WO2019101151A1

WO2019101151A1 - Pharmaceutical composition of hs-25 and hmg-coa reductase inhibitor

Info

Publication number: WO2019101151A1
Application number: PCT/CN2018/117087
Authority: WO
Inventors: 丁立; 代军; 冯春荣; 代常亮
Original assignee: 浙江海正药业股份有限公司
Priority date: 2017-11-23
Filing date: 2018-11-23
Publication date: 2019-05-31
Also published as: CN111836620A; CN111836620B; CN117085011A

Abstract

Provided by the present invention is a pharmaceutical composition, which comprises HS-25 and an HMG-CoA reductase inhibitor, and which may further comprise one or more auxiliary materials from among calcium carbonate, butylated hydroxyanisole, butylated hydroxytoluene, citric acid, sodium lauryl sulfate, polysorbate, cross-linked sodium carboxymethyl cellulose, cross-linked povidone, microcrystalline cellulose, povidone, hydroxypropyl cellulose, lactose, pregelatinized starch, magnesium stearate and talc. The composition may be made into a variety of dosage forms, and a preparation thereof has good stability and controllable quality.

Description

Medicinal composition of Heze wheat cloth and HMG-CoA reductase inhibitor

cross reference

The present application claims the priority of the Chinese patent application No. 201711183715.5 filed on November 23, 2017 by the Chinese patent application entitled "Hei Zee Maibu and HMG-CoA Reductase Inhibitor Pharmaceutical Composition", the content of which is The references are incorporated herein in their entirety.

Technical field

The invention belongs to the field of medicine, and in particular relates to a composition of Heze Maibu and HMG-CoA reductase inhibitor and application thereof.

Background technique

Cardiovascular disease is one of the most common and serious diseases that endanger human health (especially in the 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 clinical application and lipid-lowering chemical drugs in the research and development stage can be divided into statins, niacin, fibrates, bile acid chelators, polyenes and new lipid-lowering drugs according to their lipid-lowering mechanism and chemical structure. Various compound preparations. Different lipid-lowering drugs have their own advantages and disadvantages. Among them, statins are the most widely used and most effective clinically recommended lipid-lowering drugs. Commonly used drugs are: lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, long-acting fluvastatin sustained-release tablets, rosuvastatin, pitavastatin and the like. At present, the highest market share is atorvastatin. The adverse reactions of statins are less than those of other hypolipidemic drugs. There are two main types: one is the metabolic disorder caused by the inhibition of the synthesis of the cholesterol precursor mevalonate, and the other is the direct toxic effect. . The most common symptoms are mild gastrointestinal reactions, rhinitis, sinusitis, headache, sore throat, flu syndrome, arthritis, chest pain, insomnia, etc.

In recent years, the development of new dosage forms and compound combination drugs has received increasing attention. While developing new mechanisms of action to lower blood lipids, various new dosage forms and compound preparations that can alleviate adverse drug reactions and enhance therapeutic effects have also been applied to clinical applications. got a good result. Among them are: lovastatin controlled release tablets Altocor, niacin sustained release preparation Nispan, fenofibrate micronized capsules, nicotinic acid and lovastatin combination Nicostatin, ezetimibe / simvastatin compound preparation, Yiyi Maibu/Atorvastatin combination preparation, etc.

In many compound preparations and combined application studies, the study of the new cholesterol absorption inhibitor Ezetimibe and statins has attracted the most attention. The pharmacodynamic study of ezetimibe and statins found that ezetimibe and statin have good synergistic effects. However, it has been found that ezetimibe has a certain hepatotoxicity when used in combination with statins, especially when combined with a synergistic level dose, which has an adverse effect on transaminase (especially alanine aminotransferase ALT) (see for example NDA 21-445 FDA review) : Pharmacology Review (s) 117-129). This may pose a safety hazard for hyperlipidemia treatments that require long-term use.

Therefore, there is still a need in the prior art for an agent that has a good blood lipid lowering effect and is highly safe.

Summary of the invention

The present inventors have unexpectedly discovered in the study that the combination of Heze Metz and HMG-CoA reductase inhibitor not only has a good synergistic effect of lowering blood fat, but also has sufficient safety. Based on this finding, the present invention has been completed. The haize wheat cloth of the present invention is a novel intestinal cholesterol absorption inhibitor disclosed in Chinese Patent No. CN101993403A. Haize Maibu 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 comprising 0.5 to 20% by weight of Haize Maibu; and 1 to 80% by weight of at least one HMG-CoA reductase Inhibitor. The compositions of the invention are 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, fluoride One or more of statin, cerivastatin, pitavastatin and rosuvastatin or a salt thereof; the salt of the statin is pharmaceutically acceptable, and the salt is not particularly limited; preferably , in which lovastatin, simvastatin, atorvastatin, rosuvastatin, pitavastatin and rosuvastatin are in the form of calcium salts; pravastatin, fluvastatin, cerivastatin are in the form of sodium salts .

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

In one aspect of the present invention, the pharmaceutical composition may further contain an excipient which is an excipient conventionally used in the art; preferably, the excipient may be a stabilizer, a surfactant, a filler, a binder, disintegration One or more of a agent and a lubricant.

Wherein, the stabilizer may be a stabilizer conventionally used in the art, and may be, for example, a carbonate, a hydrogencarbonate or a phosphate, or an antioxidant such as butylated hydroxyanisole, citric acid or butylated hydroxytoluene. And the like, preferably, the stabilizer is at least one of calcium carbonate, butylated hydroxyanisole, citric acid or butylated hydroxytoluene.

Wherein, the surfactant may be a surfactant conventionally used in the art, and may be, for example, an anionic surfactant or a nonionic surfactant; examples of anionic surfactants are: sodium stearate, potassium stearate , sodium oleate, calcium stearate, sodium lauryl sulfate, etc.; examples of nonionic surfactants are: fatty acid sorbitan (span), polysorbate, meze (myrj), benzze (brij ), poloxamer, etc.; preferably, the surfactant is at least one of sodium lauryl sulfate or polysorbate.

Wherein, the filler may be a filler conventionally used in the art, such as starch, sugar, cellulose, inorganic salts and the like; preferably, the filler is lactose, microcrystalline cellulose, pre-glue At least one of the starches.

Wherein, the binder may be a binder conventionally used in the art, and may be, for example, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, povidone, gum arabic, sucrose, etc.; The binder is at least one of hydroxypropylcellulose and povidone.

Wherein, the disintegrant may be a disintegrator conventionally used in the art, and may be, for example, croscarmellose sodium, crospovidone, sodium carboxymethyl starch, sodium alginate, corn starch, Low-substituted hydroxypropylcellulose; preferably, the disintegrant is at least one of croscarmellose sodium and crospovidone.

Wherein, the lubricant may be a lubricant conventionally used in the art, and may be, for example, magnesium stearate, stearic acid, sodium fumarate, PEG 6000, 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 comprise 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. 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 poly-dimensional A ketone, one or more of 0.1 to 5% by weight of hydroxypropylcellulose, 10 to 50% by weight of lactose, and 0.1 to 2% by weight of magnesium stearate.

A second aspect of the present invention provides a pharmaceutical composition comprising 0.5 to 20% by weight of hydra zenet and 1 to 80% by weight of atorvastatin. Preferably, the pharmaceutical composition contains from 1 to 10% by weight of Hazel malt and from 1 to 30% by weight of atorvastatin.

In one aspect of the present aspect, the composition may also optionally comprise a stabilizer. The stabilizer may be a stabilizer conventionally used in the art; for example, it may be a carbonate, a hydrogencarbonate, a phosphate or a butylated hydroxytoluene; etc.; preferably, the stabilizer is at least one of calcium carbonate or butylated hydroxytoluene. One. The addition of calcium carbonate or butylated hydroxytoluene to the composition of the present invention is advantageous for the stability of the formulation. More preferably, the pharmaceutical composition may comprise 5 to 25% by weight of calcium carbonate and 0.005% to 0.05% by weight of butoxyl. Toluene.

