WO2019101151A1 - 一种海泽麦布和HMG-CoA还原酶抑制剂的药物组合物 - Google Patents
一种海泽麦布和HMG-CoA还原酶抑制剂的药物组合物 Download PDFInfo
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- WO2019101151A1 WO2019101151A1 PCT/CN2018/117087 CN2018117087W WO2019101151A1 WO 2019101151 A1 WO2019101151 A1 WO 2019101151A1 CN 2018117087 W CN2018117087 W CN 2018117087W WO 2019101151 A1 WO2019101151 A1 WO 2019101151A1
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Classifications
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- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
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Definitions
- 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.
- 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.
- 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.
- atorvastatin the highest market share is atorvastatin.
- statins are less than those of other hypolipidemic drugs.
- the most common symptoms are mild gastrointestinal reactions, rhinitis, sinusitis, headache, sore throat, flu syndrome, arthritis, chest pain, insomnia, etc.
- 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:
- 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.
- the HMG-CoA reductase inhibitor is a statin or a salt thereof
- the statin is, for example, lovastatin, simvastatin, atorvastatin, pravastatin, rosuvastatin, fluoride
- 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 .
- statin is atorvastatin, rosuvastatin or simvastatin.
- 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.
- 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.
- 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.
- 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.
- 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
- 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.
- 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.
- 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.
- 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.
- 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
- a pharmaceutical composition comprising 0.5 to 20% by weight of hydra zenet and 1 to 80% by weight of atorvastatin.
- the pharmaceutical composition contains from 1 to 10% by weight of Hazel malt and from 1 to 30% by weight of atorvastatin.
- 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.
- 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.
- 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.
- anionic surfactants are: sodium stearate, potassium stearate, sodium oleate, calcium stearate, sodium lauryl sulfate, and the like;
- 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.
- 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.
- 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.
- a 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.
- 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
- a pharmaceutical composition comprising 0.5 to 20% by weight of haize wheat cloth and 1 to 80% by weight of rosuvastatin.
- the pharmaceutical composition contains from 1 to 10% by weight of hexagram and from 1 to 30% by weight of rosuvastatin.
- 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. .
- 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.
- anionic surfactants are: sodium stearate, potassium stearate, sodium oleate, calcium stearate, sodium lauryl sulfate, etc.
- nonionic surfactants are: fatty acid sorbitan Disk), polysorbate, mezer (myrj), benzze (brij), poloxamer, and the like.
- 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.
- 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.
- 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:
- the HMG-CoA reductase inhibitor granule portion of the step (1) can be granulated with water as a solvent
- 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.
- a method for preparing a pharmaceutical composition comprising haize wheat cloth and atorvastatin, comprising the steps of:
- the preparation method comprises the following steps:
- 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:
- the preparation method comprises the following steps:
- 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;
- step (6) 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;
- 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:
- the preparation method comprises the following steps:
- 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.
- the preparation method comprises the following steps:
- 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 ninth aspect of the present invention provides a method for preparing a pharmaceutical composition comprising haize malbe and rosuvastatin, comprising the steps of:
- the preparation method comprises the following steps:
- 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;
- 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;
- a pharmaceutical dosage unit comprising 5 to 20 mg of methadone and 5 to 80 mg of atorvastatin.
- 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.
- the pharmaceutical dosage unit is an oral dosage unit.
- the dosage unit can optionally contain calcium carbonate as a component.
- the dosage unit may contain from 5 to 100 mg of calcium carbonate.
- the dosage unit can optionally contain calcium carbonate, butylated hydroxytoluene as a component.
- the dosage unit may contain 5 to 100 mg of calcium carbonate and 0.01 to 0.2 mg of butylated hydroxytoluene.
- the dosage unit can optionally contain sodium lauryl sulfate as a component.
- the dosage unit may contain from 0.5 to 5 mg of sodium lauryl sulfate.
- the dosage unit can optionally contain sodium lauryl sulfate, polysorbate as a component.
- the dosage unit may contain from 0.5 to 5 mg of sodium lauryl sulfate, from 0.1 to 5 mg of polysorbate.
- 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.
- 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.
- 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.
- crospovidone 0.5 to 10 mg of hydroxypropylcellulose, 10 to 250 mg of lactose, 0.1 to 10 mg of magnesium stearate.
- 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.
- the pharmaceutical dosage unit is an oral dosage unit.
- the dosage unit can optionally contain calcium carbonate as a component.
- the dosage unit may contain from 1 to 50 mg of calcium carbonate.
- the dosage unit can optionally contain calcium carbonate, butylated hydroxytoluene as a component.
- the dosage unit may contain from 1 to 50 mg of calcium carbonate and from 0.01 to 0.2 mg of butylated hydroxytoluene.
- the dosage unit can optionally contain sodium lauryl sulfate as a component.
- the dosage unit may contain from 0.5 to 10 mg of sodium lauryl sulfate.
- 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.
- 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.
- 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.
- the pharmaceutical composition containing the haize wheat cloth and the HMG-CoA reductase inhibitor according to the present invention has the following advantages:
- 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.
- 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.
- 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.
- 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.
- the preparation method of the pharmaceutical composition of the invention is simple in process, convenient in operation, and suitable for industrialized large-scale production.
- 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.
- 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.
- 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.
- the weight of tovatatin calcium is 10.83 mg.
- 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.
- Example 2 Azevastatin tablets of Heze Mbe, specifications: 5 mg / 20 mg, each piece weighing 143.50 mg, see Table 2 for the composition.
- Example 3 Azevastatin tablets of Heze Mbe, specifications: 10 mg/10 mg, each piece weighing 133.25 mg, see Table 3 for the composition.
- Example 4 Azevastatin tablets of Heze Mbe, specifications: 10 mg / 20 mg, each tablet weighs 184.50 mg, see Table 4 for the composition.
- 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.
- Example 6 Hazel Maibrizalvastatin tablets, specifications: 20 mg / 20 mg, each tablet weight 460.00 mg, see Table 6 for the composition.
- Example 7 Hazel Maibrizalvastatin tablets, specifications: 10 mg / 20 mg, each piece weighing 297.00 mg, see Table 7 for the composition.
- Example 8 Hazel Maibrizalvastatin tablets, specifications: 20 mg/10 mg, each tablet weighs 393.00 mg, and the composition is shown in Table 8.
- Example 9 Herzema mazulastatin tablets, specifications: 10 mg/10 mg, each weighing 230.00 mg, see Table 9 for the composition.
- Example 10 Heze Metz simvastatin tablets, specifications: 6 mg / 20 mg, each tablet weighs 100.00 mg, the composition is shown in Table 10.
- 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:
- 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:
- 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:
- 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:
- 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:
- 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:
- 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:
- 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:
- Example 15 Stability study of azevastatin tablets of Heze Mbe (10 mg/80 mg size)
- Example 5 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:
- Example 6 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:
- Example 17 Stability study of Heze Metz simvastatin tablets (6 mg/20 mg size)
- Example 10 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:
- Rhesus monkeys with primary hyperlipidemia blood lipid index: TC>6.22mmol/L, LDL>4.91mmol/L, HDL ⁇ 1.55mmol/L, TG>1.0mmol/L
- 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.
- the experimental grouping and testing indicators are shown in Table 22:
- 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 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.
- 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:
- 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 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.
- Example 20 Repeated dose toxicity study of Heze Metz combined with atorvastatin in Beagle dogs
- 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.
- ALT alanine aminotransferase
- AST aspartate aminotransferase
- 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.
- 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.
- 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.
- 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.
- Example 22 Azevastatin tablets of Heze Mbe, specifications: 20 mg/10 mg, each tablet weighing 480 mg, see Table 32 for the composition.
- 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.
- Example 24 Hazel mai atorvastatin tablets, specifications: 10 mg/10 mg, each tablet weighing 315 mg, see Table 34 for the composition.
- Example 25 Heze Mesobruvastatin Tablets, Specification: 20 mg/20 mg, each weighing 460 mg, see Table 35 for the composition.
- Example 26 Hazel Maibresulvastatin tablets, specifications: 20 mg/10 mg, each weighing 460 mg, see Table 36 for the composition.
- Example 27 Herzema mazulastatin tablets, specifications: 10 mg / 20 mg, each tablet weighs 295 mg, see Table 37 for the composition.
- Example 28 Hessian Maibresulvastatin tablets, specifications: 10 mg/10 mg, each tablet weighing 295 mg, see Table 38 for the composition.
- Example 29 Hazel Maibresulvastatin tablets, specifications: 20 mg / 20 mg, each tablet weighs 460 mg, see Table 39 for the composition.
- Example 30 Stability study of atorvastatin calcium tablets of Haize Maibu (20 mg/10 mg specification)
- Example 22 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:
- Example 31 Azerbaijan and atorvastatin tablets, specifications: 20 mg/10 mg, each tablet weighing 480 mg, see Table 41 for the composition.
- Example 32 Hazel mai atorvastatin tablets, specifications: 20 mg / 20 mg, each tablet weighs 630 mg, the composition is shown in Table 42.
- Example 33 Azerbaijan and atorvastatin tablets, specifications: 10 mg / 20 mg, each tablet weighing 465 mg, see Table 43 for the composition.
- 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:
- 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:
- 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:
- 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:
- 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:
- 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:
- 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:
- 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:
- Example 38 Hazel Maibrizalvastatin tablets, specifications: 20 mg/10 mg, each tablet weighing 320 mg, see Table 52 for the composition.
- Example 39 Haize Maibrizalvastatin tablets, specifications: 20 mg/5 mg, each tablet weighing 270 mg, see Table 53 for the composition.
