic synergy. However, it has been found that there is a certain liver toxicity when Ezetimibe is used in combination with statins, especially when used in combination at synergistic levels. It 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 hazard for the treatment of hyperlipidemia that requires long-term medication.

Therefore, there is still an urgent need in the prior art for drugs with good lipid-lowering effects and high safety.

Summary of the invention

The inventors unexpectedly discovered in their research that the combination of hezemib and HMG-CoA reductase inhibitors not only has a good synergistic effect in lowering blood lipids, but also has sufficient safety. Based on this discovery, the present invention was completed. The hezemib described in the present invention is a new intestinal cholesterol absorption inhibitor, which is disclosed in Chinese patent CN101993403A. Hezemib has the following structural formula:

Based on the above findings, one of the technical solutions of the present invention is: to provide a pharmaceutical composition, which contains 0.5-20% by weight of hezemib; 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, and the statin is, for example, lovastatin, simvastatin, atorvastatin, pravastatin, rosuvastatin, fluvastatin, cerivastatin, pitavastatin and rosuvastatin or one or more of their salts; the salt of the statin is pharmaceutically acceptable, and the salt is not particularly limited; preferably, lovastatin, simvastatin, atorvastatin, rosuvastatin, pitavastatin and rosuvastatin are in the form of calcium salts; pravastatin, fluvastatin and cerivastatin are in the form of sodium salts.

More preferably, the statin is atorvastatin, rosuvastatin or simvastatin.

In one aspect of this solution, 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.

The stabilizer may be a stabilizer conventionally used in the art, such as carbonate, bicarbonate or phosphate, etc., or an antioxidant such as butylated hydroxyanisole, citric acid or butylated hydroxytoluene, etc. Preferably, the stabilizer is at least one of calcium carbonate, butylated hydroxyanisole, citric acid or butylated hydroxytoluene.

Among them, the surfactant can be a surfactant conventionally used in the art, for example, it can be an anionic surfactant or a non-ionic surfactant; examples of anionic surfactants include: sodium stearate, potassium stearate, sodium oleate, calcium stearate and sodium lauryl sulfate, etc.; examples of non-ionic surfactants include: fatty acid sorbitan (Span), polysorbate, myrj, benzyl (brij), poloxamer, etc.; preferably, the surfactant is at least one of sodium lauryl sulfate or polysorbate.

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

The binder may be a conventionally used binder in the art, such as hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, povidone, gum arabic, sucrose, etc.; preferably, the binder is at least one of hydroxypropyl cellulose and povidone.

Wherein, the disintegrant can be a disintegrant conventionally used in the art, such as cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, sodium alginate, corn starch, and low-substituted hydroxypropyl cellulose; preferably, the disintegrant is at least one of cross-linked sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone.

The lubricant may be a lubricant conventionally 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.

As a preferred embodiment, the composition of the present invention may contain one or more of 1 to 25% by weight of calcium carbonate, 0.005 to 0.1% by weight of butylated hydroxytoluene, 0.1 to 10% by weight of sodium lauryl sulfate, 0.05 to 1.0% by weight of polysorbate, 1 to 10% by weight of cross-linked sodium carboxymethyl cellulose, 1 to 10% by weight of cross-linked polyvinylpyrrolidone, 10 to 50% by weight of microcrystalline cellulose, 0.1 to 5% by weight of polyvinylpyrrolidone, 0.1 to 5% by weight of hydroxypropyl cellulose, 10 to 50% by weight of lactose, and 0.1 to 2% by weight of magnesium stearate.

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

In one aspect of this solution, 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, a bicarbonate, a phosphate or butylated hydroxytoluene, etc.; preferably, the stabilizer is at least one of calcium carbonate or butylated hydroxytoluene. Adding calcium carbonate or butylated hydroxytoluene to the composition of the present invention is beneficial to the stability of the preparation. More preferably, the pharmaceutical composition may include 5 to 25% by weight of calcium carbonate and 0.005% to 0.05% by weight of butylated hydroxytoluene.

In another aspect of this scheme, the pharmaceutical composition may also optionally contain a surfactant. The surfactant may be a surfactant conventionally used in the art, for example, an anionic surfactant or a nonionic surfactant. Examples of anionic surfactants include sodium stearate, potassium stearate, sodium oleate, calcium stearate, and sodium lauryl 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 lauryl sulfate or polysorbate. Adding sodium lauryl sulfate or polysorbate to the composition of the present invention can be more conducive to the efficacy of the pharmaceutical composition. More preferably, the pharmaceutical composition may contain 0.1 to 5% by weight of sodium lauryl sulfate and 0.05% to 0.5% by weight of polysorbate.

In another aspect of this scheme, the pharmaceutical composition is in an oral form, which comprises, for example, an oral dosage unit with a total weight of 100 to 800 mg, and may further contain: one or more of a filler, a binder, a disintegrant and a lubricant. Among them, 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, methyl cellulose, 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 cross-linked sodium carboxymethyl cellulose, cross-linked povidone, sodium carboxymethyl starch, sodium alginate, corn starch, low-substituted hydroxypropyl cellulose; preferably, the disintegrant is at least one of cross-linked sodium carboxymethyl cellulose and cross-linked povidone. The lubricant may be a lubricant conventionally used in the art, such as magnesium stearate, stearic acid, sodium fumarate, PEG6000, glyceryl behenate, talc, etc.; preferably, the lubricant is magnesium stearate.

As a more preferred embodiment, the pharmaceutical composition may contain one or more of 1 to 10% by weight of cross-linked carboxymethyl cellulose sodium, 1 to 10% by weight of cross-linked polyvinylpyrrolidone, 10 to 50% by weight of microcrystalline cellulose, 0.1 to 5% by weight of polyvinylpyrrolidone, 0.1 to 5% by weight of hydroxypropyl cellulose, 10 to 50% by weight of lactose, and 0.1 to 2% by weight of magnesium stearate.

The third technical solution of the present invention is to provide a pharmaceutical composition, which contains 0.5-20% by weight of hezemibe and 1-80% by weight of rosuvastatin. Preferably, the pharmaceutical composition contains 1-10% by weight of hezemibe and 1-30% by weight of rosuvastatin.

In one aspect of this solution, the composition may optionally include a stabilizer. The stabilizer may be a stabilizer conventionally used in the art, such as a carbonate, a bicarbonate or a phosphate; preferably, the stabilizer is at least one of calcium carbonate and butylated hydroxytoluene. Adding calcium carbonate or butylated hydroxytoluene to the composition of the present invention is beneficial to the stability of the preparation. More preferably, the pharmaceutical composition may include 1 to 15% by weight of calcium carbonate and 0.005 to 0.05% by weight of butylated hydroxytoluene.

In another aspect of this scheme, the pharmaceutical composition may also optionally contain a surfactant. The surfactant may be a surfactant conventionally used in the art, for example, an anionic surfactant or a nonionic surfactant. Examples of anionic surfactants include sodium stearate, potassium stearate, sodium oleate, calcium stearate and sodium lauryl sulfate, and examples of nonionic surfactants include fatty acid sorbitan (Span), polysorbate, myrj, brij, poloxamer, etc. Preferably, the surfactant is sodium lauryl sulfate. Adding sodium lauryl sulfate to the composition of the present invention can be more conducive to the efficacy of the pharmaceutical composition. More preferably, the pharmaceutical composition may contain 0.1 to 6% by weight of sodium lauryl sulfate.

As a more preferred embodiment, the pharmaceutical composition may contain one or more of 1 to 10% by weight of cross-linked polyvinylpyrrolidone, 10 to 50% by weight of microcrystalline cellulose, 0.1 to 5% by weight of polyvinylpyrrolidone, 10 to 50% by weight of lactose, and 0.1 to 2% by weight of magnesium stearate.