In another aspect of the present aspect, the pharmaceutical composition may also optionally comprise a surfactant. The surfactant may be a surfactant conventionally used in the art, and may be, for example, an anionic surfactant or a nonionic surfactant. Examples of anionic surfactants are: sodium stearate, potassium stearate, sodium oleate, calcium stearate, sodium lauryl sulfate, and the like; examples of nonionic surfactants are: fatty acid sorbitan Disk), polysorbate, myrj, brij, poloxamer, etc.; preferably, the surfactant is at least one of sodium lauryl sulfate or polysorbate. The addition of sodium lauryl sulfate or polysorbate to the compositions of the present invention may be more beneficial to the efficacy of the pharmaceutical compositions. 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 the present invention, the pharmaceutical composition is in an oral form comprising, for example, an oral dosage unit having a total weight of from 100 to 800 mg, and further comprising: a filler, a binder, a disintegrant, and a lubricant. One or more. Wherein, the filler may be a filler conventionally used in the art, for example, may be starch, sugar, cellulose, inorganic salts, etc.; preferably, the filler is lactose, microcrystalline cellulose At least one of them. The binder may be a binder conventionally used in the art, and may be, for example, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, povidone, acacia, sucrose, etc.; preferably, The binder is at least one of hydroxypropylcellulose and povidone. The disintegrant may be a disintegrator conventionally used in the art, and may, for example, be croscarmellose sodium, crospovidone, sodium carboxymethyl starch, sodium alginate, corn starch, low substitution. Hydroxypropylcellulose; preferably, the disintegrant is at least one of croscarmellose sodium and crospovidone. The lubricant may be a lubricant conventionally used in the art, and may be, for example, magnesium stearate, stearic acid, sodium fumarate, PEG 6000, glyceryl behenate, talc, etc.; preferably, the lubrication The agent is magnesium stearate.

As a more preferred embodiment, the pharmaceutical composition may contain 1 to 10% by weight of croscarmellose sodium, 1 to 10% by weight of crospovidone, and 10 to 50% by weight of microcrystalline cellulose. 0.1 to 5% by weight of povidone, 0.1 to 5% by weight of hydroxypropylcellulose, 10 to 50% by weight of lactose, and 0.1 to 2% by weight of magnesium stearate.

A third aspect of the present invention is to provide a pharmaceutical composition comprising 0.5 to 20% by weight of haize wheat cloth and 1 to 80% by weight of rosuvastatin. Preferably, the pharmaceutical composition contains from 1 to 10% by weight of hexagram and from 1 to 30% by weight of rosuvastatin.

In one aspect of the present aspect, the composition may also optionally comprise a stabilizer. The stabilizer may be a stabilizer conventionally used in the art, and may be, for example, a carbonate, a hydrogencarbonate or a phosphate; etc.; preferably, the stabilizer is at least one of calcium carbonate and butylated hydroxytoluene. The addition of calcium carbonate or butylated hydroxytoluene to the composition of the present invention is advantageous for the stability of the formulation. More preferably, the pharmaceutical composition may comprise from 1 to 15% by weight of calcium carbonate and from 0.005 to 0.05% by weight of butylated hydroxytoluene. .

In another aspect of the present aspect, the pharmaceutical composition may also optionally comprise a surfactant. The surfactant may be a surfactant conventionally used in the art, and may be, for example, an anionic surfactant or a nonionic surfactant. Examples of anionic surfactants are: sodium stearate, potassium stearate, sodium oleate, calcium stearate, sodium lauryl sulfate, etc. Examples of nonionic surfactants are: fatty acid sorbitan Disk), polysorbate, mezer (myrj), benzze (brij), poloxamer, and the like. Preferably, the surfactant is sodium lauryl sulfate. The addition of sodium lauryl sulfate to the compositions of the present invention may be more beneficial to the efficacy of the pharmaceutical compositions. 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 1 to 10% by weight of crospovidone, 10 to 50% by weight of microcrystalline cellulose, 0.1 to 5% by weight of povidone, and 10 to 50% by weight. The weight of lactose, one or more of 0.1 to 2% by weight of magnesium stearate.

A fourth aspect of the present invention provides a method for preparing a pharmaceutical composition comprising a haize wheat cloth and an HMG-CoA reductase inhibitor, the method comprising the HMG-CoA reductase inhibitor, Heze Mai Mai Combined with optional excipients.

A fifth aspect of the present invention provides a method for preparing a pharmaceutical composition comprising a haize wheat cloth and an HMG-CoA reductase inhibitor, comprising the steps of:

(1) granulating an HMG-CoA reductase inhibitor and an optional adjuvant to obtain a HMG-CoA reductase inhibitor particle fraction;

(2) granules of Heze's wheat cloth and optional auxiliary materials, and obtain the granules of Heze Maibu;

(3) Combining the two particle fractions prepared in the above steps (1) and (2) with optional adjuvants.

Wherein the HMG-CoA reductase inhibitor granule portion of the step (1) can be granulated with water as a solvent, and the portion of the haize mai granules of the step (2) can be granulated with water, an organic solvent or a mixture thereof; preferably The portion of the Hezemeat granules of the step (2) may be granulated with water, an alcohol, chloroform, acetone, acetonitrile or the like, and a mixture thereof, preferably granulated with water, an alcohol or a mixture thereof, more preferably with an alcohol and The mixture of water is granulated, and a mixture of ethanol and water is preferably used for granulation.

According to a sixth aspect of the present invention, there is provided a method for preparing a pharmaceutical composition comprising haize wheat cloth and atorvastatin, comprising the steps of:

(1) granules atorvastatin and optional adjuvants;

(2) granules of haize wheat cloth and optional auxiliary materials;

(3) The two particle portions prepared in the above steps (1) and (2) are uniformly mixed with an optional auxiliary material.

Preferably, the preparation method comprises the following steps:

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

(2) dissolving hydroxypropylcellulose in water;

(3) adding the hydroxypropylcellulose solution obtained in the step (2) to the mixture obtained in the step (1), granulating, drying, and granulating;

(4) mixing Heze wheat cloth with lactose, microcrystalline cellulose, sodium lauryl sulfate and croscarmellose sodium;

(5) Dissolving povidone in water for use;

(6) adding the povidone solution obtained in the step (5) to the mixture obtained in the step (4), granulating, drying, and granulating;

(7) The granules after the step (3) and the step (6) are granulated, optionally mixed with croscarmellose sodium, and then uniformly mixed with magnesium stearate, and tableted.

A seventh aspect of the present invention provides a method for preparing a pharmaceutical composition comprising Heiser Maibu and Atorvastatin, comprising the steps of:

(1) granules atorvastatin and optional adjuvants;

(2) granules of haize wheat cloth and optional auxiliary materials;

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

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

(5) The first total mixed particles obtained in the above step (3) and the step (4) and the second total mixed particles are pressed into a two-layer sheet.

Preferably, the preparation method comprises the following steps:

(2) dissolving polysorbate and hydroxypropyl cellulose in water;

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

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

(5) dissolving Heze wheat cloth, butylated hydroxytoluene and povidone in an ethanol solution;

(6) adding the solution obtained in the step (5) to the mixture obtained in the step (4), granulating, drying, and granulating;

(7) the granules after the step (3) is granulated, optionally mixed with croscarmellose sodium, and then uniformly mixed with magnesium stearate to obtain a first total mixed granule;

(8) granules after the step (6) is granulated, optionally mixed with croscarmellose sodium, and then uniformly mixed with magnesium stearate to obtain a second total mixed granule;

(9) The first total mixed particles and the second total mixed particles obtained in the step (7) and the step (8) are pressed into a two-layer sheet.

