CN104940152B - A kind of pharmaceutical composition containing butanedioic acid Solifenacin - Google Patents
A kind of pharmaceutical composition containing butanedioic acid Solifenacin Download PDFInfo
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- CN104940152B CN104940152B CN201410124888.XA CN201410124888A CN104940152B CN 104940152 B CN104940152 B CN 104940152B CN 201410124888 A CN201410124888 A CN 201410124888A CN 104940152 B CN104940152 B CN 104940152B
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- butanedioic acid
- vertical compression
- lactose
- solifenacin
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Abstract
The present invention relates to a kind of pharmaceutical composition, containing drug ingedients such as butanedioic acid Solifenacin, vertical compression type lactose, sodium carboxymethyl starches, and contains adhesive and lubricant.The invention also discloses the preparation method of pharmaceutical composition.The new pharmaceutical composition impurity content of butanedioic acid Solifenacin provided by the invention is few, and drug dissolution is more preferable.
Description
Technical field
The present invention relates to pharmaceutical preparation, and in particular to a kind of pharmaceutical composition containing butanedioic acid Solifenacin and its preparation
Method.
Background technology
Butanedioic acid Solifenacin（Solifenacin Succinate, 1- azabicyclo [2.2.2] octane -8- base-(1S) -
1- phenyl -3,4- dihydro -1H- isoquinolin -2- formic acid esters succinates）It is M of new generation3Receptor antagonist, act on detrusor
On m receptor, reduce the over-activity of detrusor, so as to alleviate due to urgent urination caused by bladder muscle overacfivity, frequent micturition and
The symptoms such as urge incontinence, compared with similar drugs, it is to bladder selectivity highest, therefore curative effect is stronger, and side effect is less,
Patient has more preferable tolerance and compliance, is ICS, urinary surgery branch of Chinese Medical Association, Japanese Urology Surgery association system
The first-line treatment medicine recommended in the overactive bladder treatment guidelines ordered.
The Yuan Yan producers of butanedioic acid Solifenacin are Japanese Astellas（Astellas）Company, product takes the lead within 2004
Listed in Europe, enter within 2005 the U.S., the approval listing of 2009 Nian Huo Chinese foods Drug Administration, trade name
Vesicare (Wei Xikang).
Research confirms that Solifenacin molecule is to moisture quite sensitive, under conditions of water content is higher, butanedioic acid Suo Lina
New crystal can largely be converted into unformed shape, and unformed butanedioic acid Solifenacin is easily degraded, and generates a large amount of degradeds
Impurity, the security of medication is had a strong impact on, is pointed out in Yuan Yan house journals CN101141961B, to ensure drug safety, amber
The ratio between the content of amber acid Solifenacin degradation impurity and total amount of butanedioic acid Solifenacin and its catabolite should be controlled strictly
System below 0.4%, therefore, water content how is strictly controlled in prescription or in preparation process, avoid as far as possible Solifenacin with
Contact with moisture is the technical barrier that those skilled in the art are seeking to solve.
However, butanedioic acid Solifenacin piece is prepared using wet granulation technique in Yuan Yan house journals CN101141961B
Agent, this method inevitably make Solifenacin be contacted with water, cause degradation impurity to generate, and can not fundamentally solve amber
Sour Solifenacin contacts the problem of generating a large amount of degradation impurities with water；Patent CN101141961B points out directly to press according to powder
Prepared by piece method, contacted though avoiding Solifenacin with water, because Solifenacin or its salt have strong aggregation, directly presses
Piece method is it is difficult to ensure that the uniformity of content, and mixture can be adhered on drift in compression process.
The A2 of patent WO 2010097243, which are disclosed, to be solved direct compression method to prepare Solifenacin tablet content homogeneity poor
Prescription, i.e., add good fluidity in main ingredient butanedioic acid Solifenacin（Angle of repose is less than 36o）Lactose, microcrystalline cellulose,
The excipient such as mannitol or silica.But a collection of Solifenacin is prepared according to the prescription of the A2 embodiments 1 of WO 2010097243
Piece sample, experiment are found that while that impurity content is low, uniformity of dosage units meets《Chinese Pharmacopoeia》（2010 editions）It is required that but prepare piece
Agent is in simulation gastric environment（pH1.2）For 15min dissolution rates below 70%, dissolution rate is poor in medium.
Reported in patent EP2500013A in butanedioic acid Solifenacin add lactose, disintegrant cornstarch and other
Proper excipient mixes, and carries out direct tablet compressing, but prepares a collection of sample according to prescription described in patent Example 2, and experiment finds piece
Agent is in simulation gastric environment（pH1.2）15min dissolution rates are less than 70% in medium, and dissolution rate is still poor.
According to《Oral solid formulation Dissolution Rate Testing technological guidance's principle》（Hereinafter referred to as " guideline "）Middle biological medicament
Agent credit class understands that butanedioic acid Solifenacin belongs to the classes of BCS I（High-dissolvability-high osmosis medicine）, influence such drug oral
The rate-limiting step of infiltration rate and degree is the dissolution rate and stripping quantity of medicine afterwards.Such medicine is in vitro under normal circumstances
Dissolution rate is faster, and stripping quantity is higher, works faster.
Due in the fasted state, Entogastric lingering（Emptying）The T50% times are 15~20 minutes, if medicine is gentle
Under leaching condition（Slurry processes：50 revs/min；Simulate low gastrointestinal peristalsis speed）, its dissolution rate, can be with more than 85% in 15 minutes
The conservative dissolution for thinking medicine is not influenceed by gastric emptying, and the dissolved corrosion of preparation is similar to solution.If butanedioic acid Suo Li
For dissolution rate up to more than 85%, its action speed can be substantially better than the preparation of prior art direct compression method to that new film in 15 minutes
Butanedioic acid Solifenacin piece.
The pH of human normal gastric environment is 1.2, the pH value of gastric anacidity patient's gastric environment is 4.0, hydrochloric acid in gastric juice extremely lack and
The pH value of environment is 6.8 in small intestine, if butanedioic acid Solifenacin piece, under conditions of pH is 1.2,15 minutes dissolution rates are up to 85%
More than, then can Fast Stripping, its dissolved corrosion are not influenceed by gastric emptying under gastric environment in normal human, the dissolved corrosion of preparation
It is similar to solution, so as to quick acting.If butanedioic acid Solifenacin piece be satisfied by under above-mentioned each pH value condition 15 minutes it is molten
Out-degree can then meet different crowd medication, the patient extremely lacked for hydrochloric acid in gastric juice, can also reach its dissolved corrosion up to more than 85%
Do not influenceed by gastric emptying, quick acting.
Using prior art prescription, there is dissolution in the butanedioic acid Solifenacin tablet prepared with direct powder compression all the time
Spend the problem of poor.But in view of direct powder compression compared with wet granulation, have technique it is simple, it is with short production cycle, production
The advantages such as cost is low, heating and the influence of moisture can be especially avoided, is very suitable for the such chemical property of butanedioic acid Solifenacin
The preparation of unstable medicine.Therefore a kind of prescription suitable for direct powder compression is developed, Dissolution of Tablet is existed
Reach more than 85% dissolution in pH1.2 dissolution medium, meet the medication needs of normal person, quick acting, further,
Develop a kind of prescription of direct powder compression so that it is in 4 kinds of dissolution mediums of pH1.2, pH4.0, pH6.8 solution and water
15min dissolution rate meets all sick human needs, includes the need of the hydrochloric acid in gastric juice extremely particular patients ' of shortage all higher than 85%
Will, make its inside all patients can Fast Stripping, be very important.
The content of the invention
During in order to overcome prior art to prepare butanedioic acid Solifenacin tablet using direct powder compression, existing dissolution
Degree can not reach is higher than 85% in the environment of pH1.2, can not reach the 15min in pH4.0, pH6.8 special dissolution medium
Dissolution rate be higher than 85%, obtain can Fast Stripping, the butanedioic acid Solifenacin tablet formulation of quick acting, the present invention provide
Following technical scheme：
The invention provides a kind of pharmaceutical composition containing butanedioic acid Solifenacin：The pharmaceutical composition is simultaneously containing straight
Die mould lactose, sodium carboxymethyl starch, and adhesive and lubricant, and method for preparing tablet thereof is direct powder compression.
