CN104940152A - Pharmaceutical composition containing solifenacin succinate - Google Patents
Pharmaceutical composition containing solifenacin succinate Download PDFInfo
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- CN104940152A CN104940152A CN201410124888.XA CN201410124888A CN104940152A CN 104940152 A CN104940152 A CN 104940152A CN 201410124888 A CN201410124888 A CN 201410124888A CN 104940152 A CN104940152 A CN 104940152A
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Abstract
The invention relates to a pharmaceutical composition containing solifenacin succinate. The pharmaceutical composition is characterized by simultaneously containing direct compression lactose, sodium carboxymethyl starch, a binder and a lubricating agent. The invention also discloses a preparation method, namely a direct powder compression method of the pharmaceutical composition. The pharmaceutical composition and the preparation method thereof are not influenced by water in the preparation process, the pharmaceutical composition is low in impurity content and better in drug dissolubility, and the preparation method is more suitable for industrial production.
Description
Technical field
The present invention relates to pharmaceutical preparation, be specifically related to a kind of pharmaceutical composition containing succinic acid YM-905 and preparation method thereof.
Background technology
Succinic acid YM-905 (Solifenacin Succinate, 1-azabicyclo [2.2.2] octane-8-base-(1S)-1-phenyl-3,4-dihydro-1H-isoquinolin-2-formic acid esters succinate) is M of new generation
3receptor antagonist, act on the m receptor on detrusor, reduce the over-activity of detrusor, thus alleviate the symptom such as urgent micturition, frequent micturition and urge incontinence caused due to bladder muscle overacfivity, compared with similar drugs, it is the highest to bladder selectivity, therefore curative effect is stronger, side effect is less, patient has better toleration and compliance, is ICS, the first-line treatment medicine recommended in the overactive bladder treatment guidelines worked out of urology branch of Chinese Medical Association, Japanese Urology Surgery association.
The Yuan Yan producer of succinic acid YM-905 is Japanese Astellas (Astellas) company, product in 2004 takes the lead in going on the market in Europe, within 2005, enter the U.S., the approval listing of 2009 Nian Huo Chinese food Drug Administration, commodity are called Vesicare (Wei Xikang).
Research confirms, YM-905 molecule is to moisture quite sensitive, under the condition that water content is higher, succinic acid YM-905 crystal can be converted into unformed shape in a large number, and unformed succinic acid YM-905 is very easily degraded, generate a large amount of degradation impurity, have a strong impact on the safety of medication, point out in Yuan Yan house journal CN101141961B, for ensureing drug safety, the ratio of the total amount of the content of succinic acid YM-905 degradation impurity and succinic acid YM-905 and its catabolite should be strict controlled in less than 0.4%, therefore, how strictly water content is controlled in prescription or in preparation process, YM-905 and contact with moisture is avoided to be the technical barriers that those skilled in the art seek to solve always as far as possible.
But, wet granulation technique is adopted to prepare succinic acid YM-905 tablet in Yuan Yan house journal CN101141961B, the method inevitably makes YM-905 contact with water, cause degradation impurity to generate, fundamentally cannot solve succinic acid YM-905 and contact the problem generating a large amount of degradation impurity with water; Patent CN101141961B points out to prepare according to direct powder compression, though avoid YM-905 to contact with water, but because YM-905 or its salt have strong aggregation, direct compression process is difficult to the uniformity ensureing content, and mixture can adhere on drift in compression process.
Patent WO 2010097243 A2 discloses the prescription solving direct compression process and prepare YM-905 tablet content homogeneity difference, and (angle of repose is less than 36 namely in principal agent succinic acid YM-905, to add good fluidity
o) the excipient such as lactose, microcrystalline Cellulose, mannitol or silicon dioxide.But according to the formula preparation a collection of YM-905 sheet sample of WO 2010097243 A2 embodiment 1, although experiment finds that impurity content is low, uniformity of dosage units meets " Chinese Pharmacopoeia " (2010 editions) requirement, but 15min dissolution is below 70% in simulation gastric environment (pH1.2) medium for the tablet of preparation, and dissolution is poor.
Report in patent EP2500013A and add the mixing of lactose, disintegrating agent corn starch and other proper excipient in succinic acid YM-905, carry out direct compression, but according to formula preparation one batch sample described in patent Example 2, experiment finds tablet, and in simulation gastric environment (pH1.2) medium, 15min dissolution is lower than 70%, and dissolution is still poor.
According to Biopharmaceutics Classification in " oral solid formulation Dissolution Rate Testing technological guidance principle " (hereinafter referred to as " guideline "), succinic acid YM-905 belongs to BCS I class (high-dissolvability-high osmosis medicine), and after affecting this type of drug oral, the rate-limiting step of infiltration rate and degree is dissolution rate and the stripping quantity of medicine.This type of medicine dissolution rate is in vitro faster under normal circumstances, and stripping quantity is higher, and onset is faster.
Due in the fasted state, Entogastric lingering (emptying) the T50% time is 15 ~ 20 minutes, if medicine (slurry processes: 50 revs/min under the leaching condition of gentleness; Simulate low gastrointestinal peristalsis speed), in 15 minutes, its dissolution is more than 85%, and that can guard thinks that the stripping of medicine is not by the impact of gastric emptying, and the dissolved corrosion of preparation is similar to solution.If succinic acid YM-905 sheet dissolution in 15 minutes reaches more than 85%, its onset speed obviously can be better than succinic acid YM-905 sheet prepared by prior art direct compression process.
The pH of human normal gastric environment is 1.2, the pH value of achlorhydria Stomach in Patients environment is 4.0, gastric acid extremely lacks and the pH value of small intestinal environment is 6.8, if succinic acid YM-905 sheet is under the condition of 1.2 at pH, within 15 minutes, dissolution reaches more than 85%, then can in normal human Fast Stripping under gastric environment, its dissolved corrosion does not affect by gastric emptying, the dissolved corrosion of preparation is similar to solution, thus quick acting.If succinic acid YM-905 sheet all meets 15 minutes dissolutions under above-mentioned each pH value condition reach more than 85%, then can meet different crowd medication, for the patient that gastric acid extremely lacks, also can reach its dissolved corrosion does not affect by gastric emptying, quick acting.
Adopting prior art prescription, there is the problem of dissolution difference in the succinic acid YM-905 tablet prepared with direct powder compression all the time.But in view of direct powder compression is compared with wet granulation, there is the advantages such as technique is simple, with short production cycle, production cost is low, especially can avoid the impact of heating and moisture, be very suitable for the preparation of the medicine of this type of unstable chemcial property of succinic acid YM-905.Therefore a kind of prescription being applicable to direct powder compression is developed, enable Dissolution of Tablet in the dissolution medium of pH1.2, reach the stripping of more than 85%, meet the medication needs of normal person, quick acting, further, develop a kind of prescription of direct powder compression, make the dissolution of its 15min in pH1.2, pH4.0, pH6.8 solution and water 4 kinds of dissolution mediums all higher than 85%, meet all sick human needs, comprise the needs of the particular patients ' that gastric acid extremely lacks, make it all can Fast Stripping in the body of all patients, be very important.
Summary of the invention
In order to overcome prior art use direct powder compression prepare succinic acid YM-905 tablet time, the dissolution existed can not reach under the environment of pH1.2 higher than 85%, the dissolution of 15min in the special dissolution medium of pH4.0, pH6.8 can not be reached higher than 85%, obtaining can Fast Stripping, the succinic acid YM-905 tablet formulation of quick acting, the invention provides following technical scheme:
The invention provides a kind of pharmaceutical composition containing succinic acid YM-905: this pharmaceutical composition simultaneously containing vertical compression type lactose, carboxymethyl starch sodium, and binding agent and lubricant, and method for preparing tablet thereof is direct powder compression.
The invention provides a kind of pharmaceutical composition containing succinic acid YM-905 specifically, its composition comprises:
| Composition | Percentage by weight |
| Succinic acid YM-905 | 1.5wt%～10wt% |
| Vertical compression type lactose | 45wt%～90wt% |
| Carboxymethyl starch sodium | 0.5wt%～8wt% |
| Binding agent | 2wt%～10wt% |
| Lubricant | 0.3wt%～2wt% |
Described succinic acid YM-905 is crystal type.
