CN104800175A - Gefitinib tablet preparation method - Google Patents
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- CN104800175A CN104800175A CN201510188995.3A CN201510188995A CN104800175A CN 104800175 A CN104800175 A CN 104800175A CN 201510188995 A CN201510188995 A CN 201510188995A CN 104800175 A CN104800175 A CN 104800175A
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Abstract
The invention relates to the field of medicines, in particular to a gefitinib tablet preparation method. The gefitinib tablet mainly comprises a main medicine and auxiliary materials. The gefitinib tablet preparation method is characterized in that the gefitinib particle diameter D90 is not more than 10 [mu]m, the proportion of lactose to microcrystalline cellulose is 1: (3-7), uniform mixing is performed according to the formula dosage, and then pelletizing, drying, granulating and tabletting are carried out. The prepared gefitinib tablet is stable in property, reliable in quality and high in bioavailability.
Description
Technical field
The invention belongs to drug world, relate to a kind of antitumor drug, be specifically related to a kind of gefitinib sheet and preparation method thereof.
Background technology
Gefitinib sheet, commodity are called " Iressa ", produced by AstraZeneca UK Limited, be a kind of selectivity EGF-R ELISA (EGFR) tyrosine kinase inhibitor, be applicable to treat the Locally Advanced or the Metastatic Nsclc (NSCLC) that previously accepted chemotherapy or be unsuitable for chemotherapy.It is a kind of micromolecular compound, can enter in cell, is suppressed the activity of epidermal growth factor recipient tyrosine kinase by territory, competitive binding ATP-binding domain mode specificity.Wherein, the structural formula of described gefitinib is as follows:
As everyone knows, in oral solid formulation, the infiltration rate of medicine depends on that medicine is from the dissolving in physiological conditions of the stripping preparation or release, medicine and at gastrointestinal permeability.Therefore dissolution in vitro test can predict behavior in its body to a certain extent.The minimum dissolubility of gefitinib is 0.01mg/ml, is low-solubility; The Determination of oil-water partition coefficient LogP of gefitinib is 3.87, is high osmosis; In Biopharmaceutics Classification, belong to II class medicine.The stripping of such medicine is the rate-limiting step of drug absorption, has good In vitro-in vivo correlation.We can drug release process or as the important indicator evaluating curative effect of medication in antimer indirectly by the stripping curve that measures in external different medium for this reason.
At present, the problems such as the imitation medicine ubiquity dissolution that market is sold is poor, poor stability, in order to solve this problem, we improve the formula of medicine and preparation method in trial.
We, in order to gefitinib sheet of the present invention can be made consistent with Iressa dissolution rate in different medium, attempt much different test methods, such as adjust binding agent, disintegrating agent, surfactant consumption and by raw material micronization etc.Result of study finds, the dissolution rate impact of consumption on gefitinib of adjustment binding agent, disintegrating agent, surfactant is little; But by selecting the gefitinib of different-grain diameter can improve its dissolution, particularly we find unexpectedly when the D90 of gefitinib is not higher than 10 μm, its stripping curve ability is consistent with Iressa, and lasting, steadily and discharge completely.Therefore, the stripping of granularity on its tablet of gefitinib has appreciable impact, and namely the stripping of gefitinib sheet is relevant with particle size distribution.
The granularity that Chinese patent (201210566665X) also discloses gefitinib is relevant with drug release rate, but, in this patent, the particle size distribution of gefitinib is: D (0.1)=2 ~ 6 μm, D (0.5)=11 ~ 20 μm, D (0.9)=35 ~ 50 μm.We are found by test, although this patent improves dissolution and the stability of tablet within the specific limits, but we find in pH4.5 acetate buffer and pH6.8 phosphate buffer, and in 5% Tween 80 aqueous solution, the dissolution of this medicine is not high, and f2 value is also lower, in 5% Tween 80 aqueous solution, the dissolution of 45min also only reaches 79%, illustrates that this medicine and Iressa still exist gap on releasing effect.
