CN105456222B - Maleic acid Afatinib piece and preparation method thereof - Google Patents
Maleic acid Afatinib piece and preparation method thereof Download PDFInfo
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- CN105456222B CN105456222B CN201510973979.5A CN201510973979A CN105456222B CN 105456222 B CN105456222 B CN 105456222B CN 201510973979 A CN201510973979 A CN 201510973979A CN 105456222 B CN105456222 B CN 105456222B
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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Abstract
The invention discloses a kind of maleic acid Afatinib pieces and preparation method thereof, belong to pharmaceutical technology field.Maleic acid Afatinib piece is made of label and the film coating being wrapped in outside label, label is made of the raw material of following mass fraction: 57~61 parts of maleic acid Afatinib, 170~180 parts of Lactis Anhydrous, 60~70 parts of microcrystalline cellulose, 30~36 parts of crospovidone, silica 1 .5~2.5 part, 3~5 parts of magnesium stearate, wherein Lactis Anhydrous, microcrystalline cellulose are filler, and crospovidone is disintegrating agent, silica is glidant, and magnesium stearate is lubricant；Film coating use following mass fraction raw material: 13.5 parts of film coating pre-mix dose, 169.1 parts of water, coating weight gain 2%~4%.The tablet has quick-release characteristic, dissolves out 15min > 95%, and quality is stablized.
Description
Technical field
The present invention relates to a kind of maleic acid Afatinib pieces, also relate to the preparation method of maleic acid Afatinib piece,
Belong to pharmaceutical technology field.
Background technique
Maleic acid Afatinib (Afatinib Dimaleate, CAS:850140-73-7) also known as N- [4- [(the chloro- 4- of 3-
Fluorophenyl) amino] -7- [[(3S)-tetrahydro -3- furyl] oxygroup] -6- quinazolyl] -4- (dimethylamino) -2- crotonoyl
Amine, molecular formula: C24H25ClFN5O3.2C4H4O4, molecular weight 718.1,173 ± 7 DEG C of fusing point, dissociation constant pKa1=8.2 ± 0.1,
pKa2=5.0 ± 0.1, distribution coefficient Log P=4.7 (pH > 9), Log D=3.8 (pH7.4), structural formula is as follows:
Maleic acid Afatinib is white or yellowish-brown powder, at being highly soluble in water after salt, optimum solvent DMSO, secondly
For methanol, 1mg/ml is less than to the solubility of other most of solvents；It is soluble in the buffer solution of pH < 6, there is pH dependence
(reason be base there are 2 ionogen tertiary amines and quinuclidines).It is mainly used for treating epidermal growth factor (EGFR)
Receptor 1 is mutated positive non-small cell lung cancer (NSCLC).
Summary of the invention
The object of the present invention is to provide a kind of quick-release maleic acid Afatinib pieces, dissolve out 15min > 95%.
Meanwhile the present invention also provides a kind of preparation methods of maleic acid Afatinib piece.
In order to achieve the goal above, the technical scheme adopted by the invention is that:
Maleic acid Afatinib piece is made of label and the film coating being wrapped in outside label, and label is by following mass parts
Several raw materials are made: 57~61 parts of maleic acid Afatinib (in terms of Afatinib), and 170~180 parts of Lactis Anhydrous, microcrystalline cellulose
60~70 parts of element, 30~36 parts of crospovidone (cross-linking polyethylene pyrrolidone), silica 1 .5~2.5 part, stearic acid
3~5 parts of magnesium.
Preferably, label is made of the raw material of following mass fraction: maleic acid Afatinib (in terms of Afatinib) 59.12
Part, 175 parts of Lactis Anhydrous, 65 parts of microcrystalline cellulose, 33 parts of crospovidone (cross-linking polyethylene pyrrolidone), silica
2 parts, 4 parts of magnesium stearate.
The preferably anhydrous vertical compression lactose of the Lactis Anhydrous, granularity d90≤67 μm.Anhydrous vertical compression lactose has uniform granularity
Distribution, particle are spherical, angle of repose≤35 °, are had preferable mobility and Combination.Anhydrous vertical compression lactose compares lactose monohydrate
There is higher intrinsic solubility, it can improve the stability and dispersibility of moisture-sensitive type drug, but also can be improved inherent " molten
Performance out " especially has the function of insoluble drug to promote vivo biodistribution availability.