Described vertical compression type lactose is preferably spray-dried lactose.
Described lubricant be selected from magnesium stearate, calcium stearate, Pulvis Talci, micropowder silica gel one or more, be preferably magnesium stearate.
Described binding agent is selected from starch slurry, sodium carboxymethyl cellulose, arabic gum, hydroxypropyl cellulose, methylcellulose, ethyl cellulose, syrup, hypromellose, polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, Hydroxypropylcelliloxe, maltose, refined honey, liquid glucose, sodium alginate, Polyethylene Glycol, Magnesiumaluminumsilicate, maltodextrin, vinyl pyrrolidone/vinyl acetate co-polymer (copolyvidone), one or more in polyvinyl alcohol/polyethyleneglycol-graft copolymer.
The invention provides a kind of pharmaceutical composition more preferably containing succinic acid YM-905, its composition comprises:
| Composition | Percentage by weight |
| Succinic acid YM-905 | 2.5wt%～6wt% |
| Vertical compression type lactose | 75wt%～90wt% |
| Carboxymethyl starch sodium | 1wt%～4wt% |
| Hypromellose | 4wt%～8wt% |
| Magnesium stearate | 0.5wt%～1wt% |
The invention provides a kind of highly preferred pharmaceutical composition containing succinic acid YM-905, it consists of:
| Composition | Percentage by weight |
| Succinic acid YM-905 | 3.33wt% |
| Vertical compression type lactose | 88.67wt% |
| Carboxymethyl starch sodium | 1wt% |
| Hypromellose | 6wt% |
| Magnesium stearate | 1wt% |
Present invention also offers a kind of preparation method of succinic acid YM-905 pharmaceutical composition:
(1) weigh: take required supplementary material by recipe quantity, sieve;
(2) mix: first succinic acid YM-905 is mixed with carboxymethyl starch sodium, then vertical compression type lactose is added according to equivalent method gradation of progressively increasing, add rear mixing at every turn and cross 50 mesh sieves, then adding other pharmaceutically acceptable adjuvants such as binding agent and lubricant, mix homogeneously;
(3) tabletting, coating, to obtain final product.
Based on direct powder compression technology have time-saving energy-saving, simple process, operation few, be applicable to the advantages such as wet heat-labile medicine, present invention applicant is first with reference to the tablet composition of YM-905 described in embodiment 1 in Yuan Yan house journal CN101601673B, with direct pressing tablet after succinic acid YM-905 (6.67wt%), lactose (68.33wt%), corn starch (20wt%), hypromellose (4wt%) and magnesium stearate (1wt%) mix homogeneously, discovery friability is defective, cannot coating, carry out follow-up preparation.
In view of prior art by adding the excipient of good fluidity as lactose, microcrystalline Cellulose or mannitol etc. in succinic acid YM-905, although direct powder compression can be solved prepare YM-905 tablet content homogeneity question, the problem of YM-905 tablet powder direct compression process dissolution difference can be solved without any prior art.Present invention applicant attempts again the content (2wt% ~ 10 wt%) adjusting succinic acid YM-905 in tablet composition, increase or reduce the ratio of principal agent and other excipient, or substitute the corn starch with larger viscosity with resistance to bond excipient calcium hydrogen phosphate, compress tablet coating after mix homogeneously, and it is detected, found that, above-mentioned Dissolution of Tablet is still not improved.
Present invention applicant attempts again adding other vertical compression type excipient on above-mentioned prescription basis if vertical compression microcrystalline Cellulose is (as Avicel PH102 SCG, Avicel PH200 NF, Celldone 113, Celldone 210), vertical compression mannitol is (as PearlitolSD, PearlitolDC), vertical compression sorbitol is (as Neosorb P150 DC, Neosorb P300DC), vertical compression starch/lactose complex (as Starlac), vertical compression lactose/cellulose composite (as Cellactose80), vertical compression lactose/Microcrystalline cellulose composite (as MicroceLac100), vertical compression lactose/polyvidone complex (as Ludipress LCE) etc., found that, said method still can not make the dissolution of tablet have clear improvement.
Present invention applicant attempts again the kind and the usage ratio that change binding agent and lubricant or other excipient in prescription, binding agent is as starch slurry, sodium carboxymethyl cellulose, arabic gum, hydroxypropyl cellulose, methylcellulose, ethyl cellulose, syrup, hypromellose, polyvinylpyrrolidone, Hydroxypropylcelliloxe, maltose, refined honey, liquid glucose, sodium alginate, Polyethylene Glycol, Magnesiumaluminumsilicate etc., lubricant is as magnesium stearate, calcium stearate, Pulvis Talci, micropowder silica gel etc., tabletting after mix homogeneously coating, then dissolution test is carried out, found that its dissolution is still not improved.
Present invention applicant is in order to improve the problem of the dissolution difference of insurmountable YM-905 tablet powder direct compression process existence always, attempt again by pulverizing, modes such as (100 order ~ 200 mesh sieves) of sieving reduces particle diameter difference between succinic acid YM-905 and other excipient, causes powder layering when avoiding tabletting machine to vibrate; Or common rotary tablet compression equipment is adjusted, force feedstuff device to make powder flow in feeder and nib more equably as increased on feeding device, reduce the rotating speed of tablet machine make blanking device feedstuff sufficient, increase pressing step and avoid telling powder with the gas got rid of between powder to cause sheet to weigh uneven etc.; Or directly adopt the vertical compression type tablet machine aiming at powder vertical compression Technology design to prepare tablet, then carry out coating and detect it, found that tablet prepared by the said method dissolution in 4 kinds of dissolution mediums is all lower than 70%, dissolution is still poor.Present invention applicant on said method basis, again by disintegrating agent as carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, starch etc.; The excipient such as other filleies (as mannitol, sorbitol, pregelatinized Starch) except microcrystalline Cellulose add prescription, and it is still bad that fructufy issues after examination and approval its dissolution existing.
Present invention applicant is through a large amount of experiments, finally find between accidentally, when adopting direct powder compression to prepare YM-905 tablet, vertical compression type lactose and carboxymethyl starch sodium must be contained in tablet composition, in addition, for ensureing tablet molding, also need containing binding agent and lubricant, wherein lubricant is selected from one or more in magnesium stearate, calcium stearate, Pulvis Talci, micropowder silica gel, binding agent is selected from starch slurry, sodium carboxymethyl cellulose, arabic gum, hydroxypropyl cellulose, methylcellulose, ethyl cellulose, syrup, hypromellose, polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, Hydroxypropylcelliloxe, maltose, refined honey, liquid glucose, sodium alginate, Polyethylene Glycol, Magnesiumaluminumsilicate, maltodextrin, vinyl pyrrolidone/vinyl acetate co-polymer (copolyvidone), one or more in polyvinyl alcohol/polyethyleneglycol-graft copolymer, and the content range of each composition is necessary for 1.5wt% ~ 10wt% succinic acid YM-905,45wt% ~ 90wt% vertical compression type lactose, 0.5wt% ~ 8wt% carboxymethyl starch sodium, 2wt% ~ 10wt% binding agent and 0.3wt% ~ 2wt% lubricant, the tablet now preparing molding could meet at general patient's gastric environment, namely in pH1.2 medium 15min dissolution more than 85%, solve prior art prescription, even if the problem that dissolution is also poor in general patient's gastric environment medium that the succinic acid YM-905 tablet adopting direct powder compression to prepare exists.
Present invention applicant surprisingly finds again in further studying, when above-mentioned prescription only has use hypromellose as binding agent, the tablet of preparation surprisingly in pH1.2, pH4.0, pH6.8 solution and water four kinds of dissolution mediums 15min dissolution unexpectedly all more than 85%, the problem of dissolution difference in especial patient gastric environment pH4.0, pH6.8 solution and water 3 kinds of dissolution mediums solving that YM-905 tablet prepared by prior art prescription direct powder compression exists.
