CN106511289A - Benzenesulfonicacid lapatinib tablets and preparing method thereof - Google Patents
Benzenesulfonicacid lapatinib tablets and preparing method thereof Download PDFInfo
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- CN106511289A CN106511289A CN201510575392.9A CN201510575392A CN106511289A CN 106511289 A CN106511289 A CN 106511289A CN 201510575392 A CN201510575392 A CN 201510575392A CN 106511289 A CN106511289 A CN 106511289A
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Abstract
The invention provides benzenesulfonicacid lapatinib tablets and a preparing method thereof. The tablets comprise benzenesulfonicacid lapatinib and pregelatinized starch. By introducing the hydrophilic pregelatinized starch, the tablets have good consistency in in-vitro dissolution behavior in a pH1.0 medium and a pH6.8 medium, heading formation and clustering phenomena are avoided in the dissolution process, and the tablets show a good dissolution effect and good dissolution consistency.
Description
Technical field
The present invention relates to technical field of medicine, in particular it relates to Lapatinib Ditosylate Tablets agent and preparation method thereof.
Background technology
Toluenesulfonic acid Lapatinib (lapatinib) be by the breast carcinoma targeted therapy new drug of the researched and developed manufacture of GlaxoSmithKline PLC, in
On March 13rd, 2007 is by the checked and approved listing of Food and Drug Administration.The indication of approval is and Capecitabine at present
(Capecitabine) combined treatment late period or transitivity breast carcinoma, and patients with mastocarcinoma must first pass through other First Line medicines
Treatment.Its trade name Tykerb in the U.S., on December 14th, 2007, European drug administration (EMEA) approval
Listing of the toluenesulfonic acid Lapatinib in Europe, trade name Tyverb.Toluenesulfonic acid Lapatinib is not also in China at present
City, it is high as import drug price.At present, in anti-tumor small molecular targeted drug imatinib, Erlotinib, relax
Buddhist nun is for the master that Buddhist nun, gefitinib, Sorafenib, Dasatinib, toluenesulfonic acid Lapatinib and AMN107 have been in clinic
Want kind.
However, current toluenesulfonic acid Lapatinib preparation still has much room for improvement.
The content of the invention
It is contemplated that at least solving one of technical problem in correlation technique to a certain extent.For this purpose, one of the present invention
Purpose is to propose that a kind of result of extraction is good or the Lapatinib Ditosylate Tablets agent of dissolution good stability.
The present invention is completed based on the following discovery of inventor：
Chinese patent CN200680021941 discloses a kind of plain piece compositionss, comprising：N- { the chloro- 4- of 3- [(3- luorobenzyls) oxygen
Base] phenyl } -6- [5- ({ [2- (mesyl) ethyl] amino } methyl) -2- furyls] -4- quinazoline amine xylenesulfonates
Monohydrate (i.e. toluenesulfonic acid Lapatinib), the scope for existing are 42-48% weight；Polyvidone, the scope for existing are 5.5-7.5%
Weight；Explotab, the scope for existing are 3.5-5.5% weight；Microcrystalline Cellulose, the scope for existing are 40-46% weights
Amount；And magnesium stearate, the scope for existing is 0.8-1.2% weight, and the scope of coating is 2.5～3.5% weight (i.e. coating
Weightening 2.5～3.5%).It is found through experiments, the toluenesulfonic acid prepared by described in Chinese patent CN200680021941 draws
Handkerchief tends towards stability for Buddhist nun's tablet release profiles in pH1.0 media, but the release profiles in pH6.8 media are presented inconsistent
Phenomenon, and there is conglomeration balling in process in leaching, the above results illustrate that its In Vitro Dissolution behavior is unstable, in medium meta-alkali
Property in the environment of, can conglomeration balling-up, cause final dissolution result to be affected.For the problems referred to above, inventor has carried out depth
Enter research, through many experiments and repeatedly verify, inventors be surprised to learn that the introducing in Lapatinib Ditosylate Tablets agent prescription
Hydrophilicity condiment pregelatinized Starch can be effectively improved its In Vitro Dissolution behavior, it is to avoid conglomeration balling, show good molten
Go out stability, concordance and result of extraction.
In view of this, according to the first aspect of the invention, the invention provides a kind of Lapatinib Ditosylate Tablets agent.Root
According to embodiments of the invention, the Lapatinib Ditosylate Tablets agent includes：Toluenesulfonic acid Lapatinib；And pregelatinized Starch.
Inventor has found that, due to introducing hydrophilicity condiment pregelatinized Starch, the Lapatinib Ditosylate Tablets agent is in pH1.0 media
Preferable concordance is respectively provided with the In Vitro Dissolution behavior in pH6.8 media, and process in leaching is not in the agglomerating phenomenon of balling,
Show good result of extraction, dissolution stability and concordance.
Embodiments in accordance with the present invention, based on 80 Lapatinib Ditosylate Tablets agent, the use of toluenesulfonic acid Lapatinib
Measure as 30～35g, the consumption of pregelatinized Starch is 4～8g.In the proportion, Lapatinib Ditosylate Tablets agent performance
Go out the dissolution stability and concordance better than other ratios, if the content of pregelatinized Starch is too low, toluenesulfonic acid draws handkerchief to replace
Buddhist nun's tablet In Vitro Dissolution behavior congruence is undesirable, conglomeration balling occurs, if in advance in pH6.8 media during dissolution
The too high levels of gelling starch, then dissolution rate is too fast.