The present invention carries out bold trial on Chinese patent (201210566665X) basis for this reason, further adjustment gefitinib particle diameter, and find unexpectedly, when being controlled below 10 μm by gefitinib particle diameter D90, pH4.5 acetate buffer and pH6.8 phosphate buffer and the dissolution at 5% Tween 80 aqueous solution Chinese medicine can be improved.At the gefitinib of this particle size range, its dissolubility obviously raises.By by gefitinib micronization, increase the specific surface area of raw material, increase the contact area of raw material and adjuvant, reduce the adsorption of medicine, be conducive to the In Vitro Dissolution of medicine.
In order to increase the dissolution of this medicine further, we attempt exchanging adjuvant, further select doing by doses.Gefitinib is insoluble drug, and its dissolubility is in aqueous pH dependency, and namely in the aqueous solution that pH is lower, dissolubility is larger, and when pH4 ~ 6, dissolubility sharply declines, almost insoluble in the water of pH value about 7.After raw material micronization processes, in order to increase the dissolution of gefitinib at dissolution medium further, we surprisingly find, can reach required effect by the ratio of adjustment lactose and microcrystalline Cellulose.Finally determine after screening in a large number, when the ratio of microcrystalline Cellulose and lactose is 1:3 ~ 7, the stripping curve of gefitinib sheet of the present invention is the most similar to Iressa, and f2 value can reach more than 80.
Summary of the invention
The object of the present invention is to provide a kind of tablet containing gefitinib, this tablet has the features such as dissolution is high, good stability, low price.
Gefitinib tablet of the present invention, this tablet is containing the gefitinib of effective therapeutic dose, and the particle size distribution of this gefitinib is: D90 is not higher than 10 μm.
D represents the diameter of powder granule, particle diameter corresponding when D90 refers to that the cumulative particle sizes percentile of a sample reaches 90%.
The pharmaceutically acceptable carrier of tablet of the present invention also containing routine dose.
Concrete, tablet of the present invention, is grouped into by the one-tenth of following percentage by weight:
Wherein, the particle diameter D90 of gefitinib not higher than 10 μm, preferred gefitinib D90=8 ~ 10 μm;
Wherein, filler is selected: two kinds of mixture in microcrystalline Cellulose, lactose, and wherein the ratio of microcrystalline Cellulose and lactose is 1:3 ~ 7; The ratio of preferred microcrystalline Cellulose and lactose is 1:7.
Wherein, binding agent selects PVP K30;
Wherein, cross-linking sodium carboxymethyl cellulose selected by disintegrating agent;
Wherein, sodium lauryl sulphate selected by surfactant;
Wherein, magnesium stearate is selected in lubricant agent;
Wherein, solvent is water.
Preferably, tablet of the present invention, is made up of following raw material:
Preferably, tablet of the present invention, is made up of following raw material:
Preferably, tablet of the present invention, is made up of following raw material:
Preferably, tablet of the present invention, is made up of following raw material:
Another object of the present invention is the preparation method providing gefitinib sheet.
The present invention granulates in a wet process and obtains medicine-containing particle or powder, adds a certain amount of mix lubricant, tabletting.
Concrete, preparation method of the present invention, comprises the following steps:
(1) take PVP K30 add appropriate purified water dissolve be prepared into clear transparent solutions, stir while add sodium lauryl sulphate, stir, for subsequent use;
(2) take gefitinib and other adjuvants, cross 80 mesh sieves, for subsequent use;
(3) by step (1) (2) by wet granulation, make medicine-containing particle or powder;
(4) by the medicine-containing particle of step (3) gained or powder and mix lubricant, tabletting;
(5) stomach dissolution type Opadry is mixed with low viscosity solution, coating is carried out to gefitinib element sheet;
(6) coated tablet is carried out aluminium-plastic bubble plate packing, obtain gefitinib sheet.
The present invention prepares gained gefitinib sheet, and not only dissolution in vitro is high, and the good stability of product, even if accelerated test 6 months, its dissolution in vitro and related substance do not have significance to change yet.