Vertical compression type lactose of the present invention, special for direct compression development and Design, there is good fluidity and compressible anhydrous or lactose monohydrate, the methods such as spraying dry, fluidized bed granulation, cylinder dry can be adopted to carry out physical modification to the lactose that sieves/grind prepare voluntarily, also can be never directly buy with place of production firm to obtain.Vertical compression type lactose can be divided into different types according to different preparation methoies, as particulate lactose (as Tablettose70, Tablettose80, Tablettose100), spray-dried lactose (as Flowlac90, Flowlac100, Foremost 315), Lactis Anhydrous (as Sheffield) etc., the present invention preferably uses spray-dried lactose, comparatively other vertical compression type lactose, its powder flowbility is best, and has certain adsorption function, and the tablet content uniformity of preparation is better.
Tablet containing succinic acid YM-905 of the present invention, except containing succinic acid YM-905, vertical compression type lactose, disintegrating agent, outside binding agent and lubricant, suitably can also contain other various pharmaceutical excipients, include but not limited to that sweeting agent is (as aspartame, stevioside, saccharin sodium), foaming agent (as sodium bicarbonate), correctives is (as Fructus Citri Limoniae essence, orange essence, menthol), opacifier (as titanium dioxide), coloring agent is (as iron oxide red, iron oxide yellow), surfactant is (as sodium lauryl sulphate, poloxamer), other filleies except microcrystalline Cellulose are (as mannitol, sorbitol, pregelatinized Starch), antioxidant is (as ascorbic acid, propyl gallate) etc.A kind of described excipient can be added in right amount, or add the combination of excipient described in two or more.
Direct powder compression method of the present invention, refers to the method for directly mixture of medicine and excipient being carried out tabletting without pelletization, includes but not limited to following steps: medicine, excipient → mixing → tabletting.Wherein, the addition sequence of " mixing " process Chinese medicine and each excipient, mix number of times, incorporation time etc. and depend on the kind of medicine and excipient, percentage composition or particle diameter, and mixing arrangement (comprising such as V-type blender, container blender, high speed agitator) is not particularly limited.Generally speaking, mixed effect reaches industry production standard known in those skilled in the art, i.e. RSD value≤5% of the medicament contg of mixed powder or lower, namely represents mix homogeneously.
Preforming device comprises such as rotary tablet machine and powder vertical compression tablet machine, and generally speaking, any method can preparing compression molding product (being preferably tablet) can meet the demands, and is not particularly limited its apparatus and method.
Succinic acid YM-905 of the present invention, can be directly use conventional chemical synthetic method, the finished product that method is directly prepared as described in US20070185329A1 embodiment 1A, US20100029944A1 embodiment 1 ~ 3, US20080114028A1 embodiment 1, CN102875544A embodiment 1 and CN101711248A embodiment 1, also can make further by modes such as pulverizing, sieve that its form is more regular, particle diameter is more homogeneous, more be conducive to the mobility of mixed powder, be conducive to the uniformity of dosage units and the dissolution that improve tablet.
Binding agent of the present invention and disintegrating agent, it can be the pharmaceutical grade excipient being directly purchased from manufacturer, also can make further by modes such as pulverizing, sieve that its form is more regular, particle diameter is more homogeneous, more be conducive to the flowing of binding agent in mixed powder and dispersed, be conducive to the dissolution improving tablet.
comparative example
comparative example 1
Form according to the tablet of YM-905 described in embodiment in patent CN101601673B 1:
| Composition | Content (mg/ sheet) | Percentage by weight |
| Succinic acid YM-905 | 10 | 6.67wt% |
| Lactose | 102.5 | 68.33wt% |
| Corn starch | 30 | 20wt% |
| Hypromellose | 6 | 4wt% |
| Magnesium stearate | 1.5 | 1wt% |
According to method described in embodiment in patent CN101601673B 1, take required supplementary material by recipe quantity.. hypromellose and suitable quantity of water are mixed with binder solution; then by succinic acid YM-905 with 39% lactose mix after pulverize; then remaining lactose and corn starch is added; use fluidised bed granulator by binder solution spraying to implement damp granulation procedure; magnesium stearate is added after obtained particle drying; carry out tabletting and coating, to obtain final product.
comparative example 2
Prescription according to patent EP2500013A1 embodiment 2:
| Composition | Content (mg/ sheet) | Percentage by weight |
| Succinic acid YM-905 | 10.5 | 6.97wt% |
| Vertical compression lactose Tablettose | 100.95 | 67.1wt% |
| Corn starch | 30.00 | 19.94wt% |
| Hypromellose | 7.50 | 4.98wt% |
| Magnesium stearate | 1.50 | 1.0wt% |
Required supplementary material is taken by recipe quantity, first succinic acid YM-905 is mixed with hypromellose and corn starch, then add the vertical compression lactose of 20%, after mixing, add the vertical compression lactose of 30% again, mix homogeneously, add remaining vertical compression lactose, mix and cross 50 mesh sieves, mix homogeneously, finally add magnesium stearate mix homogeneously, use rotary tablet machine tabletting, coating, to obtain final product.
comparative example 3
Prescription according to WO 2010097243 A2 embodiment 7:
| Composition | Content (mg/ sheet) | Percentage by weight |
| Succinic acid YM-905 | 20 | 6.67wt% |
| Vertical compression lactose Tablettose | 217 | 72.33wt% |
| Corn starch | 60 | 20.00wt% |
| Magnesium stearate | 3 | 1.00wt% |
Required supplementary material is taken by recipe quantity, first succinic acid YM-905 is mixed with corn starch, then add the vertical compression lactose of 20%, after mixing, add 30% vertical compression lactose again, mix homogeneously, add remaining vertical compression lactose, mix and cross 50 mesh sieves, mix homogeneously, finally add magnesium stearate mix homogeneously, use rotary tablet machine tabletting, coating, to obtain final product.
comparative example 4
Prescription according to WO 2010097243 A2 embodiment 6:
| Composition | Content (mg/ sheet) | Percentage by weight |
| Succinic acid YM-905 | 20 | 6.67wt% |
| Mannitol | 205 | 68.33wt% |
| Corn starch | 60 | 20wt% |
| Hypromellose | 12 | 4wt% |
| Magnesium stearate | 3 | 1wt% |
By 20g succinic acid YM-905,205g mannitol mix homogeneously, added 60g corn starch and the 12g hypromellose mix homogeneously of sieve aperture 0.6mm, finally add 3g magnesium stearate mix homogeneously, press sheet mixture, coating, to obtain final product.
comparative example 5
Prescription according to WO 2010097243 A2 embodiment 4:
| Composition | Content (mg/ sheet) | Percentage by weight |
| Succinic acid YM-905 | 20 | 6.67wt% |
| Microcrystalline Cellulose | 205 | 68.3wt% |
| Corn starch | 60 | 20wt% |
| Hypromellose | 12 | 4wt% |
| Magnesium stearate | 3 | 1wt% |
By 20g succinic acid YM-905 and 205g microcrystalline Cellulose mix homogeneously, then added 60g corn starch and the 12g hypromellose mix homogeneously of sieve aperture 0.6mm, finally add 3g magnesium stearate mix homogeneously, press sheet mixture, coating, to obtain final product.
comparative example 6
| Composition | Content (mg/ sheet) | Percentage by weight |
| Succinic acid YM-905 | 10 | 6.67wt% |
| Vertical compression lactose Flowlac100 | 141.42 | 88.33wt% |
| Hypromellose | 6 | 4.0wt% |
| Magnesium stearate | 1.5 | 1.0wt% |
Required supplementary material is taken by recipe quantity, first by succinic acid YM-905,10% vertical compression lactose mix with hypromellose, then add the vertical compression lactose of 20%, after mix homogeneously, add the vertical compression lactose of 30%, after mixing, add remaining vertical compression lactose again, mix and cross 50 mesh sieves, mix homogeneously, finally adds magnesium stearate mix homogeneously, uses rotary tablet machine tabletting, coating, to obtain final product.