Embodiments in accordance with the present invention, Lapatinib Ditosylate Tablets agent include disintegrating agent, and are based on 80 toluene sulphurs
Sour Lapatinib tablet, the consumption of disintegrating agent is 0.001～0.8g.Inventors be surprised to learn that, by introducing pregelatinized Starch,
The relatively low dissolution rate and result of extraction for remaining able to ensure Lapatinib Ditosylate Tablets agent of disintegrant content, effectively can subtract
Few disintegrating agent consumption, reduces cost.
Embodiments in accordance with the present invention, disintegrating agent can be selected from carboxymethyl starch sodium, Croscarmellose Sodium, crosslinking
At least one in polyvidone, under preferable case, disintegrating agent is carboxymethyl starch sodium.Using above-mentioned disintegrating agent, can be effective
Promote the infiltration and Lapatinib Ditosylate Tablets agent of moisture in the dispersion of dissolution medium mesostroma, and do not interfere with toluene
The mobility and compressibility of sulfonic acid Lapatinib tablet.
Embodiments in accordance with the present invention, the Lapatinib Ditosylate Tablets agent include：Plain piece, the plain piece contain the first
Benzenesulfonic acid Lapatinib and the pregelatinized Starch；And film-coat, the film-coat wraps up the plain piece.Inventor's discovery,
By plain piece surface formed film-coat, and coating weight gain be 3.6-4.5% when, can effectively adjust toluenesulfonic acid Lapatinib
The rate of release of tablet so as to preferable In Vitro Dissolution behavior, while, additionally it is possible to so that Lapatinib Ditosylate Tablets
Agent has good outward appearance and performance of preferably guaranteeing the quality.
Embodiments in accordance with the present invention, in Lapatinib Ditosylate Tablets agent, based on the gross mass of plain piece, the matter of film-coat
Amount fraction can be 3.6～4.5% (i.e. coating weight gain is 3.6-4.5% weight).Under preferable case, based on the gross mass of plain piece,
The mass fraction of film-coat can be for 4.0～4.5% (i.e. coating weight gain be 4.0-4.5% weight) thus, and toluenesulfonic acid draws handkerchief to replace
Buddhist nun's tablet has optimal rate of release, and preferable In Vitro Dissolution behavior is conducive to the performance of drug effect.
And, the present inventor is found surprisingly that, when coating weight gain grinds the 2.5-3.5% of prescription from original, is adjusted to of the present invention
After the 3.6-4.5% of prescription, hence it is evident that improve Lapatinib Ditosylate Tablets agent fast problem of disintegrate in pH1.0 dissolution mediums,
Solve the problems, such as that dissolution terminal is unstable in pH6.8 dissolution mediums again, effectively alleviate hydrophobic ingredient excessively balling-up
Technical problem.
Embodiments in accordance with the present invention, Lapatinib Ditosylate Tablets agent can further include：Diluent, binding agent,
And lubricant.Wherein, diluent can be at least one in Lactose, Mannitol, Microcrystalline Cellulose, starch, excellent
Elect Microcrystalline Cellulose as；Binding agent can be selected from Povidone K 30, hydroxypropyl cellulose, starch, low viscosity hydroxypropyl first
At least one in base cellulose, preferably Povidone K 30；Lubricant can be selected from stearyl fumarate, magnesium stearate,
At least one in tristerin, preferably magnesium stearate.By using above-mentioned diluent, binding agent, and lubricant,
The dispersion of principal agent toluenesulfonic acid Lapatinib can be conducive to, while making it have good compressibility and mobility, be conducive to
Molding, and can further improve dissolution concordance and the result of extraction of Lapatinib Ditosylate Tablets agent.
Embodiments in accordance with the present invention, based on 80 Lapatinib Ditosylate Tablets agent, the consumption of diluent can be
25～35g, the consumption of binding agent can be 2.5～3.0g, and the consumption of lubricant can be 0.5～1.0g.Inventor's discovery,
In the proportion, there is good compressibility and mobility, principal agent toluenesulfonic acid to draw handkerchief to replace for Lapatinib Ditosylate Tablets agent
Buddhist nun is uniformly dispersed in substrate, it is easy to molding, while having suitable dissolution rate and dissolution concordance.
Embodiments in accordance with the present invention, based on 80 Lapatinib Ditosylate Tablets agent, Lapatinib Ditosylate Tablets agent
Can contain：Toluenesulfonic acid 30～35g of Lapatinib；27.6～32g of Microcrystalline Cellulose；0.001～0.8g of carboxymethyl starch sodium；
4～8g of pregelatinized Starch；2.5～3.0g of Povidone K 30；0.5～1.0g of magnesium stearate.Toluenesulfonic acid with the proportioning draws
Handkerchief has good dissolution concordance and suitable dissolution rate for Buddhist nun's tablet, and releases in pH1.0 media and pH6.8 media
Put curve to tend towards stability, be not in conglomeration balling, significantly improve the external molten of Lapatinib Ditosylate Tablets agent
Go on a journey and be.