Eighth of the technical solution of the present invention is to provide a method for preparing a pharmaceutical composition comprising haize wheat cloth and rosuvastatin, comprising the following steps:

(1) granulating rosuvastatin and optional adjuvants;

(2) granules of haize wheat cloth and optional auxiliary materials;

(3) The granules prepared in the above steps (1) and (2) are uniformly mixed with optional adjuvants.

Preferably, the preparation method comprises the following steps:

(1) mixing rosuvastatin with lactose, microcrystalline cellulose, calcium carbonate and crospovidone;

(2) dissolving povidone in water;

(3) adding the povidone solution obtained in the step (2) to the mixture obtained in the step (1), granulating, drying, and granulating;

(5) dissolving Heze wheat cloth and povidone in an ethanol solution;

(7) The granules after the granulation in the step (3) and the step (6) are mixed, optionally mixed with the crospovidone, and then uniformly mixed with magnesium stearate, and tableted.

Preferably, the preparation method comprises the following steps:

(2) dissolving povidone in water;

(3) adding the povidone solution obtained in the step (2) to the mixture of the step (1) for granulation, drying, and granulating;

A ninth aspect of the present invention provides a method for preparing a pharmaceutical composition comprising haize malbe and rosuvastatin, comprising the steps of:

(1) granulating rosuvastatin and optional adjuvants;

(2) granules of haize wheat cloth and optional auxiliary materials;

Preferably, the preparation method comprises the following steps:

(2) dissolving povidone in water;

(7) the granules after the step (3) is granulated, optionally mixed with crospovidone, and then uniformly mixed with magnesium stearate to obtain a first total mixed granule;

(8) The granules after the step (6) are optionally mixed with crospovidone, and then uniformly mixed with magnesium stearate to obtain a second total mixed granule;

According to a tenth aspect of the present invention, there is provided a pharmaceutical dosage unit comprising 5 to 20 mg of methadone and 5 to 80 mg of atorvastatin. Preferably, the dose of the Hazel malt is 5 mg, 10 mg or 20 mg; and the dose of the atorvastatin is 5 mg, 10 mg, 20 mg, 40 mg or 80 mg. Preferably, the pharmaceutical dosage unit is an oral dosage unit.

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

In another aspect of the present aspect, the dosage unit can optionally contain calcium carbonate, butylated hydroxytoluene as a component. 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 the present scheme, the dosage unit can optionally contain sodium lauryl sulfate as a component. Preferably, the dosage unit may contain from 0.5 to 5 mg of sodium lauryl sulfate.

In another aspect of the present aspect, the dosage unit can optionally contain sodium lauryl sulfate, polysorbate as a component. Preferably, the dosage unit may contain from 0.5 to 5 mg of sodium lauryl sulfate, from 0.1 to 5 mg of polysorbate.

In another aspect of the present invention, the dosage unit may further comprise 1 to 50 mg of croscarmellose sodium, 20 to 250 mg of microcrystalline cellulose, 0.5 to 10 mg of povidone, and 0.5 to 10 mg of hydroxy group. Propylcellulose, 10 to 250 mg of lactose, 0.1 to 10 mg of magnesium stearate.

In another aspect of the present invention, the dosage unit may further comprise 1 to 50 mg of croscarmellose sodium, 1 to 30 mg of crospovidone, 20 to 250 mg of microcrystalline cellulose, 0.5 to 10 mg. Povidone, 0.5 to 10 mg of hydroxypropylcellulose, 10 to 250 mg of lactose, 0.1 to 10 mg of magnesium stearate.

According to an eleventh aspect of the present invention, there is provided a pharmaceutical dosage unit comprising 5 to 20 mg of methadone and 5 to 80 mg of rosuvastatin, preferably, the dose of the granule is 5 mg, 10 mg or 20 mg; and the dose of the rosuvastatin is 5 mg, 10 mg, 20 mg or 40 mg. Preferably, the pharmaceutical dosage unit is an oral dosage unit.

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

In one aspect of the present aspect, the dosage unit can optionally contain calcium carbonate, butylated hydroxytoluene as a component. Preferably, the dosage unit may contain from 1 to 50 mg of calcium carbonate and from 0.01 to 0.2 mg of butylated hydroxytoluene.

In another aspect of the present scheme, the dosage unit can optionally contain sodium lauryl sulfate as a component. Preferably, the dosage unit may contain from 0.5 to 10 mg of sodium lauryl sulfate.

In another aspect of the present invention, the dosage unit may further comprise 5 to 40 mg of crospovidone, 20 to 250 mg of microcrystalline cellulose, 1 to 20 mg of povidone, 20 to 250 mg of lactose, 0.1 to 5 mg of magnesium stearate.

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

The pharmaceutical composition or the pharmaceutical dosage unit of the present invention may be in the form of a capsule, a tablet, a granule, a powder, a solution or a tablet.

The composition of the haize wheat cloth and the HMG-CoA reductase inhibitor of the present invention may be in various forms, such as a tablet, and the composition of the invention is reasonable in design, easy to prepare a suitable preparation, and the preparation has good stability. The quality is controllable.

Compared with the prior art, the pharmaceutical composition containing the haize wheat cloth and the HMG-CoA reductase inhibitor according to the present invention has the following advantages:

(1) The present invention combines Heze Metz with an HMG-CoA reductase inhibitor, particularly when the HMG-CoA reductase inhibitor is a statin, and has a good synergistic effect. It can have important clinical benefit by reducing the incidence of myocardial toxicity and the incidence of cardiovascular events by reducing the dose of statins.

(2) The pharmaceutical composition provided by the invention not only reduces the adverse reaction by reducing the dose of the statin by synergistic effect, but has higher safety and clinical adverse reaction than the combination of the similar mechanism drug and the statin drug. Fewer, the patient's medication compliance is also better.

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

(4) A small variety of excipients can be used in the pharmaceutical composition of the present invention, and the excipients can be all common excipients, and the prepared preparation has controllable quality and good stability.

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

In preclinical evaluation, Heze Metz combined with statins and ezetimibe combined with statins are pharmacologically equivalent, but the safety of Heze Maibu combined with statins is significantly better than that of ezetimibe combined with statins. Drugs are better and have greater advantages in clinical applications.

Detailed ways

The invention is described in detail below with reference to the accompanying drawings. The experimental methods in the following examples which do not specify the specific conditions are selected according to conventional methods and conditions, or according to the product specifications.

The Herzet Maibu (HS-25), Ezetimibe, atorvastatin, rosuvastatin and simvastatin used in the following examples were derived from Zhejiang Sea. Zheng Pharmaceutical Co., Ltd., or prepared according to the methods of the prior art.

It should be noted that the atorvastatin, rosuvastatin and simvastatin used in the following examples are in the form of calcium salts, and the contents thereof refer to the contents of atorvastatin, rosuvastatin and simvastatin. For example, in Example 1, a specification of 5 mg/10 mg of acesulfame atorvastatin tablets, wherein 10 mg refers to the weight of atorvastatin, if the weight of atorvastatin in the prescription is converted to A The weight of tovatatin calcium is 10.83 mg. In Example 6, the specification is 20 mg/20 mg of Herzema mazulastatin tablets, of which 20 mg refers to the weight of rosuvastatin, and if the weight of rosuvastatin in the prescription is converted to rosuvastatin The weight of calcium is 20.83 mg.

Example 1: Haazawa Maibu Atorvastatin tablets, specifications: 5 mg/10 mg, each weighing 92.25 mg, the composition is shown in Table 1.