The microcrystalline cellulose can be used it is any in PH101, PH102, PH103, PH105, PH301, PH302, preferably
PH302, granularity d90≤85 μm.Microcrystalline cellulose PH302 is free flowable imperceptible corynebacterium or powdery porous shape
Particle, color are white or near-white, and odorless, tasteless, having flowing, density is high fastly, is disintegrated fast feature.
Crospovidone is common disintegrating agent in tablet, it is generally recognized that it is nontoxic, it is nonirritant, and it is water-insoluble, it can be fast
Speed shows high capillary activity and excellent hydration capability, and almost without the tendency of gel, when wet granulation can be respectively at profit
Wet stage and drying stage are added, and can preferably play capillarity and swelling action in this way, may advantageously facilitate label
Disintegration and drug-eluting.
Silica is commonly considered as nontoxic non-stimulated auxiliary material, and it is desired that small particle and bigger serface have it
Mobility, this feature can be used to improve the mobility of dry powder during many, therefore the auxiliary material is usually used in powder vertical compression and does
Method granulating process.
Magnesium stearate is mainly as lubricant in tablet manufacturing, and property is stablized, it is generally recognized that oral, non-toxic, dosage are general
It is 0.25~5.0%, if but dosage is more than a certain range, and moisture penetrates into label when hydrophobic property will affect drug-eluting
Internal speed, energy blocking medicine dissolves out from solid dosage forms and then influences the dissolution rate of drug, therefore to the greatest extent may be used in prescription
Low concentration can be used.
The film coating use following mass fraction raw material: 12~15 parts of film coating pre-mix dose, water 165~175
Part.Coating weight gain is the 2%~6% of label quality.Preferably, 13.5 parts of film coating pre-mix dose, 169.1 parts of water；Coating increases
2%~4% is weighed, which influences the content of label and uniformity of dosage units little.Coating weight gain crosses conference and moisture is delayed to enter
Label causes label disintegration time to extend, and dissolves out slack-off.
The film coating pre-mix dose is preferredThe trade mark: 295B680001 (is had by Shanghai Ka Lekang packaging technique
The production of limit company), ingredient is hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol and polysorbate.
The preparation method of maleic acid Afatinib piece, comprising the following steps:
1) each raw material is accurately taken according to mass fraction, first by maleic acid Afatinib, Lactis Anhydrous, microcrystalline cellulose, friendship
It is uniformly mixed to join povidone, silica, adds magnesium stearate and is uniformly mixed, tabletting obtains label；
Film coating pre-mix dose is added to the water, is uniformly mixed, obtains coating solution；
2) take coating solution to label be coated to get.
33 μm of the partial size d90 < of maleic acid Afatinib, moisture < 1.0% in step 1).
First and second mixing carries out in mixing machine (model such as SYH10 three-dimensional motion mixer) in step 1), mixing
25~35Hz of frequency (preferably 30Hz) mixes 20~30min, second of 5~10min of mixing for the first time.
Tabletting carries out in tablet press machine (model such as ZPW rotary pelleting machine) in step 1), power 4kW, 50~120N of pressure；
It is preferred that 80~100N.
Coating is in seed-coating machine (lab scale such as uses BY300 coating pan, in use BG1-5 high-efficiency coating machine) in step 2)
It carries out, 35~45 DEG C of piece bed tempertaure, coating weight gain 2%~4%.
Beneficial effects of the present invention:
Maleic acid Afatinib piece is made of label and the film coating being wrapped in outside label in the present invention, and label is by raw material
Medicine maleic acid Afatinib is made with auxiliary material Lactis Anhydrous, microcrystalline cellulose, crospovidone, silica, magnesium stearate,
Middle Lactis Anhydrous, microcrystalline cellulose are filler, and crospovidone is disintegrating agent, and silica is glidant, and magnesium stearate is
Lubricant, film coating use commercially available film coating pre-mix dose, which has quick-release characteristic, dissolve out 15min > 95%, and matter
Amount is stablized.
The preparation process of maleic acid Afatinib piece is simple, easy to operate in the present invention, is suitable for large-scale production application.
