CN105456204A - Azilsartan film-controlled sustained release pellet preparation and preparation method thereof - Google Patents
Azilsartan film-controlled sustained release pellet preparation and preparation method thereof Download PDFInfo
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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Abstract
The invention discloses an azilsartan film-controlled sustained release pellet preparation, which is prepared and formed by dissolving the following raw materials in a solvent in parts by weight and spraying the dissolved materials on the periphery of a blank pellet core by virtue of a fluidized bed bottom-spraying process: 1-32 parts of azilsartan, 5-25 parts of a coating film-forming material, 1-20 parts of a disintegrating agent, 0-15 parts of a surfactant, 26-45 parts of a pore-forming agent, 1-7 parts of a binding agent, 0-8 parts of a plasticizer and 0-5 parts of an anti-sticking agent, wherein the purity of the azilsartan is above 97%. The preparation is good in dissolution rate, and the preparation is capable of effectively improving drug bioavailability in patients.
Description
Technical field
The present invention relates to Azilsartan film controlling type sustained-release pellet preparation and preparation method thereof.
Background technology
Hypertension increases clinical syndrome for main manifestations with systemic arterial pressure, is modal cardiovascular disease.Long-term hypertension can have influence on the function of the organs such as the heart, brain, kidney, finally causes the exhaustion of these organ dysfunctions.The hyperpietic of China is increasing every year day by day, endangers very serious.Hyperpietic often needs long-term prescription, for each patient, effectively can control blood pressure and the medicine of suitable long-term treatment is exactly reasonably selection.At present, in hypertension research field, the most effective material of the treatment hypertension of generally acknowledging is Azilsartan, its chemistry 2-ethyoxyl-1-[[2'-(4,5-dihydro-5-oxo-1,2 by name, 4-oxadiazole-3-base) biphenyl-4-base] methyl] benzimidazole-7-carboxylic acid, dissolubility is less, belongs to slightly solubility material, is also the Angiotensin Ⅱ receptor antagonist medicine being uniquely in late-stage clinical at present.By Japanese Takeda Pharmaceutical Company Limited, Azilsartan prodrug Azilsartan is prepared into conventional tablet at first, this medicine can be hydrolyzed to Azilsartan during gastrointestinal absorption, Azilsartan is a kind of angiotensin-ii-receptor ATI receptor subtype antagonist, can the vasoconstriction that causes of inhibition angiotensin II, thus make blood pressure drops.Domestic literature was also once reported and Azilsartan was prepared into conventional tablet, and from the medicining condition of patient, the relative sustained-release pellet preparation of conventional tablet, it often exists many defects.On the contrary, in recent years, because micropill has that local excitation is little, drug loading is large, release is stable, bioavailability is high and the feature such as good fluidity, become the focus of research worker research, along with stretching into of research, also obtain the affirmative of people gradually, be it is believed that one of ideal sustained-release preparation, but the more difficult preparation of slow controlled release micro pill of the slow controlled release micro pill preparation of insoluble drug especially film controlling type.Up to now, there is not yet bibliographical information Azilsartan and delay controlled release micro pill preparation.
Summary of the invention
The technical problem that the present invention first will solve is to provide a kind of Azilsartan film controlling type sustained-release pellet preparation, and said preparation dissolution is good, effectively can improve the bioavailability of patient medication.
Azilsartan film controlling type sustained-release pellet preparation provided by the invention, by by following material dissolution by weight in solvent, the periphery preparation adopting pressure spray process at the bottom of fluid bed to be sprayed at celphere is formed:
Wherein, the purity of described Azilsartan is more than 97%.
Further improve as the present invention, by by following material dissolution by weight in solvent, the periphery preparation adopting pressure spray process at the bottom of fluid bed to be sprayed at celphere is formed:
Further improve as the present invention, described raw material is by micronization processes, and the particle diameter of described Azilsartan is 1-5 micron; Described celphere is microcrystalline Cellulose ball, and its particle diameter is 0.8-1.2mm.
Further improve as the present invention, the periphery of described celphere is provided with pastille coating rete, described pastille coating rete weightening finish 2-15%.
Further improve as the present invention, the periphery of described celphere is provided with pastille coating rete, described pastille coating rete weightening finish 6-10%.
Further improve as the present invention, described coating filmogen comprises and being selected from: the mixture of the mixture of the mixture of polyvinyl alcohol, polyethylene pyrrole network alkane ketone, ethyl cellulose and hydroxypropyl emthylcellulose, ethyl cellulose and methylcellulose, polyacrylic resin Ⅳ, polyacrylic resin Ⅱ and polyacrylic resin Ⅲ; The mixture of polyacrylic resin Ⅲ and hydroxypropyl emthylcellulose;
Described disintegrating agent comprises and being selected from: low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch are received, carboxymethyl starch is received, the mixture of one or more in polyvinylpolypyrrolidone and crospolyvinylpyrrolidone;
Described surfactant comprises and being selected from: the mixture of one or more in sodium lauryl sulfate, poloxamer, stearyl alcohol sodium sulfonate, sodium lauryl sulphate, cetrimonium bronmide, sodium alginate and Tween 80;
Described porogen comprises and being selected from: the mixture of one or more in lactose, Polyethylene Glycol, polyvinylpyrrolidone, microcrystalline Cellulose, hydroxypropyl emthylcellulose, carbonate and bicarbonate;
Described binding agent comprises and being selected from: the mixture of one or more in sodium carboxymethyl cellulose, ethyl cellulose, starch slurry and polyvidone k30;
Described plasticizer is selected from: the mixture of one or more in triethyl citrate, dibutyl sebacate and alkenyl succinic anhydride;
Described antitackiness agent comprises and being selected from: the mixture of one or more in micropowder silica gel, Pulvis Talci and magnesium stearate.