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Abstract
本发明提供一种药物组合物,其中含有海泽麦布和HMG-CoA还原酶抑制剂,还可以包括碳酸钙、丁羟茴醚、丁羟甲苯、枸橼酸、十二烷基硫酸钠、聚山梨酯、交联羧甲基纤维素钠、交联聚维酮、微晶纤维素、聚维酮、羟丙基纤维素、乳糖、预胶化淀粉、硬脂酸镁和滑石粉中的一种或多种辅料。该组合物可以制成多种剂型,且制剂稳定性好,质量可控。
Description
交叉引用
本申请要求发明名称为“一种海泽麦布和HMG-CoA还原酶抑制剂的药物组合物”于2017年11月23日提交到中国专利局的中国专利申请201711183715.5的优先权,其内容通过引用以整体并入本文。
本发明属于医药领域,具体涉及海泽麦布和HMG-CoA还原酶抑制剂的组合物及其应用。
心血管疾病是危害人类健康(特别是中老年)最常见、最严重的疾病之一,血脂异常是动脉粥样硬化、冠心病以及其它心脑血管疾病的重要危险因素。降血脂药物对于防治心血管疾病非常重要。
目前临床应用和处在研发阶段的降脂化学药物按其降脂机理和化学结构可分为他汀类,烟酸类,贝特类,胆酸鳌合剂类,多烯类以及新型降脂药和各种复方制剂。不同降脂药各有优缺点,其中他汀类是目前临床应用最广、疗效最好、深受广大医生和患者好评的降血脂药。临床常用的药物有:洛伐他汀,辛伐他汀,普伐他汀,阿托伐他汀,氟伐他汀,长效氟伐他汀缓释片,瑞舒伐他汀,匹伐他汀等。目前市场占有率最高的是阿托伐他汀。他汀类药物的不良反应相对于其它降血脂药较少,主要有两类:一类是由胆固醇前体物质甲羟戊酸合成受抑制所造成的体内代谢障碍,另一类是直接的毒性作用。最常见的症状为轻度胃肠反应、鼻炎、鼻窦炎、头痛、咽痛、流感综合症、关节炎、胸痛、失眠等。
近年来,新剂型和复方联合用药研发愈发受到关注,在不断开发具有新作用机制降血脂药的同时,各种能减轻药物不良反应、增强疗效的新剂型和复方制剂也相继应用于临床,取得了良好的效果。其中有:洛伐他汀控释片Altocor、烟酸缓释制剂Nispan、非诺贝特微粒化胶囊、烟酸和洛伐他汀的复方制剂Nicostatin、依折麦布/辛伐他汀复方制剂、依折麦布/阿托伐他汀复方制剂等。
在众多复方制剂及联合应用研究中,新型胆固醇吸收抑制剂依折麦布(Ezetimibe)与他汀类的研究最受瞩目。对依折麦布与他汀类的药效学研究发 现,依折麦布与他汀类药物合用,均具有良好的药效协同作用。然而,已发现,依折麦布与他汀类联用时存在一定的肝毒性,尤其是在协同水平剂量下联用时对于转氨酶(特别是谷丙转氨酶ALT)具有不利影响(参见例如NDA 21-445 FDA review:Pharmacology Review(s)117-129)。这对于需要长期用药的高血脂治疗来说可能造成安全性隐患。
因此,现有技术中仍亟需降血脂效果好且安全性高的药剂。
发明内容
本发明人在研究中意外发现,海泽麦布和HMG-CoA还原酶抑制剂的组合,不仅具有很好的降血脂协同作用,而且还具有足够的安全性。在此发现的基础上,本发明得以完成。本发明所述的海泽麦布是一种新的肠道胆固醇吸收抑制剂,公开在中国专利CN101993403A中。海泽麦布具有以下的结构式:
基于上述发现,本发明的技术方案之一是:提供一种药物组合物,该组合物含有0.5~20%重量的海泽麦布;和1~80%重量的至少一种HMG-CoA还原酶抑制剂。本发明的组合物是稳定的。优选地,所述HMG-CoA还原酶抑制剂为他汀类药物或其盐,所述他汀类药物例如是洛伐他汀、辛伐他汀、阿托伐他汀、普伐他汀、罗苏伐他汀、氟伐他汀、西立伐他汀、匹伐他汀和瑞舒伐他汀或其盐中的一种或多种;所述的他汀类药物的盐是药学上可接受的,该盐没有特别的限制;优选地,其中洛伐他汀、辛伐他汀、阿托伐他汀、罗苏伐他汀、匹伐他汀和瑞舒伐他汀为钙盐形式;普伐他汀、氟伐他汀、西立伐他汀为钠盐形式。
更优选地,所述他汀类药物是阿托伐他汀、瑞舒伐他汀或辛伐他汀。
在本方案的一个方面,所述药物组合物还可以含有辅料,所述辅料为本领域常规使用的辅料;优选地,辅料可为稳定剂、表面活性剂、填充剂、粘合剂、崩解剂和润滑剂中的一种或多种。
其中,所述的稳定剂可以是本领域常规使用的稳定剂,例如可以是碳酸盐、碳酸氢盐或磷酸盐等,也可以是丁羟茴醚、枸橼酸或丁羟甲苯等抗氧剂等,优选地,所述稳定剂为碳酸钙、丁羟茴醚、枸橼酸或丁羟甲苯中的至少一种。
其中,所述的表面活性剂可以是本领域常规使用的表面活性剂,例如可以是阴离子表面活性剂或非离子表面活性剂;阴离子表面活性剂的例子有:硬脂酸钠、硬脂酸钾、油酸钠、硬脂酸钙和十二烷基硫酸钠等;非离子表面活性剂类的例子有:脂肪酸山梨坦(司盘)、聚山梨酯、卖泽(myrj)、苄泽(brij)、泊洛沙姆等;优选地,所述表面活性剂为十二烷基硫酸钠或聚山梨酯中的至少一种。
其中,所述的填充剂可以是本领域常规使用的填充剂,例如淀粉类、糖类、纤维素类和无机盐类等;优选地,所述填充剂为乳糖、微晶纤维素、预胶化淀粉中的至少一种。
其中,所述的粘合剂可以是本领域常规使用的粘合剂,例如可以是羟丙基纤维素、甲基纤维素、羧甲基纤维素、聚维酮、***胶、蔗糖等;优选地,所述粘合剂为羟丙基纤维素、聚维酮中的至少一种。
其中,所述的崩解剂可以是本领域常规使用的崩解剂,例如可以是交联羧甲基纤维素钠、交联聚维酮、羧甲基淀粉钠、海藻酸钠、玉米淀粉、低取代羟丙基纤维素;优选地,所述崩解剂为交联羧甲基纤维素钠、交联聚维酮中的至少一种。
其中,所述的润滑剂可以是本领域常规使用的润滑剂,例如可以是硬脂酸镁,硬脂酸,富马酸钠,PEG6000,山嵛酸甘油酯,滑石粉等;优选地,所述润滑剂为硬脂酸镁、滑石粉中的至少一种。
作为优选的方案,本发明的组合物可以包含1~25%重量的碳酸钙,0.005~0.1%重量的丁羟甲苯,0.1~10%重量的十二烷基硫酸钠,0.05~1.0%重量的聚山梨酯,1~10%重量的交联羧甲基纤维素钠,1~10%重量的交联聚维酮,10~50%重量的微晶纤维素,0.1~5%重量的聚维酮,0.1~5%重量的羟丙基纤维素,10~50%重量的乳糖,0.1~2%重量的硬脂酸镁中的一种或多种。
本发明的技术方案之二是:提供一种药物组合物,该组合物含有0.5~20%重量的海泽麦布和1~80%重量的阿托伐他汀。优选地,该药物组合物含有1~10%重量的海泽麦布和1~30%重量的阿托伐他汀。
在本方案的一个方面,所述组合物还可以任选地包含稳定剂。所述稳定剂可以是本领域常规使用的稳定剂;例如可以是碳酸盐、碳酸氢盐、磷酸盐或丁羟甲苯等;优选地,所述稳定剂为碳酸钙或丁羟甲苯中的至少一种。在本发明的组合物中加入碳酸钙或丁羟甲苯有利于制剂的稳定,更优选地,所述药物组合物中可以包含5~25%重量的碳酸钙,0.005%~0.05%重量的丁羟甲苯。
在本方案的另一个方面,所述药物组合物还可以任选地包含表面活性剂。所述表面活性剂可以是本领域常规使用的表面活性剂,例如可以是阴离子表面活性剂或非离子表面活性剂。阴离子表面活性剂的例子有:硬脂酸钠、硬脂酸 钾、油酸钠、硬脂酸钙和十二烷基硫酸钠等;非离子表面活性剂类的例子有:脂肪酸山梨坦(司盘)、聚山梨酯、卖泽(myrj)、苄泽(brij)、泊洛沙姆等;优选地,所述表面活性剂为十二烷基硫酸钠或聚山梨酯中的至少一种。在本发明的组合物中加入十二烷基硫酸钠或聚山梨酯可以更有利于药物组合物药效的发挥。更优选地,所述药物组合物中可以含有0.1~5%重量的十二烷基硫酸钠,0.05%~0.5%重量的聚山梨酯。
在本方案的另一个方面,所述药物组合物为口服形式,其包含例如总重量为100~800mg的口服剂量单元,还可进一步含有:填充剂、粘合剂、崩解剂和润滑剂中的一种或多种。其中,所述的填充剂可以是本领域常规使用的填充剂,例如可以是淀粉类、糖类、纤维素类和无机盐类等;优选地,所述填充剂为乳糖、微晶纤维素中的至少一种。所述的粘合剂可以是本领域常规使用的粘合剂,例如可以是羟丙基纤维素、甲基纤维素、羧甲基纤维素、聚维酮、***胶、蔗糖等;优选地,所述粘合剂为羟丙基纤维素、聚维酮中的至少一种。所述的崩解剂可以是本领域常规使用的崩解剂,例如可以是交联羧甲基纤维素钠、交联聚维酮、羧甲基淀粉钠、海藻酸钠、玉米淀粉、低取代羟丙基纤维素;优选地,所述崩解剂为交联羧甲基纤维素钠、交联聚维酮的至少一种。所述的润滑剂可以是本领域常规使用的润滑剂,例如可以是硬脂酸镁,硬脂酸,富马酸钠,PEG6000,山嵛酸甘油酯,滑石粉等;优选地,所述润滑剂为硬脂酸镁。
作为更优选的方案,所述药物组合物可以含有1~10%重量的交联羧甲基纤维素钠,1~10%重量的交联聚维酮,10~50%重量的微晶纤维素,0.1~5%重量的聚维酮,0.1~5%重量的羟丙基纤维素,10~50%重量的乳糖,0.1~2%重量的硬脂酸镁中的一种或多种。