The invention provides a kind of pharmaceutical composition specifically containing butanedioic acid Solifenacin, its composition includes：
| Composition | Percentage by weight |
| Butanedioic acid Solifenacin | 1.5wt%~10wt% |
| Vertical compression type lactose | 45wt%~90wt% |
| Sodium carboxymethyl starch | 0.5wt%~8wt% |
| Adhesive | 2wt%~10wt% |
| Lubricant | 0.3wt%~2wt% |
The butanedioic acid Solifenacin is crystal type.
The vertical compression type lactose is preferably spray-dried lactose.
One or more of the lubricant in magnesium stearate, calcium stearate, talcum powder, superfine silica gel powder, it is preferably
Magnesium stearate.
Described adhesive be selected from starch slurry, sodium carboxymethylcellulose, Arabic gum, hydroxypropyl cellulose, methylcellulose,
Ethyl cellulose, syrup, hydroxypropyl methylcellulose, polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, high substitution hydroxypropyl are fine
Dimension element, 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 containing butanedioic acid Solifenacin being more highly preferred to, its composition includes：
| Composition | Percentage by weight |
| Butanedioic acid Solifenacin | 2.5wt%~6wt% |
| Vertical compression type lactose | 75wt%~90wt% |
| Sodium carboxymethyl starch | 1wt%~4wt% |
| Hydroxypropyl methylcellulose | 4wt%~8wt% |
| Magnesium stearate | 0.5wt%~1wt% |
The invention provides a kind of highly preferred pharmaceutical composition containing butanedioic acid Solifenacin, consisting of：
| Composition | Percentage by weight |
| Butanedioic acid Solifenacin | 3.33wt% |
| Vertical compression type lactose | 88.67wt% |
| Sodium carboxymethyl starch | 1wt% |
| Hydroxypropyl methylcellulose | 6wt% |
| Magnesium stearate | 1wt% |
Present invention also offers a kind of preparation method of butanedioic acid Solifenacin pharmaceutical composition：
（1）Weigh：Required supplementary material is weighed by recipe quantity, is sieved；
（2）Mixing：First butanedioic acid Solifenacin is mixed with sodium carboxymethyl starch, then according to equivalent progressively increase method by several times plus
Enter vertical compression type lactose, mixed after adding every time and cross 50 mesh sieves, adding adhesive and lubricant etc., other are pharmaceutically acceptable
Auxiliary material, it is well mixed；
（3）Tabletting, coating, is produced.
Based on direct powder compression technology have time-saving energy-saving, simple process, process it is few, suitable for damp and hot unstable medicine
The advantages such as thing, present invention applicant is with reference first to Solifenacin described in embodiment 1 in Yuan Yan house journals CN101601673B
Tablet forms, with butanedioic acid Solifenacin（6.67wt%）, lactose（68.33wt%）, cornstarch（20wt%）, hydroxypropyl first it is fine
Dimension element（4wt%）And magnesium stearate（1wt%）Direct pressing tablet after well mixed, it is found that friability is unqualified, can not be coated,
Carry out follow-up preparation.
In view of excipient such as lactose, microcrystalline cellulose of the prior art by the addition good fluidity in butanedioic acid Solifenacin
Element or mannitol etc., although can solve the problem that direct powder compression prepares Solifenacin tablet content homogeneity question, do not have
Any prior art can solve the problems, such as Solifenacin tablet powder direct compression method dissolution rate difference.Present invention applicant attempts again
Adjust the content of butanedioic acid Solifenacin in tablet composition（2wt%~10 wt%）, increase or decrease main ingredient and other excipient
Ratio, or there is larger sticky cornstarch with resistance to bond excipient calcium monohydrogen phosphate replacement, compress tablet coating after being well mixed, and
It is detected, as a result found, above-mentioned Dissolution of Tablet is still not improved.
Present invention applicant attempts to add other vertical compression type excipient such as vertical compression crystallite fibre on the basis of above-mentioned prescription again
Dimension element（Such as Avicel PH102 SCG, Avicel PH200 NF, Celldone 113, Celldone 210）, vertical compression mannitol
（Such as PearlitolSD, PearlitolDC）, vertical compression sorbierite（Such as Neosorb P150 DC, Neosorb P300DC）, vertical compression
Starch/lactose compound（Such as Starlac）, vertical compression lactose/cellulose composite（Such as Cellactose80）, vertical compression lactose/micro-
Crystalline cellulose compound（Such as MicroceLac100）, vertical compression lactose/PVP compound（Such as Ludipress LCE）Deng as a result
It was found that the above method still can not make the dissolution rate of tablet have clear improvement.
Present invention applicant attempts to change the species and amount ratio of adhesive and lubricant or other excipient in prescription again
Example, adhesive for example starch slurry, sodium carboxymethylcellulose, Arabic gum, hydroxypropyl cellulose, methylcellulose, ethyl cellulose,
Syrup, hydroxypropyl methylcellulose, polyvinylpyrrolidone, Hydroxypropylcelliloxe, maltose, refined honey, liquid glucose, marine alga
Sour sodium, polyethylene glycol, Magnesiumaluminumsilicate etc., lubricant such as magnesium stearate, calcium stearate, talcum powder, superfine silica gel powder etc., it is well mixed
Tabletting and it is coated afterwards, then carries out dissolution test, as a result find that its dissolution rate is still not improved.
Present invention applicant is molten existing for insurmountable Solifenacin tablet powder direct compression method always in order to improve
The problem of out-degree difference, attempt again by crushing, sieving（The mesh sieve of 100 mesh ~ 200）Etc. mode reduce butanedioic acid Solifenacin and other
Particle diameter difference between excipient, avoids tabletting machine from causing powder to be layered when vibrating；Or common rotary tablet compression equipment is carried out
Adjustment, increase pressure feed device makes powder more uniformly flow into feeder and nib, reduces tabletting such as on feeding device
The rotating speed of machine makes that blanking device feed is sufficient, increase pressing step avoids telling powder and causes piece weight uneven with the gas excluded between powder
It is even etc.；Or tablet is directly prepared using the vertical compression type tablet press machine for aiming at powder vertical compression Technology design, then it is coated and to it
Detected, as a result find that dissolution rate of the tablet of above method preparation in 4 kinds of dissolution mediums is entirely below 70%, dissolution rate
Still it is poor.Present invention applicant is and fine by disintegrant such as sodium carboxymethyl starch, low substituted hydroxy-propyl on the basis of the above method
Tie up element, PVPP, Ac-Di-Sol, starch etc.；Other fillers in addition to microcrystalline cellulose（Such as sweet dew
Alcohol, sorbierite, pregelatinized starch）Prescription is added Deng excipient, it is still bad that fructufy issues after examination and approval its existing dissolution rate.
Present invention applicant is finally had found between accidentally, prepared when using direct powder compression by substantial amounts of experiment
During Solifenacin tablet, tablet composition in must contain vertical compression type lactose and sodium carboxymethyl starch, in addition, for guarantee tablet into
Type, also need containing adhesive and lubricant, wherein lubricant is in magnesium stearate, calcium stearate, talcum powder, superfine silica gel powder
It is one or more；Adhesive be selected from starch slurry, sodium carboxymethylcellulose, Arabic gum, hydroxypropyl cellulose, methylcellulose,
Ethyl cellulose, syrup, hydroxypropyl methylcellulose, polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, high substitution hydroxypropyl are fine
Dimension element, 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 respectively into
Point content range be necessary for 1.5wt%~10wt% butanedioic acids Solifenacin, 45wt%~90wt% vertical compression types lactose, 0.5wt%~
8wt% sodium carboxymethyl starches, 2wt%~10wt% adhesives and 0.3wt%~2wt% lubricants, now prepare the tablet ability of shaping
Meet that is, 15min dissolution rates more than 85%, solve prior art prescription, adopted in pH1.2 media in general patient's gastric environment
The dissolution in general patient's gastric environment medium existing for the butanedioic acid Solifenacin tablet of direct powder compression preparation
The problem of degree is also poor.
Present invention applicant again in further research surprisingly it has been found that, above-mentioned prescription only uses hydroxypropyl methylcellulose
During as adhesive, the tablet of preparation is surprisingly in four kinds of dissolution mediums of pH1.2, pH4.0, pH6.8 solution and water
15min dissolution rates all more than 85%, solve the Solifenacin piece of prior art prescription direct powder compression preparation unexpectedly
Existing for agent in 3 kinds of dissolution mediums of especial patient gastric environment pH4.0, pH6.8 solution and water the problem of dissolution rate difference.