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

Preparation:

(1) mixing a prescribed amount of atorvastatin and atorvastatin granules of lactose, microcrystalline cellulose, calcium carbonate, and croscarmellose sodium;

(2) dissolving a prescribed amount of hydroxypropylcellulose in purified water for use;

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

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

(5) Dissolving the prescription amount of povidone K30 in purified water for use;

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

(7) The granules after the granulation in the step (3) and the step (6) and the additional portion of the croscarmellose sodium are uniformly mixed, and then a prescribed amount of magnesium stearate is added thereto and uniformly mixed, and tableted.

Example 2: Azevastatin tablets of Heze Mbe, specifications: 5 mg / 20 mg, each piece weighing 143.50 mg, see Table 2 for the composition.

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

Preparation method: same as in Example 1.

Example 3: Azevastatin tablets of Heze Mbe, specifications: 10 mg/10 mg, each piece weighing 133.25 mg, see Table 3 for the composition.

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

Preparation method: same as in Example 1.

Example 4: Azevastatin tablets of Heze Mbe, specifications: 10 mg / 20 mg, each tablet weighs 184.50 mg, see Table 4 for the composition.

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

Preparation method: same as in Example 1.

Example 5: Azevastatin tablets of Heze Mbe, specifications: 10 mg/80 mg, each weighing 492.00 mg, and the composition is shown in Table 5.

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

Preparation method: same as in Example 1.

Example 6: Hazel Maibrizalvastatin tablets, specifications: 20 mg / 20 mg, each tablet weight 460.00 mg, see Table 6 for the composition.

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

Preparation:

(1) mixing the prescription amount of rosuvastatin and rosuvastatin granules of lactose, microcrystalline cellulose, calcium carbonate and crospovidone;

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

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

(4) mixing lactose, microcrystalline cellulose, sodium lauryl sulfate and crospovidone in the granule portion of Heze Maibu;

(5) dissolving the prescription amount of the granules of Heze and the granules of the granules of the granules of the granules in the ethanol solution;

(6) adding the solution obtained in the step (5) to the mixture obtained in the step (4), granulating, drying, and granulating to obtain the granules of the granules;

(7) mixing the granules after the granulation in the step (3) with the granules after the granules in the step (6), mixing them with the crospovidone of the external portion, and then adding a prescribed amount of magnesium stearate thereto. Evenly, tableting.

Example 7: Hazel Maibrizalvastatin tablets, specifications: 10 mg / 20 mg, each piece weighing 297.00 mg, see Table 7 for the composition.

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

Preparation method: same as Example 6.

Example 8: Hazel Maibrizalvastatin tablets, specifications: 20 mg/10 mg, each tablet weighs 393.00 mg, and the composition is shown in Table 8.

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

Preparation method: same as Example 6.

Example 9: Herzema mazulastatin tablets, specifications: 10 mg/10 mg, each weighing 230.00 mg, see Table 9 for the composition.

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

Preparation method: same as Example 6.

Example 10: Heze Metz simvastatin tablets, specifications: 6 mg / 20 mg, each tablet weighs 100.00 mg, the composition is shown in Table 10.

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

海泽麦布Haize Maibu	66
辛伐他汀Simvastatin	2020
乳糖lactose	48.5448.54
微晶纤维素Microcrystalline cellulose	16.18516.185
交联聚维酮Cross-linked povidone	33
聚维酮K30Povidone K30	55
丁羟茴醚Butylated hydroxyanisole	0.0250.025
枸橼酸Tannic acid	0.250.25
硬脂酸镁Magnesium stearate	11
30％乙醇溶液30% ethanol solution	适量Moderate amount
合计total	1000片1000 pieces

Preparation:

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

(2) Weighing Herzee Maibu, Simvastatin, Microcrystalline Cellulose, Lactose, Povidone K30, crospovidone according to the prescription, passing through a 40 mesh sieve, and mixing the above-mentioned sifted raw materials Uniform

(3) adding the solution obtained in the step (1) to the mixture obtained in the step (2), and performing granulation;

(4) drying and sizing the wet granules;

(5) A magnesium stearate was added thereto and mixed.

Example 11: Stability study of Azevastatin tablets of Haize Maibu (5 mg/10 mg specification)

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

Table 11. Stability data for Heze mow atorvastatin tablets (5 mg/10 mg size)

The results showed that after storage conditions of 40 ° C ± 2 ° C, RH75% ± 5% for 6 months, the content and dissolution of methacetin atorvastatin tablets (5mg/10mg) did not change significantly, impurities only slightly There is growth, indicating that the sample is relatively stable.

Method 2: The tablet prepared in Example 1 was packaged in a high-density polyethylene bottle (containing 2 g of desiccant), and placed at a temperature of 25 ° C ± 2 ° C and a humidity of 60% ± 5% for stability. Study, the test results are shown in Table 12:

Table 12. Stability data for Heze mow atorvastatin tablets (5 mg/10 mg size)

The results showed that after storage conditions of 25 ° C ± 2 ° C, RH 60% ± 5% for 24 months, the content and dissolution of methadrant atorvastatin tablets (5mg/10mg) did not change significantly, impurities only slightly There is growth, indicating that the sample is relatively stable.

Example 12: Stability study of azevastatin tablets of Heze Mbe (5mg/20mg specification)

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

Table 13. Stability data for azevastatin tablets (5 mg/20 mg size)

The results showed that after storage conditions of 40 ° C ± 2 ° C, RH75% ± 5% for 6 months, the detection indicators of Heze Mbe atorvastatin tablets (5mg / 20mg) did not change significantly, indicating that the sample More stable.

Method 2: The tablet prepared in Example 2 was packaged in a high-density polyethylene bottle (containing 2 g of desiccant), and placed at a temperature of 25 ° C ± 2 ° C and a humidity of 60% ± 5% for stability. Study, the test results are shown in Table 14:

Table 14. Stability data for azevastatin tablets (5 mg/20 mg size)

The results showed that after storage conditions of 25 ° C ± 2 ° C, RH 60% ± 5% for 24 months, the content and dissolution of methacetin atorvastatin tablets (5mg / 20mg) did not change significantly, impurities only slightly There is growth, indicating that the sample is relatively stable.

Example 13: Stability study of auzestatin tablets of Heze Mbe (10 mg/10 mg specification)

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

Table 15. Stability data for Heze mow atorvastatin tablets (10 mg/10 mg size)

The results showed that after storage conditions of 40 ° C ± 2 ° C, RH75% ± 5% for 6 months, the detection indicators of Heze Met atorvastatin tablets (10mg/10mg) showed no significant changes, indicating that the samples More stable.

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

Table 16. Stability data for Heze mow atorvastatin tablets (10 mg/10 mg size)

The results showed that after storage conditions of 25 ° C ± 2 ° C, RH60% ± 5% for 24 months, the content and dissolution of methadrant atorvastatin tablets (10mg/10mg) did not change significantly, impurities only slightly There is growth, indicating that the sample is relatively stable.

Example 14: Stability study of auzestatin tablets of Heze Mbe (10 mg/20 mg size)

Method 1: The tablets prepared in Example 4 were packaged in a high-density polyethylene bottle (containing 2 g of desiccant), and placed under the conditions of 40 ° C ± 2 ° C and RH 75% ± 5% for stability study. See Table 17:

Table 17. Stability data for Heze mow atorvastatin tablets (10 mg/20 mg size)

The results showed that the content and dissolution of atorvastatin tablets (10mg/20mg) were not significantly changed after storage conditions of 40 °C ± 2 °C and RH75% ± 5% for 6 months. There is growth, indicating that the sample is relatively stable.

Method 2: The tablet prepared in Example 4 was packaged in a high-density polyethylene bottle (containing 2 g of a desiccant), and placed under the conditions of 25 ° C ± 2 ° C and a humidity of 60% ± 5% for stability study. The results are shown in Table 18:

Table 18. Stability data for Helvastatin tablets (10 mg/20 mg size)

The results showed that the content and dissolution of atorvastatin tablets (10mg/20mg) were not significantly changed after storage conditions of 25 °C ± 2 °C and RH60% ± 5% for 24 months. There is growth, indicating that the sample is relatively stable.

