CN106389373A - Lapatinib ditosylate tablet and preparation method thereof - Google Patents
Lapatinib ditosylate tablet and preparation method thereof Download PDFInfo
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Abstract
The present invention provides a lapatinib ditosylate tablet, which is prepared from a bulk drug lapatinib ditosylate and an auxiliary material colloidal silicon dioxide according to a certain weight ratio, wherein the active ingredient is 45-60 parts, and the colloidal silicon dioxide is 0.25-2 parts. The present invention further provides a preparation method of the tablet. According to the present invention, the operability of the process is strong, the fluidity of the intermediate particles is good, the tablet weight difference is stable, the compressibility is strong, and the in vitro dissolution characteristics under different medias and the stability test results of the lapatinib ditosylate tablet of the present invention are consistent with the originally-researched preparation; and the primary pharmacological test results show that the efficacy is consistent with the original research.
Description
Technical field
The present invention relates to a kind of xylene monosulfonic acid Lapatinib tablet, belong to field of pharmaceutical preparations.
Background technology
N- { the chloro- 4- of 3- [(3- chlorobenzyl) epoxide] phenyl } -6- [5- ({ [2- (mesyl) ethyl] amino } first
Base) -2- furyl] -4- quinazoline amine xylenesulfonate monohydrate, draws also known as a hydration xylene monosulfonic acid
Handkerchief replaces Buddhist nun, as a kind of protein tyrosine kinase EGFR (EGF-R ELISA-abbreviation erbB-1)
With the 4- quinazoline amines of erbB-2 double inhibitor, it was published in patent on 01 10th, 2002
(WO02/02552).Be proved to this compound to can be used for treating various cancers simultaneously, including breast carcinoma,
Pulmonary carcinoma, bladder cancer, incidence cancer and gastric cancer.Solubility in the range of physiology correlation pH for this compound is special
Difference, for this dissolubility special difference larger, poor fluidity the medicine of specification simultaneously, using conventional preparation
Technique can not obtain required high Dissolution behaviours and good flow behavior [CN200680021941.7, medicine
Compositions].Former triturate patent (CN200680021941.7) is passed through using fluidized bed granulation technology,
With Microcrystalline Cellulose as filler, the wetting agent as fluidized bed prilling for the Povidone K 30, carboxymethylstach sodium be
Additional disintegrating agent, magnesium stearate are the preparation technology of lubricant, in technical process, can preferably protect
The mobility of exhibit material, the dissolution of tablet is also higher, can reach acceptable bioavailability.
The prescription proportioning listed in its Central Plains triturate patent is as follows:
Although above-mentioned patent solves Flow of Goods and Materials sex chromosome mosaicism using fluidization, granule is loose, finally
Dissolution is higher, but yet suffers from very big problem.Process of the test finds, N- { 3- chloro- 4- [(3-
Chlorobenzyl) epoxide] phenyl } -6- [5- ({ [2- (mesyl) ethyl] amino } methyl) -2- furyl] -4- quinoline
Oxazoline amine xylenesulfonate monohydrate viscosity is strong, and dissolubility is poor, and reaching higher bioavailability needs
Carry out strict Task-size Controlling.Generally for the type medicine, need to carry out micronization processes, but
This compound granularity is meticulous to lead to sample flocculation during stripping analysises, be unfavorable for the final dissolution of product, because
This only needs to control active component in certain particle size range.The too big material of viscosity is directly carried out simultaneously
The process of sieving of micronization processes or shaking screen is not all allowed easy to operate, therefore develops suitable active component grain
Footpath control method is the key issue of the smooth industrialized production of this product, however former grind patent do not give bright
True solution.
Therefore develop a kind of mature and stable xylene monosulfonic acid Lapatinib tablet, for Chinese pharmaceutical enterprises
It is widely popularized and have great importance.
Content of the invention
In order to solve above-mentioned technical problem, the invention provides a kind of xylene monosulfonic acid Lapatinib tablet.
Another technical scheme of the present invention there is provided the preparation method of this tablet.