Vertical compression type lactose of the present invention, be specific to direct tablet compressing exploitation design has good fluidity and can
The anhydrous or lactose monohydrate of compressibility, can use spray drying, fluidized bed granulation, roller drying the methods of to sieving/grinding
Lactose carries out physical modification and is voluntarily prepared or is directly commercially available at different production firms.Vertical compression type lactose
Different types, such as particulate lactose can be divided into according to different preparation methods（As Tablettose70, Tablettose80,
Tablettose100）, spray-dried lactose（Such as Flowlac90, Flowlac100, Foremost 315）, Lactis Anhydrous（Such as
Sheffield）Deng, it is best compared with other vertical compression type lactose, its powder flowbility present invention preferably uses spray-dried lactose, and
With certain adsorption function, the tablet content uniformity of preparation is more preferably.
Tablet of the present invention containing butanedioic acid Solifenacin, except containing butanedioic acid Solifenacin, vertical compression type lactose,
Outside disintegrant, adhesive and lubricant, it can also suitably contain other various pharmaceutical excipients, including but not limited to sweetener
（Such as Aspartame, stevioside, saccharin sodium）, foaming agent（Such as sodium acid carbonate）, flavouring（Such as lemon extract, orange essence, peppermint
Alcohol）, opacifier（Such as titanium dioxide）, colouring agent（Such as iron oxide red, iron oxide yellow）, surfactant（Such as dodecyl sulphate
Sodium, poloxamer）, other fillers in addition to microcrystalline cellulose（Such as mannitol, sorbierite, pregelatinized starch）, antioxidant
（Such as ascorbic acid, propylgallate）Deng.A kind of described excipient can be added in right amount, or is added described in two or more
The combination of excipient.
Direct powder compression method of the present invention, refer to without pelletization directly the mixed of medicine and excipient
The method that compound carries out tabletting, including but not limited to following steps：Medicine, excipient → mixing → tabletting.Wherein, " mixing " mistake
The addition sequence of medicine and each excipient in journey, number, incorporation time etc. are mixed depending on medicine and species, the percentage of excipient
Content or particle diameter, and to mixing arrangement（Including such as V-type blender, container blender, high speed agitator）It is not particularly limited.
In general, mixed effect reaches industry production standard known in those skilled in the art, i.e., the RSD of the medicament contg of mixed powder
Value≤5% or lower, that is, represent well mixed.
Preforming device includes such as rotary pelleting machine and powder vertical compression tablet press machine, it is however generally that, it is any to prepare compression
Layered product（Preferably tablet）Method can meet to require, its apparatus and method is not particularly limited.
Butanedioic acid Solifenacin of the present invention, can directly use conventional chemical synthesis method, such as
US20070185329A1 embodiments 1A, US20100029944A1 embodiment 1~3, US20080114028A1 embodiments 1,
The finished product that CN102875544A embodiments 1 and the methods described of CN101711248A embodiments 1 are directly prepared, can also be further
Make that its form is more regular, particle diameter is more homogeneous by the mode such as crush, sieve, be more beneficial for the mobility of mixed powder, be advantageous to improve
The uniformity of dosage units and dissolution rate of tablet.
Adhesive and disintegrant of the present invention, it can be the pharmaceutical grade excipient for being directly purchased from manufacturer, also may be used
So that further its form is more regular, particle diameter is more homogeneous by making in a manner of crushing, sieve etc., adhesive is more beneficial in mixed powder
Flow and dispersed, be advantageous to improve the dissolution rate of tablet.
Comparative example
Comparative example 1
Formed according to the tablet of Solifenacin described in embodiment 1 in patent CN101601673B：
| Composition | Content（Mg/ pieces） | Percentage by weight |
| Butanedioic acid Solifenacin | 10 | 6.67wt% |
| Lactose | 102.5 | 68.33wt% |
| Cornstarch | 30 | 20wt% |
| Hydroxypropyl methylcellulose | 6 | 4wt% |
| Magnesium stearate | 1.5 | 1wt% |
According to the methods described of embodiment 1 in patent CN101601673B, required supplementary material is weighed by recipe quantity.By hydroxypropyl
Methylcellulose is configured to binder solution with suitable quantity of water, is crushed after then butanedioic acid Solifenacin is mixed with 39% lactose, so
After add remaining lactose and cornstarch, binder solution is sprayed to implement wet granulation behaviour using fluidised bed granulator
Make, magnesium stearate is added after obtained particle drying, carry out tabletting and coating, produce.
Comparative example 2
According to the prescription of patent EP2500013A1 embodiments 2：
| Composition | Content（Mg/ pieces） | Percentage by weight |
| Butanedioic acid Solifenacin | 10.5 | 6.97wt% |
| Vertical compression lactose Tablettose | 100.95 | 67.1wt% |
| Cornstarch | 30.00 | 19.94wt% |
| Hydroxypropyl methylcellulose | 7.50 | 4.98wt% |
| Magnesium stearate | 1.50 | 1.0wt% |
Required supplementary material is weighed by recipe quantity, first carries out butanedioic acid Solifenacin and hydroxypropyl methylcellulose and cornstarch
Mixing, 20% vertical compression lactose is then added, 30% vertical compression lactose is added after mixing, is well mixed, adds remaining vertical compression
Lactose, mix and cross 50 mesh sieves, be well mixed, finally add magnesium stearate and be well mixed, use rotary pelleting machine tabletting, bag
Clothing, produce.
Comparative example 3
According to the prescription of the A2 embodiments 7 of WO 2010097243：
| Composition | Content（Mg/ pieces） | Percentage by weight |
| Butanedioic acid Solifenacin | 20 | 6.67wt% |
| Vertical compression lactose Tablettose | 217 | 72.33wt% |
| Cornstarch | 60 | 20.00wt% |
| Magnesium stearate | 3 | 1.00wt% |
Required supplementary material is weighed by recipe quantity, first butanedioic acid Solifenacin is mixed with cornstarch, then added
20% vertical compression lactose, 30% vertical compression lactose is added after mixing, be well mixed, add remaining vertical compression lactose, mixing and excessively 50
Mesh sieve, it is well mixed, is eventually adding magnesium stearate and is well mixed, using rotary pelleting machine tabletting, coating, produces.
Comparative example 4
According to the prescription of the A2 embodiments 6 of WO 2010097243：
| Composition | Content（Mg/ pieces） | Percentage by weight |
| Butanedioic acid Solifenacin | 20 | 6.67wt% |
| Mannitol | 205 | 68.33wt% |
| Cornstarch | 60 | 20wt% |
| Hydroxypropyl methylcellulose | 12 | 4wt% |
| Magnesium stearate | 3 | 1wt% |
By 20g butanedioic acid Solifenacins, 205g mannitol is well mixed, added sieve aperture 0.6mm 60g cornstarch and
12g hydroxypropyl methylcelluloses are well mixed, and are eventually adding 3g magnesium stearates and are well mixed, press sheet mixture, coating, are produced.
Comparative example 5
According to the prescription of the A2 embodiments 4 of WO 2010097243：
| Composition | Content（Mg/ pieces） | Percentage by weight |
| Butanedioic acid Solifenacin | 20 | 6.67wt% |
| Microcrystalline cellulose | 205 | 68.3wt% |
| Cornstarch | 60 | 20wt% |
| Hydroxypropyl methylcellulose | 12 | 4wt% |
| Magnesium stearate | 3 | 1wt% |
20g butanedioic acids Solifenacin and 205g microcrystalline celluloses are well mixed, the 60g for adding sieve aperture 0.6mm is beautiful
Rice starch and 12g hydroxypropyl methylcelluloses are well mixed, and are eventually adding 3g magnesium stearates and are well mixed, press sheet mixture, coating, i.e.,
.
Comparative example 6
| Composition | Content（Mg/ pieces） | Percentage by weight |
| Butanedioic acid Solifenacin | 10 | 6.67wt% |
| Vertical compression lactose Flowlac100 | 141.42 | 88.33wt% |
| Hydroxypropyl methylcellulose | 6 | 4.0wt% |
| Magnesium stearate | 1.5 | 1.0wt% |
Required supplementary material is weighed by recipe quantity, first by butanedioic acid Solifenacin, 10% vertical compression lactose and hydroxypropyl methylcellulose
Mixed, then add 20% vertical compression lactose, 30% vertical compression lactose is added after being well mixed, is added after mixing remaining
Vertical compression lactose, mix and simultaneously cross 50 mesh sieves, be well mixed, finally add magnesium stearate and be well mixed, using rotary pelleting machine tabletting,
Coating, is produced.