Example 15: Stability study of azevastatin tablets of Heze Mbe (10 mg/80 mg size)

The tablet prepared in Example 5 was packaged in a high-density polyethylene bottle (containing 2 g of a desiccant) and placed at a temperature (40 ° C ± 2 ° C) and humidity (RH 75% ± 5%) for stabilization. Sex studies, the results are shown in Table 19:

Table 19. Stability data for Heze mow atorvastatin tablets (10 mg/80 mg size)

The results showed that after storage conditions of 40 ° C ± 2 ° C, RH75% ± 5% for 3 months, the detection indicators of Heze Mbe Atorvastatin tablets (10mg / 80mg) did not change significantly, indicating that the sample More stable.

Example 16: Stability study of Heze Metzbrutvastatin Tablets (20/20 mg)

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

Table 20. Stability data for Hezem's Maibresulvastatin tablets (20 mg/20 mg size)

The results showed that after 10 days of storage at 50 ° C and 75% humidity, the content of the sirvastatin tablets and the related substances and dissolution were basically unchanged, indicating that the samples were stable and the quality was controllable.

Example 17: Stability study of Heze Metz simvastatin tablets (6 mg/20 mg size)

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

Table 21. Stability data for Heze Metz simvastatin tablets (6 mg/20 mg size)

The results showed that the content of haize simvastatin tablets remained unchanged after 20 days under various conditions, and the related substances increased slightly, indicating that the samples were stable and the quality was controllable.

Example 18: Pharmacodynamic study of combination of Heze Metz and Simvastatin

Rhesus monkeys with primary hyperlipidemia (blood lipid index: TC>6.22mmol/L, LDL>4.91mmol/L, HDL<1.55mmol/L, TG>1.0mmol/L), plus high fat diet to induce blood lipids Levels continued to stabilize for at least 2 weeks (see pre-dose data), oral administration of Heiszema Maibu (ie HS-25) or simvastatin, and oral administration of ezetimibe for 4 weeks. To observe the effect of single drug and simvastatin on blood lipids. The experimental grouping and testing 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 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 index in all drug-administered groups was mainly reflected in TC and LDL, and other indicators such as TG, HDL and ApoA1 did not improve significantly. HS-25 combined with simvastatin and ezetimibe combined with simvastatin was basically the same. The experimental data is shown in Table 23 and Table 24:

Impact on TC (see Table 23):

Simvastatin alone had a lowering effect on TC, compared with the model group, P < 0.05, indicating statistical differences.

The HS-25 single-use group and the ezetimibe alone group had a significant effect on reducing TC, which was superior to the simvastatin single-use group, compared with the model group, P < 0.01, indicating significant statistical differences. The pharmacodynamic effect gradually increased with the administration time, suggesting that HS-25 and ezetimibe have a certain persistence for the reduction of TC.

When HS-25 and ezetimibe were combined with simvastatin, the effect of reducing TC was better than that of HS-25 single use group, ezetimibe single use group and simvastatin single use group. Mainly reflected in the 1 week after administration, the decrease of TC was faster than that of single drug; the percentage of maximum decrease of TC (4 weeks after administration) was greater.

Impact on LDL (see Table 24):

The effect of HS-25 and ezetimibe alone or in combination with atorvastatin on LDL was consistent with TC.

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

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

Example 19: Pharmacodynamics of combination of haizemaibu and atorvastatin

The animal model of primary hyperlipidemia rhesus monkey was selected (the blood lipid index was: TC>6.22mmol/L, LDL>4.91mmol/L, HDL<1.55mmol/L, TG>1.0mmol/L), plus high fat diet. After induced, high blood lipid levels continued to be stable, oral administration of atorvastatin or combined with Heze Maibu (HS-25) or ezetimibe animals for 3 months, observed HS-25 and ezetimibe The effect of combined atorvastatin on blood lipids. The experimental grouping and testing indicators are shown in Table 25:

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

The test results show:

Atorvastatin alone or atorvastatin combined with HS-25 or ezetimibe had no significant effect on rhesus monkey weight, blood biochemistry, blood routine and blood glucose, and no abnormal clinical manifestations were observed.

The improvement of blood lipid index in all drug-administered groups was mainly reflected in TC and LDL, and other indicators such as TG, HDL, ApoA1 and ApoB did not change significantly. The experimental data is shown in Table 26 and Table 27:

Impact on TC (Table 26):

The drug efficacy reached the plateau period at 30 days after administration, and no further decrease in TC was observed after continued administration. Due to the small number of animals, the TC of the model group had some fluctuations. Therefore, the TC effect of atorvastatin alone was lower at 25%, and the percentage of TC decreased by 50% in the two groups. Better than atorvastatin single use group.

The TC content of the model group was relatively stable during the test period, and no significant fluctuations were observed, which proved that the model was stable.

Impact on LDL (Table 27)

The trend of atorvastatin alone or atorvastatin in combination with HS-25 or ezetimibe was consistent with TC.

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

Table 27. Effect of atorvastatin alone or in combination with HS-25 and ezetimibe on serum LDL in hyperlipidemia rhesus monkeys (mmol/L, %)

Example 20: Repeated dose toxicity study of Heze Metz combined with atorvastatin in Beagle dogs

Normal beagle dogs of SPF grade 6-9 months old, male and female, divided into vehicle group, atropol monotherapy group and HS-25 combined with atorvastatin group, continuous administration for 2 weeks, observation of atorvastatin The toxicity, grouping and administration of single or combined HS-25 are shown in Table 28:

Table 28. Toxicity test protocol for repeated administration of HS-25 in combination with atorvastatin in beagle dogs

experiment result shows:

This beagle dog has drooling and is associated with atorvastatin. Other indicators such as body weight, food intake, electrocardiogram, blood routine, gross anatomy and pathology were not abnormal; the decrease in blood lipids was dose-related to atorvastatin.

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

Table 29. Results of toxicity test of atorvastatin alone or HS-25 in combination with atorvastatin in Beagle dogs

Zetia's literature (see NDA 21-445 FDA review: Pharmacology Review(s) 117-129) shows that ezetimibe and atorvastatin exhibit hepatotoxicity at a dose of 0.3/1 mg/kg. And with the increase of the dose of atorvastatin, the toxicity increased; the blood lipid index is basically consistent with the liver enzyme index. The 3-week experimental data is shown in Table 30:

Table 30. Toxicity test results of atorvastatin alone or Zetia in combination with atorvastatin in Beagle dogs

Comparing the above data, the liver function of the two experiments was consistent in the blank group and the atorvastatin 10 mg/kg dose, suggesting that the data were comparable.

The comparison showed that no significant toxicity was observed in the atorvastatin monotherapy group at 10 mg/kg; the atorvastatin alone group was found to have a mild elevation of ALT at 30 mg/kg.

The toxicity of HS-25 combined with atorvastatin only showed an increase in ALT, and there was no abnormality in AST. The toxicity of Zetia combined with atorvastatin was not only increased in ALT at 3/10 and 30/10 mg/kg, but also increased in AST. high.

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 HS-25 combined with Ato The safety of statin is at least 10 times greater than the safety of Zetia combined with atorvastatin.

In addition, the toxicity of HS-25 combined with atorvastatin was 30/10, 100/10, 100/30 mg/kg ALT: 112.8, 188.3, 242.8, respectively, and the increase of ALT was small; Zetia combined with Ato The toxicity of statin was 0.3/1, /3/1, 3/10, 30/10 mg/kg for ALT: female 112.8, 156.3, 990.3, 657.0; male 88.8, 106.3, 391.5, 1133.5, ALT increased with dose. The increase was significantly greater, suggesting that hepatotoxicity is more pronounced.

