CN105267163A - Erlotinib hydrochloride tablet, and preparation method thereof - Google Patents
Erlotinib hydrochloride tablet, and preparation method thereof Download PDFInfo
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- CN105267163A CN105267163A CN201410272516.1A CN201410272516A CN105267163A CN 105267163 A CN105267163 A CN 105267163A CN 201410272516 A CN201410272516 A CN 201410272516A CN 105267163 A CN105267163 A CN 105267163A
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- erlotinid hydrochloride
- acidic materials
- erlotinid
- hydrochloride tablet
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Abstract
The invention discloses an erlotinib hydrochloride tablet, and a preparation method thereof. According to the preparation method, an acidic substance dispersion of erlotinib hydrochloride is prepared, and the erlotinib hydrochloride tablet is prepared via direct tabletting with pharmaceutically acceptable auxiliary materials. Compared with the prior art, the erlotinib hydrochloride tablet can be dissolved quickly in water, no surfactant is added, micronization treatment of the raw materials is not necessary, and the preparation method is simple.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of erlotinid hydrochloride tablet and preparation method thereof.
Background technology
Erlotinid hydrochloride sheet is a kind of small molecule anticancer drug that Genentech, Roche and Osi Pharm Inc. develop jointly, and commodity are called " Tarceva " (Erlotinib).In November, 2004 and, in JIUYUE, 2005 was examined by U.S. FDA and European EMEA, now in the listing of seven, 80, whole world country.It is a kind of EGF-R ELISA-tyrosine kinase (EGFR-TK) inhibitor, micromolecule oral drugs, the intracellular signaling pathways that it stops this receptor to mediate by suppressing the tyrosine kinase activity of human epidermal growth factor acceptor-1, stops growth of tumour cell thus and finally presents antitumor action.
The molecular formula of Erlotinib is C
22h
23n
3o
4, molecular weight 589.7, has following structural formula, and its medicinal forms is generally hydrochloride form.
In patent CN100506803C, the dissolubility of erlotinid hydrochloride is set forth.Crystal form A and crystal form B are in the solution of pH=1, and after balancing 20 minutes at 20 DEG C, dissolubility only has 0.017% and 0.003%.Erlotinid hydrochloride solubility property is not good enough, and therefore the former sheet that grinds needs in prescription, to add sodium lauryl sulphate, to improve dissolubility and the rate of dissolution of medicine.
But inventor finds in practice, after with the addition of SDS in prescription, still need to carry out micronization processes fully to medicine, effectively can promote drug-eluting.General, require that the granularity D90 of erlotinid hydrochloride raw material is less than 10 μm, namely have at least the particle diameter of the drug microparticles of more than 90% to be less than 10 μm, laser particle analyzer usually can be adopted to detect granularity.
In order to obtain enough thin erlotinid hydrochloride, industrially usually to realize in the mode of comminution by gas stream, this significantly can increase the production cost of medicine, add the exposure of medicine simultaneously, because erlotinid hydrochloride is antitumor drug, have larger toxic and side effects, this can have a negative impact to the healthy of direct labor.Superfine drug microparticles also can cause difficulty to commercial production, the dust from flying of such as larger electrostatic or more simultaneously, also can cause the adverse effects such as mixing efficiency difference.
CN103110597A discloses a kind of erlotinid hydrochloride sheet, containing the surfactant of HLB value between 10 to 20 as solubilizing agent, effectively can promote drug-eluting.But add liquid surfactant not only easy sticking, and harm may be brought to human body.Cause the difference of inside and outside physiological environment condition, In vitro-in vivo correlation is poor simultaneously.
CN103705477A discloses a kind of erlotinid hydrochloride sheet, containing the silicon dioxide accounting for prescription gross weight 2 ~ 12%, can promote stripping.But add Surfactant SDS equally.
In prior art, for solving Erlotinib poor solubility, the problem that stripping is slow, adopt micronization technology or add surfactant, consider the zest of surfactant to human body, and micropowder process raw material is to the injury of operator, preparation technology is to be improved, simultaneously when dissolution determination, dissolution medium selects 0.1mol/L hydrochloric acid, Surfactant SDS concentration is 1%, cause In vitro-in vivo correlation poor, sodium lauryl sulphate is there is not after all in human body, and because erlotinid hydrochloride dissolubility in acid is high, therefore select hydrochloric acid solution as dissolution medium, the stripping situation in other media can not be represented.
Summary of the invention
In view of the deficiencies in the prior art, inventor intends providing one not add surfactant, do not add surfactant and the leachable tablet of Erlotinib rapidly without the need to when micropowder process, stripping mensuration.
First inventor considers its dissolubility, finds under pH is the condition of 2, and dissolubility is 0.4mg/ml, corresponding to 500ml dissolution medium, i.e. and solubilized 200mg medicine.Therefore, inventor considers if by erlotinid hydrochloride and an acidic materials prepared composition prose style free from parallelism, and nature can improve its dissolubility.