Comparative example 7
| Composition | Content（Mg/ pieces） | Percentage by weight |
| Butanedioic acid Solifenacin | 10 | 6.67wt% |
| Vertical compression lactose Flowlac100 | 131 | 87.33wt% |
| Ac-Di-Sol | 1.5 | 1wt% |
| Hydroxypropyl methylcellulose | 6 | 4wt% |
| Magnesium stearate | 1.5 | 1wt% |
Required supplementary material is weighed by recipe quantity, first by butanedioic acid Solifenacin and Ac-Di-Sol and hydroxypropyl first
Cellulose is mixed, and then adds 20% vertical compression lactose, and 30% vertical compression lactose is added after being well mixed, is added after mixing
Remaining vertical compression lactose, mix and cross 50 mesh sieves, be well mixed, finally add magnesium stearate mixing, use rotary pelleting machine pressure
Piece, coating, is produced.
Comparative example 8
| Composition | Content（Mg/ pieces） | Percentage by weight |
| Butanedioic acid Solifenacin | 10 | 6.67wt% |
| Vertical compression lactose Tablettose | 129.5 | 86.34wt% |
| Low-substituted hydroxypropyl cellulose | 3 | 2wt% |
| Hydroxypropyl methylcellulose | 6 | 4wt% |
| Magnesium stearate | 1.5 | 1wt% |
Required supplementary material is weighed by recipe quantity, first by butanedioic acid Solifenacin and low-substituted hydroxypropyl cellulose and hydroxypropyl
Cellulose is mixed, and then adds 20% vertical compression lactose, and 30% vertical compression lactose is added after mixing, is added after well mixed
Remaining vertical compression lactose, mix and cross 50 mesh sieves, be well mixed, finally add magnesium stearate and be well mixed, use rotary tablet compression
Machine tabletting, coating, is produced.
Comparative example 9
| Composition | Content（Mg/ pieces） | Percentage by weight |
| Butanedioic acid Solifenacin | 10 | 6.67wt% |
| Microcrystalline cellulose | 126.43 | 84.33wt% |
| Sodium carboxymethyl starch | 1.5 | 1.0wt% |
| Hydroxypropyl methylcellulose | 9 | 6.0wt% |
| Talcum powder | 3 | 2.0wt% |
Required supplementary material is weighed by recipe quantity, first by butanedioic acid Solifenacin and sodium carboxymethyl starch and hydroxypropyl methylcellulose
Mixed, then add 20% microcrystalline cellulose, 30% microcrystalline cellulose is added after mixing, it is fine to add remaining crystallite
Dimension element, mix and cross 50 mesh sieves, be well mixed, be eventually adding magnesium stearate and be well mixed, use rotary pelleting machine tabletting, bag
Clothing, produce.
Comparative example 10
| Composition | Content（Mg/ pieces） | Percentage by weight |
| Butanedioic acid Solifenacin | 10 | 6.67wt% |
| Vertical compression lactose Flowlac100 | 128 | 85.34wt% |
| Sodium carboxymethyl starch | 3 | 2wt% |
| Hydroxypropylcelliloxe | 7.5 | 5wt% |
| Magnesium stearate | 1.5 | 1wt% |
Required supplementary material is weighed by recipe quantity, first by butanedioic acid Solifenacin and sodium carboxymethyl starch and high substitution hydroxypropyl
Cellulose is mixed, and then adds 20% vertical compression lactose, and 30% vertical compression lactose is added after being well mixed, is added after mixing
Remaining vertical compression lactose, mix and cross 50 mesh sieves, be well mixed, finally add magnesium stearate mixing, use rotary pelleting machine pressure
Piece, coating, is produced.
Comparative example 11
| Composition | Content（Mg/ pieces） | Percentage by weight |
| Butanedioic acid Solifenacin | 10 | 6.67wt% |
| Vertical compression lactose Flowlac100 | 129.5 | 86.33wt% |
| Sodium carboxymethyl starch | 3 | 2wt% |
| PVP k30 | 6 | 4wt% |
| Magnesium stearate | 1.5 | 1wt% |
Required supplementary material is weighed by recipe quantity, first enters butanedioic acid Solifenacin and sodium carboxymethyl starch and PVP k30
Row mixing, 20% vertical compression lactose is then added, 30% vertical compression lactose is added after being well mixed, added after mixing remaining straight
Lactose is pressed, mixing simultaneously crosses 50 mesh sieves, is well mixed, finally adds magnesium stearate mixing, using rotary pelleting machine tabletting, be coated,
Produce.
Comparative example 12
| Composition | Content（Mg/ pieces） | Percentage by weight |
| Butanedioic acid Solifenacin | 4 | 4wt% |
| Vertical compression lactose Flowlac100 | 90 | 90wt% |
| Sodium carboxymethyl starch | 1 | 1wt% |
| Hydroxypropyl methylcellulose | 4 | 4wt% |
| Magnesium stearate | 1 | 1wt% |
Required supplementary material is weighed by recipe quantity, first by butanedioic acid Solifenacin and sodium carboxymethyl starch and hydroxypropyl methylcellulose
Mixed, then add 20% vertical compression lactose, 30% vertical compression lactose is added after being well mixed, is added after mixing remaining
Vertical compression lactose, mix and simultaneously cross 50 mesh sieves, be well mixed, finally add magnesium stearate and be well mixed, using rotary pelleting machine tabletting,
Coating, is produced.
Comparative example 13
| Composition | Content（Mg/ pieces） | Percentage by weight |
| Butanedioic acid Solifenacin | 5 | 3.33wt% |
| Vertical compression lactose Flowlac100 | 135 | 90wt% |
| Sodium carboxymethyl starch | 2.8 | 1.87wt% |
| Hydroxypropyl methylcellulose | 6.4 | 4.27wt% |
| Magnesium stearate | 0.8 | 0.53wt% |
Required supplementary material is weighed by recipe quantity, first adds 20% vertical compression lactose Flowlac100 in stainless steel, then is added
Enter butanedioic acid Solifenacin, sodium carboxymethyl starch and hydroxypropyl methyl cellulose to be mixed, then add 30% vertical compression breast
Sugar, remaining vertical compression lactose is added after mixing, mixes and cross 50 mesh sieves, be well mixed, finally add magnesium stearate and be well mixed,
Using rotary pelleting machine tabletting, coating, produce.
Comparative example 14
| Composition | Content（Mg/ pieces） | Percentage by weight |
| Butanedioic acid Solifenacin | 5 | 3.33wt% |
| Vertical compression lactose Flowlac100 | 133 | 88.67wt% |
| Sodium carboxymethyl starch | 1.5 | 1wt% |
| Hydroxypropyl methylcellulose | 9 | 6wt% |
| Magnesium stearate | 1.5 | 1wt% |
Required supplementary material is weighed by recipe quantity, first adds 20% vertical compression lactose Flowlac100 in stainless steel, then is added
Enter butanedioic acid Solifenacin to be mixed with sodium carboxymethyl starch, then add 30% vertical compression lactose, residue is added after mixing
Vertical compression lactose, be well mixed, add hydroxypropyl methylcellulose, mix simultaneously cross 50 mesh sieves, be well mixed, finally add magnesium stearate
It is well mixed, using rotary pelleting machine tabletting, coating, produce.
Determine the dissolution rate and uniformity of dosage units of 1~14 made tablet of comparative example respectively by the following method, as a result show
In table 1.
Dissolution rate
Dissolution medium：
(1) pH1.2 dissolution mediums：2 ‰ sodium chloride+0.1mol/L hydrochloric acid solution (Japanese Pharmacopoeia:JP 15 editions).
(2) dissolution mediums of pH4. 0：PH4.0 citrate-phosphate potassium dihydrogen buffer solution (Japanese Pharmacopoeia:JP15 versions).
(3) pH6.8 dissolution mediums：PH6.8 disodium hydrogen phosphates-potassium phosphate buffer (Japanese Pharmacopoeia:JP15 versions).
(4) water dissolution medium：The aqueous solution.