Detailed description of the invention
Fig. 1 is 40mg dosage BIBW 2992 in Afatinib piece in embodiment 4 and patent document in pH4.0 buffer
In dissolution curve；
Fig. 2 is Afatinib piece and BIBW 2992 dissolution curves in pH6.8 buffer in embodiment 4；
Fig. 3 is Afatinib piece and BIBW 2992 dissolution curves in 0.1mol/L HCl solution in embodiment 4；
Fig. 4 is Afatinib piece and the dissolution curve of BIBW 2992 in an aqueous medium in embodiment 4；
Fig. 5 is in test example using the Afatinib piece of prescription 1~3 and 2992 tablet dissolution Comparative result of BIBW；
Fig. 6 is the Afatinib piece and 2992 tablet dissolution Comparative result of BIBW using prescription 4~5.
Specific embodiment
Only invention is further described in detail for following embodiments, but does not constitute any limitation of the invention.
Embodiment 1
Maleic acid Afatinib piece in the present embodiment is made of, label label and the film coating being wrapped in outside label
It is made of the raw material of following mass fraction: maleic acid Afatinib (in terms of Afatinib, 33 μm of partial size d90 <, moisture <
1.0%) 57 parts, 180 parts of anhydrous vertical compression lactose, 60 parts of microcrystalline cellulose PH105,36 parts of crospovidone, silica 1 .5
Part, 5 parts of magnesium stearate；Film coating use following mass fraction raw material: 12 parts of film coating pre-mix dose, 165 parts of water.
The preparation method of maleic acid Afatinib piece, comprising the following steps:
1) each raw material is accurately taken according to mass fraction, first by maleic acid Afatinib, anhydrous vertical compression lactose, microcrystalline cellulose
PH302, crospovidone, silica mixing 20min, mixed frequency 30Hz add magnesium stearate, mix 10min, are pressing
Power 100N lower sheeting, obtains label；
Film coating pre-mix dose is slowly added in water, it is stirring while adding, high speed shear 5min after 60min is stirred, is obtained
Coating solution；
2) take coating solution to label be coated, 40 DEG C of control sheet bed tempertaure, coating weight gain 4% to get.
Embodiment 2
Maleic acid Afatinib piece in the present embodiment is made of, label label and the film coating being wrapped in outside label
It is made of the raw material of following mass fraction: maleic acid Afatinib (in terms of Afatinib, 33 μm of partial size d90 <, moisture <
1.0%) 61 parts, 170 parts of anhydrous vertical compression lactose, 70 parts of microcrystalline cellulose PH301,30 parts of crospovidone, silica 2.5
Part, 3 parts of magnesium stearate；Film coating use following mass fraction raw material: 15 parts of film coating pre-mix dose, 175 parts of water.
The preparation method of maleic acid Afatinib piece, comprising the following steps:
1) each raw material is accurately taken according to mass fraction, first by maleic acid Afatinib, anhydrous vertical compression lactose, microcrystalline cellulose
PH302, crospovidone, silica mixing 30min, mixed frequency 30Hz add magnesium stearate, mix 5min, are pressing
Power 80N lower sheeting, obtains label；
Film coating pre-mix dose is slowly added in water, it is stirring while adding, high speed shear 5min after 60min is stirred, is obtained
Coating solution；
2) take coating solution to label be coated, 35 DEG C of control sheet bed tempertaure, coating weight gain 2% to get.
Embodiment 3
Maleic acid Afatinib piece in the present embodiment is made of, label label and the film coating being wrapped in outside label
It is made of the raw material of following mass fraction: maleic acid Afatinib (in terms of Afatinib, 33 μm of partial size d90 <, moisture <
1.0%) 59.12 parts, 175 parts of anhydrous vertical compression lactose, 65 parts of microcrystalline cellulose PH302,33 parts of crospovidone, silica 2
Part, 4 parts of magnesium stearate；Film coating use following mass fraction raw material: 13.5 parts of film coating pre-mix dose, 169.1 parts of water.
The preparation method of maleic acid Afatinib piece, comprising the following steps:
1) each raw material is accurately taken according to mass fraction, first by maleic acid Afatinib, anhydrous vertical compression lactose, microcrystalline cellulose
PH302, crospovidone, silica mixing 25min, mixed frequency 30Hz add magnesium stearate, mix 8min, are pressing
Power 120N lower sheeting, obtains label；
Film coating pre-mix dose is slowly added in water, it is stirring while adding, high speed shear 5min after 60min is stirred, is obtained
Coating solution；
2) take coating solution to label be coated, 45 DEG C of control sheet bed tempertaure, coating weight gain 4% to get.