Erlotinid hydrochloride is dissolved in the alcoholic solution of citric acid by inventor, and dry removal solvent, obtains erlotinid hydrochloride citric acid dispersion.Then by this dispersion and pharmaceutically conventional adjuvant tabletted.Prepared tablet stripping is rapid, achieves beyond thought effect.
Specifically, the present invention is realized by following technology:
The invention provides a kind of erlotinid hydrochloride tablet, comprise the dispersion that erlotinid hydrochloride and acidic materials are prepared from, and other pharmaceutically can adjuvant.
Described acidic materials be pharmaceutically can, nonvolatile acid, as one or more in fumaric acid, malic acid, tartaric acid, citric acid; Wherein, citric acid has outstanding technique effect.
Described dispersion is that erlotinid hydrochloride and acidic materials are dissolved in organic solvent, then steams and desolventizes and obtain.
Described organic solvent is preferably ethanol.
Described erlotinid hydrochloride and the weight ratio of acidic materials are 1:1-3.
Preferably, the weight ratio of erlotinid hydrochloride and acidic materials is 1:2.
Pharmaceutically can adjuvant be filler, disintegrating agent and lubricant.
Filler of the present invention is one or more in lactose, microcrystalline Cellulose, starch, pregelatinized Starch, mannitol; Disintegrating agent is one or more in carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone; Lubricant is one or more in magnesium stearate, Pulvis Talci, silicon dioxide.
The present invention also provides a kind of preparation method of above-mentioned erlotinid hydrochloride tablet, specific as follows:
Erlotinid hydrochloride, acidic materials are dissolved in organic solvent, then except desolventizing, obtains erlotinid hydrochloride acidic materials dispersion;
Dispersion is sieved, then even with disintegrating agent, filler, mix lubricant, tabletting.
Compared with prior art, the present invention's stripping in water is rapid, and need not add surfactant in preparation, do not need micronization processes raw material, preparation technology is simple.
Detailed description of the invention
Following examples further describe beneficial effect of the present invention, embodiment is only for the object of illustration, do not limit the scope of the invention, the simultaneously apparent change made according to the present invention of those of ordinary skill in the art and modification are also contained within the scope of the invention.In addition, distilling under reduced pressure of the present invention or drying under reduced pressure, be the ordinary skill in the art, be not particularly limited.
Embodiment 1
Preparation technology:
Take erlotinid hydrochloride, citric acid by above-mentioned recipe quantity, be dissolved in alcoholic solution, 50 DEG C of distilling under reduced pressure, except desolventizing, obtain erlotinid hydrochloride citric acid dispersion;
Dispersion is crossed 20 mesh sieves, then mix homogeneously with the microcrystalline Cellulose of recipe quantity, carboxymethyl starch sodium, magnesium stearate, tabletting.
Embodiment 2
Preparation technology:
Take erlotinid hydrochloride, citric acid by above-mentioned recipe quantity, be dissolved in alcoholic solution, 45 DEG C of distilling under reduced pressure, except desolventizing, obtain erlotinid hydrochloride citric acid dispersion;
Dispersion is crossed 18 mesh sieves, then mix homogeneously with the microcrystalline Cellulose of recipe quantity, lactose, polyvinylpolypyrrolidone, magnesium stearate, tabletting.
Embodiment 3
Preparation technology:
Take erlotinid hydrochloride, citric acid by above-mentioned recipe quantity, be dissolved in alcoholic solution, 45 DEG C of distilling under reduced pressure, except desolventizing, obtain erlotinid hydrochloride citric acid dispersion;
Dispersion is crossed 18 mesh sieves, then mix homogeneously with the microcrystalline Cellulose of recipe quantity, polyvinylpolypyrrolidone, magnesium stearate, tabletting.
Comparative example 1
Preparation technology:
Took erlotinid hydrochloride, the citric acid of 100 mesh sieves by above-mentioned recipe quantity, then mixed homogeneously with the microcrystalline Cellulose of recipe quantity, polyvinylpolypyrrolidone, magnesium stearate, tabletting.
Comparative example 2
Preparation technology:
Take erlotinid hydrochloride, tartaric acid by above-mentioned recipe quantity, be dissolved in alcoholic solution, 45 DEG C of distilling under reduced pressure, except desolventizing, obtain erlotinid hydrochloride tartaric acid dispersion;
Dispersion is crossed 18 mesh sieves, then mix homogeneously with the microcrystalline Cellulose of recipe quantity, polyvinylpolypyrrolidone, magnesium stearate, tabletting.
Comparative example 3
Preparation technology:
Take erlotinid hydrochloride, fumaric acid by above-mentioned recipe quantity, be dissolved in alcoholic solution, 45 DEG C of distilling under reduced pressure, except desolventizing, obtain erlotinid hydrochloride fumaric acid dispersion;
Dispersion is crossed 18 mesh sieves, then mix homogeneously with the microcrystalline Cellulose of recipe quantity, polyvinylpolypyrrolidone, magnesium stearate, tabletting.
Comparative example 4
Preparation technology:
By above-mentioned by the mistake 100 mesh sieve microcrystalline Cellulose of micronized for recipe quantity erlotinid hydrochloride (D90=8.5 micron) and recipe quantity, polyvinylpolypyrrolidone, sodium lauryl sulphate and magnesium stearate, mix homogeneously, tabletted.
