CN104971054A - Crizotinib capsule and preparation method thereof - Google Patents
Crizotinib capsule and preparation method thereof Download PDFInfo
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- CN104971054A CN104971054A CN201410154688.9A CN201410154688A CN104971054A CN 104971054 A CN104971054 A CN 104971054A CN 201410154688 A CN201410154688 A CN 201410154688A CN 104971054 A CN104971054 A CN 104971054A
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- buddhist nun
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Abstract
The invention provides crizotinib capsules and a preparation method thereof, wherein the specifications of the crizotinib capsules can be 200 mg and 250 mg, wherein the auxiliary materials in each capsule include 30-100 mg of microcrystalline cellulose, 50-200 mg of anhydrous calcium hydrophosphate, 20-50 mg of carboxymethyl starch sodium, 5-25 mg of silica gel micro powder and 1-10 mg of magnesium stearate. The preparation method includes following steps: one-step granulation in a fluidized bed, mixing and capsule filling, wherein an 80% ethanol solution is employed as a wetting agent. The preparation method solves the problems of poor flowability, high different of content quantity, low dissolution rate and poor stability of granules of the crizotinib capsules, improves the bioavailability and curative effects of the capsules and is better in curative effects.
Description
Technical field
The present invention relates to a kind of drug prescription and preparation method for the treatment of nonsmall-cell lung cancer, belong to medical manufacture field, be specifically related to a kind of gram azoles for Buddhist nun's capsule and preparation method.
Background technology
Along with medical diagnosis level improve constantly and the rapidly universal of high-end diagnostic imaging apparatus uses, the number of patients straight line being gone out breast carcinoma, pulmonary carcinoma, gastric cancer and other kinds of tumor diseases by Accurate Diagnosis rises.According to WHO statistics, 2007, the tumour patient that the whole world is newly made a definite diagnosis reached 1,200 ten thousand, and in the past few years, the patient of cancer is died from every year up to more than 7,000,000 people in the whole world.This numeral with die from the number of acute cardiovascular disease closely.Except the cancer morbidity of developing country and country of infant industry is except increasing, the cancer morbidity of the western developed country headed by the U.S. is high equally.
The statistics that WHO announces June in this year shows, the past, over 15 years, the cancer morbidity of the U.S. improve 50% than early 1990s, and the U.S. is the same with China, was all world's cancer state occurred frequently.So, during cancer therapy drug market, the world increases rapidly.Predict according to the International Monetary Fund (IMF) director: in a few years from now on, China, India, Brazil and Russia these " gold brick four countries " will become fastest-rising tumour medicine market, the world.
In fact, cancer therapy drug market in the world's is come increasing in the past few years always.According to the data display that American Medical consulting firm Frost & Sullivan announces, 2004, cancer therapy drug market, whole world total sales volume is 24,000,000,000 dollars, within 2007, surge to 39,600,000,000 dollars, and estimate this year to reach 48,000,000,000 dollars, 2009, global cancer therapy drug market will reach 55,000,000,000 dollars or higher.Between short 5 years, the global cancer therapy drug market sales revenue has turned over some.
Gram azoles is treatment nonsmall-cell lung cancer new drug for Buddhist nun, and pulmonary carcinoma is the cancer that M & M is the highest in malignant tumor now, and wherein, nonsmall-cell lung cancer (NSCLC) case accounts for 80% ~ 85% of whole cases of lung cancer.NSCLC grade malignancy is high, easy relapse and metastasis, and when generally making a definite diagnosis, the state of an illness develops into late period.Though classic chemotherapy and radiotherapy can improve the state of an illness of NSCLC patient to a certain extent, current treatment status is still undesirable.Along with people understand more and more deep to the molecular mechanism that development occurs NSCLC, the studies and clinical application of the molecular targeted therapy that specificity is high, untoward reaction is low becomes the focus of current NSCLC treatment.
Gram azoles is a kind of oral alk tyrosine kinase inhibitor for Buddhist nun, can suppress the tyrosine phosphorylation activating ALK.ALK and MET/HGF two kinds of tyrosine kinase can be suppressed, also belong to Mutiple Targets medicine.This medicine is used for the treatment of the advanced NSCLC patients of anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (ALK) gene of abnormal expression.
On August 26th, 2011, many targeting tyrosine kinase inhibitor gram azoles of MET/ALK fusion gene receptor just obtains the certification of U.S. food security bureau for Buddhist nun, and is treat in the various situations of approval for MET/ALK fusion gene positive patient." New England Journal of Medicine " editor also claims gram azoles to be " the up-to-date champion of anticancer war " for Buddhist nun, the NSCLC patient of the treatment ALK positive, no matter all have original effect as a line or the treatment of two/tri-lines.
At gram azoles, for Buddhist nun's capsule, in research process, we find that gram azoles is water-soluble hardly for Buddhist nun's crude drug, cause gram azoles lower for Buddhist nun's dissolution, affect bioavailability, make curative effect of medication poor, simultaneously because gram azoles is comparatively large for Buddhist nun's specification, supplementary product consumption is relatively less, adopts direct powder filling mobility poor, capsule fill content uniformity is comparatively large, affects product quality.
Summary of the invention
The object of the invention is to solve the problems of the technologies described above, provide a kind of and can produce qualified gram azoles continuously and stably for Buddhist nun's capsule, dissolution meets the national drug standards simultaneously, increases bioavailability, improves curative effect.It is qualified that product stability is investigated, and considerably improves the quality of product.