Embodiment 4
Maleic acid Afatinib piece in the present embodiment is made of, label label and the film coating being wrapped in outside label
It is made (1000, Afatinib 40mg/ piece) of the raw material of following quality: maleic acid Afatinib (in terms of Afatinib, partial size
33 μm of d90 <, moisture < 1.0%) 59.12g, anhydrous vertical compression lactose 175.0g, microcrystalline cellulose PH302 65.0g, it is crosslinked poly-
Tie up ketone 33.0g, silica 2.0g, magnesium stearate 4.0g；Film coating uses the raw material (1000) of following quality: 13.5g,
Water 169.1g.
The preparation method of maleic acid Afatinib piece, comprising the following steps:
1) bulk pharmaceutical chemicals moisture and size controlling:
Moisture: without equivalent moisture when measuring the moisture of maleic acid Afatinib as 0.35% (< 1.0%), therefore feeding intake；
Partial size: maleic acid Afatinib is crushed, and controls 33 μm of partial size d90 <；
2) it mixes:
Weigh the maleic acid Afatinib of recipe quantity, anhydrous vertical compression lactose, microcrystalline cellulose PH302, crospovidone and
Silica, and place it in mixing machine, suitable agate ball is added, 25min is mixed at frequency 30Hz, detects mixed powder
The angle of repose at end is 37 °, grain density 0.571g/cm3, mobility is preferable, and uniformity of dosage units is qualified, and RSD is 1.7% (<
3%)；
3) total mix: the magnesium stearate for weighing recipe quantity is added in above-mentioned mixed-powder, in mixing in three-dimensional motion mixer
10min, mixed frequency 30Hz, the uniformity of dosage units for detecting mixed-powder is qualified, RSD 0.9%；
4) tabletting: taking above-mentioned mixed-powder Φ 10mm scrobicula stamping, and pressure 90N is arranged, obtains label；
Obtained sheet chip face is smooth, glossy, friability 0.5, uniformity of dosage units qualification (RSD 1.3%), 5,10,15,
20, the accumulation dissolution rate (pH4.0 citric acid/phosphate buffer, reference fluid, revolving speed 50rpm) of 30min is followed successively by
62.4%, 94.3%, 98.7%, 98.3%, 98.6%；
5) be coated: the film coating pre-mix dose for weighing recipe quantity is slowly added into the water of recipe quantity, stirring while adding, stirring
Shearing 5min is told after 60min, obtains coating solution；
In coating pan BY300 with coating solution to label be coated, 40 DEG C of control sheet bed tempertaure, coating weight gain 3% to get；
Gained tablet clothing film is smooth, without adhesion, 5,10,15,20, the accumulation dissolution rate of 30min be followed successively by 53.2%,
93.6%, 98.7%, 98.4%, 97.8%, 7~9min of disintegration time.
Embodiment 5
Maleic acid Afatinib piece in the present embodiment is made of, label label and the film coating being wrapped in outside label
It is made (1000, Afatinib 30mg/ piece) of the raw material of following quality: maleic acid Afatinib (in terms of Afatinib, partial size
33 μm of d90 <, moisture < 1.0%) 44.34g, anhydrous vertical compression lactose 131.25g, microcrystalline cellulose PH302 48.75g, crosslinking
Povidone 24.75g, silica 1 .5g, magnesium stearate 3.0g；Film coating uses the raw material (1000) of following quality:
10.1g, water 126.8g.
