阅读说明：本技术 一种海泽麦布和HMG-CoA还原酶抑制剂的药物组合物 (Pharmaceutical composition of Haizumab and HMG-CoA reductase inhibitor ) 是由 丁立 代军 冯春荣 代常亮 于 2018-11-23 设计创作，主要内容包括：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。(The invention provides a pharmaceutical composition, which contains Haizumab and an HMG-CoA reductase inhibitor, and also can comprise one or more auxiliary materials of calcium carbonate, butylated hydroxyanisole, butylated hydroxytoluene, citric acid, sodium dodecyl sulfate, polysorbate, croscarmellose sodium, crospovidone, microcrystalline cellulose, povidone, hydroxypropyl cellulose, lactose, pregelatinized starch, magnesium stearate and talcum powder. The composition can be made into various dosage forms, and has good stability and controllable quality.)

A pharmaceutical composition comprising:

(a)0.5 to 20% by weight of Haizui mylabris;

(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 the statin is one or more selected from the group consisting of lovastatin, simvastatin, atorvastatin, pravastatin, rosuvastatin, fluvastatin, cerivastatin, pitavastatin and rosuvastatin or salts 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 of 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 selected from the group consisting of stabilizers, surfactants, fillers, binders, disintegrants and lubricants; preferably, the stabilizer is at least one of calcium carbonate, butylated hydroxyanisole, citric acid and butylated hydroxytoluene, 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, the binder is at least one of hydroxypropyl cellulose and povidone, the disintegrant is at least one of croscarmellose sodium and crospovidone, and the lubricant is at least one of magnesium stearate and talc; more preferably, the composition contains one or more of 1-25% by weight of calcium carbonate, 0.005-0.1% by weight of butylated hydroxytoluene, 0.1-10% by weight of sodium dodecyl sulfate, 0.05-1.0% by weight of polysorbate, 1-10% by weight of croscarmellose sodium, 1-10% by weight of crospovidone, 10-50% by weight of microcrystalline cellulose, 0.1-5% by weight of povidone, 0.1-5% by weight of hydroxypropyl cellulose, 10-50% by weight of lactose and 0.1-2% by weight of magnesium stearate.

The pharmaceutical composition according to claim 4, wherein the composition comprises 1-10% by weight of Haematococcus and 1-30% 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, more preferably the stabilizer is at least one of 5-25% by weight of calcium carbonate and 0.005-0.05% by weight of butylated hydroxytoluene.

The pharmaceutical composition according to claim 4 or 8, further comprising a surfactant, wherein the surfactant is preferably at least one of sodium dodecyl sulfate and polysorbate, and more preferably the surfactant is at least one of sodium dodecyl sulfate 0.1-5 wt% and polysorbate 0.05-0.5 wt%.

The pharmaceutical composition according to claim 4 or 8, further comprising one or more of a filler, a binder, a disintegrant, and a lubricant; preferably, the filler is at least one of lactose and microcrystalline cellulose, the binder is at least one of hydroxypropyl cellulose and povidone, the disintegrant is at least one of croscarmellose sodium and crospovidone, and the lubricant is magnesium stearate; more preferably, the pharmaceutical composition contains one or more of 1-10% by weight of croscarmellose sodium, 1-10% by weight of crospovidone, 10-50% by weight of microcrystalline cellulose, 0.1-5% by weight of povidone, 0.1-5% by weight of hydroxypropyl cellulose, 10-50% by weight of lactose, and 0.1-2% by weight of magnesium stearate.

The pharmaceutical composition according to claim 5, wherein the composition comprises 1-10% by weight of Haizumab and 1-30% 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, more preferably the stabilizer is at least one of calcium carbonate and butylated hydroxytoluene with a weight ratio of 1-15% and 0.005-0.05%.

The pharmaceutical composition according to claim 5 or 12, further comprising a surfactant, preferably the surfactant is sodium lauryl sulfate, and more preferably the pharmaceutical composition comprises 0.1-6% by weight of sodium lauryl sulfate.