Further improve as the present invention, inside and outside addition selected by described disintegrating agent, and interior dosage is 25-40%, and outer dosage is 60-75%.
Further improve as the present invention, described solvent is one or both the mixture be selected from alcoholic solution, Aqueous Solutions of Polyethylene Glycol and phosphate buffered solution; Described ethanol solution concentration is 60-90%, and the concentration of described Aqueous Solutions of Polyethylene Glycol is: 5-20%; The pH value of described phosphate buffered solution is 5-7.
Further improve as the present invention, the dosage≤150mg of described sustained-release pellet preparation.
The technical problem that the present invention second will solve is to provide a kind of preparation method of Azilsartan film controlling type sustained-release pellet preparation, comprises the following steps:
1) by being dissolved in solvent after above-mentioned raw material micronization by weight, sieving and being mixed to form pastille coating solution; In stirring, coating solution is placed more than 50min and make it complete swelling;
2) by celphere preheating 50-120min;
3) adopt spray mode at the bottom of fluid bed to add medicine to, the operation process of described fluid bed is by progressively slowing down soon, and described fluidized-bed process parameter is:
Pump speed 4-8rpm, temperature 30-50 DEG C, atomizing pressure 250-500kpa, rotary speed 400-550rpm, rotating disk height 6-9mm, blower fan frequency 32-50hz.
The technical problem that the present invention the 3rd will solve is the peripheral form also can being arranged to medicine layer and slow release coating membrane layer from inside to outside successively of celphere of sustained-release pellet preparation, and its preparation method comprises the following steps:
1) by celphere more than preheating 50min, by above-mentioned raw material micronization by weight;
2) above-mentioned Azilsartan by weight, after micronization and coating filmogen are dissolved in solvent, add above-mentioned antiplastering aid on demand and form medicinal liquid, stir after placing more than 50min and be sprayed at celphere periphery formation medicine carrying micropill by pressure spray process at the bottom of fluid bed; Described fluidized-bed process parameter is:
Pump speed 2-5rpm, temperature 40-60 DEG C, atomizing pressure 150-300kpa, rotary speed 200-400rpm, rotating disk height 3-6mm, blower fan frequency 42-60hz.
4) the 18-24 object medicine carrying micropill getting above-mentioned preparation is appropriate, above-mentioned raw material is by weight added in solvent and forms coating solution, be placed in fluid bed by medicine carrying micropill and adopt the end to spray mode coating to the weightening finish needed, described fluidized-bed process parameter is:
Pump speed 2-5rpm, temperature 45-65 DEG C, atomizing pressure 150-300kpa, rotary speed 300-450rpm, rotating disk height 3-6mm, blower fan frequency 45-60hz.
Spray mode at the bottom of fluid bed, the micropill smooth surface obtained is sprayed at the end, and hole is little.The viscosity acting as reduction coating solution of antitackiness agent, reduces the adhesion between micropill.Azilsartan principal agent amount is few relative to adjuvant, and principal agent can be wrapped by accessory package completely, improves the overall hydrophobic property of powder body.The purity of Azilsartan is more than 97%, and purity is high, reduces the viscosity of medicine, improves dissolution.The permeability act as increasing coating membrane of porogen, helps to obtain desirable rate of releasing drug.Celphere medicine-feeding is conducive to the release degree and the release repeatability that improve Azilsartan principal agent, and it is better than the mode that principal agent adds adjuvant granulation.Blank pill heart particle diameter selects 0.8-1.2mm, and specific surface area is large, improves drug loading, if ball microcardia, electrostatic interaction is large, and easily sticky wall, not easily participates in fluidisation, can not be complete by coating, causes medicine in process in leaching, produce prominent releasing.Preferably microcrystalline Cellulose pill footpath is 0.9-1.12mm, and blank pill heart particle diameter is less, and its drug loading is larger, and medicated layer is thinner, and its release is relatively faster.
2-15% is selected in the weightening finish of sustained release coating film, and gain in weight little being difficult to forms thin film, and repeatability is bad; Gain in weight is large affects stripping, because coating weight gain is too high, easily causes drug release too slow.Disintegrating agent preferably adopts the mixture of cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone and crosslinked polyethylene pyrrolidine, and more electedly, inside and outside addition selected by disintegrating agent, and be conducive to disintegrate because of additional, inside add and be conducive to stripping, two kinds of modes are better in conjunction with stripping.Adopt Polyethylene Glycol can suppress transformation of crystal as coating solution solvent, it has the effect of porogen and plasticizer simultaneously, not only helps stripping, and can improve the stability of medicine.
Micronization is conducive to medicine disintegration.Fluidized-bed process parameter is: thermal creep stress 30-50 DEG C, and temperature is too low, and dry slow, move, the film of formation is imperfect, and drug release feature is changed; Temperature is too high, and water evaporates is very fast, and film also can be made imperfect, changes drug release feature.Atomizing pressure selects 250-500kpa, usual atomizing pressure is crossed conference and is caused droplet very little, easy overdrying and form fine powder, or be sprayed onto on equipment inner wall and form thick film, piller fluidisation position is also abnormal, can not be formed and circulate up and down, be that coating efficiency or the piller uniformity all can be poor.