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

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

(1) granulating the HMG-CoA reductase inhibitor and optional auxiliary materials to obtain the HMG-CoA reductase inhibitor granule portion;

(2) granulating hezemib and optional auxiliary materials to obtain a hezemib granule portion;

(3) Combining the two granular parts prepared in the above steps (1) and (2) with optional auxiliary materials.

The HMG-CoA reductase inhibitor granules of step (1) can be granulated with water as solvent, and the hezemib granules of step (2) can be granulated with water, an organic solvent or a mixture thereof; preferably, the hezemib granules of step (2) can be granulated with water, alcohol, chloroform, acetone, acetonitrile or a similar solvent, and a mixture thereof, preferably with water, alcohol or a mixture thereof, more preferably with a mixture of alcohol and water, and most preferably with a mixture of ethanol and water.

The sixth technical solution of the present invention is to provide a method for preparing a pharmaceutical composition containing hezemib and atorvastatin, comprising the following steps:

(1) preparing atorvastatin and optional excipients into granules;

(2) preparing granules of hezemib and optional auxiliary materials;

(3) The two granular parts prepared in the above steps (1) and (2) are mixed evenly with optional auxiliary materials.

Preferably, the preparation method comprises the following steps:

(1) mixing atorvastatin, lactose, microcrystalline cellulose, calcium carbonate and cross-linked sodium carboxymethyl cellulose uniformly;

(2) dissolving hydroxypropyl cellulose in water;

(3) adding the hydroxypropyl cellulose solution obtained in step (2) to the mixture obtained in step (1) to granulate, dry, and size the particles;

(4) mixing hezemib, lactose, microcrystalline cellulose, sodium lauryl sulfate and croscarmellose sodium uniformly;

(5) dissolving povidone in water for later use;

(6) adding the polyvidone solution obtained in step (5) to the mixture obtained in step (4) to granulate, dry and size the particles;

(7) The granules obtained in step (3) and step (6) are optionally mixed evenly with cross-linked sodium carboxymethyl cellulose, and then optionally mixed evenly with magnesium stearate, and tableted.

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

(1) preparing atorvastatin and optional excipients into granules;

(2) preparing granules of hezemib and optional auxiliary materials;

(3) uniformly mixing the granules prepared in step (1) above with optional auxiliary materials to obtain first mixed granules;

(4) uniformly mixing the granules prepared in step (2) above with optional auxiliary materials to obtain second mixed granules;

(5) The first mixed granules and the second mixed granules obtained in the above steps (3) and (4) are pressed into a double-layer tablet.

Preferably, the preparation method comprises the following steps:

(1) mixing atorvastatin, lactose, microcrystalline cellulose, calcium carbonate and cross-linked sodium carboxymethyl cellulose uniformly;

(2) dissolving polysorbate and hydroxypropyl cellulose in water;

(3) adding the solution obtained in step (2) to the mixture obtained in step (1) to granulate, dry and size the particles;

(4) mixing lactose, microcrystalline cellulose, sodium lauryl sulfate and cross-linked polyvinylpyrrolidone uniformly;

(5) dissolving hezemib, butylated hydroxytoluene, and povidone in an ethanol solution;

(6) adding the solution obtained in step (5) to the mixture obtained in step (4) to granulate, dry and size the particles;

(7) optionally mixing the granules obtained in step (3) with cross-linked sodium carboxymethyl cellulose, and then optionally mixing them with magnesium stearate to obtain a first mixed granule;

(8) optionally mixing the granules obtained in step (6) with cross-linked sodium carboxymethyl cellulose, and then optionally mixing them with magnesium stearate to obtain a second mixed granule;

(9) The first mixed granules and the second mixed granules obtained in step (7) and step (8) are pressed into a double-layer tablet.

The eighth technical solution of the present invention is: providing a method for preparing a pharmaceutical composition containing hezemib and rosuvastatin, comprising the following steps:

(1) preparing rosuvastatin and optional excipients into granules;

(2) preparing granules of hezemib and optional auxiliary materials;

(3) Evenly mixing the particles prepared in the above steps (1) and (2) with optional auxiliary materials.

Preferably, the preparation method comprises the following steps:

(1) mixing rosuvastatin, lactose, microcrystalline cellulose, calcium carbonate and cross-linked polyvinylpyrrolidone uniformly;

(2) dissolving povidone in water;

(3) adding the polyvidone solution obtained in step (2) to the mixture obtained in step (1) to granulate, dry and granulate;

(4) mixing lactose, microcrystalline cellulose, sodium lauryl sulfate and cross-linked polyvinylpyrrolidone uniformly;

(5) dissolving hezemib and povidone in ethanol solution;

(6) adding the solution obtained in step (5) to the mixture obtained in step (4) to granulate, dry and size the particles;

(7) The granules obtained in step (3) and step (6) are mixed, optionally mixed evenly with cross-linked polyvinylpyrrolidone, and then optionally mixed evenly with magnesium stearate, and tableted.

Preferably, the preparation method comprises the following steps:

(1) mixing rosuvastatin, lactose, microcrystalline cellulose, calcium carbonate and cross-linked polyvinylpyrrolidone uniformly;

(2) dissolving povidone in water;

(3) adding the polyvidone solution obtained in step (2) to the mixture in step (1) to granulate, dry and granulate;

(4) mixing lactose, microcrystalline cellulose, sodium lauryl sulfate and cross-linked polyvinylpyrrolidone uniformly;

(5) dissolving hezemib, butylated hydroxytoluene, and povidone in an ethanol solution;

(6) adding the solution obtained in step (5) to the mixture obtained in step (4) to granulate, dry and size the particles;

(7) The granules obtained in step (3) and step (6) are mixed, optionally mixed evenly with cross-linked polyvinylpyrrolidone, and then optionally mixed evenly with magnesium stearate, and tableted.

The ninth technical solution of the present invention is to provide a method for preparing a pharmaceutical composition containing hezemib and rosuvastatin, comprising the following steps:

(1) preparing rosuvastatin and optional excipients into granules;

(2) preparing granules of hezemib and optional auxiliary materials;

(3) uniformly mixing the granules prepared in step (1) above with optional auxiliary materials to obtain first mixed granules;

(4) uniformly mixing the granules prepared in step (2) above with optional auxiliary materials to obtain second mixed granules;

(5) The first mixed granules and the second mixed granules obtained in the above steps (3) and (4) are pressed into a double-layer tablet.

Preferably, the preparation method comprises the following steps:

(1) mixing rosuvastatin, lactose, microcrystalline cellulose, calcium carbonate and cross-linked polyvinylpyrrolidone uniformly;

(2) dissolving povidone in water;

(3) adding the polyvidone solution obtained in step (2) to the mixture obtained in step (1) to granulate, dry and granulate;

(4) mixing lactose, microcrystalline cellulose, sodium lauryl sulfate and cross-linked polyvinylpyrrolidone uniformly;

(5) dissolving hezemib, butylated hydroxytoluene, and povidone in an ethanol solution;

(6) adding the solution obtained in step (5) to the mixture obtained in step (4) to granulate, dry and size the particles;

(7) optionally mixing the granules obtained in step (3) with cross-linked polyvinylpyrrolidone, and then optionally mixing them with magnesium stearate to obtain first mixed granules;

(8) optionally mixing the granules obtained in step (6) with cross-linked polyvinylpyrrolidone, and then optionally mixing them with magnesium stearate to obtain a second mixed granule;

(9) The first mixed granules and the second mixed granules obtained in step (7) and step (8) are pressed into a double-layer tablet.

The tenth technical solution of the present invention is: providing a drug dosage unit, which contains 5-20 mg of hezemibe and 5-80 mg of atorvastatin. Preferably, the dosage of hezemibe 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, the drug dosage unit is an oral dosage unit.