comparative example 7
| Composition | Content (mg/ sheet) | Percentage by weight |
| Succinic acid YM-905 | 10 | 6.67wt% |
| Vertical compression lactose Flowlac100 | 131 | 87.33wt% |
| Cross-linking sodium carboxymethyl cellulose | 1.5 | 1wt% |
| Hypromellose | 6 | 4wt% |
| Magnesium stearate | 1.5 | 1wt% |
Required supplementary material is taken by recipe quantity, first succinic acid YM-905 is mixed with cross-linking sodium carboxymethyl cellulose and hypromellose, then add the vertical compression lactose of 20%, after mix homogeneously, add the vertical compression lactose of 30%, after mixing, add remaining vertical compression lactose again, mix and cross 50 mesh sieves, mix homogeneously, finally adds magnesium stearate mixing, uses rotary tablet machine tabletting, coating, to obtain final product.
comparative example 8
| Composition | Content (mg/ sheet) | Percentage by weight |
| Succinic acid YM-905 | 10 | 6.67wt% |
| Vertical compression lactose Tablettose | 129.5 | 86.34wt% |
| Low-substituted hydroxypropyl cellulose | 3 | 2wt% |
| Hypromellose | 6 | 4wt% |
| Magnesium stearate | 1.5 | 1wt% |
Required supplementary material is taken by recipe quantity, first succinic acid YM-905 is mixed with low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose, then add the vertical compression lactose of 20%, after mixing, add the vertical compression lactose of 30% again, after mix homogeneously, add remaining vertical compression lactose, mix and cross 50 mesh sieves, mix homogeneously, finally adds magnesium stearate mix homogeneously, uses rotary tablet machine tabletting, coating, to obtain final product.
comparative example 9
| Composition | Content (mg/ sheet) | Percentage by weight |
| Succinic acid YM-905 | 10 | 6.67wt% |
| Microcrystalline Cellulose | 126.43 | 84.33wt% |
| Carboxymethyl starch sodium | 1.5 | 1.0wt% |
| Hypromellose | 9 | 6.0wt% |
| Pulvis Talci | 3 | 2.0wt% |
Required supplementary material is taken by recipe quantity, first succinic acid YM-905 is mixed with carboxymethyl starch sodium and hypromellose, then add the microcrystalline Cellulose of 20%, add the microcrystalline Cellulose of 30% after mixing again, add remaining microcrystalline Cellulose, mix and cross 50 mesh sieves, mix homogeneously, finally adds magnesium stearate mix homogeneously, uses rotary tablet machine tabletting, coating, to obtain final product.
comparative example 10
| Composition | Content (mg/ sheet) | Percentage by weight |
| Succinic acid YM-905 | 10 | 6.67wt% |
| Vertical compression lactose Flowlac100 | 128 | 85.34wt% |
| Carboxymethyl starch sodium | 3 | 2wt% |
| Hydroxypropylcelliloxe | 7.5 | 5wt% |
| Magnesium stearate | 1.5 | 1wt% |
Required supplementary material is taken by recipe quantity, first succinic acid YM-905 is mixed with carboxymethyl starch sodium and Hydroxypropylcelliloxe, then add the vertical compression lactose of 20%, after mix homogeneously, add the vertical compression lactose of 30%, after mixing, add remaining vertical compression lactose again, mix and cross 50 mesh sieves, mix homogeneously, finally adds magnesium stearate mixing, uses rotary tablet machine tabletting, coating, to obtain final product.
comparative example 11
| Composition | Content (mg/ sheet) | Percentage by weight |
| Succinic acid YM-905 | 10 | 6.67wt% |
| Vertical compression lactose Flowlac100 | 129.5 | 86.33wt% |
| Carboxymethyl starch sodium | 3 | 2wt% |
| Polyvidone k30 | 6 | 4wt% |
| Magnesium stearate | 1.5 | 1wt% |
Required supplementary material is taken by recipe quantity, first succinic acid YM-905 is mixed with carboxymethyl starch sodium and polyvidone k30, then add the vertical compression lactose of 20%, after mix homogeneously, add the vertical compression lactose of 30%, after mixing, add remaining vertical compression lactose again, mix and cross 50 mesh sieves, mix homogeneously, finally adds magnesium stearate mixing, uses rotary tablet machine tabletting, coating, to obtain final product.
comparative example 12
| Composition | Content (mg/ sheet) | Percentage by weight |
| Succinic acid YM-905 | 4 | 4wt% |
| Vertical compression lactose Flowlac100 | 90 | 90wt% |
| Carboxymethyl starch sodium | 1 | 1wt% |
| Hypromellose | 4 | 4wt% |
| Magnesium stearate | 1 | 1wt% |
Required supplementary material is taken by recipe quantity, first succinic acid YM-905 is mixed with carboxymethyl starch sodium and hypromellose, then add the vertical compression lactose of 20%, after mix homogeneously, add the vertical compression lactose of 30%, after mixing, add remaining vertical compression lactose again, mix and cross 50 mesh sieves, mix homogeneously, finally adds magnesium stearate mix homogeneously, uses rotary tablet machine tabletting, coating, to obtain final product.
comparative example 13
| Composition | Content (mg/ sheet) | Percentage by weight |
| Succinic acid YM-905 | 5 | 3.33wt% |
| Vertical compression lactose Flowlac100 | 135 | 90wt% |
| Carboxymethyl starch sodium | 2.8 | 1.87wt% |
| Hypromellose | 6.4 | 4.27wt% |
| Magnesium stearate | 0.8 | 0.53wt% |
Required supplementary material is taken by recipe quantity, first the vertical compression lactose Flowlac100 of 20% is added in mixer, add succinic acid YM-905, carboxymethyl starch sodium and hydroxypropyl emthylcellulose again to mix, then add the vertical compression lactose of 30%, after mixing, add remaining vertical compression lactose, mix and cross 50 mesh sieves, mix homogeneously, finally adds magnesium stearate mix homogeneously, uses rotary tablet machine tabletting, coating, to obtain final product.
comparative example 14
| Composition | Content (mg/ sheet) | Percentage by weight |
| Succinic acid YM-905 | 5 | 3.33wt% |
| Vertical compression lactose Flowlac100 | 133 | 88.67wt% |
| Carboxymethyl starch sodium | 1.5 | 1wt% |
| Hypromellose | 9 | 6wt% |
| Magnesium stearate | 1.5 | 1wt% |
Take required supplementary material by recipe quantity, first the vertical compression lactose Flowlac100 of 20% is added in mixer, then add succinic acid YM-905 and mix with carboxymethyl starch sodium, then the vertical compression lactose of 30% is added, add remaining vertical compression lactose after mixing again, mix homogeneously, adds hypromellose, mix and cross 50 mesh sieves, mix homogeneously, finally adds magnesium stearate mix homogeneously, uses rotary tablet machine tabletting, coating, to obtain final product.
Measure dissolution and the uniformity of dosage units of the made tablet of comparative example 1 ~ 14 by the following method respectively, result is shown in table 1.
dissolution
Dissolution medium:
(1) pH1.2 dissolution medium: 2 ‰ sodium chloride+0.1mol/L hydrochloric acid solutions (Japanese Pharmacopoeia: JP 15 editions).
(2) pH4. 0 dissolution medium: pH4.0 citrate-phosphate potassium dihydrogen buffer (Japanese Pharmacopoeia: JP15 version).
(3) pH6.8 dissolution medium: pH6.8 sodium hydrogen phosphate-potassium phosphate buffer (Japanese Pharmacopoeia: JP15 version).
(4) water dissolution medium: aqueous solution.
Dissolution medium volume: 900ml
Test method: Chinese Pharmacopoeia version in 2010 two annex X C second method paddle method
Rotating speed: 50 turns/min
uniformity of dosage units
Measure according to method under succinic acid YM-905 sheet import drugs registered standard (JX20050264) uniformity of dosage units item:
Get succinic acid YM-905 sheet 1, put in a suitable container,-acetonitrile (7: the 3) solution that adds water is appropriate, supersound process makes dissolving in 15 minutes, make in every 1ml about containing 0.5mg solution with water-acetonitrile (7: 3) solution dilution, filter, get subsequent filtrate as need testing solution, another precision takes succinic acid YM-905 reference substance 25mg, put in 50ml measuring bottle, add water-acetonitrile (7: 3) solubilize be diluted to scale, shakes up, in contrast product solution (1); Get need testing solution and each 10 μ l of reference substance solution (1), injection liquid chromatography, chromatographic condition is: octadecylsilane chemically bonded silica is filler, column temperature 40 DEG C, wavelength 210nm, with 0.05mol/L dipotassium hydrogen phosphate buffer (adjusting PH to 6.0 with phosphoric acid)-acetonitrile (70: 30) for mobility, record chromatogram, by external standard method with the content of calculated by peak area succinic acid YM-905.