本发明的技术方案之三是:提供一种药物组合物,该组合物含有0.5~20%重量的海泽麦布和1~80%重量的瑞舒伐他汀。优选地,该药物组合物含有1~10%重量的海泽麦布和1~30%重量的瑞舒伐他汀。
在本方案的一个方面,所述组合物还可以任选地包含稳定剂。所述稳定剂可以是本领域常规使用的稳定剂,例如可以是碳酸盐、碳酸氢盐或磷酸盐等;优选地,所述稳定剂为碳酸钙、丁羟甲苯中的至少一种。在本发明的组合物中加入碳酸钙或丁羟甲苯有利于制剂的稳定,更优选地,所述药物组合物中可以包含1~15%重量的碳酸钙、0.005~0.05%重量的丁羟甲苯。
在本方案的另一个方面,所述药物组合物还可以任选地包含表面活性剂。所述表面活性剂可以是本领域常规使用的表面活性剂,例如可以是阴离子表面活性剂或非离子表面活性剂。阴离子表面活性剂的例子有:硬脂酸钠、硬脂酸钾、油酸钠、硬脂酸钙和十二烷基硫酸钠等,非离子表面活性剂类的例子有:脂肪酸山梨坦(司盘)、聚山梨酯、卖泽(myrj)、苄泽(brij)、泊洛沙姆等。优 选地,所述表面活性剂为十二烷基硫酸钠。在本发明的组合物中加入十二烷基硫酸钠可以更有利于药物组合物药效的发挥。更优选地,所述药物组合物中可以含有0.1~6%重量的十二烷基硫酸钠。
作为更优选的方案,所述药物组合物可以含有1~10%重量的交联聚维酮,10~50%重量的微晶纤维素,0.1~5%重量的聚维酮,10~50%重量的乳糖,0.1~2%重量的硬脂酸镁中的一种或多种。
本发明的技术方案之四是:提供了含有海泽麦布和HMG-CoA还原酶抑制剂的药物组合物的一种制备方法,该方法包括将HMG-CoA还原酶抑制剂、海泽麦布与任选的辅料组合。
本发明的技术方案之五是:提供了一种含有海泽麦布和HMG-CoA还原酶抑制剂的药物组合物的制备方法,包括以下步骤:
(1)将HMG-CoA还原酶抑制剂与任选的辅料制成颗粒,得HMG-CoA还原酶抑制剂颗粒部分;
(2)将海泽麦布与任选的辅料制成颗粒,得海泽麦布颗粒部分;
(3)将上述步骤(1)和步骤(2)制备得到的两颗粒部分与任选的辅料组合。
其中,步骤(1)的HMG-CoA还原酶抑制剂颗粒部分可以用水作为溶剂进行制粒,步骤(2)的海泽麦布颗粒部分可以用水、有机溶剂或它们的混合物进行制粒;优选地,步骤(2)的海泽麦布颗粒部分可以用水、醇、氯仿、丙酮、乙腈或类似溶剂、以及它们的混合物进行制粒,优选用水、醇或它们的混合物进行制粒,更优选用醇和水的混合物进行制粒,最优选用乙醇和水的混合物进行制粒。
本发明的技术方案之六是:提供了一种含有海泽麦布和阿托伐他汀的药物组合物的制备方法,包括以下步骤:
(1)将阿托伐他汀与任选的辅料制成颗粒;
(2)将海泽麦布与任选的辅料制成颗粒;
(3)将上述步骤(1)和步骤(2)制备得到的两颗粒部分与任选的辅料混合均匀。
优选地,该制备方法包括以下步骤:
(1)将阿托伐他汀和乳糖、微晶纤维素、碳酸钙以及交联羧甲基纤维素钠混合均匀;
(2)将羟丙基纤维素溶于水中;
(3)将步骤(2)得到的羟丙基纤维素溶液加入步骤(1)得到的混合物中进行制粒,烘干,整粒;
(4)将海泽麦布和乳糖、微晶纤维素、十二烷基硫酸钠以及交联羧甲基纤维素钠混合均匀;
(5)将聚维酮溶于水中,备用;
(6)将步骤(5)得到的聚维酮溶液加入步骤(4)得到的混合物中进行制粒,烘干,整粒;
(7)将步骤(3)和步骤(6)整粒后的颗粒任选地与交联羧甲基纤维素钠混合均匀,然后任选地与硬脂酸镁混合均匀,压片。
本发明的技术方案之七是:提供了另一种含有海泽麦布和阿托伐他汀的药物组合物的制备方法,包括以下步骤:
(1)将阿托伐他汀与任选的辅料制成颗粒;
(2)将海泽麦布与任选的辅料制成颗粒;
(3)将上述步骤(1)制备得到的颗粒与任选的辅料混合均匀,得到第一总混颗粒;
(4)将上述步骤(2)制备得到的颗粒与任选的辅料混合均匀,得到第二总混颗粒;
(5)将上述步骤(3)、步骤(4)得到的第一总混颗粒与第二总混颗粒压制成双层片。
优选地,该制备方法包括以下步骤:
(1)将阿托伐他汀和乳糖、微晶纤维素、碳酸钙以及交联羧甲基纤维素钠混合均匀;
(2)将聚山梨酯、羟丙基纤维素溶于水中;
(3)将步骤(2)得到的溶液加入步骤(1)得到的混合物中进行制粒,烘干,整粒;
(4)将乳糖、微晶纤维素、十二烷基硫酸钠以及交联聚维酮混合均匀;
(5)将海泽麦布、丁羟甲苯、聚维酮溶于乙醇溶液中;
(6)将步骤(5)得到的溶液加入步骤(4)得到的混合物中进行制粒,烘干,整粒;
(7)将步骤(3)整粒后的颗粒任选地与交联羧甲基纤维素钠混合均匀,然后任选地与硬脂酸镁混合均匀,得到第一总混颗粒;
(8)将步骤(6)整粒后的颗粒任选地与交联羧甲基纤维素钠混合均匀,然后任选地与硬脂酸镁混合均匀,得到第二总混颗粒;
(9)将步骤(7)与步骤(8)得到的第一总混颗粒与第二总混颗粒压制成双层片。
本发明的技术方案之八是:提供了一种含有海泽麦布和瑞舒伐他汀的药物组合物的制备方法,包括以下步骤:
(1)将瑞舒伐他汀与任选的辅料制成颗粒;
(2)将海泽麦布与任选的辅料制成颗粒;
(3)将上述步骤(1)和步骤(2)制备得到的颗粒与任选的辅料混合均匀。
优选地,该制备方法,包括以下步骤:
(1)将瑞舒伐他汀和乳糖、微晶纤维素、碳酸钙以及交联聚维酮混合均匀;
(2)将聚维酮溶于水中;
(3)将步骤(2)得到的聚维酮溶液加入步骤(1)得到的混合物中进行制粒,烘干,整粒;
(4)将乳糖、微晶纤维素、十二烷基硫酸钠以及交联聚维酮混合均匀;
(5)将海泽麦布、聚维酮溶于乙醇溶液中;
(6)将步骤(5)所得溶液加入步骤(4)得到的混合物中进行制粒,烘干,整粒;
(7)将步骤(3)和步骤(6)整粒后的颗粒混合,再任选地与交联聚维酮混合均匀,然后任选地与硬脂酸镁混合均匀,压片。
优选地,该制备方法,包括以下步骤:
(1)将瑞舒伐他汀和乳糖、微晶纤维素、碳酸钙以及交联聚维酮混合均匀;
(2)将聚维酮溶于水中;
(3)将步骤(2)得到的聚维酮溶液加入步骤(1)的混合物中进行制粒,烘干,整粒;
(4)将乳糖、微晶纤维素、十二烷基硫酸钠以及交联聚维酮混合均匀;
(5)将海泽麦布、丁羟甲苯、聚维酮溶于乙醇溶液中;
(6)将步骤(5)所得溶液加入步骤(4)得到的混合物中进行制粒,烘干,整粒;
(7)将步骤(3)和步骤(6)整粒后的颗粒混合,再任选地与交联聚维酮混合均匀,然后任选地与硬脂酸镁混合均匀,压片。
本发明的技术方案之九是:提供了一种含有海泽麦布和瑞舒伐他汀的药物组合物的制备方法,包括以下步骤:
(1)将瑞舒伐他汀与任选的辅料制成颗粒;
(2)将海泽麦布与任选的辅料制成颗粒;
(3)将上述步骤(1)制备得到的颗粒与任选的辅料混合均匀,得到第一总混颗粒;
(4)将上述步骤(2)制备得到的颗粒与任选的辅料混合均匀,得到第二总混颗粒;
(5)将上述步骤(3)、步骤(4)得到的第一总混颗粒与第二总混颗粒压制成双层片。
优选地,该制备方法包括以下步骤:
(1)将瑞舒伐他汀和乳糖、微晶纤维素、碳酸钙以及交联聚维酮混合均匀;
(2)将聚维酮溶于水中;
(3)将步骤(2)得到的聚维酮溶液加入步骤(1)得到的混合物中进行制粒,烘干,整粒;
(4)将乳糖、微晶纤维素、十二烷基硫酸钠以及交联聚维酮混合均匀;
(5)将海泽麦布、丁羟甲苯、聚维酮溶于乙醇溶液中;
(6)将步骤(5)所得溶液加入步骤(4)得到的混合物中进行制粒,烘干,整粒;
(7)将步骤(3)整粒后的颗粒任选地与交联聚维酮混合均匀,然后任选地与硬脂酸镁混合均匀,得到第一总混颗粒;
(8)将步骤(6)整粒后的颗粒任选地与交联聚维酮混合均匀,然后任选地与硬脂酸镁混合均匀,得到第二总混颗粒;
(9)将步骤(7)与步骤(8)所得的第一总混颗粒与第二总混颗粒压制成双层片。
本发明的技术方案之十是:提供了一种药物剂量单元,其中含有5~20mg的海泽麦布和5~80mg的阿托伐他汀。优选地,所述海泽麦布的剂量是5mg、10mg或20mg;和所述阿托伐他汀的剂量为5mg、10mg、20mg、40mg或80mg。优选地,该药物剂量单元是一种口服剂量单元。
本方案的一个方面,该剂量单元可以任选地含有碳酸钙作为一种组分。优选地,所述剂量单元可以含5~100mg的碳酸钙。
本方案的另一个方面,该剂量单元可以任选地含有碳酸钙、丁羟甲苯作为组分。优选地,所述剂量单元可以含5~100mg的碳酸钙、0.01~0.2mg的丁羟甲苯。
在本方案的一个方面,该剂量单元可以任选地含有十二烷基硫酸钠作为组分。优选地,该剂量单元可以含有0.5~5mg的十二烷基硫酸钠。
本方案的另一个方面,该剂量单元可以任选地含有十二烷基硫酸钠、聚山梨酯作为组分。优选地,所述剂量单元可以含0.5~5mg的十二烷基硫酸钠,0.1~5mg的聚山梨酯。