The invention provides a kind of xylene monosulfonic acid Lapatinib tablet, it contains crude drug xylene monosulfonic acid
Lapatinib and adjuvant silica sol are prepared from, and its weight proportion is:
45~60 parts of xylene monosulfonic acid Lapatinib, 0.25~2 part of silica sol.
It is further preferred that the weight proportion of described crude drug and silica sol is:
45~60 parts of xylene monosulfonic acid Lapatinib, 0.5~1.5 part of silica sol.
It is further preferred that the weight proportion of described crude drug and silica sol is:
45~60 parts of xylene monosulfonic acid Lapatinib, 0.8~1.2 part of silica sol.
Colloidal silica in this amount ranges adds, and contributes to the dispersion dissolution of medicine, thus ensureing
Development and the bioequivalence of former triturate.
Wherein, described adjuvant also includes Mannitol, Microcrystalline Cellulose, disintegrating agent, binding agent, lubrication
Agent, coating pre-mixing agent, its weight proportion is:
10~30 parts of Mannitol, 15~35 parts of Microcrystalline Cellulose, 1~8 part of disintegrating agent, binding agent 1.5~6
Part, 0.3~1.8 part of lubricant, 0.5~6 part of coating pre-mixing agent.
Wherein, described disintegrating agent is cross-linking sodium carboxymethyl cellulose or carboxymethylstach sodium, binding agent are poly-
Dimension ketone K30 or Hypromellose;Described lubricant is sodium stearyl fumarate, magnesium stearate, Hard Fat
Acid, Pulvis Talci;Described tablet is to be prepared from by the crude drug of following weight proportioning and adjuvant:
45~54 parts of xylene monosulfonic acid Lapatinib, 0.5~1.5 part of silica sol, Mannitol 15-25
Part, 20~30 parts of Microcrystalline Cellulose, 2~6 parts of cross-linking sodium carboxymethyl cellulose, Hypromellose 2.5~3.5
Part, 0.8~1.5 part of magnesium stearate, 1~6 part of coating pre-mixing agent.
It is further preferred that it is to be prepared from by the crude drug of following weight proportioning and adjuvant:Dimethylbenzene
45~54 parts of sulfonic acid Lapatinib, 0.8~1.2 part of silica sol, 15~20 parts of Mannitol, crystallite
22~26 parts of cellulose, 2~4 parts of cross-linking sodium carboxymethyl cellulose, 2.5~3.5 parts of Hypromellose,
0.8~1.5 part of magnesium stearate, 1~4 part of coating pre-mixing agent;
It is further preferred that it is to be prepared from by the crude drug of following weight proportioning and adjuvant:
49~50 parts of xylene monosulfonic acid Lapatinib, 0.9~1 part of silica sol, Mannitol 18~19
Part, 24~25 parts of Microcrystalline Cellulose, 2~3 parts of cross-linking sodium carboxymethyl cellulose, Hypromellose 3~3.5
Part, 0.8~1.2 part of magnesium stearate, 1~3 part of coating pre-mixing agent;Described coating pre-mixing agent is OPADRY
17B620000.
Wherein, in described Mannitol, 50% particle diameter is less than 100 μm, and 90% particle diameter is less than 250 μm, adopts
With can preferably ensure after such particle diameter to be sufficiently mixed with active component, simultaneously to heavy dose of indissoluble
Property medicine plays more preferable peptizaiton;In described Microcrystalline Cellulose, 50% particle diameter is less than 150 μm, and 90%
Particle diameter is less than 250 μm;Described Microcrystalline Cellulose model is Microcrystalline Cellulose pH101, it is highly preferred that institute
The Microcrystalline Cellulose model stated is Microcrystalline Cellulose KG802.The consumption of cross-linking sodium carboxymethyl cellulose, one
Determining consumption in scope increases it is ensured that the more preferable dissolution of tablet, but exceedes certain limit, consumption
Bigger, more it is unfavorable for final dissolution.Described Hypromellose is preferably Hypromellose E5,
Suitable binding agent solubility and consumption can ensure that the more preferable dissolution of this product.