In one aspect of this embodiment, the dosage unit may optionally contain calcium carbonate as a component. Preferably, the dosage unit may contain 5 to 100 mg of calcium carbonate.

In another aspect of this embodiment, the dosage unit may optionally contain calcium carbonate and butylated hydroxytoluene as components. Preferably, the dosage unit may contain 5 to 100 mg of calcium carbonate and 0.01 to 0.2 mg of butylated hydroxytoluene.

In one aspect of this embodiment, the dosage unit may optionally contain sodium lauryl sulfate as a component. Preferably, the dosage unit may contain 0.5 to 5 mg of sodium lauryl sulfate.

In another aspect of this embodiment, the dosage unit may optionally contain sodium lauryl sulfate and polysorbate as components. Preferably, the dosage unit may contain 0.5 to 5 mg of sodium lauryl sulfate and 0.1 to 5 mg of polysorbate.

In another aspect of this embodiment, the dosage unit may also contain 1-50 mg of cross-linked sodium carboxymethyl cellulose, 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.

In another aspect of this embodiment, the dosage unit may also contain 1-50 mg of cross-linked carboxymethyl cellulose sodium, 1-30 mg of cross-linked polyvinylpyrrolidone, 20-250 mg of microcrystalline cellulose, 0.5-10 mg of polyvinylpyrrolidone, 0.5-10 mg of hydroxypropyl cellulose, 10-250 mg of lactose, and 0.1-10 mg of magnesium stearate.

The eleventh technical solution of the present invention is: providing a drug dosage unit, which contains 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.

In one aspect of this embodiment, the dosage unit may optionally contain calcium carbonate as a component. Preferably, the dosage unit may contain 1 to 50 mg of calcium carbonate.

In one aspect of this embodiment, the dosage unit may optionally contain calcium carbonate and butylated hydroxytoluene as components. Preferably, the dosage unit may contain 1 to 50 mg of calcium carbonate and 0.01 to 0.2 mg of butylated hydroxytoluene.

In another aspect of this embodiment, the dosage unit may optionally contain sodium lauryl sulfate as a component. Preferably, the dosage unit may contain 0.5 to 10 mg of sodium lauryl sulfate.

In another aspect of this embodiment, the dosage unit may also contain 5-40 mg of cross-linked polyvinylpyrrolidone, 20-250 mg of microcrystalline cellulose, 1-20 mg of polyvinylpyrrolidone, 20-250 mg of lactose, and 0.1-5 mg of magnesium stearate.

In the present invention, the povidone is preferably povidone K30.

The pharmaceutical composition or pharmaceutical dosage unit of the present invention can be in various dosage forms such as capsules, tablets, granules, powders, solutions or lozenges.

The composition of hezemib and HMG-CoA reductase inhibitor of the present invention can be in various forms, such as tablets. The formulation of the present invention is reasonably designed, easy to prepare into a suitable preparation, and the preparation has good stability and controllable quality.

Compared with the prior art, the pharmaceutical composition containing hezemib and an HMG-CoA reductase inhibitor of the present invention has the following advantages:

(1) The present invention combines hezemib with an HMG-CoA reductase inhibitor, especially when the HMG-CoA reductase inhibitor is a statin, which has a good pharmacodynamic synergistic effect. The occurrence of myocardial toxicity and the incidence of cardiovascular events can be reduced by reducing the dose of the statin, which has important clinical benefit value.

(2) The pharmaceutical composition provided by the present invention not only reduces adverse reactions by reducing the dosage of statins through synergistic enhancement, but also has higher safety than the combination of similar mechanism drugs and statins, fewer clinical adverse reactions, and better medication compliance of patients.

(3) The pharmaceutical composition provided by the present invention has stable properties, and the prepared preparation product can be packaged in ordinary packaging to achieve stable storage requirements.

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

(5) The preparation method of the pharmaceutical composition of the present invention has simple process, convenient operation and is suitable for large-scale industrial production.

In preclinical evaluations, the efficacy of hezemib combined with statins and ezetimibe combined with statins was equivalent, but the safety of hezemib combined with statins was significantly better than that of ezetimibe combined with statins, and it may have greater advantages in clinical applications.

DETAILED DESCRIPTION

The present invention is described in detail below in conjunction with the examples. It must be pointed out that the following examples are only used to illustrate the present invention, rather than to limit the present invention. The experimental methods in the following examples without specifying specific conditions are selected according to conventional methods and conditions, or according to the product specifications.

The HS-25, Ezetimibe, atorvastatin, rosuvastatin and simvastatin used in the following examples are from Zhejiang Hisun Pharmaceutical Co., Ltd. or are prepared by referring to the methods of the prior art.

It should be noted that the atorvastatin, rosuvastatin and simvastatin used in the following examples are all in the form of calcium salts, and their contents refer to the contents of atorvastatin, rosuvastatin and simvastatin; for example, in Example 1, the specification of Hezemibu Atorvastatin Tablets is 5mg/10mg, where 10mg refers to the weight of atorvastatin, and 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 of Hezemibu Rosuvastatin Tablets is 20mg/20mg, where 20mg refers to the weight of rosuvastatin, and if the weight of rosuvastatin in the prescription is converted to the weight of rosuvastatin calcium, it is 20.83mg.

Example 1: Hezemib atorvastatin tablets, specification: 5mg/10mg, each tablet weighs 92.25mg, the formula is shown in Table 1.

Table 1. Prescription composition of Example 1 (unit: g)

Preparation method:

(1) uniformly mixing the prescribed amount of atorvastatin and lactose, microcrystalline cellulose, calcium carbonate and cross-linked sodium carboxymethyl cellulose in the atorvastatin granules;

(2) dissolving the prescribed amount of hydroxypropyl cellulose in purified water for later use;

(3) adding the hydroxypropyl cellulose solution obtained in step (2) to the mixture obtained in step (1) to granulate, dry, and granulate to obtain atorvastatin granules;

(4) uniformly mixing the prescribed amount of hezemib and the lactose, microcrystalline cellulose, sodium lauryl sulfate and croscarmellose sodium in the hezemib granules;

(5) Dissolve the prescribed amount of povidone K30 in purified water for later use;

(6) adding the povidone K30 solution obtained in step (5) to the mixture obtained in step (4) to perform granulation, drying, and granulation to obtain hezemib granules;

(7) The granules obtained by granulation in step (3) and step (6) and the added portion of cross-linked sodium carboxymethyl cellulose are mixed uniformly, and then a prescribed amount of magnesium stearate is added thereto, mixed uniformly, and tableted.

Example 2: Hezemib atorvastatin tablets, specifications: 5 mg/20 mg, each tablet weighs 143.50 mg, the formula is shown in Table 2.

Table 2. Prescription composition of Example 2 (unit: g)

Preparation method: Same as Example 1.

Example 3: Hezemib atorvastatin tablets, specification: 10 mg/10 mg, each tablet weighs 133.25 mg, the formula is shown in Table 3.

Table 3. Prescription composition of Example 3 (unit: g)

Preparation method: Same as Example 1.

Example 4: Hezemib atorvastatin tablets, specifications: 10 mg/20 mg, each tablet weighs 184.50 mg, the formula is shown in Table 4.

Table 4. Prescription composition of Example 4 (unit: g)

Preparation method: Same as Example 1.

Example 5: Hezemib atorvastatin tablets, specifications: 10 mg/80 mg, each tablet weighs 492.00 mg, the formula is shown in Table 5.

Table 5. Prescription composition of Example 5 (unit: g)

Preparation method: Same as Example 1.