在本方案的另一个方面,该剂量单元中还可以含有1~50mg的交联羧甲基纤维素钠,20~250mg的微晶纤维素,0.5~10mg的聚维酮,0.5~10mg的羟丙基纤维素,10~250mg的乳糖,0.1~10mg硬脂酸镁。
在本方案的另一个方面,该剂量单元中还可以含有1~50mg的交联羧甲基纤维素钠,1~30mg的交联聚维酮,20~250mg的微晶纤维素,0.5~10mg的聚维酮,0.5~10mg的羟丙基纤维素,10~250mg的乳糖,0.1~10mg硬脂酸镁。
本发明的技术方案之十一是:提供了一种药物剂量单元,其中含有5~20mg的海泽麦布和5~80mg的瑞舒伐他汀,优选地,所述海泽麦布的剂量是5mg、10mg或20mg;和所述瑞舒伐他汀的剂量为5mg、10mg、20mg或40mg。优选地,该药物剂量单元是一种口服剂量单元。
本方案的一个方面,该剂量单元可以任选地含有碳酸钙作为组分。优选地,所述剂量单元可以含1~50mg的碳酸钙。
本方案的一个方面,该剂量单元可以任选地含有碳酸钙、丁羟甲苯作为组分。优选地,所述剂量单元可以含1~50mg的碳酸钙,0.01~0.2mg的丁羟甲苯。
在本方案的另一个方面,该剂量单元可以任选地含有十二烷基硫酸钠作为组分。优选地,该剂量单元可以含有0.5~10mg的十二烷基硫酸钠。
在本方案的另一个方面,该剂量单元中还可以含有5~40mg的交联聚维酮,20~250mg的微晶纤维素,1~20mg的聚维酮,20~250mg的乳糖,0.1~5mg硬脂酸镁。
在本发明中,聚维酮优选为聚维酮K30。
本发明所述的药物组合物或药物剂量单元可以是胶囊剂、片剂、颗粒剂、散剂、溶液剂或锭剂等多种剂型。
本发明所述的海泽麦布和HMG-CoA还原酶抑制剂的组合物可以是多种形式,例如片剂,本发明的组方设计合理,易于制成合适的制剂,且制剂稳定性好,质量可控。
与现有技术相比,本发明所涉及的含有海泽麦布和HMG-CoA还原酶抑制剂的药物组合物具有如下优点:
(1)本发明将海泽麦布与HMG-CoA还原酶抑制剂联用,特别是当HMG-CoA还原酶抑制剂为他汀类药物时,具有良好的药效协同作用。可以通过降低他汀类药物的剂量而减少心肌毒性的发生以及心血管事件的发生率,具有重要的临床获益价值。
(2)本发明提供的药物组合物不仅通过协同增效降低他汀类药物的给药剂量来减少不良反应,较同类机制药物与他汀类药物的复方相比具有更高的安全性,临床不良反应更少,患者的服药依从性也更好。
(3)本发明提供的药物组合物性质稳定,制成的制剂产品可采用普通包装即可达到稳定贮藏的要求。
(4)本发明所述的药物组合物中可以使用种类较少的辅料,且所述辅料可以均为常用辅料,制得的制剂质量可控,稳定性好。
(5)本发明所述的药物组合物的制备方法工艺简单,操作方便,适合工业化大生产。
在临床前的评价中,海泽麦布联合他汀类药物与依折麦布联合他汀类药物在药效上等效,但海泽麦布联合他汀类药物安全性明显较依折麦布联合他汀类药物更好,在临床应用中可具有更大的优势。
以下结合实施例对本发明进行详细说明,必须指出,以下实施例只用于说明本发明,而不是对本发明的限制。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
下述实施例所用的海泽麦布(HS-25)、依折麦布(Ezetimibe)、阿托伐他汀(atorvastatin)、瑞舒伐他汀(rosuvastatin)和辛伐他汀(simvastatin)来源于浙江海正药业股份有限公司,或参考现有技术的方法进行制备。
需要指出的是,下述实施例所用的阿托伐他汀、瑞舒伐他汀和辛伐他汀均为钙盐形式,其含量指的是阿托伐他汀、瑞舒伐他汀和辛伐他汀的含量;例如,在实施例1中,规格为5mg/10mg的海泽麦布阿托伐他汀片,其中10mg指的是阿托伐他汀的重量,若将处方中阿托伐他汀的重量换算为阿托伐他汀钙的重量,即为10.83mg。在实施例6中,规格为20mg/20mg的海泽麦布瑞舒伐他汀片,其中20mg指的是瑞舒伐他汀的重量,若将处方中瑞舒伐他汀的重量换算为瑞舒伐他汀钙的重量,即为20.83mg。
实施例1:海泽麦布阿托伐他汀片,规格:5mg/10mg,每片重92.25mg,组方见表1。
表1.实施例1的处方组成(单位:g)
制备方法:
(1)将处方量的阿托伐他汀和阿托伐他汀颗粒部分的乳糖、微晶纤维素、碳酸钙以及交联羧甲基纤维素钠混合均匀;
(2)将处方量的羟丙基纤维素溶于纯化水中,备用;
(3)将步骤(2)得到的羟丙基纤维素溶液加入步骤(1)得到的混合物中进行制粒,烘干,整粒,制得阿托伐他汀颗粒;
(4)将处方量的海泽麦布和海泽麦布颗粒部分的乳糖、微晶纤维素、十二烷基硫酸钠以及交联羧甲基纤维素钠混合均匀;
(5)将处方量的聚维酮K30溶于纯化水中,备用;
(6)将步骤(5)得到的聚维酮K30溶液加入步骤(4)得到的混合物中进行制粒,烘干,整粒,得海泽麦布颗粒;
(7)将步骤(3)和步骤(6)整粒后的颗粒以及外加部分的交联羧甲基纤维素钠混合均匀,然后向其中加入处方量的硬脂酸镁混合均匀,压片。
实施例2:海泽麦布阿托伐他汀片,规格:5mg/20mg,每片重143.50mg,组方见表2。
表2.实施例2的处方组成(单位:g)
制备方法:同实施例1。
实施例3:海泽麦布阿托伐他汀片,规格:10mg/10mg,每片重133.25mg,组方见表3。
表3.实施例3的处方组成(单位:g)
制备方法:同实施例1。
实施例4:海泽麦布阿托伐他汀片,规格:10mg/20mg,每片重184.50mg,组方见表4。
表4.实施例4的处方组成(单位:g)
制备方法:同实施例1。
实施例5:海泽麦布阿托伐他汀片,规格:10mg/80mg,每片重492.00mg,组方见表5。
表5.实施例5的处方组成(单位:g)
制备方法:同实施例1。
实施例6:海泽麦布瑞舒伐他汀片,规格:20mg/20mg,每片重460.00mg,组方见表6。
表6.实施例6的处方组成(单位:g)
制备方法:
(1)将处方量的瑞舒伐他汀和瑞舒伐他汀颗粒部分的乳糖、微晶纤维素、碳酸钙以及交联聚维酮混合均匀;
(2)将瑞舒伐他汀颗粒部分的聚维酮K30溶于纯化水中;
(3)将步骤(2)得到的聚维酮K30溶液加入步骤(1)得到的混合物中进行制粒,烘干,整粒,制得瑞舒伐他汀颗粒;
(4)将海泽麦布颗粒部分的乳糖、微晶纤维素、十二烷基硫酸钠以及交联聚维酮混合均匀;
(5)将处方量的海泽麦布和海泽麦布颗粒部分的聚维酮K30溶于乙醇溶液中;
(6)将步骤(5)得到的溶液加入步骤(4)得到的混合物中进行制粒,烘干,整粒,制得海泽麦布颗粒;
(7)将步骤(3)整粒后的颗粒与步骤(6)整粒后的颗粒混合,再与外加部分的交联聚维酮混合均匀,然后向其中加入处方量的硬脂酸镁混合均匀,压片。
实施例7:海泽麦布瑞舒伐他汀片,规格:10mg/20mg,每片重297.00mg,组方见表7。
表7.实施例7的处方组成(单位:g)
制备方法:同实施例6。
实施例8:海泽麦布瑞舒伐他汀片,规格:20mg/10mg,每片重393.00mg,组方见表8。
表8.实施例8的处方组成(单位:g)
制备方法:同实施例6。
实施例9:海泽麦布瑞舒伐他汀片,规格:10mg/10mg,每片重230.00mg,组方见表9。
表9.实施例9的处方组成(单位:g)
制备方法:同实施例6。
实施例10:海泽麦布辛伐他汀片,规格:6mg/20mg,每片重100.00mg,组方见表10。
表10.实施例10的处方组成(单位:g)
海泽麦布 | 6 |
辛伐他汀 | 20 |
乳糖 | 48.54 |
微晶纤维素 | 16.185 |
交联聚维酮 | 3 |
聚维酮K30 | 5 |
丁羟茴醚 | 0.025 |
枸橼酸 | 0.25 |
硬脂酸镁 | 1 |
30%乙醇溶液 | 适量 |
合计 | 1000片 |
制备方法:
(1)将丁羟茴醚、枸橼酸溶于适量30%乙醇溶液中;
(2)按处方量称取海泽麦布、辛伐他汀、微晶纤维素、乳糖、聚维酮K30、交联聚维酮,过40目筛,并将上述过筛后的原辅料混合均匀;
(3)将步骤(1)得到的溶液加入步骤(2)得到的混合物中,进行制粒;
(4)将湿颗粒烘干、整粒;
(5)向其中加入硬脂酸镁混合,压片。
实施例11:海泽麦布阿托伐他汀片稳定性研究(5mg/10mg规格)
方法一:将实施例1制备得到的片剂,包装于高密度聚乙烯瓶装中(内含2g干燥剂),放置于温度40℃±2℃、湿度(RH)75%±5%条件下,进行稳定性研究,试验结果见表11:
表11.海泽麦布阿托伐他汀片(5mg/10mg规格)的稳定性数据
结果显示,在储存条件为40℃±2℃、RH75%±5%放置6个月后,海泽麦布阿托伐他汀片(5mg/10mg)的含量和溶出度无明显变化,杂质仅略有增长,表明样品较为稳定。