Measure the content of 10 tablets of succinic acid YM-905 tablets according to the method described above respectively, and according to Content uniformity test (" Chinese Pharmacopoeia " 2010 editions two annex XE), the relative amount X that every sheet is 100 with labelled amount represents, asks its average
with standard deviation S [
] and the absolute value A(of difference of labelled amount and average
), as A+1.80S≤15.0, then the uniformity of dosage units of tablet conforms with the regulations.
The 15min dissolution of table 1 comparative example 1 ~ 14 and uniformity of dosage units result
In comparative example 2 ~ 5, use prior art prescription, interpolation miscibilty and the good excipient of mobility are as vertical compression type lactose, mannitol or microcrystalline Cellulose in tablets, the uniformity of dosage units of tablet can be improved, but Dissolution of Tablet is poor, in general patient's gastric environment (pH1.2) medium, 15min dissolution is all lower than 70%.
From comparative example 2,6 ~ 9 find out, though when containing vertical compression lactose, without disintegrating agent in tablet composition, even if or containing disintegrating agent, but disintegrating agent is not carboxymethyl starch sodium, or there is disintegrating agent carboxymethyl base Starch Sodium in prescription, but replace vertical compression lactose with other pharmaceutic adjuvants as microcrystalline Cellulose, all can not obtain the good tablet of 15min dissolution, only have when tablet forms as described herein, namely must contain vertical compression type lactose and disintegrating agent simultaneously, and disintegrating agent can only be carboxymethyl starch sodium (comparative example 10), in addition, for ensureing tablet molding, also need in prescription containing being selected from starch slurry, sodium carboxymethyl cellulose, arabic gum, hydroxypropyl cellulose, methylcellulose, ethyl cellulose, syrup, hypromellose, polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, Hydroxypropylcelliloxe, maltose, refined honey, liquid glucose, sodium alginate, Polyethylene Glycol, Magnesiumaluminumsilicate, maltodextrin, vinyl pyrrolidone/vinyl acetate co-polymer (copolyvidone), one or more binding agent in polyvinyl alcohol/polyethyleneglycol-graft copolymer and be selected from magnesium stearate, calcium stearate, Pulvis Talci, one or more lubricant in micropowder silica gel.The dissolution of tablet 15min in simulation gastric environment (pH1.2) this general patient's gastric environment medium of above-mentioned formula preparation, more than 90%, solves the problem of YM-905 tablet 15min dissolution difference in general patient's gastric environment medium prepared by prior art prescription direct powder compression.
And from comparative example 10 ~ 12, only have when use hypromellose as binding agent in tablet formulation but not other binding agents time, the tablet of preparation surprisingly in pH1.2, pH4.0, pH6.8 solution and water four kinds of dissolution mediums 15min dissolution all more than 90%, the problem of 15min dissolution difference in especial patient gastric environment pH4.0, pH6.8 solution and water 3 kinds of dissolution mediums solving that YM-905 tablet prepared by prior art prescription direct powder compression exists.
In comparative example 12,13, use prescription of the present invention, adopt prior art powder pressing method conventional process, namely after supplementary material sieves, disposable succinic acid YM-905 to be mixed with the adjuvant such as binding agent and disintegrating agent, add vertical compression type lactose according to equivalent method gradation of progressively increasing again, add rear mixing at every turn and sieve, or after supplementary material sieves, first a certain amount of lactose is added in mixer, then mix disposable succinic acid YM-905 is added with the adjuvant such as binding agent and disintegrating agent, finally add remaining vertical compression type lactose according to equivalent method gradation of progressively increasing, add rear mixing at every turn and sieve, but no matter adopt above-mentioned any preparation method of the prior art, the 15min dissolution of the YM-905 tablet obtained all can not get further improving, by comparative example 14, only have and both use prescription of the present invention, adopt again preparation method of the present invention, namely first a certain amount of lactose is added in mixer, then add succinic acid YM-905 to mix with disintegrating agent carboxymethyl base Starch Sodium, vertical compression type lactose is added again according to equivalent method gradation of progressively increasing, add rear mixing at every turn, finally add binding agent, the adjuvants such as lubricant, mix homogeneously, the succinic acid YM-905 tablet that the tablet prepared according to the method can realize preparing surprisingly is in simulation gastric environment (pH1.2), simulation achlorhydria Stomach in Patients environment (pH4.0), simulation gastric acid extremely lack and in small intestinal environment (pH6.8) and water four kinds of dissolution mediums the dissolution of 15min more than 95%, dissolution is very good.
In addition, present invention applicant is in order to verify the YM-905 tablet advantage compared with prior art that prescription of the present invention and preparation method are produced further, wet granulation prescription is ground again by former for comparative example 1() and comparative example 10(prescription of the present invention) made tablet, pack with air-tight bottle, at 40 DEG C, after storing 6 months under the accelerated test condition of RH75%, detect by the following method and the ratio of the growing amount calculating its oxidation product F1 and succinic acid YM-905 and catabolite total amount thereof, and using the ratio of this F1 growing amount as index, examine or check the former difference of tablet in stability of grinding direct powder compression method that wet granule compression tablet method used and the present patent application use and preparing.
the ratio of growing amount
Measure according to algoscopy under succinic acid YM-905 sheet import drugs registered standard (JX20050264) related substance item:
Get the fine powder appropriate (being about equivalent to succinic acid YM-905 50mg) of succinic acid YM-905 sheet, accurately weighed, put in 100ml measuring bottle,-acetonitrile (7: the 3) solution that adds water is appropriate, supersound process makes dissolving in 15 minutes, shakes up to scale with water-acetonitrile (7: 3) solution dilution, filter, as need testing solution; Another precision takes succinic acid YM-905 reference substance 25mg, puts in 50ml measuring bottle, and add water-acetonitrile (7: 3) solubilize be diluted to scale, shakes up, in contrast product solution (1); Precision measures reference substance solution (1) 0.5ml, puts in 100ml measuring bottle, shakes up to scale with water-acetonitrile (7: 3) solution dilution, in contrast solution (2).Get need testing solution and each 10 μ l of reference substance solution (2), injection liquid chromatography, other is according to the method under above-mentioned uniformity of dosage units item, and with method operation, record chromatogram, is calculated as follows the ratio of F1 growing amount:
Wherein,
,
and
represent the peak area of the peak area of related substance YM64250, the peak area of YM217800 and succinic acid YM-905 in test sample chromatogram respectively;
represent the concentration of reference substance (2);
represent the volume of need testing solution;
represent the average sheet weight of tablet;
represent the sample weighting amount of test sample;
represent the labelled amount of tablet.
Wherein, F1 means two oxidation products of succinic acid YM-905, i.e. related substance YM-64250 and YM-217880, its title and structure are shown in table 2.
Table 2 related substance YM-64250 and YM-217880
| Related substance | YM-64250 | YM-217880 |
| Chemical name | YM-905 nitrogen oxide | (R)-quinuclidinol-3-base-benzoyl (phenethyl) carbamate |
| Structural formula |
The succinic acid YM-905 of above comparative example 1 and comparative example 10 gained is placed 10 days respectively under the condition of high temperature (60 DEG C), high humidity (relative humidity 90 ± 5%), illumination, detect sampling in 0 day, 5 days, 10 days respectively, investigate the growing amount of YM-64250 and YM-217880 two impurity, the ratio result that the results are shown in Table 3, F1 growing amount is shown in table 4.