Prescription of the present invention is through great many of experiments screening and obtains, and inventor finds in the process of research gefitinib sheet, and the ratio of the particle size distribution size of raw material and lactose and microcrystalline Cellulose is particularly important.Gefitinib crude drug used in the present invention is produced by our company, and D90 is 30 ~ 50 μm, bulk density at 0.35 ~ 0.39g/ml, compactness 0.56 ~ 0.60g/ml.We, by the consumption of adjustment binding agent, disintegrating agent, surfactant and by methods such as raw material micronizations, found that, the dissolution rate impact of consumption on gefitinib of the consumption of adjustment binding agent, disintegrating agent, surfactant is little.And when micronized gefitinib (D90 is not higher than 10 μm) stripping is consistent with Iressa, and lasting, steadily and discharge completely.Therefore, the stripping of granularity on its tablet of gefitinib has appreciable impact.Simultaneously in order to ensure that primary drugs discharges stably, the ratio of microcrystalline Cellulose and lactose in 1:3 ~ 7, particularly should show extraordinary releasing effect in the dissolution medium of 5% tween water.
By following experiment, further illustrate beneficial effect of the present invention.
Table 1 gefitinib tablet raw material granularity investigates test data
Table 2 gefitinib sheet filler ratio screening test data
Experimental result shows: the present invention adopts wet granulation to prepare gefitinib sheet, (1) select particle diameter D90 not higher than 10 μm of gefitinibs, in 5% Tween 80 water, dissolution is better than D90 is 30 ~ 50 μm of gefitinibs, and in Chinese patent 201210566665X, the dissolution of 45min is 92.47%, 60min dissolution is 97.25%, so be better than 201210566665X by the present invention of dissolution comparative descriptions.(2) when the ratio of microcrystalline Cellulose and lactose is 1:3 ~ 7, relative to other ratios, not only improve dissolution in vitro and the stability of gefitinib sheet, also increase substantially the quality of product.
The present invention adopts particle diameter D90 not higher than the gefitinib of 10 μm, select ratio to be that 1:3 ~ 7 microcrystalline Cellulose and lactose are as filler simultaneously, the gefitinib sheet prepared according to recipe quantity, the tablet obtained is similar to the stripping curve of Iressa, and dissolution can continue, steadily and discharge completely, have good commercial promise.
Detailed description of the invention
In order to make those skilled in the art understand technical scheme of the present invention better, below in conjunction with specific embodiment, the present invention is described in further detail.
Embodiment 1 gefitinib micronization processes
By gefitinib raw material 10kg, be placed in jet mill (Kunshan Close Friend Group Co., Ltd) micronization, by the time micronized gefitinib 8.73kg, yield is 87.3%.Get gefitinib sample after micronization, detect with Mastersizer2000 Malvern laser particle size analyzer (Malvern Instr Ltd. of Britain), D90 is 8.488 μm.
Embodiment 2 gefitinib micronization processes
By gefitinib raw material 10kg, be placed in jet mill (Kunshan Close Friend Group Co., Ltd) micronization, by the time micronized gefitinib 9.21kg, yield is 92.1%.Get gefitinib sample after micronization, detect with Mastersizer2000 Malvern laser particle size analyzer (Malvern Instr Ltd. of Britain), D90 is 9.796 μm.
The preparation of embodiment 3 gefitinib sheet
A. the preparation of gefitinib element sheet
Weigh 5.0kg purified water, add 0.3kg PVP K30 under stirring and stir evenly, be mixed with clear transparent solutions, stir while add sodium lauryl sulphate, stir, for subsequent use; Take supplementary material by table 3 prescription, dropped in the multi-functional wet mixing pelletizer of G6 test-type by the supplementary material handled well, stirring at low speed 300 seconds, makes supplementary material mix homogeneously; Under stirring at low speed state, add binding agent in 120 seconds, last low velocity shear makes to make even-grained soft material for 20 seconds; Discharging, puts 20 orders in oscillating granulator and granulates by soft material; Wet granular is put 50 ± 5 DEG C of dryings, be dried to moisture 1% ~ 3%, 20 orders arrange, and with the packed bag of PE, weigh, add a certain amount of magnesium stearate mix homogeneously.During tabletting, control hardness range 9 ~ 11kg, every sheet is containing gefitinib 0.25g.