方法二:将实施例1制备得到的片剂,包装于高密度聚乙烯瓶装中(内含2g干燥剂),放置于温度25℃±2℃、湿度60%±5%条件下,进行稳定性研究,试验结果见表12:
表12.海泽麦布阿托伐他汀片(5mg/10mg规格)的稳定性数据
结果显示,在储存条件为25℃±2℃、RH60%±5%放置24个月后,海泽麦布阿托伐他汀片(5mg/10mg)的含量和溶出度无明显变化,杂质仅略有增长,表明样品较为稳定。
实施例12:海泽麦布阿托伐他汀片稳定性研究(5mg/20mg规格)
方法一:将实施例2制备得到的片剂,包装于高密度聚乙烯瓶装中(内含 2g干燥剂),放置于温度40℃±2℃、湿度75%±5%条件下,进行稳定性研究,试验结果见表13:
表13.海泽麦布阿托伐他汀片(5mg/20mg规格)的稳定性数据
结果显示,在储存条件为40℃±2℃、RH75%±5%放置6个月后,海泽麦布阿托伐他汀片(5mg/20mg)的各项检测指标均无明显变化,表明样品较为稳定。
方法二:将实施例2制备得到的片剂,包装于高密度聚乙烯瓶装中(内含2g干燥剂),放置于温度25℃±2℃、湿度60%±5%条件下,进行稳定性研究,试验结果见表14:
表14.海泽麦布阿托伐他汀片(5mg/20mg规格)的稳定性数据
结果显示,在储存条件为25℃±2℃、RH60%±5%放置24个月后,海泽麦布阿托伐他汀片(5mg/20mg)的含量和溶出度无明显变化,杂质仅略有增长,表明样品较为稳定。
实施例13:海泽麦布阿托伐他汀片稳定性研究(10mg/10mg规格)
方法一:将实施例3制备得到的片剂,包装于高密度聚乙烯瓶装中(内含2g干燥剂),放置于40℃±2℃、RH75%±5%条件下,进行稳定性研究,试验结果见表15:
表15.海泽麦布阿托伐他汀片(10mg/10mg规格)的稳定性数据
结果显示,在储存条件为40℃±2℃、RH75%±5%放置6个月后,海泽麦布阿托伐他汀片(10mg/10mg)的各项检测指标均无明显变化,表明样品较为稳定。
方法二:将实施例3制备得到的片剂,包装于高密度聚乙烯瓶装中(内含2g干燥剂),放置于25℃±2℃、湿度60%±5%条件下,进行稳定性研究,试验结果见表16:
表16.海泽麦布阿托伐他汀片(10mg/10mg规格)的稳定性数据
结果显示,在储存条件为25℃±2℃、RH60%±5%放置24个月后,海泽麦布阿托伐他汀片(10mg/10mg)的含量和溶出度无明显变化,杂质仅略有增长,表明样品较为稳定。
实施例14:海泽麦布阿托伐他汀片稳定性研究(10mg/20mg规格)
方法一:将实施例4制备的片剂,包装于高密度聚乙烯瓶装中(内含2g干燥剂),放置于40℃±2℃、RH75%±5%条件下,进行稳定性研究,结果见表17:
表17.海泽麦布阿托伐他汀片(10mg/20mg规格)的稳定性数据
结果显示,在储存条件为40℃±2℃、RH75%±5%放置6个月后,海泽麦布阿托伐他汀片(10mg/20mg)的含量和溶出度无明显变化,杂质仅略有增长,表明样品较为稳定。
方法二:将实施例4制备的片剂,包装于高密度聚乙烯瓶装中(内含2g干燥剂),放置于25℃±2℃、湿度60%±5%条件下,进行稳定性研究,结果见表18:
表18.海泽麦布阿托伐他汀片(10mg/20mg规格)的稳定性数据
结果显示,在储存条件为25℃±2℃、RH60%±5%放置24个月后,海泽麦布阿托伐他汀片(10mg/20mg)的含量和溶出度无明显变化,杂质仅略有增长,表明样品较为稳定。
实施例15:海泽麦布阿托伐他汀片稳定性研究(10mg/80mg规格)
将实施例5制备得到的片剂,包装于高密度聚乙烯瓶装中(内含2g干燥剂),放置于温度(40℃±2℃)、湿度(RH75%±5%)条件下,进行稳定性研究,结果见表19:
表19.海泽麦布阿托伐他汀片(10mg/80mg规格)的稳定性数据
结果显示,在储存条件为40℃±2℃、RH75%±5%放置3个月后,海泽麦布阿托伐他汀片(10mg/80mg)的各项检测指标均无明显变化,表明样品较为稳定。
实施例16:海泽麦布瑞舒伐他汀片稳定性研究(20/20mg)
将实施例6制备的片剂,裸片(无包装)放置于50℃、湿度75%条件下,进行稳定性研究,结果见表20:
表20.海泽麦布瑞舒伐他汀片(20mg/20mg规格)的稳定性数据
结果表明,在50℃、湿度75%条件下放置10天后,海泽麦布瑞舒伐他汀片的含量,有关物质以及溶出度基本无变化,表明样品稳定,质量可控。
实施例17:海泽麦布辛伐他汀片稳定性研究(6mg/20mg规格)
将实施例10制备得到的片剂,不带包装,分别放置于高温(60℃)、高湿(湿度92.5%,25℃)、强光(4500Lx±500Lx)条件下,进行稳定性研究,测得的稳定性数据见表21:
表21.海泽麦布辛伐他汀片(6mg/20mg规格)的稳定性数据
结果表明,在各条件下放置20天后,海泽麦布辛伐他汀片的含量基本无变化,有关物质略有增长,表明样品稳定,质量可控。
实施例18:海泽麦布与辛伐他汀联用药效学研究
选用原发性高血脂症恒河猴(血脂指标为:TC>6.22mmol/L,LDL>4.91mmol/L,HDL<1.55mmol/L,TG>1.0mmol/L),外加高脂饲料诱导血脂水平持续稳定至少2周后(见给药前数据),经口水果诱导给予海泽麦布(即HS-25)或联合辛伐他汀,并用依折麦布对照,连续经口给药4周,观察单药及联合辛伐他汀对血脂的影响。实验分组及检测指标如表22:
表22.HS-25/依折麦布联合辛伐他汀药效学方案
试验结果显示:
HS-25和依折麦布单用或联合辛伐他汀对高血脂恒河猴的体重、血生化、血常规、血糖未见明显影响,未见异常临床表现。
所有给药组血脂指标的改善主要体现在TC和LDL,其他指标如TG、HDL、APoA1无明显改善。HS-25联合辛伐他汀与依折麦布联合辛伐他汀药效基本一致。实验数据见表23和表24:
对TC的影响(见表23):
辛伐他汀单用具有降低TC的作用,与模型组比较,P<0.05,说明具有统计学差异。
HS-25单用组和依折麦布单用组具有显著降低TC的作用,优于辛伐他汀单用组,与模型组比较,P<0.01,说明具有显著的统计学差异。药效作用随给药时间逐渐增强,提示HS-25和依折麦布对TC的降低具有一定的持久性。
HS-25和依折麦布分别与辛伐他汀联用后,对TC的降低作用优于HS-25单用组、依折麦布单用组及辛伐他汀单用组。主要体现在给药后1周,TC的降低较单药更快;TC的最大降低百分比(给药后4周)更大。
对LDL的影响(见表24):
HS-25和依折麦布单用或联合阿托伐他汀对LDL的影响,与TC一致。
表23.HS-25和依折麦布单用或联合辛伐他汀对模型动物TC的影响(mmol/L和%)
表24.HS-25和依折麦布单用或联合辛伐他汀对模型动物LDL的影响(mmol/L和%)
实施例19:海泽麦布与阿托伐他汀联用药效学
选用原发性高血脂症恒河猴动物模型(血脂指标为:TC>6.22mmol/L,LDL>4.91mmol/L,HDL<1.55mmol/L,TG>1.0mmol/L),外加高脂饲料诱导, 高血脂水平持续稳定后,经口给予阿托伐他汀或者分别联合海泽麦布(HS-25)或依折麦布动物连续给药3个月,观察HS-25和依折麦布联合阿托伐他汀对血脂的影响。实验分组及检测指标如表25:
表25.HS-25/依折麦布联合阿托伐他汀药效学方案
试验结果显示:
阿托伐他汀单用或者阿托伐他汀联合HS-25或依折麦布对恒河猴体重、血生化、血常规和血糖未见明显影响,未见异常临床表现。
所有给药组的血脂指标的改善主要体现在TC和LDL,其他指标如TG、HDL、APoA1、APoB无明显改变。实验数据如表26和表27:
对TC的影响(表26):
各给药组在给药30天时药效达到平台期,继续给药未见TC进一步降低。由于动物数偏少,模型组动物的TC有一定的波动,因此总体上,阿托伐他汀单用组的降低TC作用基本在25%,两个联用组降低TC百分率在50%左右,显著优于阿托伐他汀单用组。
模型组TC含量在试验期间相对比较稳定,未见明显波动,证明本模型较为稳定。
对LDL的影响(表27)
阿托伐他汀单用或阿托伐他汀联合HS-25或依折麦布对LDL的趋势与TC一致。
表26.阿托伐他汀单用或联合HS-25和依折麦布给药90天后对高血脂症恒河猴血清TC的影响(mmol/L,%)
表27.阿托伐他汀单用或联合HS-25和依折麦布给药90天后对高血脂症恒河猴血清LDL的影响(mmol/L,%)
实施例20:海泽麦布联合阿托伐他汀在比格犬的重复给药毒性研究
SPF级6-9月龄的正常比格犬,雌雄各半,分为溶媒组、阿托伐单用组和HS-25联合阿托伐他汀组,连续给药2周,观察阿托伐他汀单用或联合HS-25的毒性,分组及给药见表28:
