CN103705477A - Tablets containing erlotinib hydrochloride and preparation method thereof - Google Patents
Tablets containing erlotinib hydrochloride and preparation method thereof Download PDFInfo
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- CN103705477A CN103705477A CN201310731093.0A CN201310731093A CN103705477A CN 103705477 A CN103705477 A CN 103705477A CN 201310731093 A CN201310731093 A CN 201310731093A CN 103705477 A CN103705477 A CN 103705477A
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- erlotinid hydrochloride
- silicon dioxide
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- hydrochloride sheet
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Abstract
The invention discloses erlotinib hydrochloride tablets which contain silica which accounts for 2-12 percent of the total weight of the erlotinib hydrochloride tablets. The dissolution can be promoted. The invention also relates to a method for preparing the tablets. The process flow is simple, special requirements on the granularity of the raw materials are avoided, and the dissolution property of the product is good.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of tablet that contains erlotinid hydrochloride and preparation method.
Background technology
The chemical name of erlotinid hydrochloride: N-(3-acetylene phenyl)-[6,7-bis-(2-methoxy ethoxy)] quinazoline-4-amine hydrochlorate, English name: Erlotinib Hydrochloride, molecular formula: C
22h
23n
3o
4hCl, molecular weight: 429.90, No. CAS: 183319-69-9.Its structural formula is as follows:
Erlotinid hydrochloride belongs to EGFR tyrosine kinase inhibitor series antineoplastic medicament, its mechanism of action by blocking-up cell membrane inside EGFR tyrosine-kinase enzymatic structure phosphorylation, block the Information Conduction of cancerous cell, and then cause growth retardation and/or the cell death of cancerous cell, reach antitumor action.Erlotinib grinds by Japanese Astellas is former the earliest, and Switzerland Hoffmann-LaRoche obtains the authorization.Obtain respectively FDA and SFDA approval listing in November, 2004 and 2007, trade name: " Erlotinib ".Clinically mainly be applicable to previously to accept local late period after at least one chemotherapy regimen failure or the nonsmall-cell lung cancer (NSCLC) of transfer.Erlotinid hydrochloride is in the listing of a plurality of countries and regions at present.
Erlotinid hydrochloride is extremely micro-yellow crystal powder of white, atomic water-soluble, and preparation specification is relatively large, is 100mg, 150mg; Therefore how improving the dissolution of active component in preparation is puzzlement the art personnel's a difficult problem.In its Patent CN100506803C, the dissolubility of erlotinid hydrochloride different crystal forms is set forth, as follows:
The dissolubility of polymorphic A, B and E be in water or aqueous buffer solutions (pH1.0) 20 ℃ be issued to balance, after 20 minutes, measure, its dissolubility is as shown in the table:
| ? | Water | Water-containing buffering liquid (pH1.0) |
| Polymorphic E | 0.191％ | 0.011％ |
| Polymorphic A | 0.194％ | 0.017％ |
| Polymorph b | 0.098％ | 0.003％ |
For solving the stripping of active component in former triturate, in prescription, added sodium lauryl sulphate, and medicine has been carried out to sufficient micronization processes.By controlling the granularity D90 of erlotinid hydrochloride raw material, be less than 10 μ m and (have at least the particle diameter of more than 90% drug microparticles to be less than 10 μ m, conventionally can adopt laser particle analyzer to detect grain diameter), increase the surface area of medicine, improve dissolubility and the rate of dissolution of medicine, thereby guarantee the dissolution of medicine.In order to obtain the erlotinid hydrochloride that particle diameter is enough little, the mode of industrial common employing comminution by gas stream realizes, can not only obviously increase the production cost of medicine like this, also to Workshop Production, operation brings inconvenience simultaneously, more dust from flying for example, surface area increases and to cause electrostatic interaction stronger, give powder bang after clear out a gathering place, preparation produces (mixing homogeneity is poor, the easy sticking of tabletting process) etc. and all makes troubles.In side, add sodium lauryl sulphate elsewhere, sodium lauryl sulphate has certain harm to health: mucosa and upper respiratory tract are had to stimulation, eye and skin are had to stimulation.Can cause respiratory system anaphylactic reaction.Preparation dirt inevitably weighs in producing, married operation, produces dirt adverse effect all can to operator's health.