Dissolution medium volume：900ml
Test method：Chinese Pharmacopoeia two annex X C the second method paddle method of version in 2010
Rotating speed：50 turns/min
Uniformity of dosage units
According to butanedioic acid Solifenacin piece import drugs registered standard（JX20050264）Method is carried out under uniformity of dosage units item
Measure：
Butanedioic acid Solifenacin piece 1 is taken, is put in a suitable container, adds water-acetonitrile (7: 3) appropriate solution, at ultrasound
Reason makes dissolving in 15 minutes, is made with the dilution of water-acetonitrile (7: 3) solution in every 1ml containing about 0.5mg solution, filtration, takes subsequent filtrate to make
For need testing solution, another precision weighs butanedioic acid Solifenacin reference substance 25mg, put in 50ml measuring bottles, adds water-acetonitrile (7: 3) molten
Liquid dissolves and is diluted to scale, shakes up, as reference substance solution (1)；Need testing solution and each 10 μ l of reference substance solution (1) are taken,
Liquid chromatograph is injected, chromatographic condition is：Octadecylsilane chemically bonded silica is filler, 40 DEG C, wavelength 210nm of column temperature, with
0.05mol/L dipotassium hydrogen phosphate buffer solutions（PH to 6.0 is adjusted with phosphoric acid）- acetonitrile (70: 30) is mobility, records chromatogram, presses
External standard method is with the content of calculated by peak area butanedioic acid Solifenacin.
Determine the content of 10 tablets of butanedioic acid Solifenacin tablets respectively according to the method described above, and according to Content uniformity test
Method（《Chinese Pharmacopoeia》2010 editions two annex XE）, every represents by 100 relative amount X of labelled amount, seeks its averageAnd mark
The poor S of standard [] and the difference of labelled amount and average absolute value A（）, as A+1.80S≤
15.0, then the uniformity of dosage units of tablet meet regulation.
The 15min dissolution rates and uniformity of dosage units result of the comparative example 1 ~ 14 of table 1
In comparative example 2~5, using prior art prescription, miscibilty and the preferable figuration of mobility are added in tablets
Agent such as vertical compression type lactose, mannitol or microcrystalline cellulose, the uniformity of dosage units of tablet can be improved, but Dissolution of Tablet is poor,
In general patient's gastric environment（pH1.2）15min dissolution rates are entirely below 70% in medium.
Find out from comparative example 2,6~9, though when containing vertical compression lactose in tablet composition, without disintegrant；Or even if contain
Disintegrant, but disintegrant is not sodium carboxymethyl starch；Or have disintegrating agent carboxymethyl base sodium starch in prescription, but with other medicines
Vertical compression lactose is replaced with auxiliary material such as microcrystalline cellulose, can not obtain the good tablet of 15min dissolution rates；Only when tablet forms
As described herein, i.e., vertical compression type lactose and disintegrant must be contained simultaneously, and disintegrant can only be sodium carboxymethyl starch（It is right
Ratio 10）, in addition, to ensure tablet shaping, also need in prescription containing be selected from starch slurry, sodium carboxymethylcellulose, Arabic gum,
Hydroxypropyl cellulose, methylcellulose, ethyl cellulose, syrup, hydroxypropyl methylcellulose, polyvinylpyrrolidone, low substitution hydroxyl
Propyl cellulose, Hydroxypropylcelliloxe, maltose, refined honey, liquid glucose, sodium alginate, polyethylene glycol, alumina silicate
Magnesium, maltodextrin, vinyl pyrrolidone/vinyl acetate co-polymer（Copolyvidone）, the grafting of polyvinyl alcohol/polyethylene glycol altogether
One or more adhesive in polymers and one kind in magnesium stearate, calcium stearate, talcum powder, superfine silica gel powder are more
The lubricant of kind.Tablet prepared by above-mentioned prescription is in simulation gastric environment（pH1.2）15min in this general patient's gastric environment medium
Dissolution rate more than 90%, solve the Solifenacin tablet of prior art prescription direct powder compression preparation in general disease
In people's gastric environment medium the problem of 15min dissolution rate differences.
And from comparative example 10~12, only when used in tablet formulation hydroxypropyl methylcellulose as adhesive rather than other
During adhesive, surprisingly 15min is molten in four kinds of dissolution mediums of pH1.2, pH4.0, pH6.8 solution and water for the tablet of preparation
Out-degree all more than 90%, solve the preparation of prior art prescription direct powder compression Solifenacin tablet it is existing
In 3 kinds of dissolution mediums of especial patient gastric environment pH4.0, pH6.8 solution and water the problem of 15min dissolution rate differences.
In comparative example 12,13, using prescription of the present invention, using prior art powder pressing method conventional process, i.e.,
After supplementary material sieving, disposably butanedioic acid Solifenacin is mixed with auxiliary materials such as adhesives and disintegrant, progressively increased according still further to equivalent
Method adds vertical compression type lactose by several times, mixes and sieves after adding every time；Or after supplementary material sieving, first a certain amount of lactose is added
In stainless steels, then disposably the auxiliary materials such as butanedioic acid Solifenacin and adhesive and disintegrant are added and mixed, finally according to
Equivalent progressively increase method by several times add remaining vertical compression type lactose, mix and sieve after adding every time；But no matter using in the prior art
Any of the above described preparation method, the 15min dissolution rates of obtained Solifenacin tablet cannot improve further；By contrasting
Example 14, prescription of the present invention is only both used, use preparation method of the present invention again, i.e., first add a certain amount of lactose
In stainless steel, then add butanedioic acid Solifenacin mixed with disintegrating agent carboxymethyl base sodium starch, according still further to equivalent progressively increase method divide
Secondary addition vertical compression type lactose, mixes after adding every time, is eventually adding the auxiliary materials such as adhesive, lubricant, be well mixed, according to the party
Tablet prepared by method can surprisingly realize the butanedioic acid Solifenacin tablet of preparation in simulation gastric environment（pH1.2）, simulation
Gastric anacidity patient's gastric environment（pH4.0）, simulation hydrochloric acid extremely lack and small intestine in environment（pH6.8）With four kinds of dissolution mediums of water
For middle 15min dissolution rate more than 95%, dissolution rate is very good.
In addition, present invention applicant in order to further verify prescription of the present invention and preparation method production Solifenacin
Tablet compared with prior art the advantages of, and by comparative example 1（Original grinds wet granulation prescription）With comparative example 10（Place of the present invention
Side）Made tablet, is packed with air-tight bottle, after being stored 6 months under the conditions of 40 DEG C, RH75% accelerated test, by the following method
Detect and calculate its oxidation product F1 growing amount and the ratio between butanedioic acid Solifenacin and its catabolite total amount, and given birth to the F1
Ratio into amount grinds the direct powder compression that wet granule compression tablet method used uses with the present patent application as index, examination original
The difference of tablet prepared by method in terms of stability.
The ratio of growing amount
According to butanedioic acid Solifenacin piece import drugs registered standard（JX20050264）Determination method is surveyed under relevant material item
It is fixed：
Take the fine powder of butanedioic acid Solifenacin piece appropriate (being approximately equivalent to butanedioic acid Solifenacin 50mg), it is accurately weighed, put
In 100ml measuring bottles, add water-acetonitrile (7: 3) appropriate solution, being ultrasonically treated 15 minutes makes dissolving, with water-acetonitrile (7: 3) solution
Scale is diluted to, is shaken up, is filtered, as need testing solution；Another precision weighs butanedioic acid Solifenacin reference substance 25mg, puts 50ml
In measuring bottle, add water-acetonitrile (7: 3) solution to dissolve and be diluted to scale, shake up, as reference substance solution (1)；Precision measures control
Product solution (1) 0.5ml, puts in 100ml measuring bottles, is diluted to scale with water-acetonitrile (7: 3) solution, shakes up, as contrast solution
(2).Need testing solution and each 10 μ l of reference substance solution (2) are taken, injects liquid chromatograph, it is other according under above-mentioned uniformity of dosage units item
Method, operated with method, record chromatogram, the ratios of F1 growing amounts is calculated as follows：
Wherein,、AndRelevant material in test sample chromatogram is represented respectively
The peak area of YM64250 peak area, YM217800 peak area and butanedioic acid Solifenacin；Represent the dense of reference substance (2)
Degree；Represent the volume of need testing solution；Represent the average piece weight of tablet；Represent the sample weighting amount of test sample；Represent
The labelled amount of tablet.
Wherein, F1 means two oxidation products of butanedioic acid Solifenacin, i.e., relevant material YM-64250 and YM-
217880, its title and structure are shown in table 2.