表28.HS-25联合阿托伐他汀重复给药在比格犬的毒性试验方案
实验结果显示:
本次比格犬个别动物出现流涎,与阿托伐他汀有关。其他指标如体重、食量、心电图、血常规、大体解剖和病理学等未见异常;血脂的降低与阿托伐他汀具有一定的剂量相关性。
本次试验的毒性主要反映在血生化中的肝功:谷丙转氨酶(ALT)和谷草转氨酶(AST),ALT较AST更为敏感,两周的实验结果见表29:
表29.阿托伐他汀单用或HS-25联合阿托伐他汀重复给药在比格犬的毒性试验结果
依折麦布(Zetia)的文献资料(参见NDA 21-445 FDA review:Pharmacology Review(s)117-129)显示依折麦布协同阿托伐他汀在0.3/1mg/kg剂量时就出现肝毒性,并随阿托伐他汀的剂量增加,毒性增加;血脂指标与肝酶指标基本一致。3周实验数据见表30:
表30.阿托伐他汀单用或Zetia联合阿托伐他汀重复给药在比格犬的毒性试验结果
以上数据对比分析,两个实验的肝功在空白组及阿托伐他汀10mg/kg剂量的水平一致,提示数据具有可对比性。
对比结果显示,阿托伐他汀单用组10mg/kg未见明显毒性;阿托伐他汀单用组30mg/kg剂量发现ALT轻度升高。
HS-25联合阿托伐他汀的毒性仅表现为ALT的增加,AST未见异常;Zetia联合阿托伐他汀的毒性在3/10和30/10mg/kg时不仅ALT升高,AST也出现升高。
HS-25联合阿托伐他汀(30/10mg/kg)的毒性为ALT:112.8;Zetia联合阿托伐他汀(0.3/1mg/kg)的毒性为:ALT:112.8;提示HS-25联合阿托伐他汀的安全性至少是Zetia联合阿托伐他汀安全性的10倍。
另外,HS-25联合阿托伐他汀的毒性在30/10、100/10、100/30mg/kg分别为ALT:112.8、188.3、242.8,可见ALT的升高幅度较小;而Zetia联合阿托伐他汀的毒性在0.3/1、/3/1、3/10、30/10mg/kg分别为ALT:雌性112.8、156.3、990.3、657.0;雄性88.8、106.3、391.5、1133.5,可见ALT随剂量增加而升高幅度显著更大,提示肝毒性更明显。
综上提示,HS-25和阿托伐他汀的复方较Zetia和阿托伐他汀的复方明显更安全,安全倍数在比格犬约为10倍。
实施例21:海泽麦布阿托伐他汀片,规格:20mg/20mg,每片重480mg,组方见表31。
表31.实施例21的处方组成(单位:g)
制备方法:
(1)将处方量的阿托伐他汀和阿托伐他汀颗粒部分的乳糖、微晶纤维素、碳酸钙以及交联羧甲基纤维素钠混合均匀;
(2)将处方量的聚山梨酯、羟丙基纤维素溶于纯化水中;
(3)将步骤(2)得到的溶液加入步骤(1)得到的混合物中进行制粒,烘干,整粒,制得阿托伐他汀颗粒;
(4)将海泽麦布颗粒部分的乳糖、微晶纤维素、十二烷基硫酸钠以及交联聚维酮混合均匀;
(5)将处方量的海泽麦布、丁羟甲苯、聚维酮K30溶于乙醇溶液中;
(6)将步骤(5)得到的溶液加入步骤(4)得到的混合物中进行制粒,烘干,整粒,制得海泽麦布颗粒;
(7)将步骤(3)整粒后的颗粒与阿托伐他汀颗粒外加部分的交联羧甲基纤维素钠混合均匀,然后向其中加入硬脂酸镁混合均匀;
(8)将步骤(6)整粒后的颗粒与海泽麦布颗粒外加部分的交联羧甲基纤维素钠混合均匀,然后向其中加入硬脂酸镁混合均匀;
(9)将步骤(7)与步骤(8)得到的颗粒压制成双层片。
实施例22:海泽麦布阿托伐他汀片,规格:20mg/10mg,每片重480mg,组方见表32。
表32.实施例22的处方组成(单位:g)
制备方法:同实施例21。
实施例23:海泽麦布阿托伐他汀片,规格:10mg/20mg,每片重315mg,组方见表33。
表33.实施例23的处方组成(单位:g)
制备方法:同实施例21。
实施例24:海泽麦布阿托伐他汀片,规格:10mg/10mg,每片重315mg,组方见表34。
表34.实施例24的处方组成(单位:g)
制备方法:同实施例21。
实施例25:海泽麦布瑞舒伐他汀片,规格:20mg/20mg,每片重460mg,组方见表35。
表35.实施例25的处方组成(单位:g)
制备方法:
(1)将处方量的瑞舒伐他汀和瑞舒伐他汀颗粒部分的乳糖、微晶纤维素、碳酸钙以及交联聚维酮混合均匀;
(2)将瑞舒伐他汀颗粒部分的聚维酮K30溶于纯化水中;
(3)将步骤(2)得到的聚维酮K30溶液加入步骤(1)得到的混合物中进行制粒,烘干,整粒,制得瑞舒伐他汀颗粒;
(4)将海泽麦布颗粒部分的乳糖、微晶纤维素、十二烷基硫酸钠以及交联聚维酮混合均匀;
(5)将处方量的海泽麦布、丁羟甲苯、海泽麦布颗粒部分的聚维酮K30溶于乙醇溶液中;
(6)将步骤(5)所得溶液加入步骤(4)得到的混合物中进行制粒,烘干,整粒,制得海泽麦布颗粒;
(7)将步骤(3)整粒后的颗粒与瑞舒伐他汀颗粒外加部分的交联聚维酮混合均匀,然后加入硬脂酸镁混合均匀;
(8)将步骤(6)整粒后的颗粒与海泽麦布颗粒外加部分的交联聚维酮混合均匀,然后加入硬脂酸镁混合均匀;
(9)将步骤(7)与步骤(8)所得的颗粒压制成双层片。
实施例26:海泽麦布瑞舒伐他汀片,规格:20mg/10mg,每片重460mg,组方见表36。
表36.实施例26的处方组成(单位:g)
制备方法:同实施例25。
实施例27:海泽麦布瑞舒伐他汀片,规格:10mg/20mg,每片重295mg,组方见表37。
表37.实施例27的处方组成(单位:g)
制备方法:同实施例25。
实施例28:海泽麦布瑞舒伐他汀片,规格:10mg/10mg,每片重295mg,组方见表38。
表38.实施例28的处方组成(单位:g)
制备方法:同实施例25。
实施例29:海泽麦布瑞舒伐他汀片,规格:20mg/20mg,每片重460mg,组方见表39。
表39.实施例29的处方组成(单位:g)
(1)将处方量的瑞舒伐他汀和瑞舒伐他汀颗粒部分的乳糖、微晶纤维素、碳酸钙以及交联聚维酮混合均匀;
(2)将瑞舒伐他汀颗粒部分的聚维酮K30溶于纯化水中;
(3)将步骤(2)得到的聚维酮K30溶液加入步骤(1)得到的混合物中进行制粒,烘干,整粒,制得瑞舒伐他汀颗粒;
(4)将海泽麦布颗粒部分的乳糖、微晶纤维素、十二烷基硫酸钠以及交联聚维酮混合均匀;
(5)将处方量的海泽麦布和海泽麦布颗粒部分的丁羟甲苯、聚维酮K30溶于乙醇溶液中;
(6)将步骤(5)所得溶液加入步骤(4)得到的混合物中进行制粒,烘干,整粒,制得海泽麦布颗粒;
(7)将步骤(3)整粒后的颗粒和步骤(6)整粒后的颗粒混合,再与外加部分的交联聚维酮混合均匀,然后加入处方量的硬脂酸镁混合均匀,压片。
实施例30:海泽麦布阿托伐他汀钙片稳定性研究(20mg/10mg规格)
将实施例22制备得到的片剂,用瓶包装后分别放置于加速条件下(40℃/75%RH),进行稳定性研究,测得的稳定性数据见表40:
表40.海泽麦布阿托伐他汀片(20mg/10mg规格)的稳定性数据
结果显示,在储存条件为40℃±2℃、RH75%±5%放置3个月后,海泽麦布阿托伐他汀片(20mg/10mg)的各项检测指标均无明显变化,表明样品较为稳定。
实施例31:海泽麦布阿托伐他汀片,规格:20mg/10mg,每片重480mg,组方见表41。
表41.实施例31的处方组成(单位:g)
制备方法:
(1)将处方量的阿托伐他汀和阿托伐他汀颗粒部分的乳糖、微晶纤维素、碳酸钙以及交联羧甲基纤维素钠混合均匀;
(2)将处方量的聚山梨酯、羟丙基纤维素溶于纯化水中;
(3)将步骤(2)得到的溶液加入步骤(1)得到的混合物中进行制粒,烘干,整粒,制得阿托伐他汀颗粒;
(4)将海泽麦布颗粒部分的乳糖、微晶纤维素、十二烷基硫酸钠以及交联聚维酮混合均匀;
(5)将处方量的海泽麦布、丁羟甲苯、聚维酮K30溶于异丙醇溶液中;
(6)将步骤(5)得到的溶液加入步骤(4)得到的混合物中进行制粒,烘干,整粒,制得海泽麦布颗粒;
(7)将步骤(3)整粒后的颗粒与阿托伐他汀颗粒外加部分的交联羧甲基纤维素钠混合均匀,然后向其中加入硬脂酸镁混合均匀;
(8)将步骤(6)整粒后的颗粒与海泽麦布颗粒外加部分的交联羧甲基纤维素钠混合均匀,然后向其中加入硬脂酸镁混合均匀;
(9)将步骤(7)与步骤(8)得到的颗粒压制成双层片。
实施例32:海泽麦布阿托伐他汀片,规格:20mg/20mg,每片重630mg,组方见表42。
表42.实施例32的处方组成(单位:g)
制备方法:同实施例31。
实施例33:海泽麦布阿托伐他汀片,规格:10mg/20mg,每片重465mg,组方见表43。
表43.实施例33的处方组成(单位:g)
制备方法:同实施例31。