The prescription of table 3 gefitinib sheet
* solvent is removed in preparation technology
B. coating
By table 4 prescription by 95% second alcohol and water mix homogeneously, stir while add coating powder, homogeneous 5 ~ 10min, continue stirring for subsequent use.Take above-mentioned gefitinib element sheet, be placed in coating pan, and set inlet temperature 30 ~ 50 DEG C, coating pan rotating speed 4 ~ 6r/min, spouting velocity 150 ~ 300ml/min, spray gun and sheet bed distance: 22 ~ 25cm, temperature of outgoing air: 30 ~ 50 DEG C, temperature of charge: 30 ~ 40 DEG C, atomization air pressure: 0.20 ~ 0.30MPa, negative pressure in seed-coating machine :-1.0 ~-0.2KPa.Heavily increase weight to setting value until sheet, stop spray coating solution, drying of blowing a cold wind over, slice after sheet temperature drop to room temperature, packed good with PE; Finally coated tablet is carried out aluminium-plastic bubble plate packing, obtain gefitinib sheet of the present invention.
The coating prescription of table 4 gefitinib sheet
| Classification | Supplementary material title | Consumption (g) | Accounting (%) |
| Element sheet | Gefitinib sheet | 9870 | 98.0 |
| Coating powder | Stomach dissolved film coating pre-mix dose | 197.4 | 2.0 |
| Solvent * | 95% ethanol | 1922.1 | / |
| Solvent * | Water | 512.5 | / |
| Gross weight | 10067.4 | 100.0 |
* solvent is removed in preparation technology
The preparation of embodiment 4 gefitinib sheet
A. the preparation of gefitinib element sheet
Weigh 5.0kg purified water, add 0.3kg PVP K30 under stirring and stir evenly, be mixed with clear transparent solutions, stir while add sodium lauryl sulphate, stir, for subsequent use; Take supplementary material by table 5 prescription, dropped in the multi-functional wet mixing pelletizer of G6 test-type by the supplementary material handled well, stirring at low speed 300 seconds, makes supplementary material mix homogeneously; Under stirring at low speed state, add binding agent in 120 seconds, last low velocity shear makes to make even-grained soft material for 20 seconds; Discharging, puts 20 orders in oscillating granulator and granulates by soft material; Wet granular is put 50 ± 5 DEG C of dryings, be dried to moisture 1% ~ 3%, 20 orders arrange, and with the packed bag of PE, weigh, add a certain amount of magnesium stearate mix homogeneously.During tabletting, control hardness range 9 ~ 11kg, every sheet is containing gefitinib 0.25g.
The prescription of table 5 gefitinib sheet
* solvent is removed in preparation technology
B. coating
By table 6 prescription by 95% second alcohol and water mix homogeneously, stir while add coating powder, homogeneous 5 ~ 10min, continue stirring for subsequent use.Take above-mentioned gefitinib element sheet, be placed in coating pan, and set inlet temperature 30 ~ 50 DEG C, coating pan rotating speed 4 ~ 6r/min, spouting velocity 150 ~ 300ml/min, spray gun and sheet bed distance: 22 ~ 25cm, temperature of outgoing air: 30 ~ 50 DEG C, temperature of charge: 30 ~ 40 DEG C, atomization air pressure: 0.20 ~ 0.30MPa, negative pressure in seed-coating machine :-1.0 ~-0.2KPa.Heavily increase weight to setting value until sheet, stop spray coating solution, drying of blowing a cold wind over, slice after sheet temperature drop to room temperature, packed good with PE; Finally coated tablet is carried out aluminium-plastic bubble plate packing, obtain gefitinib sheet of the present invention.