In patent CN103110597A, mention as simplifying production technology prescription and preparation method, inventor improves the dissolution rate of medicine by add surfactant (HLB value is between 10～20) in prescription.First preferably the surfactant of HLB value between 13～16, tween or polyoxyethylene hydrogenated Oleum Ricini are optimum, its consumption accounts for 0.25～5% of part by weight in prescription.As everyone knows, tween and polyoxyethylene hydrogenated Oleum Ricini character are not volatile compared with viscous liquid, and the pressed powders such as the liquid of 0.25～5% part by weight and active component, adjuvant are mixed, and are easy to cause mixing inhomogeneous, occur the phenomenons such as caking; The existence of volatile Auxiliary Liquid Material does not affect the process of dry granulation yet, occurs the phenomenon of sticky roller; For avoiding the phenomenon of the granule sticking in tabletting process after granulation, need to increase the consumption of lubricant magnesium stearate, magnesium stearate is hydrophobic auxiliary, its consumption increase can cause the stripping of medicine slack-off conventionally.Described in inventor, method, except the mixing apparatus of preparation is had relatively high expectations, also need be carried out special handling in the follow-up granulation of preparation, tabletting process, to guarantee carrying out smoothly of preparation production.
In sum, prior art can not very perfectly solve the stripping problem of the erlotinid hydrochloride solid preparation that is insoluble in water.
Summary of the invention
In view of the deficiencies in the prior art, the object of the invention is to by the physicochemical properties research to erlotinid hydrochloride and preparation prescription technique thereof deeply grope research, a kind of simple erlotinid hydrochloride tablet and preparation method thereof is provided.
The present invention finally finds through great many of experiments, adds after a certain amount of silicon dioxide in preparation prescription, can increase substantially the dissolution of active component in preparation, and the granularity of active component no longer affects stripping quantity and the speed of active component in preparation.By the prepared erlotinid hydrochloride tablet of method provided by the invention and commercial preparation (reference embodiment 2) contrast, through 40 ℃, accelerate 6 months, the demonstration of the room temperature study on the stability result of long-term 12 months, the present invention shows dissolution rate and stability faster compared with commercial preparation (reference embodiment 2), solve conventional commercial preparation dissolution after acceleration simultaneously and be subject to the impact of temperature and humidity, caused the incomplete and inhomogenous problem of active component stripping.Another the inventive method does not need active component to carry out special micronization processes, and preparation technology is simple, is applicable to suitability for industrialized production.
Concrete technical scheme of the present invention:
A tablet for hydrochloric Erlotinib, described tablet is grouped into by one-tenth such as erlotinid hydrochloride, silicon dioxide, adjuvants;
The invention described above tablet, the consumption optimizing prescriptions of wherein said silicon dioxide accounts for 2～12% of prescription gross weight ratio;
Further preferably, the consumption of silicon dioxide accounts for 5～8% of prescription gross weight ratio.
The invention described above tablet, the preferred medicine of described silicon dioxide adopts silicon dioxide (colloidal state), micropowder silica gel.
The invention described above tablet, described adjuvant comprises one or more in filler, binding agent, disintegrating agent, lubricant and coating materials.
Wherein said diluent is selected from one or more in microcrystalline Cellulose, lactose, pregelatinized Starch, mannitol, Icing Sugar, corn starch, calcium hydrogen phosphate, sucrose, dextrin, sodium lauryl sulphate etc.;
Wherein said disintegrating agent is selected from that carboxymethyl starch is received, one or more in cross-linked pvp, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, microcrystalline Cellulose, starch etc.;
Wherein said lubricant is selected from one or more in magnesium stearate, Pulvis Talci, micropowder silica gel, sodium lauryl sulphate, calcium stearate, aluminium-magnesium silicate, Glyceryl Behenate etc.;
Another object of the present invention is to provide a kind of method of utilizing above-mentioned formula preparation erlotinid hydrochloride tablet, comprises the steps:
(1), by the erlotinid hydrochloride of recipe quantity, silicon dioxide, all cross 80～200 mesh sieves, mix homogeneously;
(2) to adding lactose, microcrystalline Cellulose, sodium lauryl sulphate, the carboxymethyl starch of recipe quantity to receive in mixture, magnesium stearate, all cross 80～200 mesh sieves, mix homogeneously;
(3) mixture of previous step is prepared into granule by dry granulation technique, 12～40 mesh sieve granulate;
(4) granule adds after magnesium stearate mix homogeneously, and compacting in flakes;
(5) coating;
The specific embodiment
Now by following examples, further describe beneficial effect of the present invention, be interpreted as these embodiment only for the object of illustration, do not limit the scope of the invention, within the apparent change that those of ordinary skills make according to the present invention simultaneously and modification are also contained in the scope of the invention.
