CN104173313A - Rivaroxaban troche pharmaceutical composition - Google Patents
Rivaroxaban troche pharmaceutical composition Download PDFInfo
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- CN104173313A CN104173313A CN201410420048.8A CN201410420048A CN104173313A CN 104173313 A CN104173313 A CN 104173313A CN 201410420048 A CN201410420048 A CN 201410420048A CN 104173313 A CN104173313 A CN 104173313A
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Abstract
The invention belongs to the technical field of medicines, relates to a rivaroxaban troche pharmaceutical composition, and particularly relates to a pharmaceutical composition in form of a troche. The pharmaceutical composition includes rivaroxaban, a diluent, a disintegrant, an adhesive, a wetting agent and a lubricant. Each troche comprises 1-100mg of rivaroxaban. The troche can be further coated, for example, a film coated troche. The troche provided by the invention has the advantages described in specification. The rivaroxaban troche pharmaceutical composition has excellent dissolving-out performance, stability and other preparation performances.
Description
Technical field
The invention belongs to medical technical field, relate to a kind of compositions of anticoagulation medicine, the pharmaceutical composition that particularly relates to a kind of FXa inhibitor razaxaban is its tablet particularly, also relates to the preparation method of this pharmaceutical composition.
Background technology
Razaxaban is in WO01/47919, and it has lower array structure
Molecular formula C
19h
18clN
3o
5s, molecular weight 435.89, English name rivaroxaban, research and development code name BAY5927939, trade name Xarelto, CAS366789-02-8, domestic nomenclature of drug is auspicious appropriate for visiing, chinesization formal name used at school be the chloro-N-of 5-((5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl } methyl)-2-thenoyl amine, English chemistry 5-Chloro-N-by name ((5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl] and-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide.The razaxaban using is clinically a kind of pure (S)-enantiomer, and it is a kind of tasteless, non-hygroscopic, white to micro-yellow powder.Razaxaban is slightly soluble in organic solvent (for example acetone, PEG400), hardly water-soluble and water-bearing media.The product of clinical listing is oral tablet, and every containing razaxaban 10mg, 15mg or 20mg.
Razaxaban is the anticoagulation medicine of low-molecular-weight, oral administration.Described medicine directly suppresses the activity form of serine protease factor Xa (FXa).Razaxaban can and be treated various thrombotic diseases for prevention, particularly prevents and treat inaccessible and restenosis, apoplexy, transient ischemic attack and Peripheral arterial occlusive disease again after venous thrombosis (DVT), pulmonary infarction (PE), myocardial infarction, angina pectoris, angioplasty or aortocoronary bypass (aortocoronary bypass).Razaxaban is for preventing venous thromboembolism after adult patients hip joint and replacement knee in arthroplasty and the formation of pulmonary infarction.In the fields such as secondary prevention, treatment atrial fibrillation and acute coronary syndrome of Chinese patients with deep venous thrombosis, there is certain therapeutic effect simultaneously.
Spendable anticoagulant comprises unfractionated heparin (unfractionated heparin clinically at present, UFH), low molecular weight heparin (low molecular weight heparin, LMWH), vitamin K antagon warfarin (warfarin) and pentasaccharide fondaparinux sodium (fondaparinux, Arixtra).
Heparin class material, by interacting and produce anticoagulation effect with various blood clotting cascade correlation factors, is mainly used in clinically short-term antithrombotic heparin class material and is also often limited the use of in inpatient or short-term (≤2wk) prevention venous thromboembolism sexual behavior part).In view of the market opportunity is larger and each defectiveness of existing medicine, drugmaker obviously strengthens the concern of novel anticoagulation medicine research and development and throwing people.Certainly, the curative effect of these anticoagulation new drugs should at least be equivalent to existing medicine, but safety must improve, and particularly needs to reduce bleeding risk, simultaneously dosage regimen easy (if oral etc.).
Because Xa factor is that a kind of thrombin forms necessary thrombin direct thrombin inhibitor, research Xa factor inhibitor plays key effect to Effect of Anti coagulant.The member that receives much concern in oral Selective activation Xa factor inhibitor is Eliquis (Apixaban, trade name Eliquis), dabigatran, three new oral anticoagulant of razaxaban.In these three kinds of oral anticoagulants of Europe approval, to compare with preventing the standard care scheme Enoxaparin of venous thromboembolism after current bone surgery, razaxaban and Eliquis highlight advantage respectively in RECORD test and ADVANCE test.Expert represents, the result of these tests side by side, it is better that the curative effect of razaxaban seems.
Razaxaban is by Bayer and Johson & Johnson's cooperative research and development.This medicine be the efficient (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides FXa inhibitor that obtains by high flux screening as lead compound, then screen from derivative optimization a series of oxazolidinones that obtain, finally by investigations such as pharmacodynamics, pharmacokineticss, become clinical material standed for.Clinical by the III phase at present, in JIUYUE in 2008, within 15th, in Canada and European Union, obtained listing approval respectively with October 1.Now in 29 countries that comprising China, get permission listing, for preventing venous thromboembolism after adult patients hip joint and replacement knee in arthroplasty and the formation of pulmonary infarction.In theory, safety is better than in the past all anticoagulant.Through U.S. FDA approval listing, have certain therapeutic effect in the fields such as secondary prevention, treatment atrial fibrillation and acute coronary syndrome of Chinese patients with deep venous thrombosis in July, 2011 simultaneously.Razaxaban directly suppresses Xa factor by high selectivity and reaches blood coagulation resisting function, compares with traditional anticoagulation medicine, has the features such as taking convenience, onset is rapid, safety is high.
The pharmaceutical composition that existing numerous documents and materials disclose razaxaban is its tablet particularly.
CN200680045548.1 prepares the razaxaban of unformed shape and semi-stability crystal form II by dissolution method, fusion method, extrusion by melting, then is applied to, in oral administration solid pharmaceutical dosage form, can significantly improve its dissolution rate and oral administration biaavailability.But owing to using razaxaban amorphous or meta form; can be subject to pining down of stability problem; due to razaxaban, there is on the other hand the dissolubility of extreme difference; at the acceptable solvent of medicine also indissoluble in ethanol or acetone for example; by dissolution method, prepare a large amount of solvent of amorphous needs; the problem of solvent recovery and environmental conservation causes it to be difficult to realize suitability for industrialized production, adds that its fusing point is high, by fusion method, is prepared and amorphously also can be produced disadvantageous degradable component.