Detailed description of the invention
Below by way of specific embodiment, further more detailed description is done to Azilsartan film controlling type sustained-release pellet preparation provided by the invention and preparation method thereof:
Embodiment 1
Azilsartan film controlling type sustained-release pellet preparation, by by following material dissolution by weight in solvent, the periphery preparation adopting pressure spray process at the bottom of fluid bed to be sprayed at celphere is formed:
Wherein, the purity of Azilsartan is more than 97%.Raw material is by micronization processes, and the particle diameter of Azilsartan is 1 micron; Celphere is microcrystalline Cellulose ball, and its particle diameter is 0.8mm.The periphery of celphere is provided with pastille coating rete, pastille coating rete weightening finish 2%.
Coating filmogen comprises and being selected from: the mixture of ethyl cellulose and hydroxypropyl emthylcellulose;
Disintegrating agent comprises and being selected from: the mixture in low-substituted hydroxypropyl cellulose and crospolyvinylpyrrolidone;
Porogen comprises and being selected from: the mixture of one or more in lactose, Polyethylene Glycol, polyvinylpyrrolidone, microcrystalline Cellulose and bicarbonate;
Binding agent comprises and being selected from: the mixture of sodium carboxymethyl cellulose, ethyl cellulose, starch slurry and polyvidone k30;
Inside and outside addition selected by disintegrating agent, and interior dosage is 25%, and outer dosage is 75%.Solvent is alcoholic solution, and ethanol solution concentration is 60%.The dosage 150mg of sustained-release pellet preparation.
The preparation method of Azilsartan film controlling type sustained-release pellet preparation, comprises the following steps:
1) by being dissolved in solvent after above-mentioned raw material micronization by weight, sieving and being mixed to form pastille coating solution; In stirring, coating solution is placed more than 50min and make it complete swelling;
2) by celphere preheating 50min;
3) adopt spray mode at the bottom of fluid bed to add medicine to, the operation process of fluid bed is by progressively slowing down soon, and fluidized-bed process parameter is:
Pump speed 4rpm, temperature 30 DEG C, atomizing pressure 250kpa, rotary speed 400rpm, rotating disk height 6mm, blower fan frequency 32hz.
Embodiment 2
Azilsartan film controlling type sustained-release pellet preparation, by by following material dissolution by weight in solvent, the periphery preparation adopting pressure spray process at the bottom of fluid bed to be sprayed at celphere is formed:
Wherein, the purity of Azilsartan is more than 97%.Raw material is by micronization processes, and the particle diameter of Azilsartan is 2 microns; Celphere is microcrystalline Cellulose ball, and its particle diameter is 1mm.The periphery of celphere is provided with pastille coating rete, pastille coating rete weightening finish 15%.
Coating filmogen comprises and being selected from: the mixture of polyacrylic resin Ⅳ, polyacrylic resin Ⅱ and polyacrylic resin Ⅲ;
Disintegrating agent comprises and being selected from: the mixture of cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone and crospolyvinylpyrrolidone;
Porogen comprises and being selected from: the mixture of lactose, polyvinylpyrrolidone, microcrystalline Cellulose, hydroxypropyl emthylcellulose and bicarbonate;
Binding agent comprises and being selected from: the mixture in ethyl cellulose, starch slurry and polyvidone k30;
Plasticizer is selected from: the mixture of triethyl citrate, dibutyl sebacate and alkenyl succinic anhydride;
Inside and outside addition selected by disintegrating agent, and interior dosage is 40%, and outer dosage is 60%.Solvent is Aqueous Solutions of Polyethylene Glycol; The concentration of Aqueous Solutions of Polyethylene Glycol is: 5%.The dosage 100mg of sustained-release pellet preparation.
The preparation method of Azilsartan film controlling type sustained-release pellet preparation, comprises the following steps:
1) by being dissolved in solvent after above-mentioned raw material micronization by weight, sieving and being mixed to form pastille coating solution; In stirring, coating solution is placed more than 50min and make it complete swelling;
2) by celphere preheating 120min;
3) adopt spray mode at the bottom of fluid bed to add medicine to, the operation process of fluid bed is by progressively slowing down soon, and fluidized-bed process parameter is:
Pump speed 8rpm, temperature 50 C, atomizing pressure 500kpa, rotary speed 550rpm, rotating disk height 9mm, blower fan frequency 50hz.
Embodiment 3
Azilsartan film controlling type sustained-release pellet preparation, by by following material dissolution by weight in solvent, the periphery preparation adopting pressure spray process at the bottom of fluid bed to be sprayed at celphere is formed:
Wherein, the purity of described Azilsartan is more than 97%.
Raw material is by micronization processes, and the particle diameter of Azilsartan is 2 microns; Celphere is microcrystalline Cellulose ball, and its particle diameter is 0.9mm.
The periphery of celphere is provided with pastille coating rete, pastille coating rete weightening finish 10%.