The preparation method of maleic acid Afatinib piece, comprising the following steps:
1) bulk pharmaceutical chemicals moisture and size controlling:
Moisture: without equivalent moisture when measuring the moisture of maleic acid Afatinib as 0.35% (< 1.0%), therefore feeding intake；
Partial size: maleic acid Afatinib is crushed, and controls 33 μm of partial size d90 <；
2) it mixes:
Weigh the maleic acid Afatinib of recipe quantity, anhydrous vertical compression lactose, microcrystalline cellulose PH302, crospovidone and
Silica, and place it in mixing machine, suitable agate ball is added, 20min is mixed at frequency 30Hz, detects mixed powder
The uniformity of dosage units at end is qualified, and RSD is 2% (< 3%)；
3) total mix: the magnesium stearate for weighing recipe quantity is added in above-mentioned mixed-powder, in mixing in three-dimensional motion mixer
5min, mixed frequency 30Hz, the uniformity of dosage units for detecting mixed-powder is qualified, RSD 1.3%；
4) tabletting: taking above-mentioned mixed-powder Φ 9mm scrobicula stamping, and pressure 100N is arranged, obtains label；
Obtained sheet chip face is smooth, glossy, friability 0.5, uniformity of dosage units qualification (RSD 1.6%), 5,10,15,
20, the accumulation dissolution rate (ibid) of 30min is followed successively by 65.7%, 91.5%, 95.8%, 97.6%, 98.3%；
5) be coated: the film coating pre-mix dose for weighing recipe quantity is slowly added into the water of recipe quantity, stirring while adding, stirring
Shearing 5min is told after 60min, obtains coating solution；
In coating pan BY300 with coating solution to label be coated, 35 DEG C of control sheet bed tempertaure, coating weight gain 4% to get；
Gained tablet clothing film is smooth, without adhesion, 5,10,15,20, the accumulation dissolution rate of 30min be followed successively by 52.1%,
91.5%, 95.4%, 98.6%, 99.1%, 7~9min of disintegration time.
Embodiment 6
Maleic acid Afatinib piece in the present embodiment is made of, label label and the film coating being wrapped in outside label
It is made (1000, Afatinib 20mg/ piece) of the raw material of following quality: maleic acid Afatinib (in terms of Afatinib, partial size
33 μm of d90 <, moisture < 1.0%) 29.56g, anhydrous vertical compression lactose 87.5g, microcrystalline cellulose PH302 32.5g, it is crosslinked poly- dimension
Ketone 16.5g, silica 1 .0g, magnesium stearate 2.0g；Film coating uses the raw material (1000) of following quality: 6.8g, water
84.5g。
The preparation method of maleic acid Afatinib piece, comprising the following steps:
1) bulk pharmaceutical chemicals moisture and size controlling:
Moisture: without equivalent moisture when measuring the moisture of maleic acid Afatinib as 0.35% (< 1.0%), therefore feeding intake；
Partial size: maleic acid Afatinib is crushed, and controls 33 μm of partial size d90 <；
2) it mixes:
Weigh the maleic acid Afatinib of recipe quantity, anhydrous vertical compression lactose, microcrystalline cellulose PH302, crospovidone and
Silica, and place it in mixing machine, suitable agate ball is added, 30min is mixed at frequency 30Hz, detects mixed powder
The uniformity of dosage units at end is qualified, and RSD is 1.1% (< 3%)；
3) total mix: the magnesium stearate for weighing recipe quantity is added in above-mentioned mixed-powder, in mixing in three-dimensional motion mixer
8min, mixed frequency 30Hz, the uniformity of dosage units for detecting mixed-powder is qualified, RSD 1.1%；
4) tabletting: taking above-mentioned mixed-powder Φ 8mm scrobicula stamping, and pressure 80N is arranged, obtains label；
Obtained sheet chip face is smooth, glossy, friability 0.6, uniformity of dosage units qualification (RSD 1.3%), 5,10,15,
20, the accumulation dissolution rate (ibid) of 30min is followed successively by 71.2%, 92.5%, 96.6%, 97.7%, 96.8%；
5) be coated: the film coating pre-mix dose for weighing recipe quantity is slowly added into the water of recipe quantity, stirring while adding, stirring
Shearing 5min is told after 60min, obtains coating solution；
In coating pan BY300 with coating solution to label be coated, 45 DEG C of control sheet bed tempertaure, coating weight gain 4% to get；
Gained tablet clothing film is smooth, without adhesion, 5,10,15,20, the accumulation dissolution rate of 30min be followed successively by 64.5%,
91.3%, 95.6%, 97.4%, 97.6%, 7~9min of disintegration time.