In the second aspect of the invention, present invention also offers preparing the side of foregoing Lapatinib Ditosylate Tablets agent
Method.Embodiments in accordance with the present invention, the method include：By toluenesulfonic acid Lapatinib, diluent, disintegrating agent and pregelatinated
Starch mixes, and to obtain the first mixture, first mixture and binding agent is mixed, to obtain the second mixture,
The second resulting mixture is carried out into wet granulation, wet granular is obtained；The wet granular is dried and granulate successively,
Obtain dry particl；By the dry particl and mix lubricant, to obtain the 3rd mixture, by the 3rd resulting mixture
Tabletting is carried out, toluenesulfonic acid Lapatinib plain piece is obtained；The toluenesulfonic acid Lapatinib plain piece is coated, institute is obtained
State Lapatinib Ditosylate Tablets agent.Embodiments in accordance with the present invention, during tabletting, Hardness Control is in 10～15kg.
Using the method, foregoing Lapatinib Ditosylate Tablets agent can be fast and effeciently prepared, it is simple to operate,
It is easily controlled, is adapted to industrialized production.In addition, having by the Lapatinib Ditosylate Tablets agent that the method is prepared front
All feature and advantage of the Lapatinib Ditosylate Tablets agent described in face, this is no longer going to repeat them.
Embodiments in accordance with the present invention, it is the toluenesulfonic acid Lapatinib being related in the method for preparing toluenesulfonic acid Lapatinib, dilute
Release agent, disintegrating agent, pregelatinized Starch, binding agent and lubricant with described in foregoing Lapatinib Ditosylate Tablets agent
It is consistent, will not be described in detail herein.
Embodiments in accordance with the present invention, the method for preparing foregoing Lapatinib Ditosylate Tablets agent can include：By institute
State toluenesulfonic acid Lapatinib, diluent, disintegrating agent and pregelatinized Starch to cross 60 mesh sieves respectively and then mix, to obtain the
One mixture, first mixture is added in granulation pot, stirring and cutter 5 minutes is opened, then by the bonding
During agent adds the granulation pot, unlatching mixes and stirs cutter 1 minute, to obtain the second mixture, and with 20 eye mesh screens by institute
The second mixture for obtaining carries out wet granulation, obtains the wet granular；The wet granular is placed in stainless steel pallet, in
2h is placed in 60 DEG C of baking ovens, and the wet granular after drying is crossed into 20 mesh sieve granulate, obtain the dry particl；By described dry
The 3rd resulting mixture to obtain the 3rd mixture, and is carried out tabletting, obtains the first by grain and mix lubricant
Benzenesulfonic acid Lapatinib plain piece, wherein, tabletting hardness is 10～15kg；The toluenesulfonic acid Lapatinib plain piece is wrapped
Clothing, preferably coating weight gain 3.6%～4.5%, coating weight gain are 4.0%～4.5%, obtain the Lapatinib Ditosylate Tablets agent,
Wherein, piece bed tempertaure is 40 DEG C, and coating pan inlet temperature is 65 DEG C.
Lapatinib Ditosylate Tablets agent according to embodiments of the present invention, by introducing pregelatinized Starch, is somebody's turn to do ensureing which meets
On the premise of tablet standard is required, can successfully improve the stability and concordance of its release profiles in meta-alkalescence medium,
The consumption of disintegrating agent can also be effectively reduced, while so that Lapatinib Ditosylate Tablets agent has suitable rate of release, and
Which is not affected about the content of material.
Toluenesulfonic acid as obtained by preparing using Lapatinib Ditosylate Tablets agent of the present invention and preparation method thereof draws handkerchief to replace
The product of Buddhist nun's piece, which grinds Lapatinib Ditosylate Tablets agent about material pattern with the original of import and mutually compares, and inventor has found,
The preparation impurity of Lapatinib Ditosylate Tablets of the present invention is better than former triturate, and by drug influence factor
Investigate, it was demonstrated that add a hydrophilicity condiment not cause the relevant content of material of this preparation to raise in the present invention.
Beneficial effects of the present invention are embodied in：
(1) present invention effectively prevent the hydrophobic knot in the molten process in leaching of preparation due to introducing hydrophilic pregelatinized Starch
Group.In Vitro Dissolution behavior of the Lapatinib Ditosylate Tablets agent in pH1.0 media and pH6.8 media is respectively provided with preferably
Concordance, and process in leaching is not in the agglomerating phenomenon of balling, show good result of extraction, dissolution stability with it is consistent
Property, significantly improve the In Vitro Dissolution behavior of Lapatinib Ditosylate Tablets agent.
(2) by introducing pregelatinized Starch, disintegrant content is relatively low to be remained able to ensure the molten of Lapatinib Ditosylate Tablets agent
Go out speed and result of extraction, can effectively reduce disintegrating agent consumption, reduces cost.
(3) by introducing pregelatinized Starch, on the premise of ensureing which meets tablet standard requirement, which can successfully be improved
The stability of the release profiles in meta-alkalescence medium, can also effectively reduce the consumption of disintegrating agent, while so that toluenesulfonic acid
Lapatinib tablet has suitable rate of release, and does not affect which about the content of material.