Coating filmogen comprises and being selected from: the mixture of the mixture of polyvinyl alcohol, ethyl cellulose and methylcellulose, polyacrylic resin Ⅳ, polyacrylic resin Ⅱ and polyacrylic resin Ⅲ;
Disintegrating agent comprises and being selected from: carboxymethyl starch is received, carboxymethyl starch is received, the mixture of polyvinylpolypyrrolidone and crospolyvinylpyrrolidone;
Surfactant comprises and being selected from: the mixture of stearyl alcohol sodium sulfonate, cetrimonium bronmide, sodium alginate and Tween 80;
Porogen comprises and being selected from: the mixture in Polyethylene Glycol, polyvinylpyrrolidone, microcrystalline Cellulose, hydroxypropyl emthylcellulose, carbonate and bicarbonate;
Binding agent comprises and being selected from: the mixture in sodium carboxymethyl cellulose, starch slurry and polyvidone k30;
Plasticizer is selected from: the mixture in triethyl citrate and alkenyl succinic anhydride;
Antitackiness agent comprises and being selected from: the mixture of micropowder silica gel, Pulvis Talci and magnesium stearate.
Inside and outside addition selected by disintegrating agent, and interior dosage is 30%, and outer dosage is 70%.Solvent is for being selected from phosphate buffered solution, and the pH value of phosphate buffered solution is 5.The dosage 50mg of sustained-release pellet preparation.
The preparation method of Azilsartan film controlling type sustained-release pellet preparation, comprises the following steps:
1) by being dissolved in solvent after above-mentioned raw material micronization by weight, sieving and being mixed to form pastille coating solution; In stirring, coating solution is placed more than 50min and make it complete swelling;
2) by celphere preheating 100min;
3) adopt spray mode at the bottom of fluid bed to add medicine to, the operation process of fluid bed is by progressively slowing down soon, and fluidized-bed process parameter is:
Pump speed 6rpm, temperature 40 DEG C, atomizing pressure 300kpa, rotary speed 450rpm, rotating disk height 7mm, blower fan frequency 35hz.
Embodiment 4
Azilsartan film controlling type sustained-release pellet preparation, by by following material dissolution by weight in solvent, the periphery preparation adopting pressure spray process at the bottom of fluid bed to be sprayed at celphere is formed:
Raw material is by micronization processes, and the particle diameter of Azilsartan is 3 microns; Celphere is microcrystalline Cellulose ball, and its particle diameter is 1.1mm.The periphery of celphere is provided with pastille coating rete, pastille coating rete weightening finish 6%.
Coating filmogen comprises and being selected from: the mixture of polyacrylic resin Ⅲ and hydroxypropyl emthylcellulose;
Disintegrating agent comprises and being selected from: low-substituted hydroxypropyl cellulose, carboxymethyl starch are received, mixture in polyvinylpolypyrrolidone and crospolyvinylpyrrolidone;
Surfactant comprises and being selected from: the mixture in cetrimonium bronmide, sodium alginate and Tween 80;
Porogen comprises and being selected from: the mixture in polyvinylpyrrolidone, microcrystalline Cellulose, hydroxypropyl emthylcellulose, carbonate and bicarbonate;
Binding agent comprises and being selected from: the mixture of sodium carboxymethyl cellulose, ethyl cellulose, starch slurry and polyvidone k30;
Plasticizer is selected from: the mixture of triethyl citrate, dibutyl sebacate and alkenyl succinic anhydride;
Antitackiness agent comprises and being selected from: the mixture in micropowder silica gel, Pulvis Talci and magnesium stearate.
Inside and outside addition selected by disintegrating agent, and interior dosage is 32%, and outer dosage is 68%.Solvent is for being selected from Aqueous Solutions of Polyethylene Glycol, and the concentration of Aqueous Solutions of Polyethylene Glycol is: 20%; The dosage 120mg of sustained-release pellet preparation.
The preparation method of Azilsartan film controlling type sustained-release pellet preparation, comprises the following steps:
1) by being dissolved in solvent after above-mentioned raw material micronization by weight, sieving and being mixed to form pastille coating solution; In stirring, coating solution is placed more than 50min and make it complete swelling;
2) by celphere preheating 110min;
3) adopt spray mode at the bottom of fluid bed to add medicine to, the operation process of fluid bed is by progressively slowing down soon, and fluidized-bed process parameter is:
Pump speed 6rpm, temperature 32 DEG C, atomizing pressure 300kpa, rotary speed 400rpm, rotating disk height 7mm, blower fan frequency 42hz.
Embodiment 5
Azilsartan film controlling type sustained-release pellet preparation, by by following material dissolution by weight in solvent, the periphery preparation adopting pressure spray process at the bottom of fluid bed to be sprayed at celphere is formed:
Raw material is by micronization processes, and the particle diameter of Azilsartan is 3 microns; Celphere is microcrystalline Cellulose ball, and its particle diameter is 0.85mm.
The periphery of celphere is provided with pastille coating rete, pastille coating rete weightening finish 8%.