Checking embodiment
Dissolution determination.Get this product, according to dissolution method, with aqueous solution 1000ml for dissolution medium, 75 turns per minute of rotating speed, measure through 15min, determined wavelength 352nm, limit is 75% of labelled amount.
Table embodiment measurement result
| Embodiment | 0 day result (%) | 40 DEG C, 75%RH accelerates result (%) after 6 months |
| Embodiment 1 | 99.6 | 99.8 |
| Embodiment 2 | 99.7 | 99.9 |
| Embodiment 3 | 99.8 | 100.1 |
| Comparative example 1 | 65.2 | 63.1 |
| Comparative example 2 | 53.1 | 50.2 |
| Comparative example 3 | 60.4 | 53.1 |
| Comparative example 4 | 42.1 | 40.6 |
As seen from the table, embodiment of the present invention 1-3, drug-eluting is rapid, the complete stripping of 15min; Comparative example 1, and do not prepare erlotinid hydrochloride citric acid dispersion, stripping is poor; Comparative example 2,3, and replace citric acid, weak effect with tartaric acid, fumaric acid, stripping is slow; Comparative example 4, and adopt prior art, in water, carry out dissolution determination, 15min is stripping 42% only.
Claims (10)
1. an erlotinid hydrochloride tablet, is characterized in that, comprises the dispersion that erlotinid hydrochloride and acidic materials are prepared from, and other pharmaceutically can adjuvant; Described acidic materials be pharmaceutically can, nonvolatile acid.
2. a kind of erlotinid hydrochloride tablet as claimed in claim 1, is characterized in that, described acidic materials are one or more in fumaric acid, malic acid, tartaric acid, citric acid.
3. a kind of erlotinid hydrochloride tablet as claimed in claim 1, is characterized in that, described acidic materials are citric acid.
4. a kind of erlotinid hydrochloride tablet as claimed in claim 1, is characterized in that, described dispersion, is that erlotinid hydrochloride and acidic materials are dissolved in organic solvent, then steams and desolventizes and obtain.
5. a kind of erlotinid hydrochloride tablet as claimed in claim 4, is characterized in that, described organic solvent is ethanol.
6. a kind of erlotinid hydrochloride tablet as claimed in claim 1, is characterized in that, described erlotinid hydrochloride and the weight ratio of acidic materials are 1:1-3.
7. a kind of erlotinid hydrochloride tablet as claimed in claim 1, is characterized in that, the weight ratio of erlotinid hydrochloride and acidic materials is 1:2.
8. a kind of erlotinid hydrochloride tablet as claimed in claim 1, is characterized in that, pharmaceutically can adjuvant be filler, disintegrating agent and lubricant.
9. a kind of erlotinid hydrochloride tablet as claimed in claim 8, is characterized in that, described filler is one or more in lactose, microcrystalline Cellulose, starch, pregelatinized Starch, mannitol; Disintegrating agent is one or more in carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone; Lubricant is one or more in magnesium stearate, Pulvis Talci, silicon dioxide.
10. a preparation method for the erlotinid hydrochloride tablet as described in the arbitrary claim of power 1-9, specific as follows: erlotinid hydrochloride, acidic materials to be dissolved in organic solvent, except desolventizing, obtains erlotinid hydrochloride acidic materials dispersion; Dispersion is sieved, then even with disintegrating agent, filler, mix lubricant, tabletting.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410272516.1A CN105267163A (en) | 2014-06-18 | 2014-06-18 | Erlotinib hydrochloride tablet, and preparation method thereof |
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|---|---|---|---|
| CN201410272516.1A CN105267163A (en) | 2014-06-18 | 2014-06-18 | Erlotinib hydrochloride tablet, and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101084880A (en) * | 2006-06-09 | 2007-12-12 | 中国人民解放军军事医学科学院毒物药物研究所 | Biological solid dispersion of vitamin E esters derivatives and preparation method thereof |
| CN103393613A (en) * | 2013-08-14 | 2013-11-20 | 南京正宽医药科技有限公司 | Fexofenadine hydrochloride tablet and preparation method thereof |
| CN103784411A (en) * | 2012-11-01 | 2014-05-14 | 齐鲁制药(海南)有限公司 | Erlotinib hydrochloride medicinal composition and preparation method thereof |
-
2014
- 2014-06-18 CN CN201410272516.1A patent/CN105267163A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101084880A (en) * | 2006-06-09 | 2007-12-12 | 中国人民解放军军事医学科学院毒物药物研究所 | Biological solid dispersion of vitamin E esters derivatives and preparation method thereof |
| CN103784411A (en) * | 2012-11-01 | 2014-05-14 | 齐鲁制药(海南)有限公司 | Erlotinib hydrochloride medicinal composition and preparation method thereof |
| CN103393613A (en) * | 2013-08-14 | 2013-11-20 | 南京正宽医药科技有限公司 | Fexofenadine hydrochloride tablet and preparation method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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