WO2010/146179A2 is used micronization principal agent and adjuvant grinding altogether, hot-melt extruded, dry granulation technology to prepare oral solid drug composition preparation, and its dissolution rate can reach at least stripping 70% of 30min.
CN103550165A (201310504757.X, Zhejiang Huahai) relate to a kind of oral solid drug composition and preparation method thereof of the quick release that contains razaxaban, it is processed suitable pharmaceutic adjuvant by wet granulation technology, mix with razaxaban active component again, obtain the pharmaceutical composition that stripping significantly improves, particularly first pharmaceutically acceptable adjuvant is obtained not containing the blank granule of active component by wet granulation, then razaxaban and above-mentioned blank granule and extra pharmaceutically acceptable additive are mixed, make oral solid drug composition.It is simple that the preparation method that it is believed that this invention has technique, and the feature that suitability for industrialized is produced has solved the problem of preparation technology's more complicated of prior art.
CN103877060A (201410113352.8, the honest Qingjian River) discloses the composition and method of making the same that comprises razaxaban.This invention be take razaxaban as active component, by pretreatment, its particle diameter is reached below 10 μ m, and employing and hydrophilicity condiment, disintegrating agent, surfactant mix the technique of rear wet granulation, effectively raises dissolution and the dissolution rate of razaxaban.
CN1886120B (200480035106.x) proposes razaxaban to be suspended in and in binder solution, to make its hydrophiling, thereby obtains discharging fast and significantly improving the razaxaban preparation of bioavailability.
CN103705520A (201310732239.3, China Resources match section) discloses a kind of preparation method of razaxaban solid composite.Adopt the method for waterproof pulverization to pulverize razaxaban, be prepared into suspension solution simultaneously; Suspension solution is sprayed into and in other adjuvants, makes suitable granule; Further be prepared into minimum pharmaceutical dosage unit.The concrete grammar of this invention comprises the following steps: razaxaban crude drug (not micronization), binding agent, wetting agent are added to water mix homogeneously, obtain suspension solution I; Suspension solution I is carried out to waterproof pulverization, obtain suspension solution II; Adopt the mode spraying into join in the diluent of pharmaceutical composition suspension solution II, and dry granule and the powder that is prepared into razaxaban pharmaceutical composition; And granule is become to the medicinal minimum dose unit of razaxaban with powder preparation.It is believed that this invention beneficial effect comprises: solved when adopting conventional breaking method and preparing razaxaban microgranule, particle diameter can not be reduced to the problem of 5 μ m, is conducive to increase the dissolution rate of razaxaban preparation.
Tablet coating is useful in many cases, for example the tablet of different dosage adopts that different colours coating is beneficial to distinguish, tablet coating can also contribute to make active component and extraneous moisture and air from the stability with raising medicine.Yet the inventor has been found that the tablet that uses art methods to prepare, its friability performance is not enough, and this will have a strong impact on further wraps up in film-coat by tablet.
Therefore, new particularly its tablet method of its film coating tablet more particularly of razaxaban solid composite medicament of preparing is still expected to have in this area, expects that the compositions preparing by the method has the good pharmaceutical properties of one or more aspects.
Summary of the invention
The object of the present invention is to provide a kind of new particularly its tablet method of its film coating tablet more particularly of razaxaban solid composite medicament of preparing, expect that the compositions preparing by the method has the good pharmaceutical properties of one or more aspects.The present invention have been surprisingly found that, uses the film coating tablet of the present invention's formula to present the useful pharmaceutical properties of at least one aspect.The present invention is based on this discovery and be accomplished.
For this reason, first aspect present invention relates to a kind of pharmaceutical composition that is tablet form, wherein comprises: razaxaban, diluent, disintegrating agent, binding agent, wetting agent, lubricant.
According to the pharmaceutical composition of first aspect present invention any one, wherein said razaxaban is used with micronization form.In one embodiment, razaxaban has lower than 10 μ m, preferably has the particle mean size X of 1-8 μ m
50and lower than 20 μ m, preferably lower than the X of 15 μ m
90(90% ratio).
According to the pharmaceutical composition of first aspect present invention any one, in every, wherein said tablet, comprising razaxaban is 1-100mg, for example comprising razaxaban in every is 2-50mg, for example comprising razaxaban in every is 5-40mg, and for example comprising razaxaban in every is 5mg, 10mg, 15mg, 20mg, 30mg, 40mg.
According to the pharmaceutical composition of first aspect present invention any one, wherein said diluent is to be selected from following one or more: cellulose, microcrystalline Cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltose alcohol, Sorbitol, xylitol, lactose (for example Lactis Anhydrous or lactose monohydrate), D-glucose, maltose, sucrose, glucose, fructose or maltodextrin.In one embodiment, described diluent is the combination of microcrystalline Cellulose and lactose.In one embodiment, described diluent is the combination of microcrystalline Cellulose and lactose, and the two weight ratio of microcrystalline Cellulose and lactose is 0.1～10:1, for example 0.2～5:1.
According to the pharmaceutical composition of first aspect present invention any one, wherein, in the razaxaban of every 10 weight portions, the consumption of described diluent is 20-200 weight portion, for example 20-150 weight portion.
According to the pharmaceutical composition of first aspect present invention any one, wherein said disintegrating agent is to be selected from following one or more: carboxymethyl cellulose, cross-linked carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, crospovidone, low-substituted hydroxypropyl cellulose (L-HPC), carboxymethyl starch sodium, primojel, boiling starch, wheaten starch, corn starch, rice starch or potato starch.
According to the pharmaceutical composition of first aspect present invention any one, wherein, in the razaxaban of every 10 weight portions, the consumption of described disintegrating agent is 1-20 weight portion, for example 1.5-7.5 weight portion.
According to the pharmaceutical composition of first aspect present invention any one, wherein said binding agent is to be selected from following one or more: hydroxypropyl emthylcellulose (HPMC), carboxymethyl cellulose (sodium salt or calcium salt), ethyl cellulose, methylcellulose, hydroxyethyl-cellulose, ethylhydroxyethylcellulose, hydroxypropyl fiber element (HPC), L-HPC, polyvinyl pyrrolidone, polyvinyl alcohol, acrylic acid polymer and salt thereof, vinylpyrrolidone/vinyl acetate copolymer (KollidonVA64 for example, BASF), gelatin, guar gum, boiling starch, alginate or xanthan gum.In one embodiment, described binding agent is HPMC.