Maleic acid Afatinib is produced by Tianheng Medicinal Inst., Beijing in Examples 1 to 6, and anhydrous vertical compression lactose is by triumphant auspicious
Biochemical technology production, microcrystalline cellulose PH302 are produced by Japanese Asahib Kasei Chemicals Corportation, are handed over
Connection povidone is produced by BASF European Co., Ltd, and silica, magnesium stearate are produced by Huzhou Zhanwang Pharmaceutical Co., Ltd., thin
Film coating pre-mixing agent by Shanghai Colorcon Coating Technology Co., Ltd produce (Trade mark 295B680001).Mixing is adopted
With SYH10 three-dimensional motion mixer, produced by Changzhou Chuan Gan microwave dryer Co., Ltd；Tabletting is using ZPW rotation pressure
Piece machine (power 4kW) is produced by Chinese-foreign joint Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd., Shanghai；Coating uses BY300 sugar-coat
Pot, it is commercially available.
Test example
1) dissolution curve compares
BIBW 2992 are prepared (see in claim 7 referring to prescription in patent (notification number CN102056589B) and method
A,C).Measure 40mg dose tablets 5,10,15,20, the accumulation dissolution rate (ibid) of 30min be followed successively by 43.4%, 87.3%,
96.5%, default, 99.0%, 11~14min of disintegration time；Accumulation dissolution of the 20mg dose tablets in 5,10,15,20,30min
Degree is followed successively by 41.2%, 88.3%, 96.4%, 96.1%, 96.6%, 8~11min of disintegration time.
Example 4 and above-mentioned 40mg dosage Afatinib piece, test respectively its pH4.0 buffer (reference fluid),
Dissolution curve in pH6.8 buffer, 0.1mol/L HCl solution and water, as a result see the table below 1 and FIG. 1 to FIG. 4.
1 embodiment 4 of table and Afatinib piece accumulation dissolution results comparison in patent document
It can be seen that maleic acid Afatinib piece and 40mg dosage in patent document in embodiment 4 from table 1 and FIG. 1 to FIG. 4
BIBW 2992 in pH4.0 buffer, 0.1mol/L HCl solution and aqueous medium dissolve out consistency it is preferable, dissolve out 15min >
95%.Compared to this 3 kinds of media, the two dissolves out relatively slowly in pH6.8 buffer, and analysis reason is hydrogen in pH6.8 buffer
Sodium oxide molybdena reacts with Afatinib bulk pharmaceutical chemicals, forms new sodium salt, caused by causing bulk pharmaceutical chemicals solubility to reduce.
2) influence factor is tested
Example 4 and above-mentioned 40mg dosage Afatinib piece carry out influence factor experiment, influence factor and comparing result
It see the table below 2.
The related material result comparison of Afatinib piece influence factor in 2 embodiment 4 of table and patent document
From table 2 it can be seen that maleic acid Afatinib piece and 40mg dosage BIBW 2992 in patent document in embodiment 4
Degradation is serious under individual hot conditions for piece, but in embodiment 4 maleic acid Afatinib piece palliating degradation degree it is relatively small,
Total impurities are also smaller, therefore its quality is better than 40mg dosage BIBW 2992 in patent document.
3) screening of filler type and dosage
Prescription screening is carried out using uniformity of dosage units and dissolution rate as main indicator, label composition see the table below 3.
The composition of 3 prescription 1~3 of table
Maleic acid Afatinib piece is prepared according to method in prescription 1~3 and embodiment 4, detects the angle of repose of mixed-powder
36 °, 37 °, 37 ° are followed successively by, grain density is followed successively by 0.573,0.570,0.572g/cm3, mobility is preferable, and content is uniform
Degree testing result show, the average value of prescription 1~3 be followed successively by 98.3% (RSD 4.1%), 98.0% (RSD 3.3%),
97.0% (RSD 1.4%), the average value of total mix powder be followed successively by 98.8% (RSD 3.9%), 98.1% (RSD 3.4%),
97.9% (RSD 1.4%), the i.e. mixing uniformity of prescription 1 and prescription 2 poor (RSD value > 2%).With microcrystalline cellulose in prescription
The mixing uniformity of the reduction of dosage, material gradually increases, and analysis reason is caused by microcrystalline cellulose mobility of particle difference.Coating
Piece uniformity of dosage units testing result shows that the average value of prescription 1~3 is followed successively by 99.0% (RSD 3.6%), 99.0% (RSD
2.7%), 98.0% (RSD 1.1%), dissolution result see the table below 4 and Fig. 5.