The invention provides a kind of preparation method preparing described tablet, it comprises the steps:
1) xylene monosulfonic acid Lapatinib and silica sol are crossed 40~80 eye mesh screens respectively to process, claim
Take recipe quantity to mix, then cross 100~200 mesh sieves and process, and will the two mix homogeneously;
2) Microcrystalline Cellulose, Mannitol cross 80~100 mesh sieves respectively, then by Microcrystalline Cellulose, manna
Alcohol, disintegrating agent and binding agent weigh respectively according to quantity and are added to step 1) in mixture in, then in height
Mix under shearing wet granulator, mix rotating speed preferably 200~400rpm, cutter rotating velocity is preferred
200~800rpm;
3), during carrying out soft material preparation, soft material processed with purified water to above-mentioned mixing powder, speed of agitator is
200~400rpm, cutter rotating velocity is 300~1200rpm;The sieve number pelletized is 16~30 mesh;
4) granule of preparation is dried, drying temperature is 50~60 DEG C, drying moisture to 1.0~3.5%,
Dry granulate mesh number preferably 20~30 mesh of granule;
5) to step 4) in gained granule add lubricant, mixing, incorporation time be 5~10min;
6) coating, obtains tablet.
Described silica sol has stronger hydrophilicity, and using before, silica sol needs logical
Cross 40~80 eye mesh screens to process, then mix with active component, the viscosity improving active component is big, quiet
Electricity is strong, poor fluidity the shortcomings of, simultaneously for the pretreatment of active component, the particle diameter control to active component
System plays the effect of highly significant.Can be improved this using appropriate Microcrystalline Cellulose and Mannitol big simultaneously
The conglomeration of specification insoluble drug In Vitro Dissolution test piles up situation, using super-disintegrant cross-linked carboxymethyl
Sodium cellulosate and high-hydrophilic binding agent Hypromellose are conducive to the final dissolution of insoluble drug.This
Invent adopted mature preparation process stable, ensure that the stability of different batches, be suitable for current state
Interior pharmaceutical industries metaplasia is produced.
By above-mentioned specific preparation prescription, inventor finds this tablet through aforesaid operations, operability
By force, final mobility of particle is good, and tablet weight variation is stable, and compressibility is strong.Final tablet and former development
In Vitro Dissolution situation under different medium for the agent is consistent with stability test;Carry out preliminary pharmacology examination simultaneously
Test, drug effect with former grind consistent.
Brief description
The tablet of Fig. 1 embodiment 1 and dissolution in pH1.0 hydrochloric acid+0.5% Tween medium for the former triturate
Curve
The tablet of Fig. 2 embodiment 1 and former triturate are in pH4.5 acetate buffer solution+0.5% Tween medium
Stripping curve
The dissolution in purified water+1.0% Tween medium of the tablet of Fig. 3 embodiment 1 and former triturate is bent
Line
The tablet of Fig. 4 embodiment 1 and stripping curve in pH6.8+2.0% Tween medium for the former triturate
The tablet of Fig. 5 comparative example 1 and comparative example 2 is situated between in pH1.0 hydrochloric acid+0.5% tween with former triturate
Stripping curve in matter
The tablet of Fig. 6 comparative example 1 and comparative example 2 and former triturate are in pH6.8+2.0% Tween medium
Stripping curve
Specific embodiment
In order to the present invention and its acquired effect are better described, to do below in conjunction with specific embodiment
Further illustrate, but the scope of the present invention is not limited to the concrete scheme of embodiment.
The preparation of embodiment 1 xylene monosulfonic acid Lapatinib tablet of the present invention
The xylene monosulfonic acid Lapatinib tablet of the present invention, including the composition of following weight proportion:
Preparation:This dosage form can be produced using conventional tablet pharmaceutical equipment, and concrete preparation method is as follows:Will
Crude drug xylene monosulfonic acid Lapatinib and colloidal silica tentatively mix, and cross after 100 mesh sieves are processed and mix
Uniformly.Microcrystalline Cellulose and Mannitol cross 100 mesh sieves, respectively then with cross-linking sodium carboxymethyl cellulose, hydroxyl
Third methylcellulose weighs according to quantity respectively, and is added sequentially in order in above-mentioned mixture, in high shear
Mix under wet granulator, mixing rotating speed is 300rpm, cutter rotating velocity is 500rpm;It is subsequently adding purification
Water prepares soft material, and during soft material processed, speed of agitator is 300rpm, and cutter rotating velocity is 1200rpm, 24 mesh
Sieve series grain is dried to moisture 2% about under the conditions of 55 DEG C, adds recipe quantity after 24 mesh sieve granulate
Magnesium stearate mixes, and carries out intermediates content detection, determines tabletting after piece weight, uses OPADRY 17B620000
Aqueous solution is coated to gained label, obtains tablet, specification 0.25g/ piece.