Coating filmogen comprises and being selected from: the mixture of the mixture of the mixture of ethyl cellulose and hydroxypropyl emthylcellulose, ethyl cellulose and methylcellulose, polyacrylic resin Ⅳ, polyacrylic resin Ⅱ and polyacrylic resin Ⅲ;
Disintegrating agent comprises and being selected from: cross-linking sodium carboxymethyl cellulose, carboxymethyl starch are received, carboxymethyl starch is received, the mixture of polyvinylpolypyrrolidone and crospolyvinylpyrrolidone;
Surfactant comprises and being selected from: the mixture of stearyl alcohol sodium sulfonate, sodium lauryl sulphate, cetrimonium bronmide, sodium alginate and Tween 80;
Porogen comprises and being selected from: the mixture in polyvinylpyrrolidone, microcrystalline Cellulose, hydroxypropyl emthylcellulose, carbonate and bicarbonate;
Binding agent comprises and being selected from: the mixture in sodium carboxymethyl cellulose and polyvidone k30;
Plasticizer is selected from: the mixture of triethyl citrate and alkenyl succinic anhydride;
Antitackiness agent comprises and being selected from: the mixture of micropowder silica gel, Pulvis Talci and magnesium stearate.
Inside and outside addition selected by disintegrating agent, and interior dosage is 38%, and outer dosage is 62%.Solvent is the mixture being selected from Aqueous Solutions of Polyethylene Glycol and phosphate buffered solution; The concentration of Aqueous Solutions of Polyethylene Glycol is: 20%; The pH value of phosphate buffered solution is 7.The dosage 80mg of sustained-release pellet preparation.
The preparation method of Azilsartan film controlling type sustained-release pellet preparation, comprises the following steps:
1) by being dissolved in solvent after above-mentioned raw material micronization by weight, sieving and being mixed to form pastille coating solution; In stirring, coating solution is placed more than 50min and make it complete swelling;
2) by celphere preheating 70min;
3) adopt spray mode at the bottom of fluid bed to add medicine to, the operation process of fluid bed is by progressively slowing down soon, and fluidized-bed process parameter is:
Pump speed 7rpm, temperature 35 DEG C, atomizing pressure 400kpa, rotary speed 500rpm, rotating disk height 7mm, blower fan frequency 38hz.
Embodiment 6
Azilsartan film controlling type sustained-release pellet preparation, by by following material dissolution by weight in solvent, the periphery preparation adopting pressure spray process at the bottom of fluid bed to be sprayed at celphere is formed:
Raw material is by micronization processes, and the particle diameter of Azilsartan is 3 microns; Celphere is microcrystalline Cellulose ball, and its particle diameter is 1.1mm.The periphery of celphere is provided with pastille coating rete, pastille coating rete weightening finish 9%.
Coating filmogen comprises and being selected from: the mixture of the mixture of the mixture of polyvinyl alcohol, polyethylene pyrrole network alkane ketone, ethyl cellulose and hydroxypropyl emthylcellulose, ethyl cellulose and methylcellulose, polyacrylic resin Ⅳ, polyacrylic resin Ⅱ and polyacrylic resin Ⅲ; The mixture of polyacrylic resin Ⅲ and hydroxypropyl emthylcellulose;
Disintegrating agent comprises and being selected from: cross-linking sodium carboxymethyl cellulose, carboxymethyl starch are received, carboxymethyl starch is received, mixture in polyvinylpolypyrrolidone and crospolyvinylpyrrolidone;
Surfactant comprises and being selected from: the mixture in poloxamer, stearyl alcohol sodium sulfonate, sodium lauryl sulphate, cetrimonium bronmide, sodium alginate and Tween 80;
Porogen comprises and being selected from: the mixture of Polyethylene Glycol, polyvinylpyrrolidone, microcrystalline Cellulose, hydroxypropyl emthylcellulose, carbonate and bicarbonate;
Binding agent comprises and being selected from: the mixture in ethyl cellulose, starch slurry and polyvidone k30;
Plasticizer is selected from: triethyl citrate;
Antitackiness agent comprises and being selected from: micropowder silica gel.
Inside and outside addition selected by disintegrating agent, and interior dosage is 31%, and outer dosage is 69%.Solvent is the mixture being selected from alcoholic solution and Aqueous Solutions of Polyethylene Glycol; Ethanol solution concentration 70%, the concentration of Aqueous Solutions of Polyethylene Glycol is 15%.The dosage 60mg of sustained-release pellet preparation.
The preparation method of Azilsartan film controlling type sustained-release pellet preparation, comprises the following steps:
1) by being dissolved in solvent after above-mentioned raw material micronization by weight, sieving and being mixed to form pastille coating solution; In stirring, coating solution is placed more than 50min and make it complete swelling;
2) by celphere preheating 55min;
3) adopt spray mode at the bottom of fluid bed to add medicine to, the operation process of fluid bed is by progressively slowing down soon, and fluidized-bed process parameter is:
Pump speed 5rpm, temperature 31 DEG C, atomizing pressure 270kpa, rotary speed 450rpm, rotating disk height 7mm, blower fan frequency 35hz.
Embodiment 7
Azilsartan film controlling type sustained-release pellet preparation, by by following material dissolution by weight in solvent, the periphery preparation adopting pressure spray process at the bottom of fluid bed to be sprayed at celphere is formed:
Raw material is by micronization processes, and the particle diameter of Azilsartan is 2 microns; Celphere is microcrystalline Cellulose ball, and its particle diameter is 0.9mm.The periphery of celphere is provided with pastille coating rete, pastille coating rete weightening finish 11%.