(4) present invention works as the 2.5-3.5% that coating weight gain grinds prescription from original, after being adjusted to the 3.6-4.5% of prescription of the present invention,
Lapatinib Ditosylate Tablets agent fast problem of disintegrate in pH1.0 dissolution mediums is significantly improved, pH6.8 is solved again molten
Go out the unstable problem of dissolution terminal in medium, effectively alleviate the hydrophobic ingredient excessively technical problem of balling-up.Thus,
Lapatinib Ditosylate Tablets agent has optimal rate of release, and preferable In Vitro Dissolution behavior is conducive to the performance of drug effect.
(5) toluenesulfonic acid as obtained by preparing using Lapatinib Ditosylate Tablets agent of the present invention and preparation method thereof draws
Product of the handkerchief for Buddhist nun's piece, which grinds Lapatinib Ditosylate Tablets agent about material pattern with the original of import and mutually compares, it has been found that
The preparation impurity of Lapatinib Ditosylate Tablets of the present invention is better than original and grinds, and by the investigation to drug influence factor,
Demonstrate the relevant content of material for adding a hydrophilicity condiment not cause this preparation in the present invention to raise.
Description of the drawings
Dissolution of the Lapatinib Ditosylate Tablets agent that Fig. 1 is prepared in showing embodiment 1 in pH1.0 dissolution mediums
Curve；
Dissolution of the Lapatinib Ditosylate Tablets agent that Fig. 2 is prepared in showing embodiment 1 in pH6.8 dissolution mediums
Curve；
Fig. 3 shows that the Lapatinib Ditosylate Tablets agent prepared according to prescription 1-4 is molten in pH1.0 dissolution mediums
Go out curve；
Fig. 4 shows that the Lapatinib Ditosylate Tablets agent prepared according to prescription 1-4 is molten in pH6.8 dissolution mediums
Go out curve；
Fig. 5 shows that the Lapatinib Ditosylate Tablets agent prepared according to prescription 5-8 is molten in pH1.0 dissolution mediums
Go out curve；
Fig. 6 shows that the Lapatinib Ditosylate Tablets agent prepared according to prescription 5-8 is molten in pH6.8 dissolution mediums
Go out curve；
Fig. 7 shows that the Lapatinib Ditosylate Tablets agent prepared according to prescription 9-10 is molten in pH1.0 dissolution mediums
Go out curve；
Fig. 8 shows that the Lapatinib Ditosylate Tablets agent prepared according to prescription 9-10 is molten in pH6.8 dissolution mediums
Go out curve；
Fig. 9 shows the relevant content of material test chromatogram of the Lapatinib Ditosylate Tablets agent prepared according to prescription 9；
Figure 10 shows the relevant content of material test chromatograph of the Lapatinib Ditosylate Tablets agent prepared according to prescription 10
Figure；
Figure 11 shows that the relevant content of material of the Lapatinib Ditosylate Tablets agent prepared according to prescription in embodiment 1 is surveyed
Examination chromatogram.
Specific embodiment
Embodiments of the invention are described below in detail.The embodiments described below is exemplary, is only used for explaining the present invention,
And be not considered as limiting the invention.Unreceipted particular technique or condition in embodiment, according to document in the art
Described technology or condition are carried out according to product description.Agents useful for same or the unreceipted production firm person of instrument, are
Can by city available from conventional products.
The principal agent being related in example below is toluenesulfonic acid Lapatinib, and mass fraction is (not including thin film based on supplementary material
Clothing) gross mass calculate.
Embodiment 1：Original grinds Lapatinib Ditosylate Tablets agent dissolution study on the stability
F-139 prescriptions are prescription of the inventor according to Chinese patent CN200680021941, and its prescription is constituted and consumption
It is as follows：
Preparation process：
1. mix：The principal agent for weighing up, Microcrystalline Cellulose, carboxymethyl starch sodium are crossed 60 mesh sieves respectively according to recipe quantity,
Tentatively mixed in plastic bag；
2. binding agent is prepared：Mass fraction is 10% Povidone K 30 aqueous solution；
3. wet granulation：The biased sample obtained in step 1 is poured in granulation pot, stirring and cutter, mixing is opened
5min, then binding agent is poured into wherein, stirring and cutter 1min is then turned on, discharging is pelletized with 20 eye mesh screens；
4. drying oven：Wet granular is divided in stainless steel pallet, 2h in 60 DEG C of baking ovens, is placed, is taken out in the middle of determining
Body moisture and content, within control moisture 5%；
5. granulate：Dry particl crosses 20 mesh sieve granulate；
6. total mixed：In adding the granule after the magnesium stearate to granulate of recipe quantity, mix 1 minute；
7. tabletting：Theoretical piece weight is calculated according to content meter, Hardness Control is in 12kg during tabletting.
8. coating：40 DEG C of control sheet bed tempertaure, 65 DEG C of coating pan inlet temperature, coating weight gain 3%.Obtain final product toluene sulphur
Sour Lapatinib tablet, numbering are F-139 tablets.