Table 2 is about material YM-64250 and YM-217880
| Relevant material | YM-64250 | YM-217880 |
| Chemical name | Solifenacin nitrogen oxides | (R)-quinuclidinol -3- bases-benzoyl (phenethyl) carbamate |
| Structural formula |
By the butanedioic acid Solifenacin of above comparative example 1 and the gained of comparative example 10 respectively in high temperature（60℃）, high humidity（Relatively
Humidity 90 ± 5%）, place under conditions of illumination 10 days, respectively in 0 day, 5 days, sampling detection in 10 days, investigate YM-64250 and YM-
The growing amount of 217880 two impurity, the ratio result that the results are shown in Table 3, F1 growing amounts are shown in table 4.
The impurity growing amount of the comparative example 1 of table 3 and comparative example 10
The ratio of the F1 growing amounts of the comparative example 1 of table 4 and comparative example 10
| Comparative example | The ratio of 0 day F1 growing amount（%） | High temperature（60 degree）The ratio of 10 days F1 growing amounts（%） | High humidity（92.5%）The ratio of 10 days F1 growing amounts（%） | The ratio of 10 days F1 growing amounts of illumination（%） |
| 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 rate and dissolution data RSD values meet standard, but both
Under the conditions of identical primary stability, the tablet of the direct powder compression method preparation used with the present patent application（Comparative example
10）, the growing amount of two impurity of its YM-64250 and YM-217880 and the ratio of F1 growing amounts all well below Yuan Yan companies with
Tablet prepared by wet granule compression tablet method（Comparative example 1）, the oxidation impurities output in product is less, and stability is more preferable.
Embodiment
With reference to specific embodiment, the present invention is expanded on further.But these embodiments be only limitted to explanation the present invention without
It is the further restriction to protection scope of the present invention.
Embodiment 1
| Composition | Content（Mg/ pieces） | Percentage by weight |
| Butanedioic acid Solifenacin | 4.5 | 1.5wt% |
| Vertical compression lactose Tablettose70 | 270 | 90wt% |
| Sodium carboxymethyl starch | 3.5 | 1.17 wt% |
| Hydroxypropylcelliloxe | 15 | 5.33wt% |
| Superfine silica gel powder | 6 | 2wt% |
Required supplementary material is weighed by recipe quantity, first by butanedioic acid Solifenacin and sodium carboxymethyl starch and high substitution hydroxypropyl
Cellulose is mixed, and then adds 10% vertical compression lactose, and 20% vertical compression lactose is added after mixing, is well mixed, adds
30% vertical compression lactose is mixed, and adds remaining vertical compression lactose, is mixed and is crossed 50 mesh sieves, is well mixed, is eventually adding micro mist
Silica gel is well mixed, and using powder vertical compression tabletting machine, coating, is produced.
Embodiment 2
| Composition | Content（Mg/ pieces） | Percentage by weight |
| Butanedioic acid Solifenacin | 20 | 10wt% |
| Vertical compression lactose Flowlac90 | 142 | 71wt% |
| Sodium carboxymethyl starch | 16 | 8 wt% |
| Arabic gum | 20 | 10wt% |
| Talcum powder | 2 | 1wt% |
Required supplementary material is weighed by recipe quantity and crosses 50 mesh sieves respectively, first by butanedioic acid Solifenacin and sodium carboxymethyl starch
Mixed with Arabic gum, then add 20% vertical compression lactose, be well mixed, the vertical compression lactose for adding 30% is mixed
Close, add remaining vertical compression type lactose, mix and cross 50 mesh sieves, be well mixed, be eventually adding talcum powder and be well mixed, use rotation
Turn tabletting machine, be coated, produce.
Embodiment 3
| Composition | Content（Mg/ pieces） | Percentage by weight |
| Butanedioic acid Solifenacin | 10 | 10wt% |
| Vertical compression lactose Sheffield | 45 | 45wt% |
| Mannitol | 29 | 29wt% |
| Sodium carboxymethyl starch | 3.3 | 3.3 wt% |
| Ac-Di-Sol | 3.4 | 3.4 wt% |
| Hydroxypropyl methylcellulose | 8 | 8wt% |
| Calcium stearate | 1.3 | 1.3 wt% |
Required supplementary material is weighed by recipe quantity, it is first that butanedioic acid Solifenacin and sodium carboxymethyl starch, cross-linked carboxymethyl is fine
Tie up plain sodium, hydroxypropyl methylcellulose and mannitol to be mixed, then add 20% vertical compression lactose, be well mixed, add 30%
Vertical compression lactose is mixed, and adds remaining lactose, is mixed and is crossed 50 mesh sieves, be well mixed, is eventually adding calcium stearate mixing
Uniformly, using rotary pelleting machine tabletting, coating, produce.
Embodiment 4
| Composition | Content（Mg/ pieces） | Percentage by weight |
| Butanedioic acid Solifenacin | 5 | 5wt% |
| Vertical compression lactose Pharmatose DCL | 87 | 87wt% |
| Sodium carboxymethyl starch | 0.5 | 0.5wt% |
| Polyvinyl alcohol/polyethyleneglycol-graft copolymer | 6 | 6wt% |
| Magnesium stearate | 1.5 | 1.5wt% |
Required supplementary material is weighed by recipe quantity and crosses 50 mesh sieves respectively, first by butanedioic acid Solifenacin and sodium carboxymethyl starch
Mixed with polyvinyl alcohol/polyethyleneglycol-graft copolymer, then add 20% vertical compression lactose, be well mixed, add
30% vertical compression lactose is mixed, and adds remaining vertical compression lactose, is mixed and is crossed 50 mesh sieves, is well mixed, is eventually adding tristearin
Sour magnesium is well mixed, and using rotary pelleting machine tabletting, coating, is produced.
Embodiment 5
| Composition | Content（Mg/ pieces） | Percentage by weight |
| Butanedioic acid Solifenacin | 4.5 | 1.5wt% |
| Vertical compression lactose Tablettose70 | 264.6 | 88.2wt% |
| Sodium carboxymethyl starch | 24 | 8wt% |
| Magnesiumaluminumsilicate | 6 | 2wt% |
| Superfine silica gel powder | 0.9 | 0.3wt% |
Required supplementary material is weighed by recipe quantity and crosses 50 mesh sieves respectively, first by butanedioic acid Solifenacin and sodium carboxymethyl starch
Mixed with Magnesiumaluminumsilicate, then add 20% vertical compression lactose, be well mixed, the vertical compression lactose for adding 30% is mixed
Close, add remaining vertical compression lactose, mix and cross 50 mesh sieves, be well mixed, be eventually adding superfine silica gel powder and be well mixed, use rotation
Turn tabletting machine, be coated, produce.
Embodiment 6
| Composition | Content（Mg/ pieces） | Percentage by weight |
| Butanedioic acid Solifenacin | 6 | 6wt% |
| Vertical compression lactose Tablettose80 | 75 | 75wt% |
| Sorbierite | 13 | 13wt% |
| Sodium carboxymethyl starch | 1 | 1wt% |
| Hydroxypropyl methylcellulose | 4 | 4wt% |
| Magnesium stearate | 1 | 1wt% |
Required supplementary material is weighed by recipe quantity, 20% vertical compression lactose is first added into stainless steel, then adds butanedioic acid rope
Li Naxin, sodium carboxymethyl starch, sorbierite and hydroxypropyl methylcellulose are mixed, and cross 50 mesh sieves, then add 30% vertical compression breast
Sugar mixing, crosses 50 mesh sieves, continuously adds remaining vertical compression lactose and mixed, and crosses 50 mesh sieves and is well mixed, is eventually adding tristearin
Sour magnesium is well mixed, and using rotary pelleting machine tabletting, coating, is produced.
Embodiment 7
| Composition | Content（Mg/ pieces） | Percentage by weight |
| Butanedioic acid Solifenacin | 2.5 | 2.5wt% |
| Vertical compression lactose Foremost 315 | 85 | 85wt% |
| Sodium carboxymethyl starch | 4 | 4wt% |
| Hydroxypropyl methylcellulose | 8 | 8wt% |
| Magnesium stearate | 0.5 | 0.5wt% |
Required supplementary material is weighed by recipe quantity, butanedioic acid Solifenacin and sodium carboxymethyl starch are crossed into 120 mesh sieves, hydroxyl respectively
Third methylcellulose crosses 150 mesh sieves, and vertical compression lactose crosses 50 mesh sieves, and butanedioic acid Solifenacin and sodium carboxymethyl starch and hydroxypropyl first is fine
Dimension element mixing, 20% vertical compression lactose mixing is then added, 50 mesh sieves is crossed, adds 30% vertical compression lactose, crosses 50 mesh sieves, mixing
Uniformly, add remaining vertical compression lactose to be mixed and cross 50 mesh sieves, be well mixed, it is equal to be eventually adding magnesium stearate mixing
It is even, using rotary pelleting machine tabletting, coating, produce.