The tablet that prepare embodiment 1 and former triturate (Britain's GlaxoSmithKline PLC company, trade name) carry out Dissolution Rate Testing together.Dissolution Rate Testing method is with reference to FDA dissolution data base recommendation side
Method, and compare the In Vitro Dissolution situation of four kinds of different mediums together with former triturate.Dissolution side used
Method is paddle method, 55rpm, and dissolution medium is respectively pH1.0 hydrochloric acid solution+0.5% tween of 900ml, pH4.5
Acetate buffer solution+0.5% tween, pH6.8 phosphate buffer+2% tween and purified water+2% tween.Different
The dissolution medium of pH is the physiological environment in order to simulate internal different parts, the dissolution characteristic ratio of different medium
The quality conformance with former triturate relatively can be reflected to a certain extent.Result is as shown in figures 1-4, real
The tablet applying example 1 is consistent in the dissolution characteristic of different medium with former triturate.
Prepare three batch samples, the In Vitro Dissolution curve of prepared tablet so that the formulation and technology of above-described embodiment is continuous
It is consistent (Fig. 1~4), the tablet of embodiment 1 and xylene monosulfonic acid Lapatinib piece (former are ground simultaneously
Preparation, 0.25g/ piece, Britain's GlaxoSmithKline PLC company) synchronization carries out influence factor and long-time stability are tried
Test, investigation content, the change about the Key Quality attribute such as material, dissolution, testing result such as table 1 below,
Shown in 2.As can be seen that the tablet stability of embodiment 1 is good, relatively former triturate, or even have more
Good stability.
Also the tablet of the embodiment of the present invention 1 and former triturate (specification have been investigated simultaneously:0.25g/ piece, English
State's GlaxoSmithKline PLC company) relative bioavailability in beasle dog body.Given by single oral
The different xylene monosulfonic acid Lapatinib preparation of two kinds of Beagle dog, in different time points collection blood sample,
LC-MS/MS measure administration after the blood drug level of Lapatinib calculate relevant pharmacokinetic parameter, obtain
The result such as table 1 below obtaining:
Table 1 Beagle dog single oral gives internal pharmacokinetic results after embodiment 1 tablet or former triturate
By experimental result as can be seen that after beasle dog gives tablet and the former triturate of embodiment 1, blood plasma
Concentration peak time is all in 8.0h;90% credibility interval of the AUC of the tablet of embodiment 1 is in former development
In the range of the 80~125% of agent AUC;Simultaneously through paired t-test, the pharmacokinetic parameters of Lapatinib piece are being subject to
No difference of science of statistics (P between test preparation and former triturate>0.05).To sum up can determine whether, the tablet of embodiment 1
With former triturate bioequivalence.
The preparation of embodiment 2 xylene monosulfonic acid Lapatinib tablet of the present invention
The xylene monosulfonic acid Lapatinib tablet of the present invention, including the composition of following weight proportion:
Preparation:This dosage form can be produced using conventional tablet pharmaceutical equipment, and concrete preparation method is as follows:Will
Crude drug xylene monosulfonic acid Lapatinib and silica sol are crossed 150 mesh sieves and are processed, mix homogeneously.Crystallite
Cellulose and Mannitol cross 100 mesh sieves respectively, then press with cross-linking sodium carboxymethyl cellulose, Hydroxypropyl Cellulose
Amount is added sequentially to mix in above-mentioned mixture in order, mixes under bulk drug of pretreatment adds with interior granulator, mixes
Even rotating speed is 200rpm, and cutter rotating velocity is 600rpm;It is subsequently adding purified water and prepare soft material, the soft material phase processed
Between, speed of agitator is 400rpm, and cutter rotating velocity is 1000rpm, and 20 mesh sieves are pelletized under the conditions of 50 DEG C
Dry to moisture 2% about, add the sodium stearyl fumarate of recipe quantity to mix after 24 mesh sieve granulate, enter
Row intermediates content detects, determines tabletting after piece weight, with OPADRY 17B620000 aqueous solution to obtained sheet
Core is coated, coating weight gain 2%, obtains tablet, specification 0.25g/ piece, final coated tablet is in polyethylene
Plastic bottle is packed.