The coating prescription of table 6 gefitinib sheet
| Classification | Supplementary material title | Consumption (g) | Accounting (%) |
| Element sheet | Gefitinib sheet | 9900 | 98.0 |
| Coating powder | Stomach dissolved film coating pre-mix dose | 198.0 | 2.0 |
| Solvent * | 95% ethanol | 1927.9 | / |
| Solvent * | Water | 514.1 | / |
| Gross weight | 10098.0 | 100.0 |
* solvent is removed in preparation technology
The preparation of embodiment 5 gefitinib sheet
A. the preparation of gefitinib element sheet
Weigh 5.0kg purified water, add 0.37kg PVP K30 under stirring and stir evenly, be mixed with clear transparent solutions, stir while add sodium lauryl sulphate, stir, for subsequent use; Take supplementary material by table 7 prescription, dropped in wet mixing pelletizer by the supplementary material handled well, stirring at low speed 300 seconds, makes supplementary material mix homogeneously; Under stirring at low speed state, add binding agent in 120 seconds, last low velocity shear makes to make even-grained soft material for 20 seconds; Discharging, puts 20 orders in oscillating granulator and granulates by soft material; Wet granular is put 50 ± 5 DEG C of dryings, be dried to moisture 1% ~ 3%, 20 orders arrange, and with the packed bag of PE, weigh, add a certain amount of magnesium stearate mix homogeneously.During tabletting, control hardness range 9 ~ 11kg, every sheet is containing gefitinib 0.25g.
The prescription of table 7 gefitinib sheet
* solvent is removed in preparation technology
B. coating
By table 8 prescription by 95% second alcohol and water mix homogeneously, stir while add coating powder, homogeneous 5 ~ 10min, continue stirring for subsequent use.Take above-mentioned gefitinib element sheet, be placed in coating pan, and set inlet temperature 30 ~ 50 DEG C, coating pan rotating speed 4 ~ 6r/min, spouting velocity 150 ~ 300ml/min, spray gun and sheet bed distance: 22 ~ 25cm, temperature of outgoing air: 30 ~ 50 DEG C, temperature of charge: 30 ~ 40 DEG C, atomization air pressure: 0.20 ~ 0.30MPa, negative pressure in seed-coating machine :-1.0 ~-0.2KPa.Heavily increase weight to setting value until sheet, stop spray coating solution, drying of blowing a cold wind over, slice after sheet temperature drop to room temperature, packed good with PE; Finally coated tablet is carried out aluminium-plastic bubble plate packing, obtain gefitinib sheet of the present invention.
The coating prescription of table 8 gefitinib sheet
| Classification | Supplementary material title | Consumption (g) | Accounting (%) |
| Element sheet | Gefitinib sheet | 9865 | 98.0 |
| Coating powder | Stomach dissolved film coating pre-mix dose | 197.3 | 2.0 |
| Solvent * | 95% ethanol | 1925.9 | / |
| Solvent * | Water | 513.6 | / |
| Gross weight | 10062.3 | 100.0 |
* solvent is removed in preparation technology
The preparation of embodiment 6 gefitinib sheet
A. the preparation of gefitinib element sheet
Weigh 5.0kg purified water, add 0.3kg PVP K30 under stirring and stir evenly, be mixed with clear transparent solutions, stir while add sodium lauryl sulphate, stir, for subsequent use; Take supplementary material by table 9 prescription, dropped in the multi-functional wet mixing pelletizer of G6 test-type by the supplementary material handled well, stirring at low speed 300 seconds, makes supplementary material mix homogeneously; Under stirring at low speed state, add binding agent in 120 seconds, last low velocity shear makes to make even-grained soft material for 20 seconds; Discharging, puts 20 orders in oscillating granulator and granulates by soft material; Wet granular is put 50 ± 5 DEG C of dryings, be dried to moisture 1% ~ 3%, 20 orders arrange, and with the packed bag of PE, weigh, add a certain amount of magnesium stearate mix homogeneously.During tabletting, control hardness range 9 ~ 11kg, every sheet is containing gefitinib 0.25g.