4 prescription of table, 1~3 dissolution results
It can be seen that 40mg in the maleic acid Afatinib piece and patent document prepared using prescription 1~3 from table 4 and Fig. 5
Dosage BIBW 2992 are erosion type disintegration, but disintegration time is much larger than BIBW 2992.Prescription 1~3 is with crystallite fibre
The decline of element PH302 percentage in microcrystalline cellulose and milk-sugar mixture is tieed up, disintegration time also accordingly shortens, and dissolution adds
Fastly, analysis reason is that microcrystalline cellulose does not dissolve in dissolution medium, when containing large scale microcrystalline cellulose in prescription, accumulation
In dissolution rate bottom of a cup portion, the dynamics and intensity of stirring are not enough to be stirred, therefore dissolution is relatively low, in terms of another
Analysis, cellulose are corynebacterium particle, and plastic deformation is greater than elastic deformation when being under pressure, as microcrystalline cellulose PH302 exists
The increase of percentage in microcrystalline cellulose and milk-sugar mixture, piece under conditions of uniform pressure, get over by microcrystalline cellulose ratio
Big then piece hardness is bigger, and disintegration time also lengthens therewith, therefore dissolves out partially slow.
Known to comprehensive mixed-powder and the total mix content of powder uniformity, the uniformity of dosage units of tablet and dissolution results: micro-
In crystalline cellulose and milk-sugar mixture the percentage of microcrystalline cellulose to the mobility of powder mixture, the tablet content uniformity,
Tablet hardness and dissolution rate have a significant impact, and the percentage for increasing microcrystalline cellulose can increase the hardness of tablet, but can drop
The mobility of low powder material has a negative impact (RSD increase) to the uniformity of dosage units of tablet, at the same weaken preparation dissolution when
Stirring intensity.In order to balance the mobility of powder material and the hardness of tablet, the final amount for determining microcrystalline cellulose and lactose
For 65:175, the uniformity of material mixing can guarantee under the conditions of the ratio, while meeting the requirement of the mixed powder content uniformity.
4) investigation of disintegrating agent dosage
The more former product that grind of 3 disintegration time of prescription are long, dissolve out 15min < 80%, therefore intend increasing the dosage of disintegrating agent in prescription, after
Continuous to investigate, label composition see the table below 5.
The composition of 5 prescription 4~5 of table
Maleic acid Afatinib piece is prepared according to method in prescription 4~5 and embodiment 4, detects the angle of repose of mixed-powder
36 °, 37 ° are followed successively by, grain density is followed successively by 0.571,0.570g/cm3, mobility is preferable, uniformity of dosage units testing result
It has been shown that, the average value of prescription 1~3 are followed successively by 97.6% (RSD 1.5%), 97.8% (RSD 1.7%), and total mix powder is averaged
Value is followed successively by 97.5% (RSD 1.4%), 97.6% (RSD 1.4%) coating tablet uniformity of dosage units testing result is shown, prescription 1
~3 average value is followed successively by 98.2% (RSD 1.3%), 97.9% (RSD 1.5%), and dissolution result see the table below 6 and Fig. 6.
6 prescription of table, 4~5 dissolution results
It can be seen that 5 disintegration time of prescription is short compared with prescription 4, and prescription 5 increases to the dosage of disintegrating agent from table 6 and Fig. 6
After 33mg/ piece, disintegration time is better than BIBW 2992, and dissolves out 15min > 98%, belongs to Fast Stripping, it is ensured that drug
Absorption is not influenced by gastric emptying.
Claims (5)
1. maleic acid Afatinib piece, be made of label and the film coating being wrapped in outside label, it is characterised in that: label by with
The raw material of lower mass fraction is made: 57 ~ 61 parts of maleic acid Afatinib, 170 ~ 180 parts of Lactis Anhydrous, and microcrystalline cellulose 60 ~ 70
Part, 30 ~ 36 parts of crospovidone, silica 1 .5 ~ 2.5 part, 3 ~ 5 parts of magnesium stearate；The Lactis Anhydrous is anhydrous vertical compression cream
Sugar, granularity d90≤67 μm；The microcrystalline cellulose is PH302；
The maleic acid Afatinib piece is made by the method included the following steps:
1) each raw material is accurately taken according to mass fraction, it is first that maleic acid Afatinib, Lactis Anhydrous, microcrystalline cellulose, crosslinking is poly-
It is uniformly mixed to tie up ketone, silica, adds magnesium stearate and is uniformly mixed, tabletting obtains label；
Film coating pre-mix dose is added to the water, is uniformly mixed, obtains coating solution；
2) take coating solution to label be coated to get；
First and second mixing carries out in mixing machine in step 1), 25 ~ 35Hz of mixed frequency, mixes 20 ~ 30min for the first time,
Second of 5 ~ 10min of mixing；Tabletting carries out in tablet press machine in step 1), power 4kW, 50 ~ 120N of pressure；It is coated in step 2
It is carried out in seed-coating machine, 35 ~ 45 DEG C of piece bed tempertaure.