According to the pharmaceutical composition of first aspect present invention any one, wherein, in the razaxaban of every 10 weight portions, the consumption of described binding agent is 1-10 weight portion, for example 1.5-5 weight portion.In one embodiment, described binding agent water is mixed with concentration 1-20%, and the solution of 1-10% is for example used as the binding agent of wet granulation.
According to the pharmaceutical composition of first aspect present invention any one, wherein said wetting agent is to be selected from following one or more: the sodium salt of sulfated fatty alcohol ester is sodium lauryl sulfate for example, sodium lauryl sulphate, sulfosuccinate is dioctyl sodium sulphosuccinate for example, the fatty acid partial ester of polyhydric alcohol is glyceryl monostearate for example, the fatty acid partial ester of sorbitan is sorbitan monolaurate for example, the fatty acid partial ester of polyhydroxy ethylidene sorbitan is many ethylene glycol-sorbitan monolaurate for example, Polyethylene Glycol-sorbitan monostearate or Polyethylene Glycol-dehydrated sorbitol mono-fatty acid ester, polyhydroxy ethylidene fatty alcohol ether, polyhydroxy ethylidene fatty acid ester, the triglyceride of ethylene oxide-propylene oxide block copolymer (for example Pluronic) or ethoxylation.Preferably use sodium lauryl sulfate or sodium lauryl sulphate as wetting agent.
According to the pharmaceutical composition of first aspect present invention any one, wherein, in the razaxaban of every 10 weight portions, the consumption of described wetting agent is 0.2-5 weight portion, for example 0.3-3 weight portion.In one embodiment, described wetting agent is dissolved in described binder solution and uses.
According to the pharmaceutical composition of first aspect present invention any one, wherein said lubricant is to be selected from following one or more: fumaric acid, stearic acid, magnesium stearate, calcium stearate, stearyl fumarate, high molecular fatty alcohol, Polyethylene Glycol, starch (for example, wheaten starch, rice starch, corn starch or potato starch), Pulvis Talci, polymolecularity (colloid) silicon dioxide, Glyceryl Behenate, magnesium oxide, magnesium carbonate, calcium silicates.In one embodiment, preferably use Glyceryl Behenate and/or magnesium stearate as lubricant.
According to the pharmaceutical composition of first aspect present invention any one, wherein, in the razaxaban of every 10 weight portions, the consumption of described magnesium stearate is 0.1-10 weight portion, for example 0.2-5 weight portion, for example 0.5-2 weight portion.According to the pharmaceutical composition of first aspect present invention any one, wherein, in the razaxaban of every 10 weight portions, the consumption of described Glyceryl Behenate is 0.1-10 weight portion, for example 0.2-5 weight portion, for example 0.5-2 weight portion.According to the pharmaceutical composition of first aspect present invention any one, wherein the weight ratio of Glyceryl Behenate and magnesium stearate is 0.5～2:1.According to the pharmaceutical composition of first aspect present invention any one, wherein, in the razaxaban of every 10 weight portions, the consumption of described lubricant is 0.1-10 weight portion, for example 0.2-5 weight portion, for example 0.5-2 weight portion.
According to the pharmaceutical composition of first aspect present invention any one, it is tablet, and it is further by coating.For example it is film coating tablet.For this reason, as tablet, wherein above-mentioned razaxaban, diluent, disintegrating agent, binding agent, wetting agent, lubricant form the label of tablet, and this label is also called plain sheet conventionally; And coating is also called clothing layer etc. conventionally.
According to the pharmaceutical composition of first aspect present invention any one, described coating is to carry out under the condition of adding conventional coating medium that those skilled in the art are familiar with and film former (they are referred to as coating material conventionally), and these coating materials can be to be selected from following one or more: hydroxypropyl cellulose, hydroxypropyl emthylcellulose, ethyl cellulose, polyvinyl pyrrolidone, vinylpyrrolidone/vinyl acetate copolymer are (for example
vA64, BASF), polymer, EUDRAGIT NE 30 D EUDRAGIT NE 30D, methacrylic acid-methyl acrylate copolymer, propylene glycol, Polyethylene Glycol, glyceryl triacetate, triethyl citrate and/or the dye additive/pigment of copolymer, methacrylic acid or the methacrylate of copolymer, dimethylaminomethyl acrylic acid and the neutral methacrylic acid esters of Lac, acrylate and/or methacrylate and methacrylic acid trimethyl ammonium for example titanium dioxide, ferrum oxide, indigo or suitable color lake.There are many thin film coating materials that can obtain from commercial channels this area, the thin film coating material of for example can be directly buying from blocking happy Kanggong department, for example Opadry of various models
product, for example Opadry
295F640021.
According to the pharmaceutical composition that is tablet form of first aspect present invention any one, if it is by coating, described in be wrapped in the 1-6% that coatings weight outside label accounts for whole tablet total weight amount, 1-4% for example.
According to the pharmaceutical composition of first aspect present invention any one, it is tablet form, it adopts 2010 editions appendix XC dissolution method the second methods of Chinese Pharmacopoeia (oar method) 75rpm, the pH4.5 acetate buffer 900mL of usining containing 0.2% sodium lauryl sulphate detects as dissolution medium, and 30min dissolution is not less than 85%.
According to the pharmaceutical composition of first aspect present invention any one, it is tablet form, and its formula having described in arbitrary embodiment below forms.According to the pharmaceutical composition of first aspect present invention any one, it is tablet form, and its formula having described in arbitrary embodiment below forms and made by its corresponding preparation method.
According to the pharmaceutical composition of first aspect present invention any one, it is prepared by method described in second aspect present invention or third aspect any one.
Further, second aspect present invention provides the method for preparing pharmaceutical composition described in first aspect present invention any one, and it comprises the following steps:
(a) binding agent and wetting agent are dissolved in suitable quantity of water, make the concentration of binding agent in this solution reach 1-10%, then add the material medicine razaxaban through micronization processes, fully homogenize is suspended in mixed liquor medicine, obtains suspension;
(b) diluent and disintegrating agent are fully mixed in fluidized bed pelletizer, then step (a) gained suspension is sprayed in the hybrid particles of fluidized bed pelletizer to carry out wet granulation, wet granular is dry in fluid bed, obtains dried particles;
(c) make step (b) gained dried particles and mix lubricant even, be pressed into tablet; Optionally,
(d), by step (c) gained tablet wrap film clothing, obtain being the pharmaceutical composition of film coated tablet form.