The prescription of table 9 gefitinib sheet
* solvent is removed in preparation technology
B. coating
By table 10 prescription by 95% second alcohol and water mix homogeneously, stir while add coating powder, homogeneous 5 ~ 10min, continue stirring for subsequent use.Take above-mentioned gefitinib element sheet, be placed in coating pan, and set inlet temperature 30 ~ 50 DEG C, coating pan rotating speed 4 ~ 6r/min, spouting velocity 150 ~ 300ml/min, spray gun and sheet bed distance: 22 ~ 25cm, temperature of outgoing air: 30 ~ 50 DEG C, temperature of charge: 30 ~ 40 DEG C, atomization air pressure: 0.20 ~ 0.30MPa, negative pressure in seed-coating machine :-1.0 ~-0.2KPa.Heavily increase weight to setting value until sheet, stop spray coating solution, drying of blowing a cold wind over, slice after sheet temperature drop to room temperature, packed good with PE; Finally coated tablet is carried out aluminium-plastic bubble plate packing, obtain gefitinib sheet of the present invention.
The coating prescription of table 10 gefitinib sheet
| Classification | Supplementary material title | Consumption (g) | Accounting (%) |
| Element sheet | Gefitinib sheet | 9875 | 98.0 |
| Coating powder | Stomach dissolved film coating pre-mix dose | 197.5 | 2.0 |
| Solvent * | 95% ethanol | 1925.9 | / |
| Solvent * | Water | 513.6 | / |
| Gross weight | 10072.5 | 100.0 |
* solvent is removed in preparation technology
The list a company dissolution in vitro of product Iressa (Y) of the gefitinib sheet of embodiment 7 preparation method of the present invention and AstraZeneca contrasts
Gefitinib sheet (A) in Example 3, gefitinib sheet (B) in embodiment 4, gefitinib sheet (C) in embodiment 5, gefitinib sheet (D) in embodiment 6 and AstraZeneca list a company each 12 of product Iressa (Y), operate according to dissolution method (Chinese Pharmacopoeia version in 2010 two annex X C second methods), measure 1000mL dissolution medium (water respectively, 0.1mol/L hydrochloric acid solution, pH4.5 acetic acid hydrochlorate buffer solution, pH6.8 phosphate buffered solution), paddle method, rotating speed 50 revs/min, detecting instrument: rich Cohan optical fiber drug line digestion instrument, measure wavelength: 334nm.
The average accumulated dissolution determination result (n=12) of table 11 gefitinib sheet (A) and (Y)
From table 11 result, in water, 0.1mol/L acid hydrochloride salt solution, pH4.5 acetate buffer solution, pH6.8 phosphate buffered solution, similar factors f2 is all greater than 50, and the In Vitro Dissolution Similar Broken Line of A, B, C, D and Y is described.
Influence factor's test of embodiment 8 gefitinib sheet
The gefitinib sheet of Example 3, after placing 10 days respectively under being placed in high temperature (40 ± 2 DEG C), high humidity (RH75% ± 5%), high light (4500lx ± 500lx) condition, check its content, dissolution and related substance, result is as table 9.
Dissolution determination method: get this product, according to dissolution method (Chinese Pharmacopoeia version in 2010 two annex X C second methods), with 5% tween 80 1000ml for dissolution medium, rotating speed is 50 turns per minute, operate in accordance with the law, through 45 minutes time, get dissolution fluid 10ml, filter, get subsequent filtrate appropriate.According to spectrophotography (Chinese Pharmacopoeia version in 2010 two annex IV A), measure absorbance respectively at wavelength 334nm place, calculate the stripping quantity of every sheet.
Content assaying method: get this product 10, accurately weighed, porphyrize, precision takes in right amount (being about equivalent to gefitinib 25mg), puts in 50ml measuring bottle, and it is appropriate to add mobile phase, ultrasonicly make dissolving, let cool to room temperature, with above-mentioned solvent dilution to scale, shake up, filter, precision measures 5ml, is placed in 50ml measuring bottle, be diluted to scale with mobile phase, shake up.According to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 second annex V D), be filler with octadecylsilane chemically bonded silica, with 0.02% trifluoroacetic acid-acetonitrile=70:30 (with triethylamine adjust pH 3.9 ± 0.1), for mobile phase, determined wavelength is 334nm.Precision measures need testing solution 10 μ l, respectively injection liquid chromatography, record chromatogram; Separately get gefitinib reference substance, be measured in the same method.By external standard method with calculated by peak area content.