The impurity growing amount of table 3 comparative example 1 and comparative example 10
The ratio of the F1 growing amount of table 4 comparative example 1 and comparative example 10
| Comparative example | The ratio (%) of 0 day F1 growing amount | The ratio (%) of high temperature (60 degree) 10 days F1 growing amounts | The ratio (%) of high humidity (92.5%) 10 day F1 growing amount | The ratio (%) of illumination 10 days F1 growing amounts |
| Comparative example 1 | 0.05 | 0.27 | 0.14 | 0.20 |
| Comparative example 10 | 0.02 | 0.03 | 0.11 | 0.03 |
Tablet prepared by comparative example 1 and comparative example 10, its dissolution and stripping data RSD value conformance with standard, but both are under identical primary stability condition, tablet (comparative example 10) prepared by the direct powder compression method used with the present patent application, the growing amount of itself YM-64250 and YM-217880 two impurity and the ratio of F1 growing amount are all well below the Yuan Yan company tablet (comparative example 1) prepared of pelletizing press sheet method in a wet process, oxidation impurities volume of production in product is less, and stability is better.
Detailed description of the invention
Below in conjunction with specific embodiment, set forth the present invention further.But these embodiments are only limitted to the present invention instead of the further restriction to protection scope of the present invention are described.
embodiment 1
| Composition | Content (mg/ sheet) | Percentage by weight |
| Succinic acid YM-905 | 4.5 | 1.5wt% |
| Vertical compression lactose Tablettose70 | 270 | 90wt% |
| Carboxymethyl starch sodium | 3.5 | 1.17 wt% |
| Hydroxypropylcelliloxe | 15 | 5.33wt% |
| Micropowder silica gel | 6 | 2wt% |
Take required supplementary material by recipe quantity, first succinic acid YM-905 is mixed with carboxymethyl starch sodium and Hydroxypropylcelliloxe, then add the vertical compression lactose of 10%, the vertical compression lactose of 20% is added after mixing, mix homogeneously, then the vertical compression lactose adding 30% mixes, and adds remaining vertical compression lactose, mix and cross 50 mesh sieves, mix homogeneously, finally adds micropowder silica gel mix homogeneously, uses powder vertical compression tabletting machine, coating, to obtain final product.
embodiment 2
| Composition | Content (mg/ sheet) | Percentage by weight |
| Succinic acid YM-905 | 20 | 10wt% |
| Vertical compression lactose Flowlac90 | 142 | 71wt% |
| Carboxymethyl starch sodium | 16 | 8 wt% |
| Arabic gum | 20 | 10wt% |
| Pulvis Talci | 2 | 1wt% |
Take required supplementary material by recipe quantity and cross 50 mesh sieves respectively, first succinic acid YM-905 is mixed with carboxymethyl starch sodium and arabic gum, then add the vertical compression lactose of 20%, mix homogeneously, the vertical compression lactose adding 30% again mixes, add remaining vertical compression type lactose, mix and cross 50 mesh sieves, mix homogeneously, finally add Pulvis Talci mix homogeneously, use rotary tablet machine tabletting, coating, to obtain final product.
embodiment 3
| Composition | Content (mg/ sheet) | Percentage by weight |
| Succinic acid YM-905 | 10 | 10wt% |
| Vertical compression lactose Sheffield | 45 | 45wt% |
| Mannitol | 29 | 29wt% |
| Carboxymethyl starch sodium | 3.3 | 3.3 wt% |
| Cross-linking sodium carboxymethyl cellulose | 3.4 | 3.4 wt% |
| Hypromellose | 8 | 8wt% |
| Calcium stearate | 1.3 | 1.3 wt% |
Required supplementary material is taken by recipe quantity, first succinic acid YM-905 is mixed with carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, hypromellose and mannitol, then add the vertical compression lactose of 20%, mix homogeneously, add 30% vertical compression lactose again to mix, add remaining lactose, mix and cross 50 mesh sieves, mix homogeneously, finally add calcium stearate mix homogeneously, use rotary tablet machine tabletting, coating, to obtain final product.
embodiment 4
| Composition | Content (mg/ sheet) | Percentage by weight |
| Succinic acid YM-905 | 5 | 5wt% |
| Vertical compression lactose Pharmatose DCL | 87 | 87wt% |
| Carboxymethyl starch sodium | 0.5 | 0.5wt% |
| Polyvinyl alcohol/polyethyleneglycol-graft copolymer | 6 | 6wt% |
| Magnesium stearate | 1.5 | 1.5wt% |
Take required supplementary material by recipe quantity and cross 50 mesh sieves respectively, first succinic acid YM-905 is mixed with carboxymethyl starch sodium and polyvinyl alcohol/polyethyleneglycol-graft copolymer, then add the vertical compression lactose of 20%, mix homogeneously, the vertical compression lactose adding 30% again mixes, add remaining vertical compression lactose, mix and cross 50 mesh sieves, mix homogeneously, finally add magnesium stearate mix homogeneously, use rotary tablet machine tabletting, coating, to obtain final product.
embodiment 5
| Composition | Content (mg/ sheet) | Percentage by weight |
| Succinic acid YM-905 | 4.5 | 1.5wt% |
| Vertical compression lactose Tablettose70 | 264.6 | 88.2wt% |
| Carboxymethyl starch sodium | 24 | 8wt% |
| Magnesiumaluminumsilicate | 6 | 2wt% |
| Micropowder silica gel | 0.9 | 0.3wt% |
Take required supplementary material by recipe quantity and cross 50 mesh sieves respectively, first succinic acid YM-905 is mixed with carboxymethyl starch sodium and Magnesiumaluminumsilicate, then add the vertical compression lactose of 20%, mix homogeneously, the vertical compression lactose adding 30% again mixes, add remaining vertical compression lactose, mix and cross 50 mesh sieves, mix homogeneously, finally add micropowder silica gel mix homogeneously, use rotary tablet machine tabletting, coating, to obtain final product.
embodiment 6
| Composition | Content (mg/ sheet) | Percentage by weight |
| Succinic acid YM-905 | 6 | 6wt% |
| Vertical compression lactose Tablettose80 | 75 | 75wt% |
| Sorbitol | 13 | 13wt% |
| Carboxymethyl starch sodium | 1 | 1wt% |
| Hypromellose | 4 | 4wt% |
| Magnesium stearate | 1 | 1wt% |
Required supplementary material is taken by recipe quantity, first the vertical compression lactose of 20% is added mixer, then add succinic acid YM-905, carboxymethyl starch sodium, sorbitol and hypromellose and mix, cross 50 mesh sieves, then the vertical compression lactose mixing of 30% is added, cross 50 mesh sieves, continue to add remaining vertical compression lactose and mix, cross 50 mesh sieve mix homogeneously, finally add magnesium stearate mix homogeneously, use rotary tablet machine tabletting, coating, to obtain final product.
embodiment 7
| Composition | Content (mg/ sheet) | Percentage by weight |
| Succinic acid YM-905 | 2.5 | 2.5wt% |
| Vertical compression lactose Foremost 315 | 85 | 85wt% |
| Carboxymethyl starch sodium | 4 | 4wt% |
| Hypromellose | 8 | 8wt% |
| Magnesium stearate | 0.5 | 0.5wt% |
Required supplementary material is taken by recipe quantity, succinic acid YM-905 and carboxymethyl starch sodium are crossed 120 mesh sieves respectively, hypromellose crosses 150 mesh sieves, 50 mesh sieves crossed by vertical compression lactose, succinic acid YM-905 is mixed with carboxymethyl starch sodium and hypromellose, then add the vertical compression lactose mixing of 20%, cross 50 mesh sieves, then add the vertical compression lactose of 30%, cross 50 mesh sieves, mix homogeneously, then add remaining vertical compression lactose and carry out mixing and cross 50 mesh sieves, mix homogeneously, finally add magnesium stearate mix homogeneously, use rotary tablet machine tabletting, coating, to obtain final product.