Further, third aspect present invention provides preparation to be the method for the pharmaceutical composition of tablet form, in described pharmaceutical composition, comprises: razaxaban, diluent, disintegrating agent, binding agent, wetting agent, lubricant, and the method comprises the following steps:
(a) binding agent and wetting agent are dissolved in suitable quantity of water, make the concentration of binding agent in this solution reach 1-10%, then add the material medicine razaxaban through micronization processes, fully homogenize is suspended in mixed liquor medicine, obtains suspension;
(b) diluent and disintegrating agent are fully mixed in fluidized bed pelletizer, then step (a) gained suspension is sprayed in the hybrid particles of fluidized bed pelletizer to carry out wet granulation, wet granular is dry in fluid bed, obtains dried particles;
(c) make step (b) gained dried particles and mix lubricant even, be pressed into tablet; Optionally,
(d), by step (c) gained tablet wrap film clothing, obtain being the pharmaceutical composition of film coated tablet form.
According to the method for third aspect present invention any one, wherein said razaxaban is used with micronization form.In one embodiment, razaxaban has lower than 10 μ m, preferably has the particle mean size X of 1-8 μ m
50and lower than 20 μ m, preferably lower than the X of 15 μ m
90(90% ratio).
According to the method for third aspect present invention any one, in every, wherein said tablet, comprising razaxaban is 1-100mg, for example comprising razaxaban in every is 2-50mg, for example comprising razaxaban in every is 5-40mg, and for example comprising razaxaban in every is 5mg, 10mg, 15mg, 20mg, 30mg, 40mg.
According to the method for third aspect present invention any one, wherein said diluent is to be selected from following one or more: cellulose, microcrystalline Cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltose alcohol, Sorbitol, xylitol, lactose (for example Lactis Anhydrous or lactose monohydrate), D-glucose, maltose, sucrose, glucose, fructose or maltodextrin.In one embodiment, described diluent is the combination of microcrystalline Cellulose and lactose.In one embodiment, described diluent is the combination of microcrystalline Cellulose and lactose, and the two weight ratio of microcrystalline Cellulose and lactose is 0.1～10:1, for example 0.2～5:1.
According to the method for third aspect present invention any one, wherein, in the razaxaban of every 10 weight portions, the consumption of described diluent is 20-200 weight portion, for example 20-150 weight portion.
According to the method for third aspect present invention any one, wherein said disintegrating agent is to be selected from following one or more: carboxymethyl cellulose, cross-linked carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, crospovidone, low-substituted hydroxypropyl cellulose (L-HPC), carboxymethyl starch sodium, primojel, boiling starch, wheaten starch, corn starch, rice starch or potato starch.
According to the method for third aspect present invention any one, wherein, in the razaxaban of every 10 weight portions, the consumption of described disintegrating agent is 1-20 weight portion, for example 1.5-7.5 weight portion.
According to the method for third aspect present invention any one, wherein said binding agent is to be selected from following one or more: hydroxypropyl emthylcellulose (HPMC), carboxymethyl cellulose (sodium salt or calcium salt), ethyl cellulose, methylcellulose, hydroxyethyl-cellulose, ethylhydroxyethylcellulose, hydroxypropyl fiber element (HPC), L-HPC, polyvinyl pyrrolidone, polyvinyl alcohol, acrylic acid polymer and salt thereof, vinylpyrrolidone/vinyl acetate copolymer (KollidonVA64 for example, BASF), gelatin, guar gum, boiling starch, alginate or xanthan gum.In one embodiment, described binding agent is HPMC.
According to the method for third aspect present invention any one, wherein, in the razaxaban of every 10 weight portions, the consumption of described binding agent is 1-10 weight portion, for example 1.5-5 weight portion.In one embodiment, described binding agent water is mixed with concentration 1-20%, and the solution of 1-10% is for example used as the binding agent of wet granulation.
According to the method for third aspect present invention any one, wherein said wetting agent is to be selected from following one or more: the sodium salt of sulfated fatty alcohol ester is sodium lauryl sulfate for example, sodium lauryl sulphate, sulfosuccinate is dioctyl sodium sulphosuccinate for example, the fatty acid partial ester of polyhydric alcohol is glyceryl monostearate for example, the fatty acid partial ester of sorbitan is sorbitan monolaurate for example, the fatty acid partial ester of polyhydroxy ethylidene sorbitan is many ethylene glycol-sorbitan monolaurate for example, Polyethylene Glycol-sorbitan monostearate or Polyethylene Glycol-dehydrated sorbitol mono-fatty acid ester, polyhydroxy ethylidene fatty alcohol ether, polyhydroxy ethylidene fatty acid ester, the triglyceride of ethylene oxide-propylene oxide block copolymer (for example Pluronic) or ethoxylation.Preferably use sodium lauryl sulfate or sodium lauryl sulphate as wetting agent.
According to the method for third aspect present invention any one, wherein, in the razaxaban of every 10 weight portions, the consumption of described wetting agent is 0.2-5 weight portion, for example 0.3-3 weight portion.In one embodiment, described wetting agent is dissolved in described binder solution and uses.
According to the method for third aspect present invention any one, wherein said lubricant is to be selected from following one or more: fumaric acid, stearic acid, magnesium stearate, calcium stearate, stearyl fumarate, high molecular fatty alcohol, Polyethylene Glycol, starch (for example, wheaten starch, rice starch, corn starch or potato starch), Pulvis Talci, polymolecularity (colloid) silicon dioxide, Glyceryl Behenate, magnesium oxide, magnesium carbonate, calcium silicates.In one embodiment, preferably use Glyceryl Behenate and/or magnesium stearate as lubricant.
According to the method for third aspect present invention any one, wherein, in the razaxaban of every 10 weight portions, the consumption of described magnesium stearate is 0.1-10 weight portion, for example 0.2-5 weight portion, for example 0.5-2 weight portion.According to the pharmaceutical composition of first aspect present invention any one, wherein, in the razaxaban of every 10 weight portions, the consumption of described Glyceryl Behenate is 0.1-10 weight portion, for example 0.2-5 weight portion, for example 0.5-2 weight portion.According to the pharmaceutical composition of first aspect present invention any one, wherein, in the razaxaban of every 10 weight portions, the consumption of described lubricant is 0.1-10 weight portion, for example 0.2-5 weight portion, for example 0.5-2 weight portion.