Example 6: Hezemib rosuvastatin tablets, specification: 20 mg/20 mg, each tablet weighs 460.00 mg, the formula is shown in Table 6.

Table 6. Prescription composition of Example 6 (unit: g)

Preparation method:

(1) uniformly mixing the prescribed amount of rosuvastatin and the lactose, microcrystalline cellulose, calcium carbonate and cross-linked polyvinylpyrrolidone in the rosuvastatin granules;

(2) dissolving the povidone K30 in the rosuvastatin granules in purified water;

(3) adding the povidone K30 solution obtained in step (2) to the mixture obtained in step (1) to prepare granules, dry and granulate to obtain rosuvastatin granules;

(4) mixing the lactose, microcrystalline cellulose, sodium lauryl sulfate and cross-linked polyvinylpyrrolidone of the hezemib granules uniformly;

(5) dissolving the prescribed amount of hezemib and the povidone K30 in the hezemib granules in an ethanol solution;

(6) adding the solution obtained in step (5) to the mixture obtained in step (4) to granulate, dry, and granulate to obtain hezemib granules;

(7) The granules obtained by granulation in step (3) are mixed with the granules obtained by granulation in step (6), and then mixed evenly with the added portion of cross-linked polyvinylpyrrolidone, and then a prescribed amount of magnesium stearate is added thereto, mixed evenly, and tableted.

Example 7: Hezemib rosuvastatin tablets, specifications: 10 mg/20 mg, each tablet weighs 297.00 mg, the formula is shown in Table 7.

Table 7. Prescription composition of Example 7 (unit: g)

Preparation method: Same as Example 6.

Example 8: Hezemiab rosuvastatin tablets, specification: 20 mg/10 mg, each tablet weighs 393.00 mg, the formula is shown in Table 8.

Table 8. Prescription composition of Example 8 (unit: g)

Preparation method: Same as Example 6.

Example 9: Hezemiab rosuvastatin tablets, specification: 10 mg/10 mg, each tablet weighs 230.00 mg, the formula is shown in Table 9.

Table 9. Prescription composition of Example 9 (unit: g)

Preparation method: Same as Example 6.

Example 10: Hezemib simvastatin tablets, specification: 6 mg/20 mg, each tablet weighs 100.00 mg, the formula is shown in Table 10.

Table 10. Prescription composition of Example 10 (unit: g)

Hezemeb 6 Simvastatin 20 lactose 48.54 Microcrystalline cellulose 16.185 Crospovidone 3 Povidone K30 5 Butylated Hydroxyanisole 0.025 Citric acid 0.25 Magnesium Stearate 1 30% ethanol solution Moderate total 1000 pieces

Preparation method:

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

(2) Weigh hezemib, simvastatin, microcrystalline cellulose, lactose, povidone K30, and crospovidone according to the prescribed amount, pass through a 40-mesh sieve, and mix the sieved raw and excipients evenly;

(3) adding the solution obtained in step (1) to the mixture obtained in step (2) to perform granulation;

(4) drying and granulating the wet granules;

(5) Add magnesium stearate thereto, mix, and compress into tablets.

Example 11: Stability Study of Hezemib Atorvastatin Tablets (5mg/10mg Specifications)

Method 1: The tablets prepared in Example 1 were packaged in high-density polyethylene bottles (containing 2 g of desiccant), placed at a temperature of 40°C ± 2°C and a humidity (RH) of 75% ± 5%, and stability studies were performed. The test results are shown in Table 11:

Table 11. Stability data of Hezemib Atorvastatin Tablets (5 mg/10 mg)

The results showed that after being stored at 40℃±2℃ and RH75%±5% for 6 months, there was no significant change in the content and solubility of Hezemib Atorvastatin Tablets (5mg/10mg), and the impurities only increased slightly, indicating that the sample was relatively stable.

Method 2: The tablets prepared in Example 1 were packaged in high-density polyethylene bottles (containing 2 g of desiccant), placed at a temperature of 25°C ± 2°C and a humidity of 60% ± 5%, and stability studies were performed. The test results are shown in Table 12:

Table 12. Stability data of Hezemib Atorvastatin Tablets (5 mg/10 mg)

The results showed that after 24 months of storage at 25°C±2°C and RH60%±5%, there was no significant change in the content and solubility of Hezemib Atorvastatin Tablets (5mg/10mg), and the impurities only increased slightly, indicating that the sample was relatively stable.

Example 12: Stability Study of Hezemib Atorvastatin Tablets (5mg/20mg Specifications)

Method 1: The tablets prepared in Example 2 were packaged in high-density polyethylene bottles (containing 2 g of desiccant), placed at a temperature of 40°C ± 2°C and a humidity of 75% ± 5%, and stability studies were performed. The test results are shown in Table 13:

13. Stability data of Hezemib Atorvastatin Tablets (5mg/20mg)

The results showed that after being stored at 40℃±2℃ and RH75%±5% for 6 months, there was no significant change in the various test indicators of Hezemib Atorvastatin Tablets (5mg/20mg), indicating that the sample was relatively stable.

Method 2: The tablets prepared in Example 2 were packaged in high-density polyethylene bottles (containing 2 g of desiccant), placed at a temperature of 25°C ± 2°C and a humidity of 60% ± 5%, and stability studies were performed. The test results are shown in Table 14:

14. Stability data of Hezemib Atorvastatin Tablets (5mg/20mg)

The results showed that after 24 months of storage at 25°C±2°C and RH60%±5%, there was no significant change in the content and solubility of Hezemib Atorvastatin Tablets (5mg/20mg), and the impurities only increased slightly, indicating that the sample was relatively stable.

Example 13: Stability Study of Hezemib Atorvastatin Tablets (10 mg/10 mg Specification)

Method 1: The tablets prepared in Example 3 were packaged in high-density polyethylene bottles (containing 2 g of desiccant), placed at 40°C ± 2°C and RH 75% ± 5%, and stability studies were performed. The test results are shown in Table 15:

Table 15. Stability data of Hezemib Atorvastatin Tablets (10 mg/10 mg)

The results showed that after being stored at 40℃±2℃ and RH75%±5% for 6 months, there was no significant change in the various test indicators of Hezemib Atorvastatin Tablets (10mg/10mg), indicating that the sample was relatively stable.

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

16. Stability data of Hezemib Atorvastatin Tablets (10mg/10mg)

The results showed that after 24 months of storage at 25°C±2°C and RH60%±5%, there was no significant change in the content and solubility of Hezemib Atorvastatin Tablets (10mg/10mg), and the impurities only increased slightly, indicating that the sample was relatively stable.

Example 14: Stability Study of Hezemib Atorvastatin Tablets (10 mg/20 mg Specifications)

Method 1: The tablets prepared in Example 4 were packaged in high-density polyethylene bottles (containing 2 g of desiccant), placed at 40°C ± 2°C and RH 75% ± 5%, and stability studies were performed. The results are shown in Table 17:

Table 17. Stability data of Hezemib Atorvastatin Tablets (10 mg/20 mg)

The results showed that after being stored at 40℃±2℃ and RH75%±5% for 6 months, the content and solubility of Hezemib Atorvastatin Tablets (10mg/20mg) did not change significantly, and the impurities only increased slightly, indicating that the sample was relatively stable.

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

Table 18. Stability data of Hezemib Atorvastatin Tablets (10 mg/20 mg)

The results showed that after 24 months of storage at 25°C±2°C and RH60%±5%, there was no significant change in the content and solubility of Hezemib Atorvastatin Tablets (10mg/20mg), and the impurities only increased slightly, indicating that the sample was relatively stable.