Reference embodiment 1
By prescription and technique in patent CN103110597A embodiment 2, carry out formulation samples preparation;
Preparation technology:
A, KolliphorRH40 and lactose are mixed;
B, the mixture that the material except magnesium stearate is obtained with steps A mix;
C, the material of step B gained is carried out to dry granulation;
D, add magnesium stearate to mix, and compacting in flakes;
E, the coating powder that adopts commodity to be called Opadry carry out coating to slice, thin piece.
Reference embodiment 2
By prescription and technique in patent CN103110597A reference embodiment 6, carry out formulation samples preparation;
Preparation technology:
A, the material except magnesium stearate is mixed to (erlotinid hydrochloride micronization processes, D90 is 5.7 μ m);
B, the material of steps A gained is carried out to dry granulation;
C, add magnesium stearate to mix, and compacting in flakes;
D, the coating powder that adopts commodity to be called Opadry carry out coating to slice, thin piece.
Embodiment 1 (1000)
A, by recipe quantity erlotinid hydrochloride (cross 80 mesh sieves) and silicon dioxide (crossing 100 mesh sieves), mixing;
B, in the mixture of steps A, add the lactose of crossing respectively 100 mesh sieves, microcrystalline Cellulose, carboxymethyl starch sodium, a small amount of magnesium stearate of recipe quantity, mix homogeneously;
C, the mixture that above-mentioned steps B is obtained carry out dry granulation, 12 order granulate;
D, by the granule of step C gained, mixes with the magnesium stearate of residue recipe quantity, and compacting is in blocks;
E, the coating powder that adopts commodity to be called Opadry carry out coating to slice, thin piece.
Embodiment 2 (1000)
A, by the micronized erlotinid hydrochloride of recipe quantity (cross 200 mesh sieves) and silicon dioxide (crossing 100 mesh sieves), mixing;
B, in the mixture of steps A, add the lactose of crossing respectively 100 mesh sieves, microcrystalline Cellulose, carboxymethyl starch sodium, a small amount of magnesium stearate of recipe quantity, mix homogeneously;
C, the mixture that above-mentioned steps B is obtained carry out dry granulation, 12 order granulate;
D, by the granule of step C gained, mixes with the magnesium stearate of residue recipe quantity, and compacting is in blocks;
E, the coating powder that adopts commodity to be called Opadry carry out coating to slice, thin piece.
Embodiment 3 (1000)
A, recipe quantity erlotinid hydrochloride and silicon dioxide are crossed respectively to 100 mesh sieves, mix;
B, in the mixture of steps A, add the lactose of crossing respectively 100 mesh sieves, microcrystalline Cellulose, carboxymethyl starch sodium, a small amount of magnesium stearate of recipe quantity, mix homogeneously;
C, the mixture that above-mentioned steps B is obtained carry out dry granulation, 30 order granulate;
D, by the granule of step C gained, mixes with the magnesium stearate of residue recipe quantity, and compacting is in blocks;
E, the coating powder that adopts commodity to be called Opadry carry out coating to slice, thin piece.