The pharmaceutical composition according to claim 5 or 12, further comprising one or more of a filler, a binder, a disintegrant, and a lubricant; preferably, the filler is at least one of lactose and microcrystalline cellulose, the binder is at least one of hydroxypropyl cellulose and povidone, the disintegrant is at least one of croscarmellose sodium and crospovidone, and the lubricant is magnesium stearate; more preferably, the pharmaceutical composition contains one or more of 1-10% by weight of crospovidone, 10-50% by weight of microcrystalline cellulose, 0.1-5% by weight of povidone, 10-50% by weight of lactose and 0.1-2% by weight of magnesium stearate.

A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 15, comprising combining an HMG-CoA reductase inhibitor, hypezetimibe and optionally adjuvants.

The method of claim 16, comprising:

(1) preparing HMG-CoA reductase inhibitor and optional auxiliary materials into particles to obtain HMG-CoA reductase inhibitor particle parts;

(2) granulating Haizzia julibrissin and optional auxiliary materials to obtain Haizzia julibrissin granule;

(3) combining the granules prepared in step (1) and step (2) with optional adjuvants.

The preparation method according to claim 17, wherein the HMG-CoA reductase inhibitor granule fraction of step (1) is obtained by granulation with water as a solvent; the Haizumab granulate fraction of step (2) is obtained by granulation with water, an organic solvent or a mixture thereof.

The process according to claim 18, wherein the Haezetimibe granulation fraction of step (2) is granulated with water, alcohol, chloroform, acetone, acetonitrile or similar solvents, and mixtures thereof, preferably with water, alcohol and mixtures thereof, more preferably with a mixture of alcohol and water, most preferably with a mixture of ethanol and water.

A process for the preparation of a pharmaceutical composition according to any one of claims 16 to 19, comprising:

(1) preparing atorvastatin and optional auxiliary materials into granules;

(2) granulating Haizumab with optional adjuvants;

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

A process for preparing a pharmaceutical composition according to claim 20, comprising:

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

(2) dissolving hydroxypropyl cellulose in water;

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

(4) mixing Haizumab with lactose, microcrystalline cellulose, sodium dodecyl sulfate and croscarmellose sodium uniformly;

(5) dissolving povidone in water;

(6) adding the povidone solution obtained in the step (5) into the mixture obtained in the step (4) for granulation, drying and straightening;

(7) and (4) uniformly mixing the granules obtained in the step (3) and the step (6) after finishing the granules optionally with croscarmellose sodium, then uniformly mixing the granules optionally with magnesium stearate, and tabletting.

A process for the preparation of a pharmaceutical composition according to any one of claims 16 to 19, comprising:

(1) preparing atorvastatin and optional auxiliary materials into granules;

(2) granulating Haizumab with optional adjuvants;

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

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

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

A process for preparing a pharmaceutical composition according to claim 22, comprising:

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

(2) dissolving polysorbate and hydroxypropyl cellulose in water;

(3) adding the solution obtained in the step (2) into the mixture obtained in the step (1) for granulation, drying and granule finishing;

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

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

(6) adding the solution obtained in the step (5) into the mixture obtained in the step (4) for granulation, drying and granule finishing;

(7) uniformly mixing the granules obtained in the step (3) with croscarmellose sodium optionally, and then uniformly mixing the granules with magnesium stearate optionally to obtain first total mixed granules;

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

(9) and (4) pressing the first total mixed particles and the second total mixed particles obtained in the steps (7) and (8) into a double-layer tablet.

A process for the preparation of a pharmaceutical composition according to any one of claims 16 to 19, comprising:

(1) granulating rosuvastatin and optional auxiliary materials;

(2) granulating Haizumab with optional adjuvants;

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

A process for preparing a pharmaceutical composition according to claim 24, comprising:

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

(2) dissolving povidone in water;

(3) adding the povidone solution obtained in the step (2) into the mixture obtained in the step (1) for granulation, drying and straightening;

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

(5) dissolving Haizumei and polyvidone in ethanol solution;

(6) adding the solution obtained in the step (5) into the mixture obtained in the step (4) for granulation, drying and granule finishing;

(7) and (4) mixing the granules obtained in the step (3) and the step (6), optionally mixing with crospovidone uniformly, optionally mixing with magnesium stearate uniformly, and tabletting.