embodiment 8
| Composition | Content (mg/ sheet) | Percentage by weight |
| Succinic acid YM-905 | 4 | 4wt% |
| Vertical compression lactose Pharmatose DCL | 90 | 90wt% |
| Carboxymethyl starch sodium | 1 | 1wt% |
| Hypromellose | 4 | 4wt% |
| Magnesium stearate | 1 | 1wt% |
Required supplementary material is taken by recipe quantity, succinic acid YM-905 and carboxymethyl starch sodium are crossed 120 mesh sieves respectively, hypromellose crosses 150 mesh sieves, 50 mesh sieves crossed by vertical compression lactose, by succinic acid YM-905 with carboxymethyl starch sodium and hypromellose with mix, then add the vertical compression lactose mixing of 20%, cross 50 mesh sieves, then add the vertical compression lactose of 30%, cross 50 mesh sieves, mix homogeneously, then add remaining vertical compression lactose and cross 50 mesh sieves, mix, finally add magnesium stearate mix homogeneously, use rotary tablet machine tabletting, coating, to obtain final product.
embodiment 9
| Composition | Content (mg/ sheet) | Percentage by weight |
| Succinic acid YM-905 | 5 | 3.33wt% |
| Vertical compression lactose Tablettose100 | 135 | 90wt% |
| Carboxymethyl starch sodium | 2.8 | 1.87wt% |
| Hypromellose | 6.4 | 4.27wt% |
| Magnesium stearate | 0.8 | 0.53wt% |
Required supplementary material is taken by recipe quantity, first the vertical compression lactose of 20% is added in mixer, then add the mixing of succinic acid YM-905, carboxymethyl starch sodium and hypromellose, then add the vertical compression lactose of 30%, mix homogeneously, add remaining vertical compression lactose and cross 50 mesh sieves, mix, finally add magnesium stearate mix homogeneously, use rotary tablet machine tabletting, coating, to obtain final product.
embodiment 10
| Composition | Content (mg/ sheet) | Percentage by weight |
| Succinic acid YM-905 | 5 | 3.33wt% |
| Vertical compression lactose Flowlac100 | 133 | 88.67wt% |
| Carboxymethyl starch sodium | 1.5 | 1wt% |
| Hypromellose | 9 | 6wt% |
| Magnesium stearate | 1.5 | 1wt% |
Required supplementary material is taken by recipe quantity, succinic acid YM-905 and carboxymethyl starch sodium are crossed 120 mesh sieves respectively, hypromellose crosses 150 mesh sieves, 50 mesh sieves crossed by vertical compression lactose, by succinic acid YM-905, carboxymethyl starch sodium and hypromellose mix homogeneously, add the vertical compression lactose mixing of 20% again, then the vertical compression lactose of 30% is added, mix homogeneously, then add remaining vertical compression lactose and cross 50 mesh sieves, mixing, finally add magnesium stearate mix homogeneously, use rotary tablet machine tabletting, coating, to obtain final product.
embodiment 11
| Composition | Content (mg/ sheet) | Percentage by weight |
| Succinic acid YM-905 | 4.5 | 1.5wt% |
| Vertical compression lactose Tablettose70 | 270 | 90wt% |
| Carboxymethyl starch sodium | 3.5 | 1.17wt% |
| Hypromellose | 16 | 5.33wt% |
| Micropowder silica gel | 6 | 2wt% |
Take required supplementary material by recipe quantity, first the lactose of 10% is added in mixer, then add succinic acid YM-905 and carboxymethyl starch sodium mixes, then add the vertical compression lactose of 20%, add the vertical compression lactose of 30% after mixing, mix homogeneously, add remaining vertical compression lactose again to mix, add hypromellose, mix and cross 50 mesh sieves, mix homogeneously, finally add micropowder silica gel mix homogeneously, use powder vertical compression tabletting machine, coating, to obtain final product.
embodiment 12
| Composition | Content (mg/ sheet) | Percentage by weight |
| Succinic acid YM-905 | 20 | 10wt% |
| Vertical compression lactose Flowlac90 | 142 | 71wt% |
| Carboxymethyl starch sodium | 16 | 8wt% |
| Hypromellose | 20 | 10wt% |
| Pulvis Talci | 2 | 1wt% |
Take required supplementary material by recipe quantity, first the lactose of 10% is added in mixer, then add succinic acid YM-905 and carboxymethyl starch sodium mixes, then add the vertical compression lactose of 20%, add the vertical compression lactose of 30% after mixing, mix homogeneously, add remaining vertical compression lactose again to mix, add hypromellose, mix and cross 50 mesh sieves, mix homogeneously, finally add Pulvis Talci mix homogeneously, use powder vertical compression tabletting machine, coating, to obtain final product.
embodiment 13
| Composition | Content (mg/ sheet) | Percentage by weight |
| Succinic acid YM-905 | 10 | 10wt% |
| Vertical compression lactose Sheffield | 45 | 45wt% |
| Mannitol | 29 | 29wt% |
| Carboxymethyl starch sodium | 3.3 | 3.3 wt% |
| Hypromellose | 11.4 | 11.4wt% |
| Calcium stearate | 1.3 | 1.3 wt% |
Take required supplementary material by recipe quantity, first the lactose of 10% is added in mixer, then add succinic acid YM-905 and mannitol and carboxymethyl starch sodium and mix, then add the vertical compression lactose of 20%, add the vertical compression lactose of 30% after mixing, mix homogeneously, add remaining vertical compression lactose again to mix, add hypromellose, mix and cross 50 mesh sieves, mix homogeneously, finally add calcium stearate mixing, use powder vertical compression tabletting machine, coating, to obtain final product.
embodiment 14
| Composition | Content (mg/ sheet) | Percentage by weight |
| Succinic acid YM-905 | 6 | 6wt% |
| Vertical compression lactose Pharmatose DCL | 90 | 90wt% |
| Carboxymethyl starch sodium | 0.5 | 0.5wt% |
| Hypromellose | 2 | 2wt% |
| Magnesium stearate | 1.5 | 1.5wt% |
Take required supplementary material by recipe quantity, first the lactose of 10% is added in mixer, then add succinic acid YM-905 and carboxymethyl starch sodium mixes, then add the vertical compression lactose of 20%, add the vertical compression lactose of 30% after mixing, mix homogeneously, add remaining vertical compression lactose again to mix, add hypromellose, mix and cross 50 mesh sieves, mix homogeneously, finally add magnesium stearate mix homogeneously, use powder vertical compression tabletting machine, coating, to obtain final product.
embodiment 15
| Composition | Content (mg/ sheet) | Percentage by weight |
| Succinic acid YM-905 | 6 | 6wt% |
| Vertical compression lactose Tablettose80 | 75 | 75wt% |
| Sorbitol | 11 | 11wt% |
| Carboxymethyl starch sodium | 1 | 1wt% |
| Hypromellose | 6 | 6wt% |
| Magnesium stearate | 1 | 1wt% |
Take required supplementary material by recipe quantity, first the lactose of 10% is added in mixer, then add succinic acid YM-905 and carboxymethyl starch sodium mixes, then add the vertical compression lactose of 20%, add the vertical compression lactose of 30% after mixing, mix homogeneously, add remaining vertical compression lactose again to mix, add hypromellose and sorbitol, mix and cross 50 mesh sieves, mix homogeneously, finally add magnesium stearate mix homogeneously, use powder vertical compression tabletting machine, coating, to obtain final product.
embodiment 16
| Composition | Content (mg/ sheet) | Percentage by weight |
| Succinic acid YM-905 | 2.5 | 2.5wt% |
| Vertical compression lactose Foremost 315 | 85 | 85wt% |
| Carboxymethyl starch sodium | 4 | 4wt% |
| Hypromellose | 8 | 8wt% |
| Magnesium stearate | 0.5 | 0.5wt% |
Take required supplementary material by recipe quantity, first the lactose of 10% is added in mixer, then add succinic acid YM-905 and carboxymethyl starch sodium mixes, then add the vertical compression lactose of 20%, add the vertical compression lactose of 30% after mixing, mix homogeneously, add remaining vertical compression lactose again to mix, add hypromellose, cross 50 mesh sieves, mix homogeneously, finally add the mixed combination of magnesium stearate evenly, use powder vertical compression tabletting machine, coating, to obtain final product.