Embodiment 8
| Composition | Content（Mg/ pieces） | Percentage by weight |
| Butanedioic acid Solifenacin | 4 | 4wt% |
| Vertical compression lactose Pharmatose DCL | 90 | 90wt% |
| Sodium carboxymethyl starch | 1 | 1wt% |
| Hydroxypropyl methylcellulose | 4 | 4wt% |
| Magnesium stearate | 1 | 1wt% |
Required supplementary material is weighed by recipe quantity, butanedioic acid Solifenacin and sodium carboxymethyl starch are crossed into 120 mesh sieves, hydroxyl respectively
Third methylcellulose crosses 150 mesh sieves, and vertical compression lactose crosses 50 mesh sieves, and butanedioic acid Solifenacin and sodium carboxymethyl starch and hydroxypropyl first is fine
Dimension element and mixing, 20% vertical compression lactose mixing is then added, 50 mesh sieves is crossed, adds 30% vertical compression lactose, cross 50 mesh sieves, mix
Close uniformly, add remaining vertical compression lactose and cross 50 mesh sieves, mixed, be eventually adding magnesium stearate and be well mixed, used
Rotary pelleting machine tabletting, coating, is produced.
Embodiment 9
| Composition | Content（Mg/ pieces） | Percentage by weight |
| Butanedioic acid Solifenacin | 5 | 3.33wt% |
| Vertical compression lactose Tablettose100 | 135 | 90wt% |
| Sodium carboxymethyl starch | 2.8 | 1.87wt% |
| Hydroxypropyl methylcellulose | 6.4 | 4.27wt% |
| Magnesium stearate | 0.8 | 0.53wt% |
Required supplementary material is weighed by recipe quantity, first 20% vertical compression lactose is added in stainless steel, then adds butanedioic acid
Solifenacin, sodium carboxymethyl starch and hydroxypropyl methylcellulose mixing, 30% vertical compression lactose is added, is well mixed, is added remaining
Vertical compression lactose cross 50 mesh sieves, mixed, be eventually adding magnesium stearate and be well mixed, using rotary pelleting machine tabletting, coating,
Produce.
Embodiment 10
| Composition | Content（Mg/ pieces） | Percentage by weight |
| Butanedioic acid Solifenacin | 5 | 3.33wt% |
| Vertical compression lactose Flowlac100 | 133 | 88.67wt% |
| Sodium carboxymethyl starch | 1.5 | 1wt% |
| Hydroxypropyl methylcellulose | 9 | 6wt% |
| Magnesium stearate | 1.5 | 1wt% |
Required supplementary material is weighed by recipe quantity, butanedioic acid Solifenacin and sodium carboxymethyl starch are crossed into 120 mesh sieves, hydroxyl respectively
Third methylcellulose crosses 150 mesh sieves, and vertical compression lactose crosses 50 mesh sieves, and butanedioic acid Solifenacin, sodium carboxymethyl starch and hydroxypropyl first is fine
Dimension element is well mixed, adds 20% vertical compression lactose mixing, then adds 30% vertical compression lactose, is well mixed, adds surplus
Remaining vertical compression lactose and 50 mesh sieves excessively, mixing, are eventually adding magnesium stearate and are well mixed, and using rotary pelleting machine tabletting, are coated,
Produce.
Embodiment 11
| Composition | Content（Mg/ pieces） | Percentage by weight |
| Butanedioic acid Solifenacin | 4.5 | 1.5wt% |
| Vertical compression lactose Tablettose70 | 270 | 90wt% |
| Sodium carboxymethyl starch | 3.5 | 1.17wt% |
| Hydroxypropyl methylcellulose | 16 | 5.33wt% |
| Superfine silica gel powder | 6 | 2wt% |
Required supplementary material is weighed by recipe quantity, first 10% lactose is added in stainless steel, adds butanedioic acid Suo Lina
New and sodium carboxymethyl starch is mixed, and then adds 20% vertical compression lactose, and 30% vertical compression lactose is added after mixing, and mixing is equal
It is even, add remaining vertical compression lactose and mixed, add hydroxypropyl methylcellulose, mix and cross 50 mesh sieves, be well mixed, finally
Add superfine silica gel powder to be well mixed, using powder vertical compression tabletting machine, coating, produce.
Embodiment 12
| Composition | Content（Mg/ pieces） | Percentage by weight |
| Butanedioic acid Solifenacin | 20 | 10wt% |
| Vertical compression lactose Flowlac90 | 142 | 71wt% |
| Sodium carboxymethyl starch | 16 | 8wt% |
| Hydroxypropyl methylcellulose | 20 | 10wt% |
| Talcum powder | 2 | 1wt% |
Required supplementary material is weighed by recipe quantity, first 10% lactose is added in stainless steel, adds butanedioic acid Suo Lina
New and sodium carboxymethyl starch is mixed, and then adds 20% vertical compression lactose, and 30% vertical compression lactose is added after mixing, and mixing is equal
It is even, add remaining vertical compression lactose and mixed, add hydroxypropyl methylcellulose, mix and cross 50 mesh sieves, be well mixed, finally
Add talcum powder to be well mixed, using powder vertical compression tabletting machine, coating, produce.
Embodiment 13
| Composition | Content（Mg/ pieces） | Percentage by weight |
| Butanedioic acid Solifenacin | 10 | 10wt% |
| Vertical compression lactose Sheffield | 45 | 45wt% |
| Mannitol | 29 | 29wt% |
| Sodium carboxymethyl starch | 3.3 | 3.3 wt% |
| Hydroxypropyl methylcellulose | 11.4 | 11.4wt% |
| Calcium stearate | 1.3 | 1.3 wt% |
Required supplementary material is weighed by recipe quantity, first 10% lactose is added in stainless steel, adds butanedioic acid Suo Lina
New and mannitol and sodium carboxymethyl starch are mixed, and then add 20% vertical compression lactose, and 30% vertical compression breast is added after mixing
Sugar, it is well mixed, adds remaining vertical compression lactose and mixed, add hydroxypropyl methylcellulose, mixes and cross 50 mesh sieves, mixing
Uniformly, calcium stearate mixing is eventually adding, using powder vertical compression tabletting machine, coating, is produced.
Embodiment 14
| Composition | Content（Mg/ pieces） | Percentage by weight |
| Butanedioic acid Solifenacin | 6 | 6wt% |
| Vertical compression lactose Pharmatose DCL | 90 | 90wt% |
| Sodium carboxymethyl starch | 0.5 | 0.5wt% |
| Hydroxypropyl methylcellulose | 2 | 2wt% |
| Magnesium stearate | 1.5 | 1.5wt% |
Required supplementary material is weighed by recipe quantity, first 10% lactose is added in stainless steel, adds butanedioic acid Suo Lina
New and sodium carboxymethyl starch is mixed, and then adds 20% vertical compression lactose, and 30% vertical compression lactose is added after mixing, and mixing is equal
It is even, add remaining vertical compression lactose and mixed, add hydroxypropyl methylcellulose, mix and cross 50 mesh sieves, be well mixed, finally
Add magnesium stearate to be well mixed, using powder vertical compression tabletting machine, coating, produce.
Embodiment 15
| Composition | Content（Mg/ pieces） | Percentage by weight |
| Butanedioic acid Solifenacin | 6 | 6wt% |
| Vertical compression lactose Tablettose80 | 75 | 75wt% |
| Sorbierite | 11 | 11wt% |
| Sodium carboxymethyl starch | 1 | 1wt% |
| Hydroxypropyl methylcellulose | 6 | 6wt% |
| Magnesium stearate | 1 | 1wt% |
Required supplementary material is weighed by recipe quantity, first 10% lactose is added in stainless steel, adds butanedioic acid Suo Lina
New and sodium carboxymethyl starch is mixed, and then adds 20% vertical compression lactose, and 30% vertical compression lactose is added after mixing, and mixing is equal
It is even, add remaining vertical compression lactose and mixed, add hydroxypropyl methylcellulose and sorbierite, mix and cross 50 mesh sieves, mixing
Uniformly, it is eventually adding magnesium stearate to be well mixed, using powder vertical compression tabletting machine, coating, produces.