Example 15: Stability Study of Hezemib Atorvastatin Tablets (10 mg/80 mg Specifications)

The tablets prepared in Example 5 were packaged in high-density polyethylene bottles (containing 2 g of desiccant), placed under temperature (40°C ± 2°C) and humidity (RH 75% ± 5%) conditions, and stability studies were performed. The results are shown in Table 19:

Table 19. Stability data of Hezemib Atorvastatin Tablets (10 mg/80 mg)

The results showed that after being stored at 40℃±2℃ and RH75%±5% for 3 months, there was no significant change in the various test indicators of Hezemib Atorvastatin Tablets (10mg/80mg), indicating that the sample was relatively stable.

Example 16: Stability Study of Hezemib and Bresuvastatin Tablets (20/20 mg)

The tablets prepared in Example 6, bare tablets (without packaging), were placed at 50° C. and 75% humidity to conduct stability studies. The results are shown in Table 20:

Table 20. Stability data of Hezemibrevastatin tablets (20 mg/20 mg)

The results showed that after being placed at 50°C and 75% humidity for 10 days, the content, related substances and solubility of Hezemiabresuvastatin tablets remained basically unchanged, indicating that the sample was stable and the quality was controllable.

Example 17: Stability Study of Hezemib Simvastatin Tablets (6 mg/20 mg Specifications)

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

Table 21. Stability data of Hezemib-Simvastatin Tablets (6 mg/20 mg)

The results showed that after 20 days of storage under various conditions, the content of Hezemib Simvastatin Tablets remained basically unchanged, and the related substances increased slightly, indicating that the sample was stable and the quality was controllable.

Example 18: Pharmacodynamic study of the combination of hezemib and simvastatin

Primary hyperlipidemia rhesus monkeys (blood lipid index: TC>6.22mmol/L, LDL>4.91mmol/L, HDL<1.55mmol/L, TG>1.0mmol/L) were selected, and high-fat diet was added to induce blood lipid levels to remain stable for at least 2 weeks (see pre-drug data). Hezemib (i.e., HS-25) or combined with simvastatin was given orally through fruit induction, and ezetimibe was used as a control. The oral administration lasted for 4 weeks to observe the effects of single drug and combined with simvastatin on blood lipids. The experimental groups and test indicators are shown in Table 22:

Table 22. Pharmacodynamics of HS-25/ezetimibe combined with simvastatin

The test results show:

HS-25 and ezetimibe alone or in combination with simvastatin had no significant effect on the body weight, blood biochemistry, blood routine, and blood glucose of hyperlipidemic rhesus monkeys, and no abnormal clinical manifestations were observed.

The improvement of blood lipid indexes in all drug-treated groups was mainly reflected in TC and LDL, and other indexes such as TG, HDL, and APoAl did not improve significantly. The efficacy of HS-25 combined with simvastatin and ezetimibe combined with simvastatin was basically the same. The experimental data are shown in Table 23 and Table 24:

Impact on TC (see Table 23):

Simvastatin alone had the effect of reducing TC, compared with the model group, P < 0.05, indicating a statistically significant difference.

The HS-25 and ezetimibe groups alone significantly reduced TC, which was better than the simvastatin group alone. Compared with the model group, P < 0.01, indicating a significant statistical difference. The pharmacodynamic effect gradually increased with the administration time, indicating that HS-25 and ezetimibe have a certain persistence in reducing TC.

The combined use of HS-25 and ezetimibe with simvastatin respectively had a better effect on reducing TC than the HS-25 alone group, ezetimibe alone group and simvastatin alone group. This was mainly reflected in that the reduction of TC was faster than that of the single drug one week after administration; the maximum reduction percentage of TC (4 weeks after administration) was greater.

Effects on LDL (see Table 24):

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

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

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

Example 19: Pharmacodynamics of Hezemib combined with Atorvastatin

A primary hyperlipidemia rhesus monkey animal model (blood lipid index: TC>6.22mmol/L, LDL>4.91mmol/L, HDL<1.55mmol/L, TG>1.0mmol/L) was selected and induced with a high-fat diet. After the hyperlipidemia level remained stable, atorvastatin was orally administered orally or combined with hezemib (HS-25) or ezetimibe for 3 consecutive months to observe the effects of HS-25 and ezetimibe combined with atorvastatin on blood lipids. The experimental groups and test indicators are shown in Table 25:

Table 25. Pharmacodynamics of HS-25/ezetimibe combined with atorvastatin

The test results show:

Atorvastatin alone or in combination with HS-25 or ezetimibe had no significant effect on the body weight, blood biochemistry, blood routine and blood glucose of rhesus monkeys, and no abnormal clinical manifestations were observed.

The improvement of blood lipid indexes in all drug-administered groups was mainly reflected in TC and LDL, and other indexes such as TG, HDL, APoAl, and APoB did not change significantly. The experimental data are shown in Table 26 and Table 27:

Impact on TC (Table 26):

The efficacy of each drug group reached a plateau at 30 days of drug administration, and no further reduction in TC was observed with continued drug administration. Due to the small number of animals, the TC of the model group animals fluctuated to a certain extent. Therefore, overall, the TC reduction effect of the atorvastatin monotherapy group was basically 25%, and the TC reduction percentage of the two combination groups was about 50%, which was significantly better than the atorvastatin monotherapy group.

The TC content in the model group was relatively stable during the experiment, with no significant fluctuations, proving that this model is relatively stable.

Effects on LDL (Table 27)

The trends of atorvastatin alone or atorvastatin combined with HS-25 or ezetimibe on LDL were consistent with TC.

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

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, %)

Example 20: Repeated-dose toxicity study of hezemib combined with atorvastatin in beagle dogs

SPF normal beagle dogs aged 6-9 months, half male and half female, were divided into a vehicle group, an atorvastatin group, and a HS-25 combined with atorvastatin group. The drugs were administered for 2 consecutive weeks to observe the toxicity of atorvastatin alone or in combination with HS-25. The grouping and drug administration are shown in Table 28:

Table 28. Toxicity study protocol of repeated administration of HS-25 combined with atorvastatin in beagle dogs

The experimental results show:

Some beagles drooled, which was related to atorvastatin. Other indicators such as body weight, food intake, electrocardiogram, blood routine, gross anatomy and pathology were normal; the reduction of blood lipids was dose-related to atorvastatin.

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

Table 29. Results of toxicity study of atorvastatin alone or HS-25 combined with atorvastatin in repeated administration in beagle dogs

Literature data on Zetia (see NDA 21-445 FDA review: Pharmacology Review (s) 117-129) show that ezetimibe combined with atorvastatin causes hepatotoxicity at a dose of 0.3/1 mg/kg, and the toxicity increases with increasing doses of atorvastatin; blood lipid indexes are basically consistent with liver enzyme indexes. The 3-week experimental data is shown in Table 30:

Table 30. Results of toxicity studies in beagle dogs with repeated administration of atorvastatin alone or Zetia combined with atorvastatin

Comparative analysis of the above data showed that the liver function of the two experiments was consistent in the blank group and the atorvastatin 10 mg/kg dose level, indicating that the data are comparable.

The comparison results showed that no obvious toxicity was observed in the atorvastatin monotherapy group at a dose of 10 mg/kg; a slight increase in ALT was found in the atorvastatin monotherapy group at a dose of 30 mg/kg.

The toxicity of HS-25 combined with atorvastatin was only manifested as an increase in ALT, and no abnormality was found in AST; the toxicity of Zetia combined with atorvastatin was not only an increase in ALT but also an increase in AST at 3/10 and 30/10 mg/kg.

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

In addition, the toxicity of HS-25 combined with atorvastatin at 30/10, 100/10, and 100/30 mg/kg were ALT: 112.8, 188.3, and 242.8, respectively, indicating that the increase in ALT was small; while the toxicity of Zetia combined with atorvastatin at 0.3/1, /3/1, 3/10, and 30/10 mg/kg were ALT: 112.8, 156.3, 990.3, and 657.0 in females; 88.8, 106.3, 391.5, and 1133.5 in males, indicating that the increase in ALT was significantly greater with increasing dose, suggesting that liver toxicity was more obvious.