embodiment 17
| Composition | Content (mg/ sheet) | Percentage by weight |
| Succinic acid YM-905 | 5 | 3.33wt% |
| Vertical compression lactose Tablettose100 | 135 | 90wt% |
| Carboxymethyl starch sodium | 2.8 | 1.87wt% |
| Hypromellose | 6.4 | 4.27wt% |
| Magnesium stearate | 0.8 | 0.53wt% |
Take required supplementary material by recipe quantity, first the lactose of 10% is added in mixer, then add succinic acid YM-905 and carboxymethyl starch sodium mixes, then add the vertical compression lactose of 20%, add the vertical compression lactose of 30% after mixing, mix homogeneously, add remaining vertical compression lactose again to mix, add hypromellose, mix and cross 50 mesh sieves, mix homogeneously, finally add magnesium stearate, use powder vertical compression tabletting machine, coating, to obtain final product.
embodiment 18
| Composition | Content (mg/ sheet) | Percentage by weight |
| Succinic acid YM-905 | 5 | 3.33wt% |
| Vertical compression lactose Flowlac100 | 133 | 88.67wt% |
| Carboxymethyl starch sodium | 1.5 | 1wt% |
| Hypromellose | 9 | 6wt% |
| Magnesium stearate | 1.5 | 1wt% |
Take required supplementary material by recipe quantity, first the lactose of 10% is added in mixer, then add succinic acid YM-905 and carboxymethyl starch sodium mixes, then add the vertical compression lactose of 20%, add the vertical compression lactose of 30% after mixing, mix homogeneously, add remaining vertical compression lactose again to mix, add hypromellose, mix and cross 50 mesh sieves, mix homogeneously, finally add magnesium stearate mix homogeneously, use powder vertical compression tabletting machine, coating, to obtain final product.
Measure the made tablet content uniformity of embodiment 1 ~ 18 and stripping homogeneity respectively, and tablet packed with air-tight bottle, 40 DEG C, under the accelerated test condition of RH75% storage measure the ratio of its F1 growing amount after 6 months, result is shown in table 5.
The ratio of table 5 embodiment 1 ~ 18F1 growing amount, uniformity of dosage units and 15min dissolution results
Claims (10)
1., containing the pharmaceutical composition of succinic acid YM-905, it is characterized in that this pharmaceutical composition simultaneously containing vertical compression type lactose and carboxymethyl starch sodium, and binding agent and lubricant, and method for preparing tablet thereof is direct powder compression.
2. the pharmaceutical composition containing succinic acid YM-905 according to claim 1, is characterized in that described pharmaceutical composition contains:
。
3. the pharmaceutical composition containing succinic acid YM-905 according to claim 1 ~ 2 any one, is characterized in that described succinic acid YM-905 is crystal type.
4. the pharmaceutical composition containing succinic acid YM-905 according to claim 1 ~ 2 any one, is characterized in that described vertical compression type lactose is preferably spray-dried lactose.
5. according to claim 1 ~ 2 any one containing the pharmaceutical composition of succinic acid YM-905, it is characterized in that described lubricant is selected from magnesium stearate, calcium stearate, Pulvis Talci, micropowder silica gel one or more, be preferably magnesium stearate.
6. the pharmaceutical composition containing succinic acid YM-905 according to claim 1 ~ 2 any one, it is characterized in that described binding agent is selected from starch slurry, sodium carboxymethyl cellulose, arabic gum, hydroxypropyl cellulose, methylcellulose, ethyl cellulose, syrup, hypromellose, polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, Hydroxypropylcelliloxe, maltose, refined honey, liquid glucose, sodium alginate, Polyethylene Glycol, Magnesiumaluminumsilicate, maltodextrin, vinyl pyrrolidone/vinyl acetate co-polymer (copolyvidone), one or more in polyvinyl alcohol/polyethyleneglycol-graft copolymer.
7. the pharmaceutical composition containing succinic acid YM-905 according to claim 1 ~ 2 any one, its feature is hypromellose at described binding agent.
8. the pharmaceutical composition containing succinic acid YM-905 according to claim 1, is characterized in that described pharmaceutical composition contains:
。
9. the pharmaceutical composition containing succinic acid YM-905 according to claim 1, is characterized in that described pharmaceutical composition contains:
。
10. the pharmaceutical composition containing succinic acid YM-905 described in any one according to claims 1 to 9, is characterized in that the preparation method of described pharmaceutical composition is:
Weigh: take required supplementary material by recipe quantity, sieve;
Mixing: first mixed with carboxymethyl starch sodium by succinic acid YM-905, then adds vertical compression type lactose according to equivalent method gradation of progressively increasing, and adds rear mixing and mistake 50 mesh sieves at every turn, then adds other pharmaceutically acceptable adjuvants such as binding agent and lubricant, mix homogeneously;
Tabletting, coating, to obtain final product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410124888.XA CN104940152B (en) | 2014-03-31 | 2014-03-31 | A kind of pharmaceutical composition containing butanedioic acid Solifenacin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410124888.XA CN104940152B (en) | 2014-03-31 | 2014-03-31 | A kind of pharmaceutical composition containing butanedioic acid Solifenacin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104940152A true CN104940152A (en) | 2015-09-30 |
| CN104940152B CN104940152B (en) | 2017-12-29 |
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| CN201410124888.XA Active CN104940152B (en) | 2014-03-31 | 2014-03-31 | A kind of pharmaceutical composition containing butanedioic acid Solifenacin |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104523628A (en) * | 2014-12-24 | 2015-04-22 | 乐普药业股份有限公司 | Succinic acid solifenacin tablet capable of achieving direct powder compression and preparation method of succinic acid solifenacin tablet |
| CN105012961A (en) * | 2014-04-17 | 2015-11-04 | 江苏神龙药业有限公司 | Stable pharmaceutical composition and preparation method thereof |
| CN105395494A (en) * | 2015-11-27 | 2016-03-16 | 浙江华义医药有限公司 | Medicine composition containing succinic acid solifenacin and preparation method of medicine composition |
| CN111686083A (en) * | 2020-06-10 | 2020-09-22 | 石药集团中奇制药技术（石家庄）有限公司 | Ilaprazole enteric-coated tablet |
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| EP2500013A1 (en) * | 2011-03-15 | 2012-09-19 | Alfred E. Tiefenbacher GmbH & Co. KG | Pharmaceutical composition comprising solifenacin |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105012961A (en) * | 2014-04-17 | 2015-11-04 | 江苏神龙药业有限公司 | Stable pharmaceutical composition and preparation method thereof |
| CN105012961B (en) * | 2014-04-17 | 2020-07-21 | 燃点(南京)生物医药科技有限公司 | Stable pharmaceutical composition and preparation method thereof |
| CN104523628A (en) * | 2014-12-24 | 2015-04-22 | 乐普药业股份有限公司 | Succinic acid solifenacin tablet capable of achieving direct powder compression and preparation method of succinic acid solifenacin tablet |
| CN104523628B (en) * | 2014-12-24 | 2017-08-25 | 乐普药业股份有限公司 | It is a kind of can direct powder compression butanedioic acid Solifenacin tablet and preparation method thereof |
| CN105395494A (en) * | 2015-11-27 | 2016-03-16 | 浙江华义医药有限公司 | Medicine composition containing succinic acid solifenacin and preparation method of medicine composition |
| CN111686083A (en) * | 2020-06-10 | 2020-09-22 | 石药集团中奇制药技术（石家庄）有限公司 | Ilaprazole enteric-coated tablet |
| CN111686083B (en) * | 2020-06-10 | 2022-04-22 | 石药集团中奇制药技术（石家庄）有限公司 | Ilaprazole enteric-coated tablet |
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| CN104940152B (en) | 2017-12-29 |
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Effective date of registration: 20190228 Address after: 620010 Meishan Economic Development Zone, Meishan City, Sichuan Province Patentee after: Sichuan Gowell Pharmaceutical Co., Ltd. Address before: 610041 No. 201, No. 201, No. 402, Building C, 6 Jiuxing Avenue, Chengdu High-tech Zone, Sichuan Province Patentee before: Chengdu state bio medicine Co., Ltd. |
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