According to the method for third aspect present invention any one, wherein institute's den of monsters pharmaceutical composition is tablet, and it is further by coating.For example it is film coating tablet.For this reason, as tablet, wherein above-mentioned razaxaban, diluent, disintegrating agent, binding agent, wetting agent, lubricant form the label of tablet, and this label is also called plain sheet conventionally; And coating is also called clothing layer etc. conventionally.
According to the method for third aspect present invention any one, described coating is to carry out under the condition of adding conventional coating medium that those skilled in the art are familiar with and film former (they are referred to as coating material conventionally), and these coating materials can be to be selected from following one or more: hydroxypropyl cellulose, hydroxypropyl emthylcellulose, ethyl cellulose, polyvinyl pyrrolidone, vinylpyrrolidone/vinyl acetate copolymer are (for example
vA64, BASF), polymer, EUDRAGIT NE 30 D EUDRAGIT NE 30D, methacrylic acid-methyl acrylate copolymer, propylene glycol, Polyethylene Glycol, glyceryl triacetate, triethyl citrate and/or the dye additive/pigment of copolymer, methacrylic acid or the methacrylate of copolymer, dimethylaminomethyl acrylic acid and the neutral methacrylic acid esters of Lac, acrylate and/or methacrylate and methacrylic acid trimethyl ammonium for example titanium dioxide, ferrum oxide, indigo or suitable color lake.
According to the method for third aspect present invention any one, if wherein said, be the pharmaceutical composition of tablet form by coating, described in be wrapped in the 1-6% that coatings weight outside label accounts for whole tablet total weight amount, 1-4% for example.
According to the method for third aspect present invention any one, wherein said pharmaceutical composition is tablet form, it adopts 2010 editions appendix XC dissolution method the second methods of Chinese Pharmacopoeia (oar method) 75rpm, the pH4.5 acetate buffer 900mL of usining containing 0.2% sodium lauryl sulphate detects as dissolution medium, and 30min dissolution is not less than 85%.
Further, fourth aspect present invention provides pharmaceutical composition of the present invention for preventing and/or treating the purposes of disease, and described disease is for example myocardial infarction, angina pectoris (comprising irregular angor), the obstruction again after angioplasty or aortocoronary bypass and restenosis, cerebrum block, transient ischemic attack, the closed disease of peripheral arterial, pulmonary infarction or degree of depth phlebothrombosis of thromboembolic disorders especially.
Arbitrary embodiment of applicable equally other the arbitrary embodiment of arbitrary technical characterictic that arbitrary embodiment of either side of the present invention or this either side has or other either side, as long as they can be not conflicting, certainly, at where applicable each other, necessary words can be done suitably to modify to individual features.Be further described with feature to various aspects of the present invention below.
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if when the expressed implication of these documents and the present invention are inconsistent, be as the criterion with statement of the present invention.In addition, various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art, nonetheless, the present invention still wishes at this, these terms and phrase to be described in more detail and to be explained, the term of mentioning and phrase, if any inconsistent with known implication, are as the criterion with the implication that the present invention was explained.
In the present invention if not otherwise indicated, the % relating to is w/w percent.
Known in this field, sodium lauryl sulfate is also called sodium lauryl sulphate etc., and their title can be general.
Razaxaban (Rivaroxaban) is gone through the novel anticoagulant of 10 years cooperative research and development by Bayer Bitterfeld GmbH medicine and Johnson Co., be first direct oral Xa factor inhibitor of the whole world.Its energy high selectivity and contestable suppress Xa factor and the prothrombin activity of free and combination, in dosage-dependence mode, extend activated partial thromboplastin time plate (APTT) and prothrombin time (PT), thereby prolongation clotting time, reduces thrombin and forms.It is high that it has bioavailability, and treatment spectrum of disease is wide, and dose-effect relationship is stable, convenient oral, the feature that bleeding risk is low.In October, 2008, in Canada and European Union's listing that gets the Green Light, commodity are called Xarelto.The listing of the 2011 Nian U.S., so far more than 50 country's listings in the whole world.Go on the market in June, 2009 in the Chinese approval of import, commodity are by name visit auspicious appropriate.The domestic existing specification 10mg of China, the imitated specification of my company is 10mg.
Razaxaban is also the venothrombotic medicine of control.After Orthopaedics Major Operation, venous thromboembolism (VTE) incidence rate is higher, one of patients'perioperative main causes of death, the major reason of unexpected death in Ye Shi hospital, prevention to Orthopaedics Major Operation VTE, can reduce risk of venous thrombosis, alleviate patient suffering, reduce medical expense.Be mainly used in clinically preventing the formation of hip joint and knee prosthesis postoperative patient person deep venous thrombosis (DVT) and pulmonary infarction (PE).Also can be used for preventing non-valvular Patients With Atrial Fibrillation apoplexy and non-central nervous system's property thromboembolism, reduce the risk of coronary syndrome recurrence etc.
According to Amy bodyguard market research agency (IMS Health) data show, within 2008, the global antithrombotic reagent market sales revenue is 18,000,000,000 dollars, increase by 16% on a year-on-year basis, 2009 annual rate of growth are 7.95%, reach 19,500,000,000 dollars, the whole world seven large drug market antithrombotic rate of increase are 7.13%, and market prospect is wide.Within 2012, razaxaban global marketing volume is 6.67 hundred million dollars, and within 2013, global marketing volume reaches 21.24 hundred million dollars.Being the oral new drug of the anticoagulation of first listing over 50 years after warfarin, is another milestone in anticoagulation therapy field and potential lethal thrombus prevention field.
The specific embodiment
By the following examples, can conduct further description the present invention, yet scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and is not deviating under the prerequisite of the spirit and scope of the present invention, can carry out various variations and modification to the present invention.The present invention carries out generality and/or concrete description to the material and the test method that use in test.Although be well known in the art for realizing many materials and the operational approach that the object of the invention used, the present invention still does to describe in detail as far as possible at this.