Stripping curve is determined：
The F-139 tablets that investigation is prepared are in two media：Release in vitro behavior in pH1.0 and pH6.8, due to
The medicine is insoluble drug, can be to add cosolvent in media as well by regulation, through the effects, in every kind of medium
2% Tween 80 is added all as cosolvent.Release profiles assay method is：Paddle method, 900ml media, 37 DEG C of surveys
Fixed, what parallel assay determined F-139 tablet dissolutions twice, twice the results are shown in Table 1 and table 2 and Fig. 1 and Fig. 2, its
Middle F-139 (1) and F-139 (2) represent the stripping curve that parallel test twice is measured.
From the result of Fig. 1 and Fig. 2, the tablet for preparing (F-139), in pH1.0 media, release profiles become
In stable, but release profiles in the ph 6.8 media are presented inconsistent phenomenon, and can go out in process in leaching
Existing conglomeration balling-up, the above results show that its In Vitro Dissolution behavior is unstable, in the environment of medium meta-alkalescence, can conglomeration
Balling-up, causes final dissolution result to be affected.
Embodiment 2：The behavioral implications of hydrophilicity condiment p-methyl benzenesulfonic acid Lapatinib tablet In Vitro Dissolution is investigated
In this embodiment, inventor introduces hydrophilic in Lapatinib Ditosylate Tablets agent prescription 1- prescriptions 4 respectively
Adjuvant：Pregelatinized Starch, hydroxypropylcellulose, Lactose, Mannitol, to improve the body of Lapatinib Ditosylate Tablets agent
The concordance of outer dissolved corrosion, specifically, prepares Lapatinib Ditosylate Tablets agent according to following prescription 1-4, so respectively
The dissolution situation of the tablet for preparing is investigated afterwards.
Prescription 1：
Prescription 2：
Prescription 3：
Prescription 4：
Preparation method：
1 mixing：The principal agent for weighing up, Microcrystalline Cellulose, carboxymethyl starch sodium, hydrophilicity condiment are first crossed 60 mesh respectively
Sieve, is tentatively mixed in plastic bag；
2. binding agent is prepared：Mass fraction is 10% Povidone K 30 aqueous solution；
3. wet granulation：Biased sample obtained by step 1 is poured in granulation pot, stirring and cutter, mixing is opened
5min, then binding agent is poured into wherein, it is stirred for cutting and opens 1min, discharging is pelletized with 20 eye mesh screens；
4. drying oven：Wet granular is divided in stainless steel pallet, 2h is placed in 60 DEG C of baking oven punchings, is taken out in the middle of determining
Body moisture and content, within control moisture 5%；
5. granulate：Dry particl crosses 20 mesh sieve granulate；
6. total mixed：In adding the granule after the magnesium stearate to granulate of recipe quantity, mix 1 minute；
7. tabletting：Theoretical piece weight is calculated according to content meter, Hardness Control is in 12kg during tabletting.
8. coating：40 DEG C of control sheet bed tempertaure, 65 DEG C of coating pan inlet temperature, coating weight gain 3%.
Stripping curve is investigated：
The Lapatinib Ditosylate Tablets agent for preparing is determined in two media according to the method in embodiment 1：pH1.0
With in pH6.8 In Vitro Dissolution curve (because the medicine is insoluble drug, by regulation can be in media as well addition cosolvent,
Jing investigates the Tween 80 for determining that every kind of medium all adds 2%), testing result is shown in Table 1- tables 2 and Fig. 3-Fig. 4.
Table 1：PH1.0+2% Tween 80 media
| Dissolution | 5min | 10min | 15min | 20min | 30min | 60min |
| F-139(1) | 8.2 | 40.0 | 65.7 | 82.3 | 89.0 | 94.1 |
| F-139(2) | 7.3 | 38.1 | 66.5 | 79.2 | 89.0 | 93.9 |
| Prescription 1 | 6.4 | 29.2 | 46.3 | 55.1 | 60.3 | 64.0 |
| Prescription 2 | 20.2 | 62.2 | 76.1 | 81.1 | 87.7 | 93.6 |
| Prescription 3 | 12.7 | 45.3 | 56.6 | 61.3 | 69.8 | 78.0 |
| Prescription 4 | 4.8 | 27.4 | 49.7 | 63.8 | 75.0 | 85.8 |
Table 2：PH6.8+2% Tween 80 media
| Dissolution | 10min | 20min | 30min | 60min | 120min | 180min | 360min |
| F-139(1) | 35.3 | 55.3 | 60.4 | 64.3 | 66.8 | 69.6 | 74.6 |
| F-139(2) | 37.6 | 56 | 59.5 | 65.4 | 73 | 78.9 | 91.3 |
| Prescription 1 | 23.1 | 38.4 | 42.1 | 47.7 | 55.8 | 61.1 | 65.3 |
| Prescription 2 | 37.5 | 56.4 | 61.9 | 72.1 | 78 | 82.5 | 95 |
| Prescription 3 | 24.6 | 46.9 | 51.6 | 56.3 | 61 | 63.4 | 70.1 |
| Prescription 4 | 35.3 | 51 | 55.3 | 58.7 | 60.9 | 63.0 | 68.9 |
From the result of table 1, table 2, Fig. 3 and Fig. 4, the hydrophilicity condiment of prescription 2 elects pregelatinized Starch as to pH6.8
In medium, dissolution terminal improvement is optimal, therefore preferably introduces pregelatinized Starch in Lapatinib Ditosylate Tablets agent.