The preparation of embodiment 3 xylene monosulfonic acid Lapatinib tablet of the present invention
The xylene monosulfonic acid Lapatinib tablet of the present invention, including the composition of following weight proportion:
Preparation:This dosage form can be produced using conventional tablet pharmaceutical equipment, and concrete preparation method is as follows:Will
Crude drug xylene monosulfonic acid Lapatinib and colloidal silica are crossed 200 mesh sieves and are processed, mix homogeneously.Crystallite
Cellulose KG802 and Mannitol cross 80 mesh sieves, respectively then with cross-linking sodium carboxymethyl cellulose, hydroxypropyl first
Cellulose is added sequentially to above-mentioned mixture in order and mixes under bulk drug of pretreatment adds with interior granulator, mixes and turns
Fast 400rpm, cutter rotating velocity 600rpm;It is subsequently adding purified water and prepares soft material, speed of agitator is 400rpm,
Cutter rotating velocity is 800rpm, and 16 mesh sieves are pelletized and dried under the conditions of 50 DEG C to moisture 2% about, pass through
The magnesium stearate adding recipe quantity after 24 mesh sieve granulate mixes, and carries out intermediates content detection, determines piece weight
Tabletting afterwards, is coated to gained label with OPADRY 17B620000 aqueous solution, and coating weight gain 3% obtains
Tablet, specification 0.25g/ piece, final coated tablet is packed in vinyon bottle.
The preparation of embodiment 4 xylene monosulfonic acid Lapatinib tablet of the present invention
The xylene monosulfonic acid Lapatinib tablet of the present invention, including the composition of following weight proportion:
Preparation:This dosage form can be produced using conventional tablet pharmaceutical equipment, and concrete preparation method is as follows:Will
Crude drug xylene monosulfonic acid Lapatinib and colloidal silica are crossed 200 mesh sieves and are processed, mix homogeneously.Crystallite
Cellulose and Mannitol cross 100 mesh sieves respectively, then press with cross-linking sodium carboxymethyl cellulose, Povidone K 30
Amount is added sequentially to mix under bulk drug of pretreatment adds with interior granulator in above-mentioned mixture in order, mixes rotating speed
400rpm, the preferred 600rpm of cutter rotating velocity;It is subsequently adding purified water and prepares soft material, speed of agitator is
400rpm, cutter rotating velocity is 600rpm;24 mesh sieves are pelletized and are dried under the conditions of 55 DEG C to moisture 2% left side
The right side, adds the magnesium stearate of recipe quantity to mix after 24 mesh sieve granulate, carries out intermediates content detection,
Determine tabletting after piece weight, with OPADRY 17B620000 aqueous solution, gained label is coated, coating increases
Weigh 2%, obtain tablet, specification 0.25g/ piece, final coated tablet is packed in vinyon bottle.
Test proves, embodiment 2-4 has the experiment effect being equal to embodiment 1.