Embodiment 4 (1000)
A, recipe quantity erlotinid hydrochloride and silicon dioxide are crossed respectively to 200 mesh sieves, mix;
B, in the mixture of steps A, add the lactose of crossing respectively 100 mesh sieves, microcrystalline Cellulose, carboxymethyl starch sodium, a small amount of magnesium stearate of recipe quantity, mix homogeneously;
C, the mixture that above-mentioned steps B is obtained carry out dry granulation, 30 order granulate;
D, by the granule of step C gained, mixes with the magnesium stearate of residue recipe quantity, and compacting is in blocks;
E, the coating powder that adopts commodity to be called Opadry carry out coating to slice, thin piece.
Embodiment 5 (1000)
A, by the erlotinid hydrochloride of recipe quantity (cross 80 mesh sieves) and silicon dioxide (crossing 100 mesh sieves), mixing;
B, in the mixture of steps A, add the lactose of crossing respectively 100 mesh sieves, microcrystalline Cellulose, carboxymethyl starch sodium, a small amount of magnesium stearate of recipe quantity, mix homogeneously;
C, the mixture that above-mentioned steps B is obtained carry out dry granulation, 20 order granulate;
D, by the granule of step C gained, mixes with the magnesium stearate of residue recipe quantity, and compacting is in blocks;
E, the coating powder that adopts commodity to be called Opadry carry out coating to slice, thin piece.
Slice, thin piece to embodiment 1～6 with reference embodiment 1～2 preparation, carry out the detection of stripping curve, detection method is: Chinese Pharmacopoeia version dissolution method the second method slurry method in 2010, the hydrochloric acid solution that dissolution medium is pH1.0+1.0%SDS, volume is 1000ml, and rotating speed is 75 turn/min; Stripping curve the results are shown in Table 1.
Table 1 stripping curve
Comparing embodiment 1～5 and reference embodiment 2, add after appropriate silicon dioxide, and erlotinid hydrochloride is without micronization processes, and common sieving can reach good stripping result and dissolution rate faster.
Comparing embodiment 1 and embodiment 2, after adding the silicon dioxide of isodose, the slice, thin piece that the erlotinid hydrochloride of the common erlotinid hydrochloride sieving and micronization processes makes, stripping result and speed zero difference.Further illustrate and add after silicon dioxide, size is eliminated on the impact of stripping.
Comparing embodiment 1 is known with embodiment 5, adds after appropriate silicon dioxide in prescription, even not with disintegrating agent (embodiment 5), the dissolution rate of slice, thin piece can be not influenced yet, and stripping is very fast and complete.
Embodiment 1,5 and reference embodiment 1,2 are carried out to the stability test of 40 ℃ and room temperature condition and investigate, the results are shown in Table 2.
The stability test of table 240 ℃ and room temperature condition is investigated
[note] RSD is the relative standard deviation of 6 stripping data, its embodiment be the homogeneity of stripping result between sheet and sheet, the difference between the larger explanation sheet of numerical value and sheet is larger.
Study on the stability result shows, the tablet stability of embodiment 1,5 preparations and the homogeneity of dissolution are all better than reference embodiment 1 and 2.
Claims (8)
1. an erlotinid hydrochloride sheet, is grouped into by one-tenth such as erlotinid hydrochloride, silicon dioxide, adjuvants; The consumption that it is characterized in that silicon dioxide accounts for 2～12% of prescription gross weight ratio.
2. erlotinid hydrochloride sheet as claimed in claim 1, is characterized in that the consumption optimizing prescriptions of silicon dioxide accounts for 5～8% of gross weight ratio.
3. erlotinid hydrochloride sheet as claimed in claim 1, is characterized in that the preferred medicine of silicon dioxide adopts silicon dioxide (colloidal state), micropowder silica gel.
4. erlotinid hydrochloride sheet adjuvant as claimed in claim 1 comprises one or more in diluent, binding agent, disintegrating agent, lubricant and coating materials.
5. erlotinid hydrochloride sheet adjuvant diluent as claimed in claim 4 is selected from one or more in microcrystalline Cellulose, lactose, pregelatinized Starch, mannitol, Icing Sugar, corn starch, calcium hydrogen phosphate, sucrose, dextrin, sodium lauryl sulphate etc.
Erlotinid hydrochloride sheet adjuvant disintegrating agent as claimed in claim 4 be selected from that carboxymethyl starch is received, one or more in cross-linked pvp, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, microcrystalline Cellulose, starch etc.