In summary, the combination of HS-25 and atorvastatin is significantly safer than the combination of Zetia and atorvastatin, and the safety factor is about 10 times that of Beagle dogs.

Example 21: Azevastatin tablets of Heze Mbe, specifications: 20 mg / 20 mg, each tablet weighs 480 mg, and the composition is shown in Table 31.

Table 31. Prescription composition of Example 21 (unit: g)

Preparation:

(2) dissolving a prescribed amount of polysorbate or hydroxypropylcellulose in purified water;

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

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

(7) mixing the granules after the step (3) with the atorvastatin granules and the croscarmellose sodium, and then adding magnesium stearate to the mixture;

(8) mixing the granules after the granulation in the step (6) with the croscarmellose sodium of the granules of the granules of the granules, and then adding the magnesium stearate to the mixture;

(9) The granules obtained in the step (7) and the step (8) are pressed into a two-layer sheet.

Example 22: Azevastatin tablets of Heze Mbe, specifications: 20 mg/10 mg, each tablet weighing 480 mg, see Table 32 for the composition.

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

Preparation method: same as Example 21.

Example 23: Azevastatin tablets of Haize Maibu, specifications: 10 mg / 20 mg, each tablet weighs 315 mg, and the composition is shown in Table 33.

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

Preparation method: same as Example 21.

Example 24: Hazel mai atorvastatin tablets, specifications: 10 mg/10 mg, each tablet weighing 315 mg, see Table 34 for the composition.

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

Preparation method: same as Example 21.

Example 25: Heze Mesobruvastatin Tablets, Specification: 20 mg/20 mg, each weighing 460 mg, see Table 35 for the composition.

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

Preparation:

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

(5) dissolving the prescription amount of the povidone K30 of the granules of Heze, the butyl hydroxytoluene and the granules of the granules in the ethanol solution;

(7) mixing the granules after the step (3) with the crocetin granules and the crospovidone of the rosuvastatin granules, and then uniformly adding the magnesium stearate;

(8) mixing the granules after the step (6) with the crospovidone of the additional portion of the granules of the granules of the granules, and then uniformly adding the magnesium stearate;

Example 26: Hazel Maibresulvastatin tablets, specifications: 20 mg/10 mg, each weighing 460 mg, see Table 36 for the composition.

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

Preparation method: same as Example 25.

Example 27: Herzema mazulastatin tablets, specifications: 10 mg / 20 mg, each tablet weighs 295 mg, see Table 37 for the composition.

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

Preparation method: same as Example 25.

Example 28: Hessian Maibresulvastatin tablets, specifications: 10 mg/10 mg, each tablet weighing 295 mg, see Table 38 for the composition.

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

Preparation method: same as Example 25.

Example 29: Hazel Maibresulvastatin tablets, specifications: 20 mg / 20 mg, each tablet weighs 460 mg, see Table 39 for the composition.

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

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

(5) dissolving the prescription amount of hexamethylene toluene and povidone K30 in the granule portion of Heze and Maizhe Maibu in an ethanol solution;

(7) mixing the granules after the step (3) and the granules after the step (6), and then uniformly mixing with the added portion of the crospovidone, and then adding a prescribed amount of magnesium stearate to be uniformly mixed. Tableting.

Example 30: Stability study of atorvastatin calcium tablets of Haize Maibu (20 mg/10 mg specification)

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

Table 40. Stability data for Heze mow atorvastatin tablets (20 mg/10 mg size)

The results showed that after storage conditions of 40 ° C ± 2 ° C, RH75% ± 5% for 3 months, the detection indicators of Heze Mbe Atorvastatin tablets (20mg / 10mg) showed no significant changes, indicating that the sample More stable.

Example 31: Azerbaijan and atorvastatin tablets, specifications: 20 mg/10 mg, each tablet weighing 480 mg, see Table 41 for the composition.

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

Preparation:

(5) dissolving the prescribed amount of Haize Maibu, butylated hydroxytoluene, povidone K30 in an isopropyl alcohol solution;

Example 32: Hazel mai atorvastatin tablets, specifications: 20 mg / 20 mg, each tablet weighs 630 mg, the composition is shown in Table 42.

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

Preparation method: same as Example 31.

Example 33: Azerbaijan and atorvastatin tablets, specifications: 10 mg / 20 mg, each tablet weighing 465 mg, see Table 43 for the composition.

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

Preparation method: same as Example 31.

Example 34: Stability study of auzestatin tablets of Heze Mbe (20 mg/20 mg size)

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

Table 44. Stability data for Heze mow atorvastatin tablets (20 mg/20 mg size)

The results showed that after storage conditions of 40 ° C ± 2 ° C, RH75% ± 5% for 3 months, the content and dissolution of the atorvastatin tablets (20mg/10mg) of Heze Maibu did not change significantly, the impurities are only slightly There is growth, indicating that the sample is relatively stable.

Method 2: The tablets prepared in Example 21 were placed in a double aluminum package and placed under the conditions of 25 ° C ± 2 ° C and a humidity of 60% ± 5% for stability studies. The test results are shown in Table 45:

Table 45. Stability data for Heze mow atorvastatin tablets (20 mg/20 mg size)

The results showed that the content and dissolution of atorvastatin tablets (20mg/20mg) were not significantly changed after storage conditions of 25 °C ± 2 °C and RH60% ± 5% for 9 months. There is growth, indicating that the sample is relatively stable.

Example 35: Stability study of auzestatin tablets of Heze Mbe (20 mg/10 mg size)

Method 1: The tablets prepared in Example 22 were placed in a double aluminum package and placed under the conditions of 40 ° C ± 2 ° C and RH 75% ± 5% for stability studies. The test results are shown in Table 46:

Table 46. Stability data for Heze mow atorvastatin tablets (20 mg/10 mg size)

Method 2: The tablets prepared in Example 22 were placed in a double aluminum package and placed under the conditions of 25 ° C ± 2 ° C and a humidity of 60% ± 5% for stability studies. The test results are shown in Table 47:

Table 47. Stability data for azevastatin tablets (20 mg/10 mg size)

The results showed that there was no significant change in the content and dissolution of atorvastatin tablets (20 mg/10 mg) after 15 months of storage at 25 °C ± 2 °C and RH 60% ± 5%. There is growth, indicating that the sample is relatively stable.

Example 36: Stability study of auzestatin tablets of Heze Mbe (10 mg/20 mg size)

Method 1: The tablets prepared in Example 23 were placed in a double aluminum package and placed under the conditions of 40 ° C ± 2 ° C and RH 75% ± 5% for stability study. The test results are shown in Table 48:

Table 48. Stability data for azevastatin tablets (10 mg/20 mg size)

The results showed that the content and dissolution of atorvastatin tablets (10mg/20mg) were not significantly changed after storage conditions of 40 °C ± 2 °C and RH75% ± 5% for 3 months. There is growth, indicating that the sample is relatively stable.

Method 2: The tablets prepared in Example 23 were placed in a double aluminum package and placed under the conditions of 25 ° C ± 2 ° C and a humidity of 60 % ± 5% for stability studies. The test results are shown in Table 49:

Table 49. Stability data for azevastatin tablets (10 mg/20 mg size)

The results showed that after storage conditions of 25 ° C ± 2 ° C, RH 60% ± 5% for 9 months, the content and dissolution of methacetin atorvastatin tablets (10mg / 20mg) did not change significantly, impurities only slightly There is growth, indicating that the sample is relatively stable.