Embodiment 5 xylene monosulfonic acid Lapatinib additive of tablet comparative selection of the present invention is tested
Inventor is by the partial supplementary material such as silica sol in xylene monosulfonic acid Lapatinib tablet of the present invention
Save, and adjust the consumption of other adjuvants, be prepared into comparative example 1 and comparative example 2;And enter with the former medicine that grinds
Row contrast, concrete test is as follows:
Comparative example 1
A kind of xylene monosulfonic acid Lapatinib tablet, including the composition of following weight proportion:
Preparation:This dosage form can be produced using conventional tablet pharmaceutical equipment, and concrete preparation method is as follows:Will
Crude drug xylene monosulfonic acid Lapatinib is crossed 200 mesh sieves and is processed.Microcrystalline Cellulose and Mannitol cross 100 respectively
Mesh sieve, is then weighed respectively by recipe quantity with cross-linking sodium carboxymethyl cellulose, Hypromellose, and presses
Order is added sequentially to mix in above-mentioned crude drug, is subsequently adding purified water and prepares soft material, speed of agitator
For 300rpm, cutter rotating velocity is 1200rpm, and 20 mesh sieves are pelletized and dried to moisture 2% under the conditions of 55 DEG C
Left and right, adds the magnesium stearate of recipe quantity to mix after 24 mesh sieve granulate, carries out intermediates content detection,
Determine tabletting after piece weight, obtain final product.With OPADRY 17B620000 aqueous solution, gained label is coated,
Coating weight gain 3%, obtains tablet, specification 0.25g/ piece, final coated tablet is wrapped in vinyon bottle
Dress.
Comparative example 2
A kind of xylene monosulfonic acid Lapatinib tablet, including the composition of following weight proportion:
Preparation:This dosage form can be produced using conventional tablet pharmaceutical equipment, and concrete preparation method is as follows:Will
Crude drug xylene monosulfonic acid Lapatinib is crossed 150 mesh sieves and is processed.Microcrystalline Cellulose and Mannitol cross 100 respectively
Mesh sieve, then weighs according to quantity respectively with cross-linking sodium carboxymethyl cellulose, Hypromellose, and in order
It is added sequentially to mix in crude drug, mix rotating speed 200rpm, cutter rotating velocity 400rpm;It is subsequently adding pure
Change water and prepare soft material, speed of agitator is 400rpm, cutter rotating velocity is 800rpm.20 mesh sieves are pelletized after 50 DEG C
Under the conditions of dry to moisture 2% about, after 24 mesh sieve granulate add recipe quantity sodium stearyl fumarate mix
Even, carry out intermediates content detection, determine tabletting after piece weight, with OPADRY 17B620000 aqueous solution pair
Gained label is coated, coating weight gain 2%, obtains tablet, specification 0.25g/ piece, final coated tablet in
Vinyon bottle is packed.
Tablet (specification prepared by comparative example 1 and comparative example 2:0.25g/ piece) and former triturate (specification:
0.25g/ piece, Britain's GlaxoSmithKline PLC company, trade name) carry out Dissolution Rate Testing together.
Dissolution Rate Testing method with reference to FDA dissolution data base recommend method, dissolving-out method used be paddle method,
55rpm, dissolution medium is respectively pH1.0 hydrochloric acid solution+0.5% tween of 900ml, pH6.8 phosphoric acid delays
Rush liquid+2% tween.The dissolution medium of different pH is the physiological environment in order to simulate internal different parts,
The dissolution characteristic of different medium relatively can reflect the quality conformance with former triturate to a certain extent.
(see Fig. 5, Fig. 6)
Shown by above-mentioned result of the test, comparative example 1, the sample of comparative example 2 and former triturate are in pH1.0
Stripping curve under hydrochloric acid and pH6.8 phosphate buffer differs greatly, and final dissolution is significantly lower than former grinding
Preparation.
Claims (10)
1. a kind of xylene monosulfonic acid Lapatinib tablet it is characterised in that:By containing following weight proportioning
Crude drug xylene monosulfonic acid Lapatinib and adjuvant silica sol are prepared from:
45~60 parts of xylene monosulfonic acid Lapatinib, 0.25~2 part of silica sol.
2. tablet according to claim 1 it is characterised in that:Described crude drug and adjuvant colloid
The weight proportion of silicon dioxide is:
45~60 parts of xylene monosulfonic acid Lapatinib, 0.5~1.5 part of silica sol.
3. tablet according to claim 1 and 2 it is characterised in that:Described adjuvant also includes sweet
Reveal alcohol, Microcrystalline Cellulose, disintegrating agent, binding agent, lubricant, coating pre-mixing agent, its weight proportion is:
10~30 parts of Mannitol, 15~35 parts of Microcrystalline Cellulose, 1~8 part of disintegrating agent, binding agent 1.5~6
Part, 0.3~1.8 part of lubricant, 0.5~6 part of coating pre-mixing agent;
Described disintegrating agent is carboxymethylstach sodium, one or two mixing in cross-linking sodium carboxymethyl cellulose;
Binding agent is Hypromellose, Povidone K 30, one or more mixing in Hydroxypropyl Cellulose;
Described lubricant is one of sodium stearyl fumarate, magnesium stearate, stearic acid, Pulvis Talci or two kinds
Above mixing.