Embodiment 3：The impact of pregelatinized Starch and disintegrating agent consumption to dissolved corrosion
From the testing result in embodiment 2, after introducing pregelatinized Starch, Lapatinib tablet is solved molten in vitro
Go on a journey as inconsistent and process in leaching conglomeration balling-up problem, further to pregelatinized Starch and disintegrating agent in the embodiment
Consumption investigated.
Prescription 5：
Prescription 6：
Prescription 7：
Prescription 8：
Preparation method with embodiment 2, stripping curve detection method with embodiment 1, dissolution testing result be shown in Table 3, table 4,
Fig. 5 and Fig. 6.
Table 3：PH1.0+2% Tween 80 media
| Dissolution | 5min | 10min | 15min | 20min | 30min | 60min |
| F-139(1) | 8.2 | 40.0 | 65.7 | 82.3 | 89.0 | 94.1 |
| F-139(2) | 7.3 | 38.1 | 66.5 | 79.2 | 89.0 | 93.9 |
| Prescription 5 | 19.5 | 61.9 | 77.4 | 84.6 | 89.6 | 93.0 |
| Prescription 6 | 7.4 | 51.6 | 67.8 | 75.8 | 83.1 | 91.4 |
| Prescription 7 | 6.8 | 37.3 | 61.4 | 74.1 | 87.0 | 93.2 |
| Prescription 8 | 16.2 | 59.3 | 71.6 | 78.9 | 86.2 | 92.2 |
Table 4：PH6.8+2% Tween 80 media
| Dissolution | 10min | 20min | 30min | 60min | 120min | 180min | 360min |
| F-139(1) | 35.3 | 55.3 | 60.4 | 64.3 | 66.8 | 69.6 | 74.6 |
| F-139(2) | 37.6 | 56 | 59.5 | 65.4 | 73 | 78.9 | 91.3 |
| Prescription 5 | 37.6 | 56.0 | 59.5 | 65.4 | 73.0 | 78.9 | 91.3 |
| Prescription 6 | 23.7 | 53.4 | 62.4 | 69.1 | 73.7 | 79.0 | 84.7 |
| Prescription 7 | 22.7 | 49.5 | 57.5 | 65.0 | 74.7 | 80.6 | 91.7 |
| Prescription 8 | 23.5 | 50.2 | 57.1 | 66.4 | 75.7 | 83.5 | 90.8 |
From the result of table 3, table 4, Fig. 5 and Fig. 6, prescription 5, prescription 6 and the explanation regulation disintegrating agent of prescription 7
Dissolved corrosion of the amount p-methyl benzenesulfonic acid Lapatinib tablet of carboxymethylstach sodium in pH1.0 dissolution mediums has an impact, and collapses
It is few that the solution many dissolutions of agent can be faster than disintegrating agent, but dissolution rate is all relatively fast, even if the consumption of disintegrating agent drops to 0
Rate of release is still very fast；The consumption p-methyl benzenesulfonic acid Lapatinib tablet of disintegrator carboxymethylstarch sodium is in pH6.8 dissolutions
Dissolved corrosion in medium affects little.And comparing prescription 6 and prescription 8, the amount of pregelatinized Starch is right in above-mentioned change
The dissolution of two media affects all smaller.The above results illustrate, introduce pregelatinized Starch, can effectively reduce disintegrate
The consumption of agent, or even it is not added with disintegrating agent, it is also possible to meet disintegrate requirement.
Embodiment 4：The impact of coating weight gain p-methyl benzenesulfonic acid Lapatinib tablet dissolved corrosion
Prescription 9：
Preparation technology：
1 mixing：The principal agent for weighing up, Microcrystalline Cellulose, carboxymethyl starch sodium, pregelatinized Starch are first crossed 60 mesh respectively
Sieve, is tentatively mixed in plastic bag；
2. binding agent is prepared：10% Povidone K 30 aqueous solution；
3. wet granulation：1 step biased sample is poured in granulation pot, stirring and cutter are opened, mixes 5min, then
Binding agent is poured into wherein, cutting is stirred for and is opened 1min, discharging is pelletized with 20 eye mesh screens；
4. drying oven：Wet granular is divided in stainless steel pallet, 2h is placed in 60 DEG C of baking oven punchings, is taken out in the middle of determining
Body moisture and content, within control moisture 5%；
5. granulate：Dry particl crosses 20 mesh granulate；
6. total mixed：In adding the granule after the magnesium stearate to granulate of recipe quantity, mix 1 minute；
7. tabletting：Theoretical piece weight is calculated according to content meter, Hardness Control is in 13kg during tabletting.
8. coating：40 DEG C of control sheet bed tempertaure, 65 DEG C of coating pan inlet temperature, coating weight gain 3.6%.