Example 37: Stability study of haize mappa atorvastatin tablets (10 mg/10 mg specification)

Method 1: The tablets prepared in Example 24 were placed in a double aluminum package and placed under the 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 Heze Metz atorvastatin tablets (10 mg/10 mg size)

The results showed that after storage conditions of 40 ° C ± 2 ° C, RH75% ± 5% for 3 months, the content and dissolution of the atorvastatin tablets (10mg/10mg) of Heze Maibu did not change significantly, the impurities are only slightly There is growth, indicating that the sample is relatively stable.

Method 2: The tablets prepared in Example 24 were placed in a double aluminum package and placed under the conditions of 25 ° C ± 2 ° C and a humidity of 60% ± 5% for stability studies. The test results are shown in Table 51:

Table 51. Stability data for Heze mow atorvastatin tablets (10 mg/10 mg size)

The results showed that after storage conditions of 25 ° C ± 2 ° C, RH60% ± 5% for 9 months, the content and dissolution of methadrant atorvastatin tablets (10mg/10mg) did not change significantly, impurities only slightly There is growth, indicating that the sample is relatively stable.

Example 38: Hazel Maibrizalvastatin tablets, specifications: 20 mg/10 mg, each tablet weighing 320 mg, see Table 52 for the composition.

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

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

(7) The granules after the granulation in the step (3) and the granules after the granules in the step (6) are mixed, and then a prescribed amount of magnesium stearate is added thereto and uniformly mixed, and tableted.

Example 39: Haize Maibrizalvastatin tablets, specifications: 20 mg/5 mg, each tablet weighing 270 mg, see Table 53 for the composition.

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

Preparation method: same as Example 38.

Claims

A pharmaceutical composition comprising:

(a) 0.5 to 20% by weight of Heze wheat cloth;

(b) 1 to 80% by weight of at least one HMG-CoA reductase inhibitor.
The pharmaceutical composition according to claim 1, wherein the HMG-CoA reductase inhibitor is a statin or a salt thereof.
The pharmaceutical composition according to claim 2, wherein said statin is selected from the group consisting of lovastatin, simvastatin, atorvastatin, pravastatin, rosuvastatin, fluvastatin, cerivastatin One or more of pitavastatin and rosuvastatin or a salt thereof.
The pharmaceutical composition according to claim 3, wherein the statin is atorvastatin.
The pharmaceutical composition according to claim 3, wherein the statin is rosuvastatin.
The pharmaceutical composition according to claim 3, wherein the statin is simvastatin.
The pharmaceutical composition according to any one of claims 1 to 6, further comprising one or more excipients of a stabilizer, a surfactant, a filler, a binder, a disintegrant, and a lubricant; preferably The stabilizer is at least one of calcium carbonate, butylated hydroxyanisole, citric acid, and butylated hydroxytoluene, and the surfactant is at least one of sodium lauryl sulfate and polysorbate. The filler is at least one of lactose, microcrystalline cellulose, and pregelatinized starch, and the binder is at least one of hydroxypropylcellulose and povidone, and the disintegrant is a cross-linking agent. At least one of sodium carboxymethylcellulose and crospovidone, wherein the lubricant is at least one of magnesium stearate and talc; more preferably, the composition contains 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 crosslinked carboxymethyl Cellulose sodium, 1 to 10% by weight of crospovidone, 10 to 50% by weight of microcrystalline cellulose, 0.1 to 5% by weight of poly-dimensional , 0.1 to 5% by weight of hydroxypropyl cellulose, 10 to 50% by weight of lactose, magnesium stearate 0.1 to 2% by weight of one or more.
The pharmaceutical composition according to claim 4, which comprises 1 to 10% by weight of pirimibe and 1 to 30% by weight of atorvastatin.
The pharmaceutical composition according to claim 4 or 8, further comprising a stabilizer, preferably, the stabilizer is at least one of calcium carbonate and butylated hydroxytoluene, and more preferably, the stabilizer is 5 to At least one of 25% by weight of calcium carbonate and 0.005 to 0.05% by weight of butylated hydroxytoluene.
The pharmaceutical composition according to claim 4 or 8, which further contains a surfactant, preferably, the surfactant is at least one of sodium lauryl sulfate and polysorbate, more preferably, The surfactant is at least one of 0.1 to 5% by weight of sodium lauryl sulfate and 0.05 to 0.5% by weight of polysorbate.
The pharmaceutical composition according to claim 4 or 8, which further comprises one or more of a filler, a binder, a disintegrant and a lubricant; preferably, the filler is lactose or microcrystalline fiber In at least one of the above, the binder is at least one of hydroxypropylcellulose and povidone, and the disintegrant is croscarmellose sodium or crospovidone. At least one, the lubricant is magnesium stearate; more preferably, the pharmaceutical composition contains 1 to 10% by weight of croscarmellose sodium, and 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 hydroxypropylcellulose, 10 to 50% by weight of lactose, 0.1 to 2% by weight of stearin One or more of magnesium sulfate.
The pharmaceutical composition according to claim 5, which comprises 1 to 10% by weight of haize wheat cloth and 1 to 30% by weight of rosuvastatin.
The pharmaceutical composition according to claim 5 or 12, further comprising a stabilizer, preferably the stabilizer is at least one of calcium carbonate and butylated hydroxytoluene, and more preferably, the stabilizer is 1 to 15% by weight of calcium carbonate, at least one of 0.005 to 0.05% by weight of butylated hydroxytoluene.
The pharmaceutical composition according to claim 5 or 12, which further contains a surfactant, preferably, the surfactant is sodium lauryl sulfate, and more preferably, the pharmaceutical composition contains 0.1 to 6% Weight of sodium lauryl sulfate.
The pharmaceutical composition according to claim 5 or 12, which further comprises one or more of a filler, a binder, a disintegrant and a lubricant; preferably, the filler is lactose or microcrystalline fiber In at least one of the above, the binder is at least one of hydroxypropylcellulose and povidone, and the disintegrant is croscarmellose sodium or crospovidone. At least one of the lubricants is magnesium stearate; more preferably, the pharmaceutical composition contains 1 to 10% by weight of crospovidone, 10 to 50% by weight of microcrystalline cellulose, 0.1 to One or more of 5% by weight of povidone, 10 to 50% by weight of lactose, and 0.1 to 2% by weight of magnesium stearate.
A method of producing a pharmaceutical composition according to any one of claims 1 to 15, comprising combining an HMG-CoA reductase inhibitor, Haizeme, and an optional adjuvant.
The preparation method of claim 16, comprising:

(1) granulating an HMG-CoA reductase inhibitor and an optional adjuvant to obtain a HMG-CoA reductase inhibitor particle fraction;

(2) granules of Heze's wheat cloth and optional auxiliary materials, and obtain the granules of Heze Maibu;

(3) Combining the granules prepared in the above steps (1) and (2) with optional adjuvants.
The production method according to claim 17, wherein the HMG-CoA reductase inhibitor particle portion of the step (1) is obtained by granulating with water as a solvent; and the portion of the Heze wheat cloth granule of the step (2) is water, The organic solvent or a mixture thereof is obtained by granulation.
The production method according to claim 18, wherein the portion of the granules of the granules of the zebras of the step (2) is obtained by granulating with water, an alcohol, chloroform, acetone, acetonitrile or the like, and a mixture thereof, preferably with water, The granulation of the alcohol and a mixture thereof is more preferably carried out by granulating a mixture of an alcohol and water, and it is preferably obtained by granulating a mixture of ethanol and water.
A method of preparing a pharmaceutical composition according to any one of claims 16 to 19, comprising:

(1) granules atorvastatin and optional adjuvants;

(2) granules of haize wheat cloth and optional auxiliary materials;

(3) The granules prepared in the above steps (1) and (2) are uniformly mixed with optional adjuvants.
A method of preparing a pharmaceutical composition according to claim 20, comprising:

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

(2) dissolving hydroxypropylcellulose in water;

