CN104997745B - A kind of alpha-crystal form imatinib mesylate dispersible tablet and preparation method thereof - Google Patents
A kind of alpha-crystal form imatinib mesylate dispersible tablet and preparation method thereof Download PDFInfo
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- CN104997745B CN104997745B CN201510508164.XA CN201510508164A CN104997745B CN 104997745 B CN104997745 B CN 104997745B CN 201510508164 A CN201510508164 A CN 201510508164A CN 104997745 B CN104997745 B CN 104997745B
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Abstract
The present invention discloses a kind of alpha-crystal form imatinib mesylate dispersible tablet, it includes the component of following parts by weight：1 part of alpha-crystal form imatinib mesylate solid dispersions, 0.5 1 parts of diluent, 0.1 0.5 parts of disintegrant, 0.05 0.1 parts of glidant, 0.01 0.02 parts of lubricant, 0.01 0.02 parts of stabilizer.Present invention also offers the preparation method of the alpha-crystal form imatinib mesylate dispersible tablet.Alpha-crystal form imatinib mesylate dispersible tablet dissolution rate of the present invention is good, and stability is high, and preparation method is simple, is suitable for mass producing.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, is related to a kind of alpha-crystal form imatinib mesylate formulations and preparation method thereof, tool
Body is related to a kind of alpha-crystal form imatinib mesylate dispersible tablet and preparation method thereof.
Background technology
The chemical name of alpha-crystal form imatinib mesylate is 4- (4- methyl isophthalic acids-piperazine) methyl-N-4- methyl -3-4- (3-
Pyridine) -2- pyrimdinyl-amino phenyl-benzamide mesylates, molecular formula C29H31N7O·CH4SO3, molecular weight 589.7,
No. CAS：220127-57-1, English name：Imatinib Mesylate.Structural formula is：
Alpha-crystal form imatinib mesylate is by being researched and developed by Novartis Co., Ltd, is that correlation occurs for the tumour of first listing in the whole world
Signal transduction inhibitor, is clinically used for the chronic phase of the chronic myelogenous leukemia (Ph+CML) for the treatment of Philadelphia Chromosome Positive, adds
Fast phase or rapid change period, treat the adult patient for the malignant gastrointestinal stromal tumors (GIST) that cannot be cut off and/or shift.The product
Kind listed first in the U.S. in May, 2001, subsequently enter the multinational markets such as Europe, Australia, Japan, Canada, and in
2002 in Discussion on Chinese Listed.Orphan's medicine status is obtained in states such as the U.S., European Union and Japan at present, " lattice arrange its trade name
Defend "Its formulation is conventional capsule and general thin coating tablet.
Novartis Co., Ltd discloses more than two kinds of imatinib mesylate in Chinese patent application application number 98807303.X
Crystal form thing α and β.Alpha-crystal form is characterized in showing that α types exist with hygroscopicity, the bad acicular crystal of mobility, its XRPD collection of illustrative plates
4.9,10.5,14.9,16.5,17.7,18.1,18,6,19.1,21.3,21.6,22.7,23.2,23.8,24.9,27.4,
There is absworption peak at 28.0 and 28.6 ± 0.2 degree of 2 θ.Beta crystal is characterized in that Thermodynamically stable, hygroscopicity are small below 140 DEG C, flows
The dynamic non-needle like crystals that property is good, is easy to store and processes.Its XRPD collection of illustrative plates is shown in 9.7,13.9,14.7,17.5,18.2,
There is absworption peak at 20.0,20.6,21.1,22.1,22.7,23.8,29.8 and 30.8 ± 0.2 degree of 2 θ.
Novartis Co., Ltd patent application WO99/03854 discloses two kinds of crystal forms of α and β of alpha-crystal form imatinib mesylate, and
The mobility of beta crystal is stated in this application, draws moist, heat endurance and is significantly better than that alpha-crystal form, is adapted to industrialized production, on
Crystal form used in city's product Gleevec is beta crystal.The alpha-crystal form imatinib mesylate of alpha-crystal form has quiet there are light, poor compressibility
The defects of electric, be considered being not suitable for industrialized production.Overcome the alpha-crystal form imatinib mesylate of the crystal form of α poor fluidity, can
The defects of poor, electrostatic interaction of pressure property is strong, sticky strong, prepare dative row hygienic articles are equivalent, reliable and stable alpha-crystal form methanesulfonic acid she
The problem of imatinib dispersible tablet is this area urgent need to resolve, and Novartis's patent is broken through, benefit one of challenge of compatriots.