In summary, the combination of HS-25 and atorvastatin is significantly safer than the combination of Zetia and atorvastatin, with a safety factor of about 10 times in beagles.

Example 21: Hezemib atorvastatin tablets, specification: 20 mg/20 mg, each tablet weighs 480 mg, the formula is shown in Table 31.

31. The formula composition of Example 21 (unit: g)

Preparation method:

(1) uniformly mixing the prescribed amount of atorvastatin and lactose, microcrystalline cellulose, calcium carbonate and cross-linked sodium carboxymethyl cellulose in the atorvastatin granules;

(2) Dissolve the prescribed amount of polysorbate and hydroxypropyl cellulose in purified water;

(3) adding the solution obtained in step (2) to the mixture obtained in step (1) to prepare granules, drying, and granulating to obtain atorvastatin granules;

(4) mixing the lactose, microcrystalline cellulose, sodium lauryl sulfate and cross-linked polyvinylpyrrolidone of the hezemib granules uniformly;

(5) dissolving the prescribed amount of hezemib, butylated hydroxytoluene, and povidone K30 in an ethanol solution;

(6) adding the solution obtained in step (5) to the mixture obtained in step (4) to granulate, dry, and granulate to obtain hezemib granules;

(7) mixing the granules obtained in step (3) and the croscarmellose sodium added to the atorvastatin granules evenly, and then adding magnesium stearate thereto and mixing evenly;

(8) mixing the granules obtained in step (6) with the cross-linked sodium carboxymethyl cellulose added to the hezemib granules, and then adding magnesium stearate thereto and mixing them evenly;

(9) The granules obtained in step (7) and step (8) are compressed into a double-layer tablet.

Example 22: Hezemib atorvastatin tablets, specifications: 20 mg/10 mg, each tablet weighs 480 mg, the formula is shown in Table 32.

Table 32. Prescription composition of Example 22 (unit: g)

Preparation method: Same as Example 21.

Example 23: Hezemib atorvastatin tablets, specifications: 10 mg/20 mg, each tablet weighs 315 mg, the formula is shown in Table 33.

Table 33. Prescription composition of Example 23 (unit: g)

Preparation method: Same as Example 21.

Example 24: Hezemib atorvastatin tablets, specification: 10 mg/10 mg, each tablet weighs 315 mg, the formula is shown in Table 34.

Table 34. Prescription composition of Example 24 (unit: g)

Preparation method: Same as Example 21.

Example 25: Hezemiab rosuvastatin tablets, specification: 20 mg/20 mg, each tablet weighs 460 mg, the formula is shown in Table 35.

Table 35. Prescription composition of Example 25 (unit: g)

Preparation method:

(1) uniformly mixing the prescribed amount of rosuvastatin and the lactose, microcrystalline cellulose, calcium carbonate and cross-linked polyvinylpyrrolidone in the rosuvastatin granules;

(2) dissolving the povidone K30 in the rosuvastatin granules in purified water;

(3) adding the povidone K30 solution obtained in step (2) to the mixture obtained in step (1) to prepare granules, dry and granulate to obtain rosuvastatin granules;

(4) mixing the lactose, microcrystalline cellulose, sodium lauryl sulfate and cross-linked polyvinylpyrrolidone of the hezemib granules uniformly;

(5) dissolving the prescribed amount of hezemib, butylated hydroxytoluene, and povidone K30 in the hezemib granules in an ethanol solution;

(6) adding the solution obtained in step (5) to the mixture obtained in step (4) to granulate, dry, and granulate to obtain hezemib granules;

(7) mixing the granules obtained in step (3) and the cross-linked polyvinylpyrrolidone added to the rosuvastatin granules evenly, and then adding magnesium stearate and mixing evenly;

(8) mixing the granules sized in step (6) and the cross-linked polyvinylpyrrolidone added to the hezemib granules evenly, and then adding magnesium stearate and mixing evenly;

(9) The granules obtained in step (7) and step (8) are compressed into a double-layer tablet.

Example 26: Hezemiab rosuvastatin tablets, specifications: 20 mg/10 mg, each tablet weighs 460 mg, the formula is shown in Table 36.

Table 36. Prescription composition of Example 26 (unit: g)

Preparation method: Same as Example 25.

Example 27: Hezemiab rosuvastatin tablets, specifications: 10 mg/20 mg, each tablet weighs 295 mg, the formula is shown in Table 37.

Table 37. Prescription composition of Example 27 (unit: g)

Preparation method: Same as Example 25.

Example 28: Hezemiab rosuvastatin tablets, specification: 10 mg/10 mg, each tablet weighs 295 mg, the formula is shown in Table 38.

Table 38. Prescription composition of Example 28 (unit: g)

Preparation method: Same as Example 25.

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

Table 39. Prescription composition of Example 29 (unit: g)

(1) uniformly mixing the prescribed amount of rosuvastatin and the lactose, microcrystalline cellulose, calcium carbonate and cross-linked polyvinylpyrrolidone in the rosuvastatin granules;

(2) dissolving the povidone K30 in the rosuvastatin granules in purified water;

(3) adding the povidone K30 solution obtained in step (2) to the mixture obtained in step (1) to prepare granules, dry and granulate to obtain rosuvastatin granules;

(4) mixing the lactose, microcrystalline cellulose, sodium lauryl sulfate and cross-linked polyvinylpyrrolidone of the hezemib granules uniformly;

(5) dissolving the prescribed amount of hezemib and butylated hydroxytoluene and povidone K30 in the hezemib granules in an ethanol solution;

(6) adding the solution obtained in step (5) to the mixture obtained in step (4) to granulate, dry, and granulate to obtain hezemib granules;

(7) The granules obtained by granulation in step (3) and the granules obtained by granulation in step (6) are mixed, and then mixed evenly with the added portion of cross-linked polyvinylpyrrolidone, and then a prescribed amount of magnesium stearate is added, mixed evenly, and tableted.

Example 30: Stability Study of Hezemib Atorvastatin Calcium Tablets (20mg/10mg Specifications)

The tablets prepared in Example 22 were packaged in bottles and placed under accelerated conditions (40°C/75%RH) for stability study. The measured stability data are shown in Table 40:

Table 40. Stability data of Hezemib Atorvastatin Tablets (20 mg/10 mg)

The results showed that after being stored at 40℃±2℃ and RH75%±5% for 3 months, there was no significant change in the various test indicators of Hezemib Atorvastatin Tablets (20mg/10mg), indicating that the sample was relatively stable.

Example 31: Hezemib atorvastatin tablets, specifications: 20 mg/10 mg, each tablet weighs 480 mg, the formula is shown in Table 41.

Table 41. Prescription composition of Example 31 (unit: g)

Preparation method:

(1) uniformly mixing the prescribed amount of atorvastatin and lactose, microcrystalline cellulose, calcium carbonate and cross-linked sodium carboxymethyl cellulose in the atorvastatin granules;

(2) Dissolve the prescribed amount of polysorbate and hydroxypropyl cellulose in purified water;

(3) adding the solution obtained in step (2) to the mixture obtained in step (1) to prepare granules, drying, and granulating to obtain atorvastatin granules;

(4) mixing the lactose, microcrystalline cellulose, sodium lauryl sulfate and cross-linked polyvinylpyrrolidone of the hezemib granules uniformly;

(5) dissolving the prescribed amount of hezemib, butylated hydroxytoluene, and povidone K30 in isopropanol solution;

(6) adding the solution obtained in step (5) to the mixture obtained in step (4) to granulate, dry, and granulate to obtain hezemib granules;

(7) mixing the granules obtained in step (3) and the croscarmellose sodium added to the atorvastatin granules evenly, and then adding magnesium stearate thereto and mixing evenly;

(8) mixing the granules obtained in step (6) with the cross-linked sodium carboxymethyl cellulose added to the hezemib granules, and then adding magnesium stearate thereto and mixing them evenly;

(9) The granules obtained in step (7) and step (8) are compressed into a double-layer tablet.