2. maleic acid Afatinib piece according to claim 1, it is characterised in that: 59.12 parts of maleic acid Afatinib, nothing
175 parts, 65 parts of microcrystalline cellulose, 33 parts of crospovidone, 2 parts of silica, 4 parts of magnesium stearate of water and milk sugar.
3. maleic acid Afatinib piece according to claim 1, it is characterised in that: film coating uses following mass fraction
Raw material: 12 ~ 15 parts of film coating pre-mix dose, 165 ~ 175 parts of water, coating weight gain be label quality 2% ~ 6%.
4. maleic acid Afatinib piece according to claim 3, it is characterised in that: film coating uses following mass fraction
Raw material: 13.5 parts of film coating pre-mix dose, 169.1 parts of water；Coating weight gain 2% ~ 4%.
5. the preparation method of maleic acid Afatinib piece as described in any one of claim 1 ~ 4, it is characterised in that: including following
Step:
1) each raw material is accurately taken according to mass fraction, it is first that maleic acid Afatinib, Lactis Anhydrous, microcrystalline cellulose, crosslinking is poly-
It is uniformly mixed to tie up ketone, silica, adds magnesium stearate and is uniformly mixed, tabletting obtains label；
Film coating pre-mix dose is added to the water, is uniformly mixed, obtains coating solution；
2) take coating solution to label be coated to get；
First and second mixing carries out in mixing machine in step 1), 25 ~ 35Hz of mixed frequency, mixes 20 ~ 30min for the first time,
Second of 5 ~ 10min of mixing；Tabletting carries out in tablet press machine in step 1), power 4kW, 50 ~ 120N of pressure；It is coated in step 2
It is carried out in seed-coating machine, 35 ~ 45 DEG C of piece bed tempertaure.
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| CN106074427A (en) * | 2016-07-31 | 2016-11-09 | 合肥远志医药科技开发有限公司 | A kind of maleic acid Afatinib tablet and preparation method thereof |
| CN110833534B (en) * | 2018-08-15 | 2022-10-25 | 四川科伦药物研究院有限公司 | Afatinib maleate tablet and preparation method thereof |
| CN109528667A (en) * | 2018-12-19 | 2019-03-29 | 石家庄海瑞药物科技有限公司 | One kind is up to gram for Buddhist nun's pharmaceutical composition and preparation method thereof |
| CN113133977B (en) * | 2020-01-20 | 2024-03-15 | 鲁南制药集团股份有限公司 | Afatinib maleate tablet and preparation method thereof |
| CN114028369B (en) * | 2021-11-22 | 2023-06-13 | 常州市第四制药厂有限公司 | Amitriptyline hydrochloride preparation composition and preparation method thereof |
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| CN102056589A (en) * | 2008-06-06 | 2011-05-11 | 贝林格尔.英格海姆国际有限公司 | Solid pharmaceutical formulations comprising BIBW 2992 |
| CN105147614A (en) * | 2015-08-13 | 2015-12-16 | 河北神威药业有限公司 | Solid preparation containing BIBW 2992MA2 and preparation method thereof |
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| LT2451445T (en) * | 2009-07-06 | 2019-06-25 | Boehringer Ingelheim International Gmbh | Process for drying of bibw2992, of its salts and of solid pharmaceutical formulations comprising this active ingredient |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102056589A (en) * | 2008-06-06 | 2011-05-11 | 贝林格尔.英格海姆国际有限公司 | Solid pharmaceutical formulations comprising BIBW 2992 |
| CN105147614A (en) * | 2015-08-13 | 2015-12-16 | 河北神威药业有限公司 | Solid preparation containing BIBW 2992MA2 and preparation method thereof |
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