In following instantiation part, as do not mentioned in addition, the tablet providing provides formula with every consumption; When prepared by reality, with the amounts of 10000/batches, feed intake.If not otherwise indicated, material medicine razaxaban used is used with micronization form, has the particle mean size X of 1-8 μ m
50and lower than the X of 15 μ m
90(90% ratio).While carrying out tabletting below, if not otherwise indicated, use the flat row tabletting of rushing in of suitable diameter, make the hardness of plain sheet within the scope of 60-80N.
embodiment 1: prepare razaxaban tablet
prescription forms (mg/ sheet):
Label:
Razaxaban (micronization) 20.0mg
Microcrystalline Cellulose 35.0mg
Lactose monohydrate 22.9mg
Cross-linked carboxymethyl cellulose (Ac-Di-
fMC) 3.0mg
Hydroxypropyl emthylcellulose (5cp) 3.0mg
Sodium lauryl sulfate 0.5mg
Magnesium stearate 0.6mg;
Coating:
Hydroxypropyl emthylcellulose (15cp) 1.5mg
The Polyethylene Glycol 0.5mg of molecular weight 3350
Titanium dioxide 0.5mg;
Amount to 87.5mg.
Method for making: hydroxypropyl emthylcellulose and sodium lauryl sulfate is soluble in water.Micronized razaxaban is suspended in this solution.Thus preparation suspension the fluidized bed prilling stage as wet granulation liquid spray to the mixed-powder material of the fluidized state being formed by microcrystalline Cellulose, lactose monohydrate and cross-linked carboxymethyl cellulose.After the granule of dried and screened (0.8mm mesh width) gained, add and mix magnesium stearate.The mixture that gets final product tabletting obtaining is thus pressed into the tablet (this tablet can be described as label or plain sheet) of 6mm diameter and hardness 60-80N.Using coating material with suitable quantity of water dissolving/suspendible as coating solution, use this coating solution to carry out coating to above-mentioned plain sheet, obtain film coating tablet.
embodiment 2: prepare razaxaban tablet
prescription forms (mg/ sheet):
Label:
Razaxaban (micronization) 5mg
Microcrystalline Cellulose 40mg
Lactose monohydrate 33.9mg
Cross-linked carboxymethyl cellulose (Ac-Di-
fMC) 3mg
Hydroxypropyl emthylcellulose (3cp) 2mg
Sodium lauryl sulfate 0.5mg
Magnesium stearate 0.6mg;
Coating:
Hydroxypropyl emthylcellulose (15cp) 1.5mg
The Polyethylene Glycol 0.5mg of molecular weight 400
Iron oxide yellow 0.1mg
Titanium dioxide 0.4mg;
Amount to 87.5mg.
Method for making: the method for making according to embodiment 1 is carried out.
embodiment 3: prepare razaxaban tablet
Prescription and method for making are with reference to embodiment 1, and different is only cross-linked carboxymethyl cellulose wherein to be replaced with to the cross-linking sodium carboxymethyl cellulose of equivalent.
embodiment 4: prepare razaxaban tablet
Prescription and method for making are with reference to embodiment 2, and different is only cross-linked carboxymethyl cellulose wherein to be replaced with to the cross-linking sodium carboxymethyl cellulose of equivalent.
embodiment 5: prepare razaxaban tablet
Prescription forms (mg/ sheet):
Razaxaban 10mg
Microcrystalline Cellulose (PH101) 40mg
Lactose monohydrate 27.9mg
Hydroxypropyl emthylcellulose 3mg
Cross-linking sodium carboxymethyl cellulose 3mg
Sodium lauryl sulphate 0.5mg
Magnesium stearate 0.6mg
Opadry (295F640021) 2mg.
1) razaxaban (not micronization), HPMC (E5), sodium lauryl sulphate are added to about 5ml water mix homogeneously, obtain suspension solution I;
2) suspension solution I high-speed stirred ball mill is carried out to wet grinding pulverizing, obtain suspension solution II (through measuring its granularity with Ma Erwen laser particle size analyzer, wherein the d of razaxaban (0.5) is that 1.73, d (0.9) is 4.24);
3) microcrystalline Cellulose PH101, lactose monohydrate, cross-linking sodium carboxymethyl cellulose are added in fluid bed to fluidisation mix homogeneously;
4) adopt fluid bed to be injected to step 3 suspension solution II) the diluent of compositions in, and the dry granule I that is prepared into razaxaban pharmaceutical composition;
5) granule I is added to magnesium stearate mix homogeneously, obtain granule II; And
6) granule II tabletting, the heavy 85mg of sheet, is plain sheet.
Then above gained element sheet is used to Opadry
295F640021 carries out coating, obtains coated tablet.
embodiment 6: prepare razaxaban tablet
The present embodiment carries out 5 tests, is expressed as embodiment 61, embodiment 62, embodiment 63, embodiment 64, embodiment 65.In above-mentioned 5 tests, with reference to formula and the method for embodiment 1-5, different respectively, magnesium stearate is wherein replaced with to the Glyceryl Behenate of equivalent and adds in corresponding process.Obtain five batches of plain sheets and be respectively embodiment 61, embodiment 62, embodiment 63, embodiment 64, embodiment 65, and corresponding 5 batches of coated tablets.
embodiment 7: prepare razaxaban tablet
The present embodiment carries out 5 tests, is expressed as embodiment 71, embodiment 72, embodiment 73, embodiment 74, embodiment 75.In above-mentioned 5 tests, with reference to formula and the method for embodiment 1-5, different respectively, when adding magnesium stearate, also add the Glyceryl Behenate with this magnesium stearate equivalent.Obtain five batches of plain sheets and be respectively embodiment 71, embodiment 72, embodiment 73, embodiment 74, embodiment 75, and corresponding 5 batches of coated tablets.
embodiment 8: prepare razaxaban tablet
Prescription forms (mg/ sheet):
Razaxaban (micronization) 10.0mg
Microcrystalline Cellulose 25mg
Lactose monohydrate 125mg
Cross-linking sodium carboxymethyl cellulose 7.5mg
Hydroxypropyl emthylcellulose (5cp) 5mg
Sodium lauryl sulfate 0.3mg
Glyceryl Behenate 1.33mg
Magnesium stearate 0.67mg;
Method for making: carry out with reference to embodiment 1, Glyceryl Behenate adds together with magnesium stearate, obtains plain sheet; This element sheet is used the coating material of embodiment 1 to carry out coating, and clothing layer accounts for 2.2% of final tablet total weight, obtains coated tablet.