实施例34:海泽麦布阿托伐他汀片稳定性研究(20mg/20mg规格)
方法一:将实施例21制备得到的片剂,采用双铝包装,放置于40℃±2℃、RH75%±5%条件下,进行稳定性研究,试验结果见表44:
表44.海泽麦布阿托伐他汀片(20mg/20mg规格)的稳定性数据
结果显示,在储存条件为40℃±2℃、RH75%±5%放置3个月后,海泽麦布阿托伐他汀片(20mg/10mg)的含量和溶出度无明显变化,杂质仅略有增长,表明样品较为稳定。
方法二:将实施例21制备得到的片剂,采用双铝包装,放置于25℃±2℃、湿度60%±5%条件下,进行稳定性研究,试验结果见表45:
表45.海泽麦布阿托伐他汀片(20mg/20mg规格)的稳定性数据
结果显示,在储存条件为25℃±2℃、RH60%±5%放置9个月后,海泽麦布阿托伐他汀片(20mg/20mg)的含量和溶出度无明显变化,杂质仅略有增长,表明样品较为稳定。
实施例35:海泽麦布阿托伐他汀片稳定性研究(20mg/10mg规格)
方法一:将实施例22制备得到的片剂,采用双铝包装,放置于40℃±2℃、RH75%±5%条件下,进行稳定性研究,试验结果见表46:
表46.海泽麦布阿托伐他汀片(20mg/10mg规格)的稳定性数据
结果显示,在储存条件为40℃±2℃、RH75%±5%放置3个月后,海泽麦布阿托伐他汀片(20mg/10mg)的含量和溶出度无明显变化,杂质仅略有增长,表明样品较为稳定。
方法二:将实施例22制备得到的片剂,采用双铝包装,放置于25℃±2℃、湿度60%±5%条件下,进行稳定性研究,试验结果见表47:
表47.海泽麦布阿托伐他汀片(20mg/10mg规格)的稳定性数据
结果显示,在储存条件为25℃±2℃、RH60%±5%放置9个月后,海泽麦布阿托伐他汀片(20mg/10mg)的含量和溶出度无明显变化,杂质仅略有增长,表明样品较为稳定。
实施例36:海泽麦布阿托伐他汀片稳定性研究(10mg/20mg规格)
方法一:将实施例23制备得到的片剂,采用双铝包装,放置于40℃±2℃、RH75%±5%条件下,进行稳定性研究,试验结果见表48:
表48.海泽麦布阿托伐他汀片(10mg/20mg规格)的稳定性数据
结果显示,在储存条件为40℃±2℃、RH75%±5%放置3个月后,海泽麦布阿托伐他汀片(10mg/20mg)的含量和溶出度无明显变化,杂质仅略有增长,表明样品较为稳定。
方法二:将实施例23制备得到的片剂,采用双铝包装,放置于25℃±2℃、湿度60%±5%条件下,进行稳定性研究,试验结果见表49:
表49.海泽麦布阿托伐他汀片(10mg/20mg规格)的稳定性数据
结果显示,在储存条件为25℃±2℃、RH60%±5%放置9个月后,海泽麦布阿托伐他汀片(10mg/20mg)的含量和溶出度无明显变化,杂质仅略有增长,表明样品较为稳定。
实施例37:海泽麦布阿托伐他汀片稳定性研究(10mg/10mg规格)
方法一:将实施例24制备得到的片剂,采用双铝包装,放置于40℃±2℃、RH75%±5%条件下,进行稳定性研究,试验结果见表50:
表50海泽麦布阿托伐他汀片(10mg/10mg规格)的稳定性数据
结果显示,在储存条件为40℃±2℃、RH75%±5%放置3个月后,海泽麦布阿托伐他汀片(10mg/10mg)的含量和溶出度无明显变化,杂质仅略有增长,表明样品较为稳定。
方法二:将实施例24制备得到的片剂,采用双铝包装,放置于25℃±2℃、湿度60%±5%条件下,进行稳定性研究,试验结果见表51:
表51.海泽麦布阿托伐他汀片(10mg/10mg规格)的稳定性数据
结果显示,在储存条件为25℃±2℃、RH60%±5%放置9个月后,海泽麦布阿托伐他汀片(10mg/10mg)的含量和溶出度无明显变化,杂质仅略有增长,表明样品较为稳定。
实施例38:海泽麦布瑞舒伐他汀片,规格:20mg/10mg,每片重320mg,组方见表52。
表52.实施例38的处方组成(单位:g)
(1)将处方量的瑞舒伐他汀和瑞舒伐他汀颗粒部分的乳糖、微晶纤维素、碳酸钙以及交联聚维酮混合均匀;
(2)将瑞舒伐他汀颗粒部分的聚维酮K30溶于纯化水中;
(3)将步骤(2)得到的聚维酮K30溶液加入步骤(1)得到的混合物中进行制粒,烘干,整粒,制得瑞舒伐他汀颗粒;
(4)将海泽麦布颗粒部分的乳糖、微晶纤维素、十二烷基硫酸钠以及交联聚维酮混合均匀;
(5)将处方量的海泽麦布和海泽麦布颗粒部分的丁羟甲苯、聚维酮K30溶于乙醇溶液中;
(6)将步骤(5)所得溶液加入步骤(4)得到的混合物中进行制粒,烘干,整粒,制得海泽麦布颗粒;
(7)将步骤(3)整粒后的颗粒和步骤(6)整粒后的颗粒混合,然后向其中加入处方量的硬脂酸镁混合均匀,压片。
实施例39:海泽麦布瑞舒伐他汀片,规格:20mg/5mg,每片重270mg,组方见表53。
表53.实施例38的处方组成(单位:g)
制备方法:同实施例38。
Claims (43)
- 一种药物组合物,其中含有:(a)0.5~20%重量的海泽麦布;(b)1~80%重量的至少一种HMG-CoA还原酶抑制剂。
- 根据权利要求1所述的药物组合物,其中所述HMG-CoA还原酶抑制剂是他汀类药物或其盐。
- 根据权利要求2所述的药物组合物,其中所述他汀类药物是选自洛伐他汀、辛伐他汀、阿托伐他汀、普伐他汀、罗苏伐他汀、氟伐他汀、西立伐他汀、匹伐他汀和瑞舒伐他汀或其盐中的一种或多种。
- 根据权利要求3所述的药物组合物,其中所述他汀类药物为阿托伐他汀。
- 根据权利要求3所述的药物组合物,其中所述他汀类药物为瑞舒伐他汀。
- 根据权利要求3所述的药物组合物,其中所述他汀类药物为辛伐他汀。
- 根据权利要求1~6中任一项所述的药物组合物,其进一步含有稳定剂、表面活性剂、填充剂、粘合剂、崩解剂和润滑剂中的一种或多种辅料;优选地,所述稳定剂为碳酸钙、丁羟茴醚、枸橼酸、丁羟甲苯中的至少一种,所述表面活性剂为十二烷基硫酸钠,聚山梨酯中的至少一种,所述填充剂为乳糖、微晶纤维素、预胶化淀粉中的至少一种,所述粘合剂为羟丙基纤维素、聚维酮中的至少一种,所述崩解剂为交联羧甲基纤维素钠、交联聚维酮中的至少一种,所述的润滑剂为硬脂酸镁、滑石粉中的至少一种;更优选地,所述组合物含有1~25%重量的碳酸钙,0.005~0.1%重量的丁羟甲苯,0.1~10%重量的十二烷基硫酸钠,0.05~1.0%重量的聚山梨酯,1~10%重量的交联羧甲基纤维素钠,1~10%重量的交联聚维酮,10~50%重量的微晶纤维素,0.1~5%重量的聚维酮,0.1~5%重量的羟丙基纤维素,10~50%重量的乳糖,0.1~2%重量的硬脂酸镁中的一种或多种。
- 根据权利要求4所述的药物组合物,其中含有1~10%重量的海泽麦布和1~30%重量的阿托伐他汀。
- 根据权利要求4或8所述的药物组合物,其中还含有稳定剂,优选地,所述稳定剂为碳酸钙、丁羟甲苯中的至少一种,更优选地,所述稳定剂为5~25%重量的碳酸钙、0.005~0.05%重量的丁羟甲苯中的至少一种。
- 根据权利要求4或8所述的药物组合物,其中还含有表面活性剂,优选地,所述表面活性剂为十二烷基硫酸钠、聚山梨酯中的至少一种,更优选地,所述表面活性剂为0.1~5%重量的十二烷基硫酸钠、0.05~0.5%重量的聚山梨酯中的至少一种。
- 根据权利要求4或8所述的药物组合物,其中还含有填充剂、粘合剂、崩解剂和润滑剂中的一种或多种;优选地,所述填充剂为乳糖、微晶纤维素中的至少一种,所述粘合剂为羟丙基纤维素、聚维酮中的至少一种,所述崩解剂为交联羧甲基纤维素钠、交联聚维酮中的至少一种,所述润滑剂为硬脂酸镁;更优选地,所述药物组合物含有1~10%重量的交联羧甲基纤维素钠,1~10%重量的交联聚维酮,10~50%重量的微晶纤维素,0.1~5%重量的聚维酮,0.1~5%重量的羟丙基纤维素,10~50%重量的乳糖,0.1~2%重量的硬脂酸镁中的一种或多种。
- 根据权利要求5所述的药物组合物,其中含有1~10%重量的海泽麦布,1~30%重量的瑞舒伐他汀。
- 根据权利要求5或12所述的药物组合物,其中还含有稳定剂,优选地,所述稳定剂为碳酸钙、丁羟甲苯中的至少一种,更优选地,所述稳定剂为1~15%重量的碳酸钙,0.005~0.05%重量的丁羟甲苯中的至少一种。
- 根据权利要求5或12所述的药物组合物,其中还含有表面活性剂,优选地,所述表面活性剂为十二烷基硫酸钠,更优选地,所述药物组合物含有0.1~6%重量的十二烷基硫酸钠。
- 根据权利要求5或12所述的药物组合物,其中还含有填充剂、粘合剂、崩解剂和润滑剂中的一种或多种;优选地,所述填充剂为乳糖、微晶纤维素中的至少一种,所述粘合剂为羟丙基纤维素、聚维酮中的至少一种,所述崩解剂为交联羧甲基纤维素钠、交联聚维酮中的至少一种,所述的润滑剂为硬脂酸镁;更优选地,所述药物组合物含有1~10%重量的交联聚维酮,10~50%重量的微晶纤维素,0.1~5%重量的聚维酮,10~50%重量的乳糖,0.1~2%重量的硬脂酸镁中的一种或多种。