The content of the invention
In order to solve deficiency of the prior art, the first technical problem to be solved by the present invention is to provide a kind of alpha-crystal form
Imatinib mesylate dispersible tablet, it includes the component of following parts by weight：1 part of alpha-crystal form imatinib mesylate solid dispersions,
0.5-1 parts of diluent, 0.1-0.5 parts of disintegrant, 0.05-0.1 parts of glidant, 0.01-0.02 parts of lubricant, stabilizer 0.01-
0.02 part.
The diluent is selected from calcium monohydrogen phosphate and/or PEARLITOL 25C.
The disintegrant is selected from sodium carboxymethylcellulose and/or polyvinylpyrrolidone.
The glidant is selected from talcum powder and/or silica.
The lubricant is preferably magnesium stearate.
One or more of the stabilizer in calcium gluconate, sodium alginate and sodium succinate.
Preferably, the stabilizer is calcium gluconate, sodium alginate and sodium succinate mass ratio 2:1:1 mixture.
The alpha-crystal form imatinib mesylate solid dispersions, are prepared by following steps：
(1) 10-20g alpha-crystal form imatinib mesylates are dissolved in 10-30ml organic solvents, obtain solution 1；
(2) 40-60g solid carriers are dissolved in 150-300ml organic solvents, obtain solution 2；
(3) solution 1 is added in solution 2 while stirring, rotary evaporation at 30-55 DEG C, after removing organic solvent, freezed
Obtain powdered alpha-crystal form imatinib mesylate solid dispersions.
The organic solvent is selected from dichloromethane and/or chloroform, is preferably dichloromethane.
The solid carrier is selected from polyethylene pyrrole network alkanone and/or poloxamer, is preferably polyethylene pyrrole network alkanone and pool
Luo Shamu mass ratioes 3:1-4:1 mixture.
Present invention also offers the preparation method of the alpha-crystal form imatinib mesylate dispersible tablet, it includes the following steps：
(1) alpha-crystal form imatinib mesylate solid dispersions are prepared；
(2) alpha-crystal form imatinib mesylate solid dispersions, diluent, disintegrant, glidant, lubrication are weighed by proportioning
Agent and stabilizer, are uniformly mixed；
(3) prepared using powder pressing method, packaging, you can the alpha-crystal form imatinib mesylate dispersible tablet of the present invention is made.
In the present invention,
Calcium monohydrogen phosphate, No. CAS：7789-77-7,
PEARLITOL 25C, No. CAS：69-65-8,
Sodium carboxymethylcellulose, No. CAS：9004-32-4,
Polyvinylpyrrolidone, No. CAS：84057-81-8,
Calcium gluconate, No. CAS：299-28-5,
Sodium alginate, No. CAS：9005-38-3,
Sodium succinate, No. CAS：150-90-3,
Poloxamer, No. CAS：9003-11-6.
Alpha-crystal form imatinib mesylate dispersible tablet dissolution rate of the present invention is good, and stability is high, and preparation method letter
It is single, it is suitable for mass producing.
Embodiment
The present invention is specifically described below by embodiment, it is necessary to which indicated herein is that following embodiments are only used
It is further described in the present invention, it is impossible to be interpreted as limiting the scope of the invention.The people that is skilled in technique in the field
Member can make the present invention some nonessential modifications and adaptations according to the content of the invention described above.
The solid dispersions of alpha-crystal form imatinib mesylate described in embodiment, prepare by the following method：
(1) 20g alpha-crystal form imatinib mesylates are dissolved in 15ml dichloromethane, obtain solution 1；
(2) 45g solid carriers are dissolved in 200ml dichloromethane, obtain solution 2；
(3) solution 1 is added in solution 2 while stirring, rotary evaporation at 40 DEG C, after removing dichloromethane, freezed
To powdered alpha-crystal form imatinib mesylate solid dispersions.
The preparation method of the dispersible tablet of alpha-crystal form imatinib mesylate described in embodiment, it includes the following steps：
(1) alpha-crystal form imatinib mesylate solid dispersions are prepared；
(2) alpha-crystal form imatinib mesylate solid dispersions, diluent, disintegrant, glidant, lubrication are weighed by proportioning
Agent and stabilizer, are uniformly mixed；
(3) prepared using powder pressing method, use Key works Drug packing PTP In Aluminium Foil Packings.
Embodiment 1
Alpha-crystal form imatinib mesylate dispersible tablet, it includes the component of following parts by weight：Alpha-crystal form imatinib mesylate
Solid dispersions 1g, PEARLITOL 25C 1g, sodium carboxymethylcellulose 0.3g, talcum powder 0.05g, magnesium stearate 0.02g, stabilizer
0.01g。
The stabilizer is calcium gluconate, sodium alginate and sodium succinate mass ratio 2:1:1 mixture.