embodiment 9: prepare razaxaban tablet
Prescription forms:
Razaxaban (micronization) 10mg
Microcrystalline Cellulose 20mg
Lactose monohydrate 4mg
Cross-linking sodium carboxymethyl cellulose 1.5mg
Hydroxypropyl emthylcellulose (5cp) 1.5mg
Sodium lauryl sulfate 3mg
Glyceryl Behenate 0.17mg
Magnesium stearate 0.33mg;
Method for making: carry out with reference to embodiment 1, Glyceryl Behenate adds together with magnesium stearate, is pressed into tablet with every containing active component 40mg, obtains plain sheet; This element sheet is used the coating material of embodiment 1 to carry out coating, and clothing layer accounts for 2.2% of final tablet total weight, obtains coated tablet.
test example 1: friability detects
The plain sheet that above embodiment 1-9 gained is whole batches, getting 10g for every batch measures, with reference to two appendix XG of Chinese Pharmacopoeia version in 2010 " tablet friability inspection technique ", less loss weight detects these tablets (should be less than 1.0% when pharmacopeia regulation is rotated 100 times according to rotating less loss weight after 250 times under pharmacopeia appointed condition, otherwise think that this kind of tablet is defective, in Long-term Storage transportation, have wearing and tearing.The facility of the present invention for investigating, number of revolutions changes into 250 times, with less loss weight, evaluates tablet character, if less loss weight is excessive, is unfavorable for the coating of tablet, because there will be stronger tablet wearing and tearing in coating process).
Result: the plain sheet of whole batches of gained in embodiment 1-6, less loss weight is all in 1.21～1.76% scopes, and for example the plain sheet less loss weight of embodiment 61 is 1.53%; The plain sheet of whole batches of gained in embodiment 7-9, less loss weight is all in 0.12～0.29% scope, and for example the plain sheet less loss weight of embodiment 71 is 0.18%.Above embodiment 7-9 is used the standby tablet of fluid-bed marumerization legal system.Inventor, in supplementary test, obtains 7 batches of tablets by the film-making technique (preparation technology who records with reference to CN103877060A embodiment 1) of the mixing wet granulation of these formula more solitos of embodiment 7-9.The plain sheet of these 7 batches of tablets detects according to above-mentioned friability detection method, and result less loss weight all, in 1.13～1.56% scopes, shows to show that the tablet producing technology without fluid-bed marumerization method of the present invention is difficult to obtain the above-mentioned technique effect of the present invention.
test example 2: study on the stability
The plain sheet that above embodiment 1-9 gained is whole batches, uses aluminum-plastic composite membrane bag hermetic package by them, puts at 42 ℃ of temperature and places May (this disposes and also can be described as in the present invention high-temperature treatment).According to following HPLC method, measure each tablet at the forward and backward related substance of high-temperature treatment.
【HPLC】：
According to high performance liquid chromatography (two appendix V D of Chinese Pharmacopoeia version in 2010), measure;
Chromatographic condition and system suitability: with octadecylsilane chemically bonded silica, be filler (using Purospher Star RP-18 post in this test, 55mm * 4.0mm, 3 μ m); The phosphoric acid solution of 0.01mol/L of take is mobile phase A, by acetonitrile, is Mobile phase B, and following table is carried out gradient elution:
| Time (minute) | A(％) | B(％) |
| 0 | 90 | 10 |
| 18 | 50 | 50 |
Detection wavelength is 250nm, and column temperature is 45 ℃, flow velocity 1ml/min;
The preparation of need testing solution: get 20, test sample tablet, accurately weighed, porphyrize, precision takes in right amount (being approximately equivalent to razaxaban 20mg), put in 100ml measuring bottle, add mixed solvent (phosphoric acid solution=3 of acetonitrile-0.01mol/L: 2) about 60ml, supersound process makes razaxaban dissolve for approximately 15 minutes, lets cool to room temperature, with mixed solvent, be diluted to scale, shake up, filter, get subsequent filtrate as need testing solution;
Algoscopy: precision measures need testing solution 10 μ l, injection liquid chromatography, record chromatogram, calculate each impurity peaks with respect to the area percent (also can be described as content (%)) of main peak, the identification of each impurity peaks is determined with respect to the relative retention time (RRT) of main peak with this impurity peaks.RRT<0.3 scope is the peaks such as solvent, adjuvant, ignores, and only investigates the impurity peaks situation of change of RRT>0.3 scope.
Have been found that, each tablet sample is after high-temperature treatment, in the scope of RRT=0.84 ± 0.10, there is the impurity peaks of different sizes in the tablet of different batches, and when each batch of tablet do not carry out high-temperature treatment, the impurity in this RRT=0.84 ± 0.10 scope (this impurity can be described as RRT0.84 in the present invention) peak is less than quantitative limit (can think that now they are 0% with respect to the area percent of main peak) substantially.Specifically: the plain sheet of whole batches of gained in embodiment 1-6, RRT0.84 content all reaches in 0.43～0.76% scope, and for example the RRT0.84 content of the plain sheet of embodiment 61 is 0.58%; The plain sheet of whole batches of gained in embodiment 7-9, RRT0.84 content all reaches in 0.07～0.19% scope, and for example the RRT0.84 content of the plain sheet of embodiment 71 is 0.11%.
test example 3: the dissolution of measuring tablet
Getting the plain sheet of whole batches of above embodiment 1-9 gained and coated tablet and commercially available razaxaban sheet (visits auspicious appropriate, 10mg), adopt 2010 editions appendix XC dissolution method the second methods of Chinese Pharmacopoeia (oar method) 75rpm, the pH4.5 acetate buffer 900mL of usining containing 0.2% sodium lauryl sulphate detects as dissolution medium, measures their dissolutions when 30min.
As a result, (visit auspicious appropriately, 10mg), their dissolution is all in 91～97% scopes for the plain sheet that embodiment 1-9 gained is whole batches and coated tablet and commercially available razaxaban sheet.For the tablet of each embodiment, coating and not coating have no obvious dissolution difference (differing all in 2 percentage points).For five batches of plain sheets that obtain in embodiment 6, between the plain sheet of their its corresponding embodiment 1-5, also have no obvious dissolution difference (differing all in 3 percentage points).For five batches of plain sheets that obtain in embodiment 7, between the plain sheet of their its corresponding embodiment 1-5, also have no obvious dissolution difference (differing all in 2.5 percentage points).In addition, and commercially available razaxaban sheet (visit auspicious appropriate, 10mg) use said method to measure.Visible tablet of the present invention and prior art tablet have no notable difference aspect dissolution.