- 一种如权利要求1~15任一项所述的药物组合物的制备方法,包括将HMG-CoA还原酶抑制剂、海泽麦布与任选的辅料组合。
- 如权利要求16的制备方法,包括:(1)将HMG-CoA还原酶抑制剂与任选的辅料制成颗粒,得HMG-CoA还原酶抑制剂颗粒部分;(2)将海泽麦布与任选的辅料制成颗粒,得海泽麦布颗粒部分;(3)将上述步骤(1)和步骤(2)制备得到的颗粒与任选的辅料组合。
- 如权利要求17所述的制备方法,其中,步骤(1)的HMG-CoA还原酶抑制剂颗粒部分是用水作为溶剂进行制粒得到的;步骤(2)的海泽麦布颗粒部分是用水、有机溶剂或它们的混合物进行制粒得到的。
- 如权利要求18所述的制备方法,其中,步骤(2)的海泽麦布颗粒部分是用水、醇、氯仿、丙酮、乙腈或类似溶剂、以及它们的混合物进行制粒得 到的,优选用水、醇以及它们的混合物进行制粒得到的,更优选用醇和水的混合物进行制粒得到的,最优选用乙醇和水的混合物进行制粒得到的。
- 如权利要求16~19任一项所述的药物组合物的制备方法,包括:(1)将阿托伐他汀与任选的辅料制成颗粒;(2)将海泽麦布与任选的辅料制成颗粒;(3)将上述步骤(1)和步骤(2)制备得到的颗粒与任选的辅料混合均匀。
- 如权利要20所述的药物组合物的制备方法,包括:(1)将阿托伐他汀和乳糖、微晶纤维素、碳酸钙以及交联羧甲基纤维素钠混合均匀;(2)将羟丙基纤维素溶于水中;(3)将步骤(2)得到的羟丙基纤维素溶液加入步骤(1)得到的混合物中进行制粒,烘干,整粒;(4)将海泽麦布和乳糖、微晶纤维素、十二烷基硫酸钠以及交联羧甲基纤维素钠混合均匀;(5)将聚维酮溶于水中;(6)将步骤(5)得到的聚维酮溶液加入步骤(4)得到的混合物中进行制粒,烘干,整粒;(7)将步骤(3)和步骤(6)整粒后的颗粒任选地与交联羧甲基纤维素钠混合均匀,然后任选地与硬脂酸镁混合均匀,压片。
- 如权利要求16~19任一项所述的药物组合物的制备方法,包括:(1)将阿托伐他汀与任选的辅料制成颗粒;(2)将海泽麦布与任选的辅料制成颗粒;(3)将上述步骤(1)制备得到的颗粒与任选的辅料混合均匀,得到第一总混颗粒;(4)将上述步骤(2)制备得到的颗粒与任选的辅料混合均匀,得到第二总混颗粒;(5)将上述步骤(3)、步骤(4)得到的第一总混颗粒和第二总混颗粒压制成双层片。
- 如权利要求22所述的药物组合物的制备方法,包括:(1)将阿托伐他汀和乳糖、微晶纤维素、碳酸钙以及交联羧甲基纤维素钠混合均匀;(2)将聚山梨酯、羟丙基纤维素溶于水中;(3)将步骤(2)得到的溶液加入步骤(1)得到的混合物中进行制粒,烘干,整粒;(4)将乳糖、微晶纤维素、十二烷基硫酸钠以及交联聚维酮混合均匀;(5)将海泽麦布、丁羟甲苯、聚维酮溶于乙醇溶液中;(6)将步骤(5)得到的溶液加入步骤(4)得到的混合物中进行制粒,烘干,整粒;(7)将步骤(3)整粒后的颗粒任选地与交联羧甲基纤维素钠混合均匀,然后任选地与硬脂酸镁混合均匀,得到第一总混颗粒;(8)将步骤(6)整粒后的颗粒任选地与交联羧甲基纤维素钠混合均匀,然后任选地与硬脂酸镁混合均匀,得到第二总混颗粒;(9)将步骤(7)与步骤(8)得到的第一总混颗粒与第二总混颗粒压制成双层片。
- 如权利要求16~19任一项所述的药物组合物的制备方法,包括:(1)将瑞舒伐他汀与任选的辅料制成颗粒;(2)将海泽麦布与任选的辅料制成颗粒;(3)将上述步骤(1)和步骤(2)制备得到的颗粒与任选的辅料混合均匀。
- 如权利要求24所述的药物组合物的制备方法,包括:(1)将瑞舒伐他汀和乳糖、微晶纤维素、碳酸钙以及交联聚维酮混合均匀;(2)将聚维酮溶于水中;(3)将步骤(2)得到的聚维酮溶液加入步骤(1)得到的混合物中进行制粒,烘干,整粒;(4)将乳糖、微晶纤维素、十二烷基硫酸钠以及交联聚维酮混合均匀;(5)将海泽麦布、聚维酮溶于乙醇溶液中;(6)将步骤(5)所得溶液加入步骤(4)得到的混合物中进行制粒,烘干,整粒;(7)将步骤(3)和步骤(6)整粒后的颗粒混合,再任选地与交联聚维酮混合均匀,然后任选地与硬脂酸镁混合均匀,压片。
- 如权利要求24所述的药物组合物的制备方法,包括:(1)将瑞舒伐他汀和乳糖、微晶纤维素、碳酸钙以及交联聚维酮混合均匀;(2)将聚维酮溶于水中;(3)将步骤(2)得到的聚维酮溶液加入步骤(1)得到的混合物中进行制粒,烘干,整粒;(4)将乳糖、微晶纤维素、十二烷基硫酸钠以及交联聚维酮混合均匀;(5)将海泽麦布、丁羟甲苯、聚维酮溶于乙醇溶液中;(6)将步骤(5)所得溶液加入步骤(4)得到的混合物中进行制粒,烘干,整粒;(7)将步骤(3)和步骤(6)整粒后的颗粒混合,再任选地与交联聚维酮混合均匀,然后任选地与硬脂酸镁混合均匀,压片。
- 如权利要求16~19任一项所述的药物组合物的制备方法,包括:(1)将瑞舒伐他汀与任选的辅料制成颗粒;(2)将海泽麦布与任选的辅料制成颗粒;(3)将上述步骤(1)制备得到的颗粒与任选的辅料混合均匀,得到第一总混颗粒;(4)将上述步骤(2)制备得到的颗粒与任选的辅料混合均匀,得到第二总混颗粒;(5)将上述步骤(3)、步骤(4)得到的第一总混颗粒与第二总混颗粒压制成双层片。
- 如权利要求27所述的药物组合物的制备方法,包括:(1)将瑞舒伐他汀和乳糖、微晶纤维素、碳酸钙以及交联聚维酮混合均匀;(2)将聚维酮溶于水中;(3)将步骤(2)得到的聚维酮溶液加入步骤(1)得到的混合物中进行制粒,烘干,整粒;(4)将乳糖、微晶纤维素、十二烷基硫酸钠以及交联聚维酮混合均匀;(5)将海泽麦布、丁羟甲苯、聚维酮溶于乙醇溶液中;(6)将步骤(5)所得溶液加入步骤(4)得到的混合物中进行制粒,烘干,整粒;(7)将步骤(3)整粒后的颗粒任选地与交联聚维酮混合均匀,然后任选地与硬脂酸镁混合均匀,得到第一总混颗粒;(8)将步骤(6)整粒后的颗粒任选地与交联聚维酮混合均匀,然后任选地与硬脂酸镁混合均匀,得到第二总混颗粒;(9)将步骤(7)与步骤(8)所得的第一总混颗粒与第二总混颗粒压制成双层片。
- 一种药物剂量单元,其中含有5~20mg的海泽麦布,5~80mg的阿托伐他汀。
- 根据权利要求29所述的药物剂量单元,其中,所述海泽麦布的剂量为5mg、10mg或20mg;所述阿托伐他汀的剂量为5mg、10mg、20mg、40mg或80mg。
- 根据权利要求29或30所述的药物剂量单元,其中还含有5~100mg的碳酸钙。
- 根据权利要求29或30所述的药物剂量单元,其中还含有5~100mg的碳酸钙,0.01~0.2mg的丁羟甲苯。
- 根据权利要求29或30所述的药物剂量单元,其中还含有0.5~5mg的十二烷基硫酸钠。
- 根据权利要求29或30所述的药物剂量单元,其中还含有0.5~5mg的十二烷基硫酸钠,0.1~5mg的聚山梨酯。
- 根据权利要求29或30所述的药物剂量单元,其中还含有1~50mg的交联羧甲基纤维素钠,20~250mg的微晶纤维素,0.5~10mg的聚维酮,0.5~10mg的羟丙基纤维素,10~250mg的乳糖,0.1~10mg硬脂酸镁。
- 根据权利要求29或30所述的药物剂量单元,其中还含有1~50mg的交联羧甲基纤维素钠,1~30mg的交联聚维酮,20~250mg的微晶纤维素,0.5~10mg的聚维酮,0.5~10mg的羟丙基纤维素,10~250mg的乳糖,0.1~10mg硬脂酸镁。
- 一种药物剂量单元,其中含有5~20mg的海泽麦布,5~80mg的瑞舒伐他汀。
- 根据权利要求37所述的药物剂量单元,其中,所述海泽麦布的剂量为5mg、10mg或20mg;所述瑞舒伐他汀的剂量为5mg、10mg、20mg或40mg。
- 根据权利要求37或38所述的药物剂量单元,其中还含有1~50mg的碳酸钙。
- 根据权利要求37或38所述的药物剂量单元,其中还含有1~50mg的碳酸钙,0.01~0.2mg的丁羟甲苯。
- 根据权利要求37或38所述的药物剂量单元,其中还含有0.5~10mg的十二烷基硫酸钠。
- 根据权利要求37或38所述的药物剂量单元,其中还含有5~40mg的交联聚维酮,20~250mg的微晶纤维素,1~20mg的聚维酮,20~250mg的乳糖,0.1~5mg硬脂酸镁。
- 权利要求1~15中任一项的药物组合物或权利要求29~42中的任一项的药物剂量单元,该药物组合物或药物剂量单元为胶囊剂、片剂、颗粒剂、散剂、溶液剂或锭剂。
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