Used solid carrier is polyethylene pyrrole network alkane during preparing alpha-crystal form imatinib mesylate solid dispersions
Ketone and poloxamer mass ratio 4:1 mixture.
Embodiment 2
Prepared as described in Example 1.
Used solid carrier replaces with polyethylene pyrrole during preparing alpha-crystal form imatinib mesylate solid dispersions
Network alkanone.
Embodiment 3
Used solid carrier replaces with Bo Luosha during preparing alpha-crystal form imatinib mesylate solid dispersions
Nurse.
Embodiment 4
Prepared as described in Example 1.
Used solid carrier replaces with polyethylene pyrrole during preparing alpha-crystal form imatinib mesylate solid dispersions
Network alkanone and poloxamer mass ratio 1:1 mixture.
Embodiment 5
Prepared as described in Example 1, the stabilizer replaces with calcium gluconate and sodium succinate mass ratio 1:1
Mixture.
Embodiment 6
Prepared as described in Example 1, the stabilizer replaces with calcium gluconate and sodium alginate mass ratio 1:1
Mixture.
Embodiment 7
Prepared as described in Example 1, the stabilizer replaces with sodium alginate and sodium succinate mass ratio 1:1
Mixture.
1 dissolution rate test of test case
According to Chinese Pharmacopoeia version annex the second methods of XC in 2010, her horse of alpha-crystal form methanesulfonic acid is replaced made from measure embodiment 1-6
The dissolution rate of Buddhist nun's dispersible tablet.Specific method is：Using phosphate buffer (pH6.8) 900ml as dissolution medium, rotating speed is per minute
50 turns, operate in accordance with the law, during through 5min, take solution appropriate respectively, filter, discard 10ml primary filtrates, take subsequent filtrate as test sample
Solution；Separately take reference substance appropriate, it is accurately weighed, add methanol to dissolve and quantify dilution solution in every 1ml containing about 0.28mg is made,
Precision measures 1ml, puts in 50ml measuring bottles, is diluted to scale with dissolution medium, shakes up, as reference substance solution.Precision, which measures, to be supplied
Test sample solution and each 100 μ l of reference substance solution, are injected separately into liquid chromatograph, record chromatogram.By external standard method in terms of peak area
Calculate every bag of stripping quantity.Limit is the 70% of labelled amount, should meet regulation.Test result is shown in Table 1.
Table 1：Dissolution rate test result
| Embodiment | 5min dissolution rates (%) |
| Embodiment 1 | 95.4 |
| Embodiment 2 | 93.7 |
| Embodiment 3 | 93.4 |
| Embodiment 4 | 94.2 |
| Embodiment 5 | 94.9 |
| Embodiment 6 | 95.1 |
| Embodiment 7 | 94.5 |
2 stability test of test case
Alpha-crystal form imatinib mesylate dispersible tablet made from 1-7 is accelerated to protect under conditions of 40 DEG C, 75% relative humidity
Deposit 3 months, 6 months and 12 months, then further take out medicine and test its crystal phenomenon, probation stability.Test result is shown in Table
2。
Table 2：Stability test result
| Embodiment | 3 months | 6 months | 12 months |
| Embodiment 1 | All alpha-crystal forms, no crystal phenomenon. | All alpha-crystal forms, no crystal phenomenon. | All alpha-crystal forms, no crystal phenomenon. |
| Embodiment 2 | All alpha-crystal forms, no crystal phenomenon. | All alpha-crystal forms, no crystal phenomenon. | All alpha-crystal forms, no crystal phenomenon. |
| Embodiment 3 | All alpha-crystal forms, no crystal phenomenon. | All alpha-crystal forms, no crystal phenomenon. | All alpha-crystal forms, no crystal phenomenon. |
| Embodiment 4 | All alpha-crystal forms, no crystal phenomenon. | All alpha-crystal forms, no crystal phenomenon. | All alpha-crystal forms, no crystal phenomenon. |
| Embodiment 5 | All alpha-crystal forms, no crystal phenomenon. | All alpha-crystal forms, no crystal phenomenon. | 10.8% alpha-crystal form is converted into beta crystal. |
| Embodiment 6 | All alpha-crystal forms, no crystal phenomenon. | All alpha-crystal forms, no crystal phenomenon. | 4.5% alpha-crystal form is converted into beta crystal. |
| Embodiment 7 | All alpha-crystal forms, no crystal phenomenon. | All alpha-crystal forms, no crystal phenomenon. | 6.2% alpha-crystal form is converted into beta crystal. |
The alpha-crystal form imatinib mesylate dispersible tablet 5min dissolution rates of the present invention it can be seen from test case 1-2 results
Height, and crystal phenomenon does not occur after accelerating 6 months under conditions of 40 DEG C, 75% relative humidity, stability is high.Especially implement
Example 1, used solid carrier is polyethylene pyrrole network alkanone and poloxamer matter during preparing alpha-crystal form imatinib mesylate
Measure ratio 4:1 mixture, compared with polyethylene pyrrole network alkanone or poloxamer is used alone in embodiment 2-3, dissolution rate higher, with
Embodiment 4 uses polyethylene pyrrole network alkanone and poloxamer mass ratio 1:1 mixture is compared, dissolution rate also higher.