Claims (10)
1. a pharmaceutical composition that is tablet form, wherein comprises: razaxaban, diluent, disintegrating agent, binding agent, wetting agent, lubricant.
2. according to the pharmaceutical composition of claim 1, in every, wherein said tablet, comprising razaxaban is 1-100mg.
3. according to the pharmaceutical composition of claim 1, wherein said diluent is to be selected from following one or more: cellulose, microcrystalline Cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltose alcohol, Sorbitol, xylitol, lactose (for example Lactis Anhydrous or lactose monohydrate), D-glucose, maltose, sucrose, glucose, fructose or maltodextrin; For example, in the razaxaban of every 10 weight portions, the consumption of described diluent is 20-200 weight portion, for example 20-150 weight portion.
4. according to the pharmaceutical composition of claim 1, wherein said disintegrating agent is to be selected from following one or more: carboxymethyl cellulose, cross-linked carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, crospovidone, low-substituted hydroxypropyl cellulose (L-HPC), carboxymethyl starch sodium, primojel, boiling starch, wheaten starch, corn starch, rice starch or potato starch; For example, in the razaxaban of every 10 weight portions, the consumption of described disintegrating agent is 1-20 weight portion, for example 1.5-7.5 weight portion.
5. according to the pharmaceutical composition of claim 1, wherein said binding agent is to be selected from following one or more: hydroxypropyl emthylcellulose (HPMC), carboxymethyl cellulose (sodium salt or calcium salt), ethyl cellulose, methylcellulose, hydroxyethyl-cellulose, ethylhydroxyethylcellulose, hydroxypropyl fiber element (HPC), L-HPC, polyvinyl pyrrolidone, polyvinyl alcohol, acrylic acid polymer and salt thereof, vinylpyrrolidone/vinyl acetate copolymer (KollidonVA64 for example, BASF), gelatin, guar gum, boiling starch, alginate or xanthan gum, for example, in the razaxaban of every 10 weight portions, the consumption of described binding agent is 1-10 weight portion, for example 1.5-5 weight portion.
6. according to the pharmaceutical composition of claim 1, wherein said wetting agent is to be selected from following one or more: the sodium salt of sulfated fatty alcohol ester is sodium lauryl sulfate for example, sodium lauryl sulphate, sulfosuccinate is dioctyl sodium sulphosuccinate for example, the fatty acid partial ester of polyhydric alcohol is glyceryl monostearate for example, the fatty acid partial ester of sorbitan is sorbitan monolaurate for example, the fatty acid partial ester of polyhydroxy ethylidene sorbitan is many ethylene glycol-sorbitan monolaurate for example, Polyethylene Glycol-sorbitan monostearate or Polyethylene Glycol-dehydrated sorbitol mono-fatty acid ester, polyhydroxy ethylidene fatty alcohol ether, polyhydroxy ethylidene fatty acid ester, the triglyceride of ethylene oxide-propylene oxide block copolymer (for example Pluronic) or ethoxylation, for example, in the razaxaban of every 10 weight portions, the consumption of described wetting agent is 0.2-5 weight portion, for example 0.3-3 weight portion.
7. according to the pharmaceutical composition of claim 1, wherein said lubricant is to be selected from following one or more: fumaric acid, stearic acid, magnesium stearate, calcium stearate, stearyl fumarate, high molecular fatty alcohol, Polyethylene Glycol, starch (for example, wheaten starch, rice starch, corn starch or potato starch), Pulvis Talci, polymolecularity (colloid) silicon dioxide, Glyceryl Behenate, magnesium oxide, magnesium carbonate, calcium silicates; For example, in the razaxaban of every 10 weight portions, the consumption of described lubricant is 0.1-10 weight portion, for example 0.2-5 weight portion, for example 0.5-2 weight portion.
8. according to the pharmaceutical composition of claim 1, it is tablet, and it is further by coating; For example it is film coating tablet.
9. pharmaceutical composition according to Claim 8, described coating material can be to be selected from following one or more: hydroxypropyl cellulose, hydroxypropyl emthylcellulose, ethyl cellulose, polyvinyl pyrrolidone, vinylpyrrolidone/vinyl acetate copolymer are (for example
vA64, BASF), for example titanium dioxide, ferrum oxide, indigo or suitable color form sediment for polymer, EUDRAGIT NE 30 D EUDRAGIT NE 30D, methacrylic acid-methyl acrylate copolymer, propylene glycol, Polyethylene Glycol, glyceryl triacetate, triethyl citrate and/or the dye additive/pigment of copolymer, methacrylic acid or the methacrylate of copolymer, dimethylaminomethyl acrylic acid and the neutral methacrylic acid esters of Lac, acrylate and/or methacrylate and methacrylic acid trimethyl ammonium; For example, if the pharmaceutical composition that is tablet form by coating, described in be wrapped in the 1-6% that coatings weight outside label accounts for whole tablet total weight amount, 1-4% for example; For example, the pharmaceutical composition that is tablet form adopts 2010 editions appendix XC dissolution method the second methods of Chinese Pharmacopoeia (oar method) 75rpm, the pH4.5 acetate buffer 900mL of usining containing 0.2% sodium lauryl sulphate detects as dissolution medium, and 30min dissolution is not less than 85%; For example, its formula having described in arbitrary embodiment forms.
10. the method for preparing the pharmaceutical composition of claim 1-9 any one, it comprises the following steps:
(a) binding agent and wetting agent are dissolved in suitable quantity of water, make the concentration of binding agent in this solution reach 1-10%, then add the material medicine razaxaban through micronization processes, fully homogenize is suspended in mixed liquor medicine, obtains suspension;
(b) diluent and disintegrating agent are fully mixed in fluidized bed pelletizer, then step (a) gained suspension is sprayed in the hybrid particles of fluidized bed pelletizer to carry out wet granulation, wet granular is dry in fluid bed, obtains dried particles;
(c) make step (b) gained dried particles and mix lubricant even, be pressed into tablet; Optionally,
(d), by step (c) gained tablet wrap film clothing, obtain being the pharmaceutical composition of film coated tablet form.
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| CN116850173A (en) * | 2023-06-06 | 2023-10-10 | 上海泰楚生物技术有限公司 | Application of dihydromyricetin in preparation of medicine of blood coagulation X factor FXa inhibitor |
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