Related substance detection method: get the need testing solution under assay item, injection liquid chromatography, record chromatogram, in need testing solution chromatogram, each impurity peak area sum must not be greater than the main peak area (0.4%) of contrast solution.
Influence factor's result of the test of table 12 gefitinib sheet
From the result of study of table 12, the gefitinib sheet that the embodiment of the present invention 3 obtains is placed 10 days under high temperature, high humidity and intense light conditions, its character, dissolution, related substance and content are showed no significant change, and AstraZeneca lists a company, product Iressa (Y) slightly changes at related substance, dissolution and content.This shows the gefitinib sheet of gained of the present invention quality quite stable under high temperature, high humidity, high optical condition.Other embodiments of the invention 4-6 also has identical superior stablizing effect.
The accelerated test of embodiment 9 gefitinib sheet
Gefitinib sheet (A) in treating excess syndrome agent example 3, the gefitinib sheet (B) implemented in example 4, the gefitinib sheet (C) implemented in example 5, implement gefitinib sheet (D) in example 6 and AstraZeneca and to list a company product Iressa (Y), being placed in temperature is 40 ± 2 DEG C, place in the climatic chamber of humidity RH75% ± 5%, sample respectively once 0 month, 1 month, 2 months, 3 months, 6 the end of month, check its character, content, dissolution and related substance.Result of the test is as shown in table 13.
The accelerated test result of table 13 gefitinib sheet
From the result of study of table 10, the gefitinib sheet that the embodiment of the present invention 3, embodiment 4, embodiment 5 obtain is accelerated test (40 ± 2 DEG C, RH75% ± 5%) after 6 months, its related substance, content and dissolution are showed no significant change, but, the list a company dissolution of product Iressa (Y) of AstraZeneca slightly declines, and related substance slightly rises.
Gefitinib sheet stable in properties provided by the invention can be described thus, reliable in quality, sample is not subject to because the short-terms such as transport depart from the situation of holding conditions and affects quality.
The long term test of embodiment 10 gefitinib
Gefitinib sheet (C) in gefitinib sheet (A) in Example 3, the gefitinib sheet (B) in embodiment 4, embodiment 5 and the gefitinib sheet (D) in embodiment 6, being placed in temperature is 25 ± 2 DEG C, place in the climatic chamber of humidity RH60% ± 10%, sample respectively once 0 month, 3 months, 6 the end of month, check its content, dissolution and related substance.Result of the test is as shown in table 14.
The long-term test results of table 14 gefitinib sheet
From the result of study of table 11, the gefitinib sheet that the embodiment of the present invention 3, embodiment 4, embodiment 5 obtain is in long term test (25 ± 2 DEG C, RH60% ± 5%) after 6 months, and its related substance, content and dissolution are showed no significant change.
As can be seen here, the result of study of long term test and the result of study of accelerated test basically identical, this illustrates gefitinib sheet stable in properties provided by the invention, reliable in quality.
Embodiment 11 the present invention compares with existing product (Chinese patent 201210566665.X's)
(1) comparison of similar factors f2
In 4 kinds of different dissolution mediums, product of the present invention compares with patent 201210566665.X: in hydrochloric acid solution, general trend is the same; In pH4.5 solution, the similar factors (f2=88,82,87,90) of product of the present invention is all high than (f2=72) of patent 201210566665.X; In pH6.8 solution, the present invention the similar factors (f2=83,84,83,83) of product all high than (f2=73) of patent 201210566665.X; In water, the present invention the similar factors (f2=89,80,84,91) of product slightly low than (f2=87) of patent 201210566665.X.
Table 15 the present invention and 201210566665.X dissolution compare
(2) stability compares
Compare with patent 201210566665.X, product of the present invention through the accelerated test of 6 months and long term test related substance unchanged, be 0.06%; Content remains on more than 98%, without significant change; Dissolution remains on more than 90%, without significant change; And although patent 201210566665.X only has the data of long term test, in stripping, (about about 89%) is all low than dissolution of the present invention (more than 90%), has downward trend.
Claims (10)
1. the tablet containing gefitinib, is made up of the raw material of following percentage by weight:
Wherein, described gefitinib particle diameter D90 is not higher than 10 μm.