(3) adding the hydroxypropylcellulose solution obtained in the step (2) to the mixture obtained in the step (1), granulating, drying, and granulating;

(4) mixing Heze wheat cloth with lactose, microcrystalline cellulose, sodium lauryl sulfate and croscarmellose sodium;

(5) dissolving povidone in water;

(6) adding the povidone solution obtained in the step (5) to the mixture obtained in the step (4), granulating, drying, and granulating;

(7) The granules after the step (3) and the step (6) are granulated, optionally mixed with croscarmellose sodium, and then uniformly mixed with magnesium stearate, and tableted.
A method of preparing a pharmaceutical composition according to any one of claims 16 to 19, comprising:

(1) granules atorvastatin and optional adjuvants;

(2) granules of haize wheat cloth and optional auxiliary materials;

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

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

(5) The first total mixed particles and the second total mixed particles obtained in the above steps (3) and (4) are pressed into a two-layer sheet.
A method of preparing a pharmaceutical composition according to claim 22, comprising:

(1) mixing atorvastatin with 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) to the mixture obtained in the step (1), granulating, drying, and granulating;

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

(5) dissolving Heze wheat cloth, butylated hydroxytoluene and povidone in an ethanol solution;

(6) adding the solution obtained in the step (5) to the mixture obtained in the step (4), granulating, drying, and granulating;

(7) the granules after the step (3) is granulated, optionally mixed with croscarmellose sodium, and then uniformly mixed with magnesium stearate to obtain a first total mixed granule;

(8) granules after the step (6) is granulated, optionally mixed with croscarmellose sodium, and then uniformly mixed with magnesium stearate to obtain a second total mixed granule;

(9) The first total mixed particles and the second total mixed particles obtained in the step (7) and the step (8) are pressed into a two-layer sheet.
A method of preparing a pharmaceutical composition according to any one of claims 16 to 19, comprising:

(1) granulating rosuvastatin and optional adjuvants;

(2) granules of haize wheat cloth and optional auxiliary materials;

(3) The granules prepared in the above steps (1) and (2) are uniformly mixed with optional adjuvants.
A method of preparing a pharmaceutical composition according to claim 24, comprising:

(1) mixing rosuvastatin with lactose, microcrystalline cellulose, calcium carbonate and crospovidone;

(2) dissolving povidone in water;

(3) adding the povidone solution obtained in the step (2) to the mixture obtained in the step (1), granulating, drying, and granulating;

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

(5) dissolving Heze wheat cloth and povidone in an ethanol solution;

(6) adding the solution obtained in the step (5) to the mixture obtained in the step (4), granulating, drying, and granulating;

(7) The granules after the granulation in the step (3) and the step (6) are mixed, optionally mixed with the crospovidone, and then uniformly mixed with magnesium stearate, and tableted.
A method of preparing a pharmaceutical composition according to claim 24, comprising:

(1) mixing rosuvastatin with lactose, microcrystalline cellulose, calcium carbonate and crospovidone;

(2) dissolving povidone in water;

(3) adding the povidone solution obtained in the step (2) to the mixture obtained in the step (1), granulating, drying, and granulating;

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

(5) dissolving Heze wheat cloth, butylated hydroxytoluene and povidone in an ethanol solution;

(6) adding the solution obtained in the step (5) to the mixture obtained in the step (4), granulating, drying, and granulating;

(7) The granules after the granulation in the step (3) and the step (6) are mixed, optionally mixed with the crospovidone, and then uniformly mixed with magnesium stearate, and tableted.
A method of preparing a pharmaceutical composition according to any one of claims 16 to 19, comprising:

(1) granulating rosuvastatin and optional adjuvants;

(2) granules of haize wheat cloth and optional auxiliary materials;

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

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

(5) The first total mixed particles obtained in the above step (3) and the step (4) and the second total mixed particles are pressed into a two-layer sheet.
The method of preparing a pharmaceutical composition according to claim 27, comprising:

(1) mixing rosuvastatin with lactose, microcrystalline cellulose, calcium carbonate and crospovidone;

(2) dissolving povidone in water;

(3) adding the povidone solution obtained in the step (2) to the mixture obtained in the step (1), granulating, drying, and granulating;

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

(5) dissolving Heze wheat cloth, butylated hydroxytoluene and povidone in an ethanol solution;

(6) adding the solution obtained in the step (5) to the mixture obtained in the step (4), granulating, drying, and granulating;

(7) the granules after the step (3) is granulated, optionally mixed with crospovidone, and then uniformly mixed with magnesium stearate to obtain a first total mixed granule;

(8) The granules after the step (6) are optionally mixed with crospovidone, and then uniformly mixed with magnesium stearate to obtain a second total mixed granule;

(9) The first total mixed particles and the second total mixed particles obtained in the step (7) and the step (8) are pressed into a two-layer sheet.
A pharmaceutical dosage unit comprising 5-20 mg of methadone and 5 to 80 mg of atorvastatin.
The pharmaceutical dosage unit according to claim 29, wherein the dose of the haize mousse is 5 mg, 10 mg or 20 mg; and the dose of the atorvastatin is 5 mg, 10 mg, 20 mg, 40 mg or 80 mg.
The pharmaceutical dosage unit according to claim 29 or 30, which further contains 5 to 100 mg of calcium carbonate.
The pharmaceutical dosage unit according to claim 29 or 30, which further contains 5 to 100 mg of calcium carbonate and 0.01 to 0.2 mg of butylated hydroxytoluene.
The pharmaceutical dosage unit according to claim 29 or 30, which further contains 0.5 to 5 mg of sodium lauryl sulfate.
The pharmaceutical dosage unit according to claim 29 or 30, which further comprises 0.5 to 5 mg of sodium lauryl sulfate and 0.1 to 5 mg of polysorbate.
The pharmaceutical dosage unit according to claim 29 or 30, which further comprises 1 to 50 mg of croscarmellose sodium, 20 to 250 mg of microcrystalline cellulose, 0.5 to 10 mg of povidone, 0.5 to 10 mg of Hydroxypropyl cellulose, 10 to 250 mg of lactose, 0.1 to 10 mg of magnesium stearate.
The pharmaceutical dosage unit according to claim 29 or 30, which further comprises 1 to 50 mg of croscarmellose sodium, 1 to 30 mg of crospovidone, 20 to 250 mg of microcrystalline cellulose, 0.5 to 10 mg of povidone, 0.5 to 10 mg of hydroxypropylcellulose, 10 to 250 mg of lactose, and 0.1 to 10 mg of magnesium stearate.
A pharmaceutical dosage unit comprising 5-20 mg of haize wheat cloth and 5 to 80 mg of rosuvastatin.
The pharmaceutical dosage unit according to claim 37, wherein the dose of the Herzet Maibu is 5 mg, 10 mg or 20 mg; and the dose of the rosuvastatin is 5 mg, 10 mg, 20 mg or 40 mg.
The pharmaceutical dosage unit according to claim 37 or 38, which further contains 1 to 50 mg of calcium carbonate.
The pharmaceutical dosage unit according to claim 37 or 38, which further contains 1 to 50 mg of calcium carbonate and 0.01 to 0.2 mg of butylated hydroxytoluene.
The pharmaceutical dosage unit according to claim 37 or 38, which further contains 0.5 to 10 mg of sodium lauryl sulfate.
The pharmaceutical dosage unit according to claim 37 or 38, which further comprises 5 to 40 mg of crospovidone, 20 to 250 mg of microcrystalline cellulose, 1 to 20 mg of povidone, 20 to 250 mg of lactose, 0.1 ~ 5 mg of magnesium stearate.
The pharmaceutical composition according to any one of claims 1 to 15 or the pharmaceutical dosage unit according to any one of claims 29 to 42, which is a capsule, a tablet, a granule, a powder, a solution Agent or lozenge.