Coating filmogen comprises and being selected from: the mixture of the mixture of the mixture of ethyl cellulose and hydroxypropyl emthylcellulose, ethyl cellulose and methylcellulose, polyacrylic resin Ⅳ, polyacrylic resin Ⅱ and polyacrylic resin Ⅲ;
Disintegrating agent comprises and being selected from: low-substituted hydroxypropyl cellulose, carboxymethyl starch are received, carboxymethyl starch is received, mixture in polyvinylpolypyrrolidone and crospolyvinylpyrrolidone;
Surfactant comprises and being selected from: the mixture of sodium lauryl sulphate, cetrimonium bronmide, sodium alginate and Tween 80;
Porogen comprises and being selected from: the mixture of Polyethylene Glycol, polyvinylpyrrolidone, microcrystalline Cellulose, hydroxypropyl emthylcellulose, carbonate and bicarbonate;
Binding agent comprises and being selected from: the mixture of sodium carboxymethyl cellulose and polyvidone k30;
Plasticizer is selected from: the mixture of triethyl citrate, dibutyl sebacate and alkenyl succinic anhydride;
Antitackiness agent comprises and being selected from: magnesium stearate.
Inside and outside addition selected by disintegrating agent, and interior dosage is 33%, and outer dosage is 67%.Solvent is be selected from the mixture in alcoholic solution, Aqueous Solutions of Polyethylene Glycol and phosphate buffered solution; Ethanol solution concentration is 90%, and the concentration of Aqueous Solutions of Polyethylene Glycol is 15%; The pH value of phosphate buffered solution is 6.The dosage 60mg of sustained-release pellet preparation.
The preparation method of Azilsartan film controlling type sustained-release pellet preparation, comprises the following steps:
1) by being dissolved in solvent after above-mentioned raw material micronization by weight, sieving and being mixed to form pastille coating solution; In stirring, coating solution is placed more than 50min and make it complete swelling;
2) by celphere preheating 90min;
3) adopt spray mode at the bottom of fluid bed to add medicine to, the operation process of fluid bed is by progressively slowing down soon, and fluidized-bed process parameter is:
Pump speed 5rpm, temperature 40 DEG C, atomizing pressure 420kpa, rotary speed 510rpm, rotating disk height 7mm, blower fan frequency 37hz.
Embodiment 8
Azilsartan film controlling type sustained-release pellet preparation, by by following material dissolution by weight in solvent, the periphery preparation adopting pressure spray process at the bottom of fluid bed to be sprayed at celphere is formed:
Raw material is by micronization processes, and the particle diameter of Azilsartan is 4 microns; Celphere is microcrystalline Cellulose ball, and its particle diameter is 0.87mm.The periphery of celphere is provided with pastille coating rete, pastille coating rete weightening finish 8%.
Coating filmogen comprises and being selected from: the mixture of the mixture of the mixture of polyvinyl alcohol, polyethylene pyrrole network alkane ketone, ethyl cellulose and hydroxypropyl emthylcellulose, ethyl cellulose and methylcellulose, polyacrylic resin Ⅳ, polyacrylic resin Ⅱ and polyacrylic resin Ⅲ; The mixture of polyacrylic resin Ⅲ and hydroxypropyl emthylcellulose;
Disintegrating agent comprises and being selected from: low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch are received, carboxymethyl starch is received, the mixture of polyvinylpolypyrrolidone and crospolyvinylpyrrolidone;
Surfactant comprises and being selected from: the mixture in poloxamer, sodium lauryl sulphate, cetrimonium bronmide, sodium alginate and Tween 80;
Porogen comprises and being selected from: the mixture of lactose, Polyethylene Glycol, polyvinylpyrrolidone, microcrystalline Cellulose, hydroxypropyl emthylcellulose, carbonate and bicarbonate;
Binding agent comprises and being selected from: the mixture of sodium carboxymethyl cellulose, ethyl cellulose, starch slurry and polyvidone k30;
Plasticizer is selected from: the mixture of triethyl citrate, dibutyl sebacate and alkenyl succinic anhydride;
Antitackiness agent comprises and being selected from: the mixture of micropowder silica gel, Pulvis Talci and magnesium stearate.
Inside and outside addition selected by disintegrating agent, and interior dosage is 28%, and outer dosage is 62%.
Solvent is the mixture being selected from alcoholic solution and Aqueous Solutions of Polyethylene Glycol and phosphate buffered solution; Ethanol solution concentration is 90%, and the concentration of Aqueous Solutions of Polyethylene Glycol is 15%; The pH value of phosphate buffered solution is 6.The dosage 60mg of sustained-release pellet preparation.
The preparation method of Azilsartan film controlling type sustained-release pellet preparation, comprises the following steps:
1) by being dissolved in solvent after above-mentioned raw material micronization by weight, sieving and being mixed to form pastille coating solution; In stirring, coating solution is placed 150min and make it complete swelling;
2) by celphere preheating 85min;
3) adopt spray mode at the bottom of fluid bed to add medicine to, the operation process of fluid bed is by progressively slowing down soon, and fluidized-bed process parameter is:
Pump speed 7rpm, temperature 31 DEG C, atomizing pressure 270kpa, rotary speed 470rpm, rotating disk height 7mm, blower fan frequency 43hz.
Table 1 embodiment 1-embodiment 8 mode of appearance is investigated
Above table shows that the slow-release micro-pill mode of appearance obtained is good.
Table 2 embodiment 1-embodiment 8 cumulative release percentage rate is investigated
Above-described embodiment 1-embodiment 6 cumulative release percentage rate shows, obtained slow-release micro-pill has obvious sustained releasing character.