A process for preparing a pharmaceutical composition according to claim 24, comprising:

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

(2) dissolving povidone in water;

(3) adding the povidone solution obtained in the step (2) into the mixture obtained in the step (1) for granulation, drying and straightening;

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

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

(6) adding the solution obtained in the step (5) into the mixture obtained in the step (4) for granulation, drying and granule finishing;

(7) and (4) mixing the granules obtained in the step (3) and the step (6), optionally mixing with crospovidone uniformly, optionally mixing with magnesium stearate uniformly, and tabletting.

A process for the preparation of a pharmaceutical composition according to any one of claims 16 to 19, comprising:

(1) granulating rosuvastatin and optional auxiliary materials;

(2) granulating Haizumab with optional adjuvants;

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

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

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

A process for preparing a pharmaceutical composition according to claim 27, comprising:

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

(2) dissolving povidone in water;

(3) adding the povidone solution obtained in the step (2) into the mixture obtained in the step (1) for granulation, drying and straightening;

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

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

(6) adding the solution obtained in the step (5) into the mixture obtained in the step (4) for granulation, drying and granule finishing;

(7) uniformly mixing the granules obtained in the step (3) with crospovidone optionally, and then uniformly mixing the granules with magnesium stearate optionally to obtain first total mixed granules;

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

(9) and (4) pressing the first total mixed particles and the second total mixed particles obtained in the steps (7) and (8) into a double-layer tablet.

A pharmaceutical dosage unit comprising 5-20 mg Haizumab and 5-80 mg atorvastatin.

The pharmaceutical dosage unit of claim 29, wherein the dose of Haizumab is 5mg, 10mg or 20 mg; the dose of atorvastatin is 5mg, 10mg, 20mg, 40mg or 80 mg.

A pharmaceutical dosage unit according to claim 29 or 30, further comprising 5-100 mg of calcium carbonate.

A pharmaceutical dosage unit according to claim 29 or 30, further comprising 5-100 mg of calcium carbonate and 0.01-0.2 mg of butylated hydroxytoluene.

A pharmaceutical dosage unit according to claim 29 or 30, further comprising 0.5-5 mg of sodium lauryl sulphate.

The pharmaceutical dosage unit according to claim 29 or 30, further comprising 0.5-5 mg of sodium lauryl sulfate, 0.1-5 mg of polysorbate.

The pharmaceutical dosage unit according to claim 29 or 30, further comprising 1-50 mg croscarmellose sodium, 20-250 mg microcrystalline cellulose, 0.5-10 mg povidone, 0.5-10 mg hydroxypropylcellulose, 10-250 mg lactose, 0.1-10 mg magnesium stearate.

The pharmaceutical dosage unit according to claim 29 or 30, further comprising 1-50 mg croscarmellose sodium, 1-30 mg crospovidone, 20-250 mg microcrystalline cellulose, 0.5-10 mg povidone, 0.5-10 mg hydroxypropyl cellulose, 10-250 mg lactose, 0.1-10 mg magnesium stearate.

A pharmaceutical dosage unit comprising 5-20 mg Haizumabu and 5-80 mg rosuvastatin.

The pharmaceutical dosage unit of claim 37, wherein the dose of Haizumab is 5mg, 10mg or 20 mg; the dosage of the rosuvastatin is 5mg, 10mg, 20mg or 40 mg.

The pharmaceutical dosage unit according to claim 37 or 38, further comprising 1-50 mg of calcium carbonate.

A pharmaceutical dosage unit according to claim 37 or 38, further comprising 1-50 mg of calcium carbonate, 0.01-0.2 mg of butylated hydroxytoluene.

A pharmaceutical dosage unit according to claim 37 or 38, further comprising 0.5 to 10mg of sodium lauryl sulphate.

The pharmaceutical dosage unit according to claim 37 or 38, further comprising 5-40 mg crospovidone, 20-250 mg microcrystalline cellulose, 1-20 mg povidone, 20-250 mg lactose, 0.1-5 mg magnesium stearate.

A pharmaceutical composition according to any one of claims 1 to 15 or a pharmaceutical dosage unit according to any one of claims 29 to 42 in the form of a capsule, tablet, granule, powder, solution or lozenge.