Prescription 10：
Preparation technology：
1 mixing：The principal agent for weighing up, Microcrystalline Cellulose, carboxymethyl starch sodium, pregelatinized Starch are first crossed 60 mesh respectively
Sieve, is tentatively mixed in plastic bag；
2. binding agent is prepared：10% Povidone K 30 aqueous solution；
3. wet granulation：1 step biased sample is poured in granulation pot, stirring and cutter are opened, mixes 5min, then
Binding agent is poured into wherein, cutting is stirred for and is opened 1min, discharging is pelletized with 20 eye mesh screens；
4. drying oven：Wet granular is divided in stainless steel pallet, 2h is placed in 60 DEG C of baking oven punchings, is taken out in the middle of determining
Body moisture and content, within control moisture 5%；
5. granulate：Dry particl crosses 20 mesh granulate；
6. total mixed：In adding the granule after the magnesium stearate to granulate of recipe quantity, mix 1 minute；
7. tabletting：Theoretical piece weight is calculated according to content meter, Hardness Control is in 11kg during tabletting.
8. coating：40 DEG C of control sheet bed tempertaure, 65 DEG C of coating pan inlet temperature, coating weight gain 4.5%.
With embodiment 1, testing result is shown in Table 5, table 6, Fig. 7 and Fig. 8 to stripping curve detection method.
Table 5：PH1.0+2% Tween 80 media
| Dissolution | 5min | 10min | 15min | 20min | 30min | 60min |
| F-139(1) | 8.2 | 40.0 | 65.7 | 82.3 | 89.0 | 94.1 |
| F-139(2) | 7.3 | 38.1 | 66.5 | 79.2 | 89.0 | 93.9 |
| Prescription 9 | 10.4 | 39.1 | 66.2 | 78.4 | 88.7 | 94.7 |
| Prescription 10 | 11.4 | 43.7 | 71.4 | 83.1 | 90.0 | 95.3 |
Table 6：PH6.8+2% Tween 80 media
| Dissolution | 10min | 20min | 30min | 60min | 120min | 180min | 360min |
| F-139(1) | 35.3 | 55.3 | 60.4 | 64.3 | 66.8 | 69.6 | 74.6 |
| F-139(2) | 37.6 | 56 | 59.5 | 65.4 | 73 | 78.9 | 91.3 |
| Prescription 9 | 18.8 | 44.0 | 52.7 | 61.0 | 73.8 | 82.7 | 92.3 |
| Prescription 10 | 22.6 | 47.1 | 52.4 | 59.8 | 70.3 | 79.1 | 93.1 |
From the result of table 5, table 6, Fig. 7 and Fig. 8, coating weight gain increases so that Lapatinib Ditosylate Tablets agent
In pH1.0 dissolution mediums, dissolution rate reaches and grinds coherence request with original, while so that Lapatinib Ditosylate Tablets
Agent dissolution terminal in pH6.8 dissolution mediums is more stable.The present invention grinds the 2.5-3.5% of prescription when coating weight gain from original,
After being adjusted to the 3.6-4.5% of prescription of the present invention, hence it is evident that improve Lapatinib Ditosylate Tablets agent and be situated between in pH1.0 dissolutions
The fast problem of disintegrate in matter, in solving the problems, such as pH6.8 dissolution mediums again, dissolution terminal is unstable, effectively alleviates thin
Water constituent is excessive and the technical problem of balling-up.Thus illustrate, control bag increases weight in the range of 3.6%～4.5%, can make
Obtain Lapatinib Ditosylate Tablets agent and there is optimal dissolution rate, be conducive to the performance of drug effect.
Determine prescription of the present invention 9, and the Lapatinib Ditosylate Tablets agent for preparing of prescription 10 in it is relevant
Material and prescription being ground with the original described in embodiment 1 and being compared, prescription 9, prescription 10 and original grind toluenesulfonic acid drawing
Handkerchief replaces the HPLC collection of illustrative plates of Buddhist nun's tablet and its testing result to see Fig. 9-Figure 11 respectively.As a result show, introduce pregelatinized Starch
Afterwards, the toluenesulfonic acid as obtained by preparing using Lapatinib Ditosylate Tablets agent of the present invention and preparation method thereof draws handkerchief to replace
The product of Buddhist nun's piece, which grinds Lapatinib Ditosylate Tablets agent about material pattern with the original of import and mutually compares, and inventor has found,
The preparation impurity of Lapatinib Ditosylate Tablets of the present invention is better than former triturate.
Embodiment 5：The preparation of Lapatinib Ditosylate Tablets agent
Prescription 11：
Prescription 12：
Prescription 13：
Prescription 14：
Prescription 15：
Prescription 16：
Prescription 17：
Prescription 18：
Prescription 19：
Prescription 20：
With embodiment 4, difference is that the coating weight gain of prescription 11- prescriptions 20 is respectively 3.6%, 3.7% to preparation method,
3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, Hardness Control during tabletting respectively 10kg,
15kg、11kg、12kg、12kg、13kg、13kg、14kg、14kg、12kg。
Embodiment 6：Factors influencing
By the 20 prepared Lapatinib Ditosylate Tablets agent for obtaining of prescription 11- prescriptions in embodiment 5 respectively at intense light irradiation
Penetrate (LUX), humidity 92.50%, place 0 day, 5 days and 10 days under conditions of 60 degrees Celsius of temperature, then survey
Determine the relevant content of material in Lapatinib Ditosylate Tablets agent.Testing result is shown in Table 7.