Embodiment 9
The component proportion of the Azilsartan film controlling type sustained-release pellet preparation of the present embodiment, with embodiment 1, has difference only and is:
The celphere periphery of sustained-release pellet preparation sets gradually into medicine layer from inside to outside and eases up and release the form of coating rete, and its preparation method comprises the following steps:
1) by celphere preheating 60min, by above-mentioned raw material micronization by weight;
2) above-mentioned Azilsartan by weight, after micronization and coating filmogen are dissolved in solvent, add above-mentioned antiplastering aid on demand and form medicinal liquid, stir after placing 70min and be sprayed at celphere periphery formation medicine carrying micropill by pressure spray process at the bottom of fluid bed; Described fluidized-bed process parameter is:
Pump speed 2rpm, temperature 40 DEG C, atomizing pressure 150kpa, rotary speed 200rpm, rotating disk height 3mm, blower fan frequency 42hz.
4) the 18 object medicine carrying micropills getting above-mentioned preparation are appropriate, added in solvent by above-mentioned raw material by weight and form coating solution, and be placed in fluid bed by medicine carrying micropill and adopt the end to spray mode coating to the weightening finish needed, described fluidized-bed process parameter is:
Pump speed 2rpm, temperature 45 C, atomizing pressure 150kpa, rotary speed 300rpm, rotating disk height 3mm, blower fan frequency 45hz.
Embodiment 10
The component proportion of the Azilsartan film controlling type sustained-release pellet preparation of the present embodiment, with embodiment 2, has difference only and is:
The celphere periphery of sustained-release pellet preparation sets gradually into medicine layer from inside to outside and eases up and release the form of coating rete, and its preparation method comprises the following steps:
1) by celphere preheating 80min, by above-mentioned raw material micronization by weight;
2) above-mentioned Azilsartan by weight, after micronization and coating filmogen are dissolved in solvent, add above-mentioned antiplastering aid on demand and form medicinal liquid, stir after placing 60min and be sprayed at celphere periphery formation medicine carrying micropill by pressure spray process at the bottom of fluid bed; Described fluidized-bed process parameter is:
Pump speed 5rpm, temperature 60 C, atomizing pressure 300kpa, rotary speed 400rpm, rotating disk height 6mm, blower fan frequency 60hz.
4) the 24 object medicine carrying micropills getting above-mentioned preparation are appropriate, added in solvent by above-mentioned raw material by weight and form coating solution, and be placed in fluid bed by medicine carrying micropill and adopt the end to spray mode coating to the weightening finish needed, described fluidized-bed process parameter is:
Pump speed 5rpm, temperature 65 DEG C, atomizing pressure 300kpa, rotary speed 450rpm, rotating disk height 6mm, blower fan frequency 60hz.
Embodiment 11
The component proportion of the Azilsartan film controlling type sustained-release pellet preparation of the present embodiment, with embodiment 3, has difference only and is:
The celphere periphery of sustained-release pellet preparation sets gradually into medicine layer from inside to outside and eases up and release the form of coating rete, and its preparation method comprises the following steps:
1) by celphere preheating 100min, by above-mentioned raw material micronization by weight;
2) above-mentioned Azilsartan by weight, after micronization and coating filmogen are dissolved in solvent, add above-mentioned antiplastering aid on demand and form medicinal liquid, stir after placing 80min and be sprayed at celphere periphery formation medicine carrying micropill by pressure spray process at the bottom of fluid bed; Described fluidized-bed process parameter is:
Pump speed 3rpm, temperature 48 DEG C, atomizing pressure 200kpa, rotary speed 300rpm, rotating disk height 4mm, blower fan frequency 50hz.
4) the 20 object medicine carrying micropills getting above-mentioned preparation are appropriate, added in solvent by above-mentioned raw material by weight and form coating solution, and be placed in fluid bed by medicine carrying micropill and adopt the end to spray mode coating to the weightening finish needed, described fluidized-bed process parameter is:
Pump speed 4rpm, temperature 60 C, atomizing pressure 280kpa, rotary speed 400rpm, rotating disk height 5mm, blower fan frequency 50hz.
Table 3 embodiment 9-embodiment 11 mode of appearance is investigated
Table 4 embodiment 9-embodiment 11 cumulative release percentage rate is investigated
Above-mentioned specific embodiment has carried out detailed elaboration to principle of the present invention and embodiment, and it act as understands design of the present invention for helping; For one of ordinary skill in the art, according to thought of the present invention, can make a change for detailed description of the invention and application scope, but described change all should be considered as within concept of the present invention.
Claims (10)
1. Azilsartan film controlling type sustained-release pellet preparation, it is characterized in that by by following material dissolution by weight in solvent, the periphery preparation adopting pressure spray process at the bottom of fluid bed to be sprayed at celphere is formed:
Wherein, the purity of described Azilsartan is more than 97%.
2. Azilsartan film controlling type sustained-release pellet preparation according to claim 1, it is characterized in that by by following material dissolution by weight in solvent, the periphery preparation adopting pressure spray process at the bottom of fluid bed to be sprayed at celphere is formed:
3. Azilsartan film controlling type sustained-release pellet preparation according to claim 1 and 2, is characterized in that: described raw material is by micronization processes, and the particle diameter of described Azilsartan is 1-5 micron; Described celphere is microcrystalline Cellulose ball, and its particle diameter is 0.8-1.2mm.