7. erlotinid hydrochloride sheet adjuvant lubricant as claimed in claim 4 is selected from one or more in magnesium stearate, Pulvis Talci, micropowder silica gel, sodium lauryl sulphate, calcium stearate, aluminium-magnesium silicate, Glyceryl Behenate etc.
8. prepare the preparation method of erlotinid hydrochloride sheet as claimed in claim 1, its step is as follows:
(1) erlotinid hydrochloride of recipe quantity and silicon dioxide being crossed to 80～200 mesh sieves mixes;
(2) step (1) mixture further mixes after adding pharmaceutically acceptable additive;
(3) mixture of step (2) is prepared into granule by dry granulation technique;
(4) granule adds after mix lubricant, and compacting in flakes.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104288114A (en) * | 2014-10-27 | 2015-01-21 | 成都新恒创药业有限公司 | Erlotinib hydrochloride pharmaceutical composition without containing surfactant |
| CN105030705A (en) * | 2015-06-29 | 2015-11-11 | 孙丽华 | Anti-cancer drug erlotinib hydrochloride tablet and preparation method thereof |
| CN105362239A (en) * | 2014-09-01 | 2016-03-02 | 深圳信立泰药业股份有限公司 | Medicine composition containing erlotinib hydrochloride and preparation method of medicine composition |
| CN105769872A (en) * | 2014-12-25 | 2016-07-20 | 成都康弘药业集团股份有限公司 | Rapidly-dissolving mosapride citrate composition |
| CN109602715A (en) * | 2019-02-21 | 2019-04-12 | 江苏豪森药业集团有限公司 | Erlotinib Hydrochloride tablet and preparation method thereof |
| CN115812969A (en) * | 2021-12-13 | 2023-03-21 | 浙江康恩贝集团医疗保健品有限公司 | Sweet orange flavor B-family tablet and preparation method thereof |
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| CN101352424A (en) * | 2008-09-16 | 2009-01-28 | 天津市中央药业有限公司 | Cefdinir dispersible tablet and preparation method thereof |
| CN103110597A (en) * | 2013-02-02 | 2013-05-22 | 浙江华海药业股份有限公司 | Erlotinib hydrochloride tablets and preparation method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101352424A (en) * | 2008-09-16 | 2009-01-28 | 天津市中央药业有限公司 | Cefdinir dispersible tablet and preparation method thereof |
| CN103110597A (en) * | 2013-02-02 | 2013-05-22 | 浙江华海药业股份有限公司 | Erlotinib hydrochloride tablets and preparation method thereof |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105362239A (en) * | 2014-09-01 | 2016-03-02 | 深圳信立泰药业股份有限公司 | Medicine composition containing erlotinib hydrochloride and preparation method of medicine composition |
| CN104288114A (en) * | 2014-10-27 | 2015-01-21 | 成都新恒创药业有限公司 | Erlotinib hydrochloride pharmaceutical composition without containing surfactant |
| CN105769872A (en) * | 2014-12-25 | 2016-07-20 | 成都康弘药业集团股份有限公司 | Rapidly-dissolving mosapride citrate composition |
| CN105769872B (en) * | 2014-12-25 | 2019-05-03 | 成都康弘药业集团股份有限公司 | A kind of mosapride citrate composition of Fast Stripping |
| CN105030705A (en) * | 2015-06-29 | 2015-11-11 | 孙丽华 | Anti-cancer drug erlotinib hydrochloride tablet and preparation method thereof |
| CN105030705B (en) * | 2015-06-29 | 2018-02-13 | 青岛市肿瘤医院 | A kind of cancer therapy drug erlotinib Hydrochloride tablet and preparation method thereof |
| CN109602715A (en) * | 2019-02-21 | 2019-04-12 | 江苏豪森药业集团有限公司 | Erlotinib Hydrochloride tablet and preparation method thereof |
| CN115812969A (en) * | 2021-12-13 | 2023-03-21 | 浙江康恩贝集团医疗保健品有限公司 | Sweet orange flavor B-family tablet and preparation method thereof |
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Application publication date: 20140409 |