2. tablet according to claim 1, is characterized in that,
Wherein, filler is selected: two kinds of mixture in microcrystalline Cellulose, lactose, and wherein the ratio of microcrystalline Cellulose and lactose is 1:3 ~ 7;
Wherein, binding agent selects PVP K30;
Wherein, cross-linking sodium carboxymethyl cellulose selected by disintegrating agent;
Wherein, sodium lauryl sulphate selected by surfactant;
Wherein, magnesium stearate is selected in lubricant agent;
Wherein, solvent is water.
3. tablet according to claim 1, is characterized in that, wherein the ratio of microcrystalline Cellulose and lactose is 1:7.
4. tablet according to claim 1, is characterized in that, particle diameter D90=8 ~ 10 μm of gefitinib.
5. tablet according to claim 1, is characterized in that, is made up of following raw material:
6. tablet according to claim 1, is characterized in that, is made up of following raw material:
7. tablet according to claim 1, is characterized in that, is made up of following raw material:
8. tablet according to claim 1, is characterized in that, is made up of following raw material:
9. tablet according to claim 1, is characterized in that, is made up of following raw material:
A. the preparation of gefitinib element sheet
B. coating
10. the preparation method of tablet described in claim 1, comprises the following steps:
(1) take PVP K30 add appropriate purified water dissolve be prepared into clear transparent solutions, stir while add sodium lauryl sulphate, stir, for subsequent use;
(2) take gefitinib and other adjuvants, cross 80 mesh sieves, for subsequent use;
(3) by step (1) (2) by wet granulation, make medicine-containing particle or powder;
(4) by the medicine-containing particle of step (3) gained or powder and mix lubricant, tabletting;
(5) stomach dissolution type Opadry is mixed with low viscosity solution, coating is carried out to gefitinib element sheet;
(6) coated tablet is carried out aluminium-plastic bubble plate packing, obtain gefitinib sheet.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105687156A (en) * | 2016-03-04 | 2016-06-22 | 四川美大康华康药业有限公司 | Gefitinib composite tablets and preparation method thereof |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106913544A (en) * | 2015-12-28 | 2017-07-04 | 山东新时代药业有限公司 | A kind of Gefitinib tablet of Fast Stripping and preparation method thereof |
| CN106913544B (en) * | 2015-12-28 | 2019-08-30 | 山东新时代药业有限公司 | A kind of Gefitinib tablet of Fast Stripping and preparation method thereof |
| CN105687156A (en) * | 2016-03-04 | 2016-06-22 | 四川美大康华康药业有限公司 | Gefitinib composite tablets and preparation method thereof |
| CN107007562A (en) * | 2017-02-16 | 2017-08-04 | 南京优科制药有限公司 | A kind of Gefitinib tablet and preparation method thereof |
| CN107007562B (en) * | 2017-02-16 | 2020-10-27 | 南京优科制药有限公司 | Gefitinib tablet and preparation method thereof |
| CN109394685A (en) * | 2017-08-15 | 2019-03-01 | 江苏恒瑞医药股份有限公司 | A kind of pharmaceutical composition and preparation method thereof of VEGFR inhibitor |
| CN109394685B (en) * | 2017-08-15 | 2021-04-06 | 江苏恒瑞医药股份有限公司 | VEGFR inhibitor pharmaceutical composition and preparation method thereof |
| CN111035619A (en) * | 2018-10-12 | 2020-04-21 | 四川科伦药物研究院有限公司 | Gefitinib tablet and preparation method thereof |
| CN111035619B (en) * | 2018-10-12 | 2023-02-28 | 四川科伦药物研究院有限公司 | Gefitinib tablet and preparation method thereof |
| CN110101668A (en) * | 2019-05-29 | 2019-08-09 | 华东理工大学 | A kind of preparation method of Gefitinib composite particles |
| CN114762650A (en) * | 2021-01-11 | 2022-07-19 | 廊坊新龙立机械制造有限公司 | Method for processing material with poor bulk density into medicament with predetermined specification |
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Application publication date: 20150729 |