4. tablet according to claim 3 it is characterised in that:Described tablet is by following weight
The raw material of proportioning and adjuvant are prepared from:
45~54 parts of xylene monosulfonic acid Lapatinib, 0.5~1.5 part of silica sol, Mannitol 15~25
Part, 20~30 parts of Microcrystalline Cellulose, 2~6 parts of cross-linking sodium carboxymethyl cellulose, Hypromellose 2.5~3.5
Part, 0.8~1.5 part of magnesium stearate, 1~6 part of coating pre-mixing agent.
5. tablet according to claim 4 it is characterised in that:It is former by following weight proportioning
Material medicine and adjuvant are prepared from:
45~54 parts of xylene monosulfonic acid Lapatinib, 0.8~1.2 part of silica sol, Mannitol 15~20
Part, 22~26 parts of Microcrystalline Cellulose, 2~4 parts of cross-linking sodium carboxymethyl cellulose, Hypromellose 2.5~3.5
Part, 0.8~1.5 part of magnesium stearate, 1~4 part of coating pre-mixing agent;Described coating pre-mixing agent is OPADRY
17B620000.
6. tablet according to claim 5 it is characterised in that:It is former by following weight proportioning
Material medicine and adjuvant are prepared from:
49~50 parts of xylene monosulfonic acid Lapatinib, 0.9~1 part of silica sol, Mannitol 18~19
Part, 24~25 parts of Microcrystalline Cellulose, 2~3 parts of cross-linking sodium carboxymethyl cellulose, Hypromellose 3~3.5
Part, 0.8~1.2 part of magnesium stearate, 1~3 part of coating pre-mixing agent;Described coating pre-mixing agent is OPADRY
17B620000.
7. the tablet described in claim 3~6 any one it is characterised in that:In described Mannitol
50% particle diameter is less than 100 μm, and 90% particle diameter is less than 250 μm.
8. the tablet described in claim 3~6 any one it is characterised in that:Described microcrystalline cellulose
In element, 50% particle diameter is less than 150 μm, and 90% particle diameter is less than 250 μm.
9. the tablet described in claim 3~6 any one it is characterised in that:Described Microcrystalline Cellulose
Model Microcrystalline Cellulose pH101, it is highly preferred that described Microcrystalline Cellulose model is Microcrystalline Cellulose
KG802.
10. a kind of method preparing the tablet described in claim 3~9 any one, it includes walking as follows
Suddenly:
1) xylene monosulfonic acid Lapatinib and silica sol are crossed 40~80 eye mesh screens respectively to process, claim
Take recipe quantity to mix, then cross 100~200 mesh sieves and process, and will the two mix homogeneously;
2) Microcrystalline Cellulose, Mannitol cross 60~100 mesh sieves respectively, then by Microcrystalline Cellulose, manna
Alcohol, disintegrating agent and binding agent weigh respectively according to quantity and are added to step 1) in mixture in, then in height
Mix homogeneously under shearing wet granulator, mixes rotating speed preferably 200~400rpm, and cutter rotating velocity is preferred
200~800rpm;
3), during carrying out soft material preparation, soft material processed with purified water to above-mentioned mixing powder, speed of agitator is
200~400rpm, cutter rotating velocity is 300~1200rpm;The sieve number pelletized is 16~30 mesh;
4) granule of preparation is dried, drying temperature is 50~60 DEG C, drying moisture to 1.0~3.5%,
Dry granulate mesh number preferably 16~24 mesh of granule;
5) to step 4) in gained granule add lubricant, mixing, incorporation time be 5~10min;
6) coating, obtains tablet.
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CN101203211A (en) * | 2005-04-19 | 2008-06-18 | 史密丝克莱恩比彻姆(科克)有限公司 | Pharmaceutical composition |
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