Table 7：Relevant material testing result
As shown in Table 7, by the investigation to drug influence factor, it was demonstrated that add hydrophilic in the present invention
Adjuvant does not cause the relevant content of material of this preparation to raise, Lapatinib Ditosylate Tablets agent quality of the present invention
Stablize controllable, especially, when coating weight gain is 4.0～4.5%, the quality of the present invention is more excellent.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specific example ",
Or the description of " some examples " etc. means the specific features, structure, material or the feature bag that describe with reference to the embodiment or example
It is contained at least one embodiment or example of the present invention.In this manual, to the schematic representation of above-mentioned term necessarily
It is directed to identical embodiment or example.And, the specific features of description, structure, material or feature can be arbitrary
Combined in individual or multiple embodiments or example in an appropriate manner.Additionally, in the case of not conflicting, the skill of this area
The feature of the different embodiments or example described in this specification and different embodiments or example can be combined by art personnel
And combination.
Although embodiments of the invention have been shown and described above, it is to be understood that above-described embodiment be it is exemplary,
It is not considered as limiting the invention, one of ordinary skill in the art within the scope of the invention can be to above-described embodiment
It is changed, changes, replacing and modification.
Claims (10)
1. a kind of Lapatinib Ditosylate Tablets agent, it is characterised in that include：
Toluenesulfonic acid Lapatinib；And
Pregelatinized Starch.
2. Lapatinib Ditosylate Tablets agent according to claim 1, it is characterised in that based on 80 toluene
Sulfonic acid Lapatinib tablet, the consumption of the toluenesulfonic acid Lapatinib is 30～35g, and the consumption of the pregelatinized Starch is
4～8g.
3. Lapatinib Ditosylate Tablets agent according to claim 1, it is characterised in that include：
Disintegrating agent, and 80 Lapatinib Ditosylate Tablets agent are based on, the consumption of the disintegrating agent is 0.001～0.8g.
4. Lapatinib Ditosylate Tablets agent according to claim 3, it is characterised in that the disintegrating agent is selected from carboxylic
Methyl starch sodium, Croscarmellose Sodium, the preferably at least one in polyvinylpolypyrrolidone, carboxymethyl starch sodium.
5. Lapatinib Ditosylate Tablets agent according to claim 1, it is characterised in that include：
Plain piece, the plain piece contain the xylene monosulfonic acid toluenesulfonic acid Lapatinib and the pregelatinized Starch；And
Film-coat, the film-coat wrap up the plain piece.
6. Lapatinib Ditosylate Tablets agent according to claim 5, it is characterised in that the total matter based on the plain piece
Amount, the mass fraction of the film-coat is 3.6%～4.5%, preferably 4.0%～4.5%.
7. the Lapatinib Ditosylate Tablets agent according to any one of claim 1～6, it is characterised in that further wrap
Include：
Diluent, the diluent are at least one in Lactose, Mannitol, Microcrystalline Cellulose, starch, preferably
Microcrystalline Cellulose；
Binding agent, described adhesive are fine selected from Povidone K 30, hydroxypropyl cellulose, starch, low viscosity hydroxypropyl methyl
At least one in dimension element, preferably Povidone K 30；
Lubricant, the lubricant are at least one in stearyl fumarate, magnesium stearate, tristerin, excellent
Elect magnesium stearate as.
8. Lapatinib Ditosylate Tablets agent according to claim 7, it is characterised in that based on 80 toluene
Sulfonic acid Lapatinib tablet,
The consumption of the diluent is 25～35g,
The consumption of described adhesive is 2.5～3.0g,
The consumption of the lubricant is 0.5～1.0g.
9. Lapatinib Ditosylate Tablets agent according to claim 8, it is characterised in that based on 80 toluene
Sulfonic acid Lapatinib tablet, stating Lapatinib Ditosylate Tablets agent includes：
Toluenesulfonic acid 30～35g of Lapatinib；
27.6～32g of Microcrystalline Cellulose；
0.001～0.8g of carboxymethyl starch sodium；
4～8g of pregelatinized Starch；
2.5～3.0g of Povidone K 30；
00.5～1.0g of magnesium stearate.
10. a kind of method of the Lapatinib Ditosylate Tablets agent prepared any one of claim 1～9, its feature exist
In, including：
Xylene monosulfonic acid toluenesulfonic acid Lapatinib, diluent, disintegrating agent and pregelatinized Starch are mixed, the first mixing is obtained
Thing；
First mixture and binding agent are mixed, to obtain the second mixture, second mixture wet method is carried out into
Granulation, obtains wet granular；
The wet granular is dried and granulate successively, dry particl is obtained；
By the dry particl and mix lubricant, to obtain the 3rd mixture, the 3rd mixture is carried out into tabletting, is obtained
To plain piece；
The plain piece is coated, the Lapatinib Ditosylate Tablets agent is obtained,
Optionally, during the tabletting Hardness Control in 10～15kg, described bed tempertaure is 40 DEG C, coating pan inlet temperature is
65℃。
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