Example 32: Hezemib atorvastatin tablets, specification: 20 mg/20 mg, each tablet weighs 630 mg, the formula is shown in Table 42.

Table 42. Prescription composition of Example 32 (unit: g)

Preparation method: Same as Example 31.

Example 33: Hezemib atorvastatin tablets, specifications: 10 mg/20 mg, each tablet weighs 465 mg, the formula is shown in Table 43.

Table 43. Prescription composition of Example 33 (unit: g)

Preparation method: Same as Example 31.

Example 34: Stability Study of Hezemib Atorvastatin Tablets (20 mg/20 mg Specification)

Method 1: The tablets prepared in Example 21 were packaged in double aluminum packaging and placed under conditions of 40°C ± 2°C and RH 75% ± 5% for stability study. The test results are shown in Table 44:

Table 44. Stability data of Hezemib Atorvastatin Tablets (20 mg/20 mg)

The results showed that after being stored at 40℃±2℃ and RH75%±5% for 3 months, the content and solubility of Hezemib Atorvastatin Tablets (20mg/10mg) did not change significantly, and the impurities only increased slightly, indicating that the sample was relatively stable.

Method 2: The tablets prepared in Example 21 were packaged in double aluminum packaging and placed at 25°C ± 2°C and 60% ± 5% humidity to conduct stability studies. The test results are shown in Table 45:

Table 45. Stability data of Hezemib Atorvastatin Tablets (20 mg/20 mg)

The results showed that after being stored at 25°C±2°C and RH60%±5% for 9 months, there was no significant change in the content and solubility of Hezemib Atorvastatin Tablets (20mg/20mg), and the impurities only increased slightly, indicating that the sample was relatively stable.

Example 35: Stability Study of Hezemib Atorvastatin Tablets (20 mg/10 mg Specifications)

Method 1: The tablets prepared in Example 22 were packaged in double aluminum packaging and placed at 40°C ± 2°C and RH 75% ± 5% to conduct stability studies. The test results are shown in Table 46:

Table 46. Stability data of Hezemib Atorvastatin Tablets (20 mg/10 mg)

The results showed that after being stored at 40℃±2℃ and RH75%±5% for 3 months, the content and solubility of Hezemib Atorvastatin Tablets (20mg/10mg) did not change significantly, and the impurities only increased slightly, indicating that the sample was relatively stable.

Method 2: The tablets prepared in Example 22 were packaged in double aluminum packaging and placed at 25°C ± 2°C and 60% ± 5% humidity to conduct stability studies. The test results are shown in Table 47:

Table 47. Stability data of Hezemib Atorvastatin Tablets (20 mg/10 mg)

The results showed that after being stored at 25°C±2°C and RH60%±5% for 9 months, there was no significant change in the content and solubility of Hezemib Atorvastatin Tablets (20mg/10mg), and the impurities only increased slightly, indicating that the sample was relatively stable.

Example 36: Stability Study of Hezemib Atorvastatin Tablets (10 mg/20 mg Specifications)

Method 1: The tablets prepared in Example 23 were packaged in double aluminum packaging and placed at 40°C ± 2°C and RH 75% ± 5% to conduct stability studies. The test results are shown in Table 48:

Table 48. Stability data of Hezemib Atorvastatin Tablets (10 mg/20 mg)

The results showed that after being stored at 40℃±2℃ and RH75%±5% for 3 months, the content and solubility of Hezemib Atorvastatin Tablets (10mg/20mg) did not change significantly, and the impurities only increased slightly, indicating that the sample was relatively stable.

Method 2: The tablets prepared in Example 23 were packaged in double aluminum packaging and placed at 25°C ± 2°C and 60% ± 5% humidity to conduct stability studies. The test results are shown in Table 49:

Table 49. Stability data of Hezemib Atorvastatin Tablets (10 mg/20 mg)

The results showed that after being stored at 25°C±2°C and RH60%±5% for 9 months, there was no significant change in the content and solubility of Hezemib Atorvastatin Tablets (10mg/20mg), and the impurities only increased slightly, indicating that the sample was relatively stable.

Example 37: Stability Study of Hezemib Atorvastatin Tablets (10 mg/10 mg Specification)

Method 1: The tablets prepared in Example 24 were packaged in double aluminum packaging and placed under conditions of 40°C ± 2°C and RH 75% ± 5% for stability study. The test results are shown in Table 50:

Table 50 Stability data of Hezemibu Atorvastatin Tablets (10 mg/10 mg specification)

The results showed that after being stored at 40℃±2℃ and RH75%±5% for 3 months, there was no significant change in the content and solubility of Hezemib Atorvastatin Tablets (10mg/10mg), and the impurities only increased slightly, indicating that the sample was relatively stable.

Method 2: The tablets prepared in Example 24 were packaged in double aluminum packaging and placed at 25°C ± 2°C and 60% ± 5% humidity to conduct stability studies. The test results are shown in Table 51:

Table 51. Stability data of Hezemib Atorvastatin Tablets (10 mg/10 mg)

The results showed that after being stored at 25°C±2°C and RH60%±5% for 9 months, the content and solubility of Hezemib Atorvastatin Tablets (10mg/10mg) did not change significantly, and the impurities only increased slightly, indicating that the sample was relatively stable.

Example 38: Hezemiab rosuvastatin tablets, specifications: 20 mg/10 mg, each tablet weighs 320 mg, the formula is shown in Table 52.

Table 52. Prescription composition of Example 38 (unit: g)

(1) uniformly mixing the prescribed amount of rosuvastatin and the lactose, microcrystalline cellulose, calcium carbonate and cross-linked polyvinylpyrrolidone in the rosuvastatin granules;

(2) dissolving the povidone K30 in the rosuvastatin granules in purified water;

(3) adding the povidone K30 solution obtained in step (2) to the mixture obtained in step (1) to prepare granules, dry and granulate to obtain rosuvastatin granules;

(4) mixing the lactose, microcrystalline cellulose, sodium lauryl sulfate and cross-linked polyvinylpyrrolidone of the hezemib granules uniformly;

(5) dissolving the prescribed amount of hezemib and butylated hydroxytoluene and povidone K30 in the hezemib granules in an ethanol solution;

(6) adding the solution obtained in step (5) to the mixture obtained in step (4) to granulate, dry, and granulate to obtain hezemib granules;

(7) Mixing the granules obtained by granulation in step (3) and the granules obtained by granulation in step (6), adding a prescribed amount of magnesium stearate thereto, mixing well, and tableting.

Example 39: Hezemiab rosuvastatin tablets, specifications: 20 mg/5 mg, each tablet weighs 270 mg, the formula is shown in Table 53.

Table 53. Prescription composition of Example 38 (unit: g)

Preparation method: Same as Example 38.

Claims (34)

1. A pharmaceutical composition comprising:

(a) 0.5-20% by weight of ezetimibe;

(b) 1 to 80% by weight of at least one HMG-CoA reductase inhibitor, wherein the HMG-CoA reductase inhibitor is atorvastatin or a salt thereof.