Embodiment 16
| Composition | Content（Mg/ pieces） | Percentage by weight |
| Butanedioic acid Solifenacin | 2.5 | 2.5wt% |
| Vertical compression lactose Foremost 315 | 85 | 85wt% |
| Sodium carboxymethyl starch | 4 | 4wt% |
| Hydroxypropyl methylcellulose | 8 | 8wt% |
| Magnesium stearate | 0.5 | 0.5wt% |
Required supplementary material is weighed by recipe quantity, first 10% lactose is added in stainless steel, adds butanedioic acid Suo Lina
New and sodium carboxymethyl starch is mixed, and then adds 20% vertical compression lactose, and 30% vertical compression lactose is added after mixing, and mixing is equal
It is even, add remaining vertical compression lactose and mixed, add hydroxypropyl methylcellulose, cross 50 mesh sieves, be well mixed, be eventually adding hard
Fatty acid magnesium is mixed to be combined uniformly, using powder vertical compression tabletting machine, coating, is produced.
Embodiment 17
| Composition | Content（Mg/ pieces） | Percentage by weight |
| Butanedioic acid Solifenacin | 5 | 3.33wt% |
| Vertical compression lactose Tablettose100 | 135 | 90wt% |
| Sodium carboxymethyl starch | 2.8 | 1.87wt% |
| Hydroxypropyl methylcellulose | 6.4 | 4.27wt% |
| Magnesium stearate | 0.8 | 0.53wt% |
Required supplementary material is weighed by recipe quantity, first 10% lactose is added in stainless steel, adds butanedioic acid Suo Lina
New and sodium carboxymethyl starch is mixed, and then adds 20% vertical compression lactose, and 30% vertical compression lactose is added after mixing, and mixing is equal
It is even, add remaining vertical compression lactose and mixed, add hydroxypropyl methylcellulose, mix and cross 50 mesh sieves, be well mixed, finally
Magnesium stearate is added, using powder vertical compression tabletting machine, coating, is produced.
Embodiment 18
| Composition | Content（Mg/ pieces） | Percentage by weight |
| Butanedioic acid Solifenacin | 5 | 3.33wt% |
| Vertical compression lactose Flowlac100 | 133 | 88.67wt% |
| Sodium carboxymethyl starch | 1.5 | 1wt% |
| Hydroxypropyl methylcellulose | 9 | 6wt% |
| Magnesium stearate | 1.5 | 1wt% |
Required supplementary material is weighed by recipe quantity, first 10% lactose is added in stainless steel, adds butanedioic acid Suo Lina
New and sodium carboxymethyl starch is mixed, and then adds 20% vertical compression lactose, and 30% vertical compression lactose is added after mixing, and mixing is equal
It is even, add remaining vertical compression lactose and mixed, add hydroxypropyl methylcellulose, mix and cross 50 mesh sieves, be well mixed, finally
Add magnesium stearate to be well mixed, using powder vertical compression tabletting machine, coating, produce.
The made tablet content uniformity of embodiment 1~18 and dissolution homogeneity are determined respectively, and by tablet with air-tight bottle bag
Dress, the ratio of its F1 growing amount is determined after being stored 6 months under the conditions of 40 DEG C, RH75% accelerated test, is as a result shown in table 5.
Ratio, uniformity of dosage units and the 15min dissolution results of the embodiment 1 ~ 18F1 growing amounts of table 5
Claims (10)
1. a kind of pharmaceutical composition containing butanedioic acid Solifenacin, it is characterised in that described pharmaceutical composition contains：
And the preparation method of pharmaceutical composition is direct powder compression.
2. the pharmaceutical composition according to claim 1 containing butanedioic acid Solifenacin, it is characterised in that the butanedioic acid
Solifenacin is crystal type.
3. the pharmaceutical composition according to claim 1 containing butanedioic acid Solifenacin, it is characterised in that the vertical compression type
Lactose is spray-dried lactose.
4. the pharmaceutical composition according to claim 1 containing butanedioic acid Solifenacin, it is characterised in that the lubricant
One or more in magnesium stearate, calcium stearate, talcum powder, superfine silica gel powder.
5. the pharmaceutical composition according to claim 4 containing butanedioic acid Solifenacin, it is characterised in that the lubricant
For magnesium stearate.
6. the pharmaceutical composition according to claim 1 containing butanedioic acid Solifenacin, it is characterised in that described adhesive
Selected from starch slurry, sodium carboxymethylcellulose, Arabic gum, methylcellulose, ethyl cellulose, syrup, hydroxypropyl methylcellulose, poly-
Vinylpyrrolidone, low-substituted hydroxypropyl cellulose, Hydroxypropylcelliloxe, maltose, refined honey, liquid glucose, marine alga
Sour sodium, polyethylene glycol, Magnesiumaluminumsilicate, maltodextrin, vinyl pyrrolidone/vinyl acetate co-polymer, polyvinyl alcohol/poly- second
One or more in glycol graft copolymer.
7. the pharmaceutical composition according to claim 1 containing butanedioic acid Solifenacin, its feature are in described adhesive
Hydroxypropyl methylcellulose.
8. the pharmaceutical composition according to claim 1 containing butanedioic acid Solifenacin, it is characterised in that the medicine group
Compound contains：
9. the pharmaceutical composition according to claim 1 containing butanedioic acid Solifenacin, it is characterised in that the medicine group
Compound contains：
10. the pharmaceutical composition containing butanedioic acid Solifenacin described in any one according to claims 1 to 9, its
The preparation method for being characterised by described pharmaceutical composition is：
Weigh：Required supplementary material is weighed by recipe quantity, is sieved；
Mixing：First butanedioic acid Solifenacin is mixed with sodium carboxymethyl starch, then according to equivalent progressively increase method by several times add vertical compression
Type lactose, mixed after adding every time and cross 50 mesh sieves, added adhesive and lubricant, be well mixed；
Tabletting, coating, is produced.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| 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 |
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| 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 |
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| CN104940152A CN104940152A (en) | 2015-09-30 |
| CN104940152B true CN104940152B (en) | 2017-12-29 |
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| Application Number | Title | Priority Date | Filing Date |
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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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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| 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 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101141961A (en) * | 2004-12-27 | 2008-03-12 | 安斯泰来制药株式会社 | Stable particular pharmaceutical composition of solifenacin or salt thereof |
| CN101601673A (en) * | 2004-03-25 | 2009-12-16 | 安斯泰来制药株式会社 | The compositions that is used for solifenacin or its salt of solid preparation |
| WO2010097243A2 (en) * | 2009-02-27 | 2010-09-02 | Krka, D. D., Novo Mesto | Process for forming solid oral dosage forms of solifenacin and its pharmaceutically acceptable salts |
| EP2500013A1 (en) * | 2011-03-15 | 2012-09-19 | Alfred E. Tiefenbacher GmbH & Co. KG | Pharmaceutical composition comprising solifenacin |
-
2014
- 2014-03-31 CN CN201410124888.XA patent/CN104940152B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101601673A (en) * | 2004-03-25 | 2009-12-16 | 安斯泰来制药株式会社 | The compositions that is used for solifenacin or its salt of solid preparation |
| CN101141961A (en) * | 2004-12-27 | 2008-03-12 | 安斯泰来制药株式会社 | Stable particular pharmaceutical composition of solifenacin or salt thereof |
| WO2010097243A2 (en) * | 2009-02-27 | 2010-09-02 | Krka, D. D., Novo Mesto | Process for forming solid oral dosage forms of solifenacin and its pharmaceutically acceptable salts |
| EP2500013A1 (en) * | 2011-03-15 | 2012-09-19 | Alfred E. Tiefenbacher GmbH & Co. KG | Pharmaceutical composition comprising solifenacin |
Non-Patent Citations (1)
| Title |
|---|
| 索利那新治疗膀胱过度活动症4周疗效分析;陈燕，等;《第三军医大学学报》;20110115;第33卷(第1期);第104-105页 * |
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| CN104940152A (en) | 2015-09-30 |
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Address after: 610041, No. 2, building 4, No. 201, building C, nine Hing Road, 6 hi tech Zone, Sichuan, Chengdu, 402 Applicant after: Chengdu state bio medicine Co., Ltd. Address before: 610041 Sichuan Province, Chengdu hi tech Zone, No. nine Hing Road, building C, No. 6, building No. 2, No. 201 Applicant before: Chengdu Guohong Medicine Co., Ltd. |
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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. |