4. Azilsartan film controlling type sustained-release pellet preparation according to claim 1 and 2, is characterized in that: the periphery of described celphere is provided with pastille coating rete, described pastille coating rete weightening finish 2-15%.
5. Azilsartan film controlling type sustained-release pellet preparation according to claim 1 and 2, is characterized in that: the periphery of described celphere is provided with pastille coating rete, described pastille coating rete weightening finish 6-10%.
6. Azilsartan film controlling type sustained-release pellet preparation according to claim 1 and 2, is characterized in that: described coating filmogen comprises and being selected from: the mixture of the mixture of the mixture of polyvinyl alcohol, polyethylene pyrrole network alkane ketone, ethyl cellulose and hydroxypropyl emthylcellulose, ethyl cellulose and methylcellulose, polyacrylic resin Ⅳ, polyacrylic resin Ⅱ and polyacrylic resin Ⅲ; The mixture of polyacrylic resin Ⅲ and hydroxypropyl emthylcellulose;
Described disintegrating agent comprises and being selected from: low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch are received, carboxymethyl starch is received, the mixture of one or more in polyvinylpolypyrrolidone and crospolyvinylpyrrolidone;
Described surfactant comprises and being selected from: the mixture of one or more in sodium lauryl sulfate, poloxamer, stearyl alcohol sodium sulfonate, sodium lauryl sulphate, cetrimonium bronmide, sodium alginate and Tween 80;
Described porogen comprises and being selected from: the mixture of one or more in lactose, Polyethylene Glycol, polyvinylpyrrolidone, microcrystalline Cellulose, hydroxypropyl emthylcellulose, carbonate and bicarbonate;
Described binding agent comprises and being selected from: the mixture of one or more in sodium carboxymethyl cellulose, ethyl cellulose, starch slurry and polyvidone k30;
Described plasticizer is selected from: the mixture of one or more in triethyl citrate, dibutyl sebacate and alkenyl succinic anhydride;
Described antitackiness agent comprises and being selected from: the mixture of one or more in micropowder silica gel, Pulvis Talci and magnesium stearate.
7. Azilsartan film controlling type sustained-release pellet preparation according to claim 6, is characterized in that: inside and outside addition selected by described disintegrating agent, and interior dosage is 25-40%, and outer dosage is 60-75%.
8. Azilsartan film controlling type sustained-release pellet preparation according to claim 1, is characterized in that: described solvent is one or both the mixture be selected from alcoholic solution, Aqueous Solutions of Polyethylene Glycol and phosphate buffered solution; Described ethanol solution concentration is 60-90%, and the concentration of described Aqueous Solutions of Polyethylene Glycol is: 5-20%; The pH value of described phosphate buffered solution is 5-7.
9., according to arbitrary described Azilsartan film controlling type sustained-release pellet preparation of claim 1-8, it is characterized in that: the dosage≤150mg of described sustained-release pellet preparation.
10. a preparation method for arbitrary described Azilsartan film controlling type sustained-release pellet preparation of claim 1-9, is characterized in that comprising the following steps:
1) by being dissolved in solvent after above-mentioned raw material micronization by weight, sieving and being mixed to form pastille coating solution; In stirring, coating solution is placed more than 50min and make it complete swelling;
2) by celphere preheating 50-120min;
3) adopt spray mode at the bottom of fluid bed to add medicine to, the operation process of described fluid bed is by progressively slowing down soon, and described fluidized-bed process parameter is:
Pump speed 4-8rpm, temperature 30-50 DEG C, atomizing pressure 250-500kpa, rotary speed 400-550rpm, rotating disk height 6-9mm, blower fan frequency 32-50hz.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108434113A (en) * | 2018-04-11 | 2018-08-24 | 安徽中医药大学 | Azilsartan osmotic pump type controlled release tablets and preparation method thereof |
| JP2018154596A (en) * | 2017-03-17 | 2018-10-04 | 東和薬品株式会社 | Azilsartan-containing solid pharmaceutical composition |
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| WO2010075347A2 (en) * | 2008-12-23 | 2010-07-01 | Takeda Pharmaceutical Company Limited | Methods of treating hypertension with at least one angiotensin ii receptor blocker and chlorthalidone |
| CN103211798A (en) * | 2012-01-18 | 2013-07-24 | 北京天衡药物研究院 | Losartan potassium membrane controlled-release pellet capsule |
| CN103933000A (en) * | 2014-05-06 | 2014-07-23 | 山东新时代药业有限公司 | Azilsartan tablet and preparation method thereof |
| CN104644588A (en) * | 2015-02-13 | 2015-05-27 | 山东鲁抗立科药业有限公司 | Azilsartan intragastric-floating sustained release tablet and preparation method thereof |
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| CN103211798A (en) * | 2012-01-18 | 2013-07-24 | 北京天衡药物研究院 | Losartan potassium membrane controlled-release pellet capsule |
| CN103933000A (en) * | 2014-05-06 | 2014-07-23 | 山东新时代药业有限公司 | Azilsartan tablet and preparation method thereof |
| CN104644588A (en) * | 2015-02-13 | 2015-05-27 | 山东鲁抗立科药业有限公司 | Azilsartan intragastric-floating sustained release tablet and preparation method thereof |
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| JP2018154596A (en) * | 2017-03-17 | 2018-10-04 | 東和薬品株式会社 | Azilsartan-containing solid pharmaceutical composition |
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