2. The pharmaceutical composition of claim 1, further comprising one or more excipients selected from the group consisting of 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, butylated hydroxytoluene, the surfactant is at least one of sodium dodecyl sulfate, polysorbate, the filler is at least one of lactose, microcrystalline cellulose, pregelatinized starch, the binder is at least one of hydroxypropyl cellulose, povidone, the disintegrant is at least one of croscarmellose sodium, crospovidone, and the lubricant is at least one of magnesium stearate, talc.

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

5. The pharmaceutical composition according to claim 1, wherein it comprises 1-10% by weight of ezetimibe and 1-30% by weight of atorvastatin.

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 5 to 25% by weight of calcium carbonate and 0.005 to 0.05% by weight of butylated hydroxytoluene.

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

10. The pharmaceutical composition of claim 9, wherein the surfactant is at least one of sodium dodecyl sulfate, polysorbate.

11. The pharmaceutical composition according to claim 9, wherein the surfactant is at least one of sodium dodecyl sulfate 0.1-5% by weight, polysorbate 0.05-0.5% by weight.

12. The pharmaceutical composition of 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, microcrystalline cellulose, the binder is at least one of hydroxypropyl cellulose, povidone, the disintegrant is at least one of croscarmellose sodium, crospovidone, and the lubricant is magnesium stearate.

14. The pharmaceutical composition of claim 12, wherein the pharmaceutical composition comprises one or more of 1-10% by weight of croscarmellose sodium, 1-10% by weight of crospovidone, 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, 0.1-2% by weight of magnesium stearate.

15. A process for the preparation of a pharmaceutical composition as claimed in any one of claims 1 to 14, comprising combining HMG-CoA reductase inhibitor, ezetimibe and optionally an adjuvant.

16. The method of manufacturing of claim 15, comprising:

(1) Granulating the HMG-CoA reductase inhibitor and optional auxiliary materials to obtain a granule part of the HMG-CoA reductase inhibitor;

(2) Granulating the ezetimibe and optional auxiliary materials to obtain a ezetimibe granule part;

(3) And (3) combining the particles prepared in the step (1) and the step (2) with optional auxiliary materials.

17. The production process according to claim 16, wherein the HMG-CoA reductase inhibitor pellet fraction of step (1) is obtained by granulating with water as a solvent; the ezetimibe granule part in the step (2) is obtained by granulating with water, an organic solvent or a mixture thereof.

18. The process of claim 17, wherein the portion of the ezetimibe particles of step (2) is obtained by granulating with water, alcohols, chloroform, acetone, acetonitrile, and mixtures thereof.

19. The process of claim 18, wherein the portion of the ezetimibe particles of step (2) is obtained by granulating with water, an alcohol, and mixtures thereof.

20. The process of claim 18, wherein the portion of the ezetimibe particles of step (2) is obtained by granulating a mixture of alcohol and water.

21. The process of claim 18, wherein the portion of the ezetimibe particles of step (2) is obtained by granulating a mixture of ethanol and water.

22. A process for the preparation of a pharmaceutical composition as claimed in any one of claims 15 to 21 comprising:

(1) Granulating atorvastatin and optional excipients;

(2) Granulating the ezetimibe and optional auxiliary materials;

(3) And (3) uniformly mixing the particles prepared in the step (1) and the step (2) with optional auxiliary materials.

23. A method of preparing a pharmaceutical composition according to claim 22, comprising:

(1) Uniformly mixing atorvastatin, lactose, microcrystalline cellulose, calcium carbonate and croscarmellose sodium;

(2) Dissolving hydroxypropyl cellulose in water;

(3) Adding the hydroxypropyl cellulose solution obtained in the step (2) into the mixture obtained in the step (1) for granulating, drying and finishing;

(4) Uniformly mixing the ezetimibe, lactose, microcrystalline cellulose, sodium dodecyl sulfate and croscarmellose sodium;

(5) Dissolving povidone in water;

(6) Adding the povidone solution obtained in the step (5) into the mixture obtained in the step (4) for granulating, drying and finishing;

(7) And (3) optionally uniformly mixing the granules subjected to the granule finishing in the step (3) and the step (6) with croscarmellose sodium, and then optionally uniformly mixing with magnesium stearate, and tabletting.

24. A process for the preparation of a pharmaceutical composition as claimed in any one of claims 15 to 21 comprising:

(1) Granulating atorvastatin and optional excipients;

(2) Granulating the ezetimibe and optional auxiliary materials;

(3) Uniformly mixing the particles prepared in the step (1) with optional auxiliary materials to obtain first total mixed particles;

(4) Uniformly mixing the particles prepared in the step (2) with optional auxiliary materials to obtain second total mixed particles;

(5) And (3) pressing the first total mixed particles and the second total mixed particles obtained in the step (3) and the step (4) into a double-layer tablet.

25. A method of preparing a pharmaceutical composition according to claim 24, comprising:

(1) Uniformly mixing atorvastatin, lactose, microcrystalline cellulose, calcium carbonate and croscarmellose sodium;

(2) Dissolving polysorbate and hydroxypropyl cellulose in water;

(3) Adding the solution obtained in the step (2) into the mixture obtained in the step (1) for granulating, drying and finishing;

(4) Uniformly mixing lactose, microcrystalline cellulose, sodium dodecyl sulfate and crospovidone;

(5) Dissolving ezetimibe, butylated hydroxytoluene and povidone in an ethanol solution;

(6) Adding the solution obtained in the step (5) into the mixture obtained in the step (4) for granulating, drying and finishing;

(7) Uniformly mixing the granules subjected to the granule finishing in the step (3) with crosslinked sodium carboxymethyl cellulose, and then uniformly mixing the granules with magnesium stearate to obtain first total mixed granules;

(8) Uniformly mixing the granules subjected to the granule finishing in the step (6) with crosslinked sodium carboxymethyl cellulose, and then uniformly mixing the granules with magnesium stearate to obtain second total mixed granules;

(9) And (3) pressing the first total mixed particles and the second total mixed particles obtained in the step (7) and the step (8) into a double-layer tablet.

26. A pharmaceutical dosage unit comprising 5 to 20mg of ezetimibe and 5 to 80mg of atorvastatin.

27. The pharmaceutical dosage unit of claim 26, wherein the dose of ezetimibe is 5mg, 10mg, or 20mg; the dosage of the atorvastatin is 5mg, 10mg, 20mg, 40mg or 80mg.

28. A pharmaceutical dosage unit according to claim 26 or 27, further comprising 5 to 100mg of calcium carbonate.

29. A pharmaceutical dosage unit according to claim 26 or 27, further comprising 5 to 100mg of calcium carbonate, 0.01 to 0.2mg of butylated hydroxytoluene.

30. A pharmaceutical dosage unit according to claim 26 or 27, further comprising 0.5 to 5mg of sodium dodecyl sulphate.

31. A pharmaceutical dosage unit according to claim 26 or 27, further comprising 0.5 to 5mg sodium dodecyl sulphate and 0.1 to 5mg polysorbate.

32. A pharmaceutical dosage unit according to claim 26 or 27, which further comprises 1 to 50mg of croscarmellose sodium, 20 to 250mg of microcrystalline cellulose, 0.5 to 10mg of povidone, 0.5 to 10mg of hydroxypropyl cellulose, 10 to 250mg of lactose, and 0.1 to 10mg of magnesium stearate.

33. A pharmaceutical dosage unit according to claim 26 or 27, which further comprises 1 to 50mg of croscarmellose sodium, 1 to 30mg of crospovidone, 20 to 250mg of microcrystalline cellulose, 0.5 to 10mg of povidone, 0.5 to 10mg of hydroxypropyl cellulose, 10 to 250mg of lactose, 0.1 to 10mg of magnesium stearate.

34. The pharmaceutical composition of claim 1 or the pharmaceutical dosage unit of any one of claims 26 to 27, which is a capsule, tablet, granule, powder, solution or lozenge.