For embodiment 1 compared with embodiment 5-7, embodiment 1 has used calcium gluconate, sodium alginate and sodium succinate matter
Measure ratio 2:1:The stabilizer of 1 compounding, uses wherein any two kinds to be used as stabilizer, effect is more preferable, acceleration environment than embodiment 5-7
It is lower to preserve 12 months, crystal phenomenon does not occur.
Claims (5)
1. a kind of alpha-crystal form imatinib mesylate dispersible tablet, it is characterised in that include the component of following parts by weight：Alpha-crystal form first sulphur
Sour 1 part of Imatinib solid dispersions, 0.5-1 parts of diluent, 0.1-0.5 parts of disintegrant, 0.05-0.1 parts of glidant, lubricant
0.01-0.02 parts, 0.01-0.02 parts of stabilizer；The stabilizer is calcium gluconate, sodium alginate and sodium succinate mass ratio
2:1:1 mixture；
The alpha-crystal form imatinib mesylate solid dispersions, are prepared by following steps：
(1) 10-20g alpha-crystal form imatinib mesylates are dissolved in 10-30ml organic solvents, obtain solution 1；
(2) 40-60g solid carriers are dissolved in 150-300ml organic solvents, obtain solution 2；
(3) solution 1 is added in solution 2 while stirring, rotary evaporation at 30-55 DEG C, after removing organic solvent, freezed；
The solid carrier is polyethylene pyrrole network alkanone and poloxamer mass ratio 3:1-4:1 mixture.
2. alpha-crystal form imatinib mesylate dispersible tablet as claimed in claim 1, it is characterised in that：The diluent is selected from phosphorus
Sour hydrogen calcium and/or PEARLITOL 25C.
3. alpha-crystal form imatinib mesylate dispersible tablet as claimed in claim 1, it is characterised in that：The disintegrant is selected from carboxylic
Sodium carboxymethylcellulose pyce and/or polyvinylpyrrolidone.
4. alpha-crystal form imatinib mesylate dispersible tablet as claimed in claim 1, it is characterised in that：The organic solvent is selected from
Dichloromethane and/or chloroform.
5. the preparation method of alpha-crystal form imatinib mesylate dispersible tablet any one of claim 1-4, it includes step as follows
Suddenly：
(1) alpha-crystal form imatinib mesylate solid dispersions are prepared；
(2) by proportioning weigh alpha-crystal form imatinib mesylate solid dispersions, diluent, disintegrant, glidant, lubricant and
Stabilizer, mixing；
(3) the alpha-crystal form imatinib mesylate dispersible tablet is prepared using powder pressing method.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102836159A (en) * | 2011-06-24 | 2012-12-26 | 南京圣和药业有限公司 | Dasatinib dispersoid, preparation method thereof and application thereof in tablets |
| CN103768030A (en) * | 2014-01-15 | 2014-05-07 | 青岛市肿瘤医院 | Crizotinib dispersible tablet and preparation method thereof |
| CN103784412A (en) * | 2014-01-15 | 2014-05-14 | 青岛市肿瘤医院 | Icotinib hydrochloride dispersible tablet and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102836159A (en) * | 2011-06-24 | 2012-12-26 | 南京圣和药业有限公司 | Dasatinib dispersoid, preparation method thereof and application thereof in tablets |
| CN103768030A (en) * | 2014-01-15 | 2014-05-07 | 青岛市肿瘤医院 | Crizotinib dispersible tablet and preparation method thereof |
| CN103784412A (en) * | 2014-01-15 | 2014-05-14 | 青岛市肿瘤医院 | Icotinib hydrochloride dispersible tablet and preparation method thereof |
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Effective date of registration: 20190903 Address after: Room 1, block B, block 602-606, No. 3, Zhong Sheng Middle Road, Beijing economic and Technological Development Zone, Beijing, China Patentee after: Beijing generous Pharmaceutical Technology Co., Ltd. Address before: Room 1310, Building 10, No. 7 Courtyard, Songyu North Road, Chaoyang District, Beijing Co-patentee before: Shao Hua Patentee before: He Long |