We find for during Buddhist nun's capsule at exploitation gram azoles, gram azoles is water-soluble hardly for Buddhist nun's crude drug, adopt ordinary recipe preparation gram azoles for Buddhist nun's capsule, dissolution only has 60%, we screen meticulously to each supplementary product consumption, finally determine that every supplementary product consumption scope is respectively microcrystalline Cellulose 30 ~ 100mg, calcium phosphate dibasic anhydrous 50 ~ 200mg, carboxymethylstach sodium 20 ~ 50mg, micropowder silica gel 5 ~ 25mg, magnesium stearate 1 ~ 10mg.
By obtaining prescription dosage optimization, filler microcrystalline Cellulose consumption is 50 ~ 70mg, calcium phosphate dibasic anhydrous consumption consumption is 80 ~ 120mg, carboxymethylstach sodium consumption is 30mg.
The different production technology of our paper examines of preparation process screening stage is on the impact of preparation, and the capsule production technology as traditional is pulverizing, mixing, soft material processed, granule processed, drying, adds mix lubricant, intermediates content mensuration, encapsulating capsule, packaging.The capsule related substance of this explained hereafter is comparatively large, and dissolution is lower.
We adopt the method for the direct fill capsule of powder to prepare gram azoles for Buddhist nun's capsule, but due to mobility lower, fill capsule content uniformity is out comparatively large, and product quality is also against regulation.
Finally we select the method for fluidized bed granulation to prepare gram azoles for Buddhist nun's capsule, in to binding agent screening, we have selected HPMC, HPC, PVP etc., gram azoles prepared is larger for Buddhist nun's capsule related substance, affect product quality, finally we select 80% alcoholic solution as wetting agent, gram azoles prepared is little for Buddhist nun's capsule particle good fluidity, related substance, and dissolution is high, and bioavailability is high.
Preparation method is as follows: take gram azoles of recipe quantity for Buddhist nun, microcrystalline Cellulose, calcium phosphate dibasic anhydrous, mix homogeneously, prepares 80% alcoholic solution and make wetting agent with being connected on fluid bed.Mixture is added in fluid bed, opens blower fan and make mixture be in suspended state, add wetting agent and make wet granular, dry 30 minutes.Take out granule, add the hard disk fatty acid magnesium of recipe quantity, micropowder silica gel, mix homogeneously, survey granule content, according to granule content encapsulating capsule.Finished product detection.Packaging both obtained.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is specifically addressed, but content of the present invention is not limited thereto.
Embodiment 1:
Gram azoles is for Buddhist nun's capsule (recipe quantity 1000 capsule)
Gram azoles is for Buddhist nun's capsule (recipe quantity 1000 capsule)
Preparation technology: take gram azoles of recipe quantity for Buddhist nun, calcium phosphate dibasic anhydrous, microcrystalline Cellulose, carboxymethylstach sodium, mix homogeneously, prepares 80% alcoholic solution and make wetting agent with being connected on fluid bed.Mixture is added in fluid bed, opens blower fan and make mixture be in suspended state, add binding agent and make wet granular, dry 30 minutes.Take out granule, add the hard disk fatty acid magnesium of recipe quantity, micropowder silica gel, mix homogeneously, survey granule content, according to granule content fill capsule.Finished product detection.Packaging both obtained.
Embodiment 2
Gram azoles is for Buddhist nun's capsule (recipe quantity 1000 capsule)
Preparation technology: take gram azoles of recipe quantity for Buddhist nun, calcium phosphate dibasic anhydrous, microcrystalline Cellulose, carboxymethylstach sodium, mix homogeneously, prepares 80% alcoholic solution and make wetting agent with being connected on fluid bed.Mixture is added in fluid bed, opens blower fan and make mixture be in suspended state, add binding agent and make wet granular, dry 30 minutes.Take out granule, add the hard disk fatty acid magnesium of recipe quantity, micropowder silica gel, mix homogeneously, survey granule content, according to granule content fill capsule.Finished product detection.Packaging both obtained.
Embodiment 3
Gram azoles is for Buddhist nun's capsule (recipe quantity 1000 capsule)
Preparation technology: take gram azoles of recipe quantity for Buddhist nun, calcium phosphate dibasic anhydrous, microcrystalline Cellulose, carboxymethylstach sodium, mix homogeneously, prepares 80% alcoholic solution and make wetting agent with being connected on fluid bed.Mixture is added in fluid bed, opens blower fan and make mixture be in suspended state, add binding agent and make wet granular, dry 30 minutes.Take out granule, add the hard disk fatty acid magnesium of recipe quantity, micropowder silica gel, mix homogeneously, survey granule content, according to granule content fill capsule.Finished product detection.Packaging both obtained.
Embodiment 4
Gram azoles is for Buddhist nun's capsule (recipe quantity 1000 capsule)
Preparation technology: take gram azoles of recipe quantity for Buddhist nun, calcium phosphate dibasic anhydrous, microcrystalline Cellulose, carboxymethylstach sodium, mix homogeneously, prepares 80% alcoholic solution and make wetting agent with being connected on fluid bed.Mixture is added in fluid bed, opens blower fan and make mixture be in suspended state, add binding agent and make wet granular, dry 30 minutes.Take out granule, add the hard disk fatty acid magnesium of recipe quantity, micropowder silica gel, mix homogeneously, survey granule content, according to granule content fill capsule.Finished product detection.Packaging both obtained.
Embodiment 5: gram azoles is for Buddhist nun's capsule stability study
According to the investigation project listed by the stability test declaring clinical research quality standard and Chinese Pharmacopoeia version in 2010 two annex " medicine stability test guideline " capsule, we have carried out study on the stability to this product.
Influence factor tests
Temperature influence factor tests test method: sample thief 1 batch, removing outer package, place 10 days under being placed in temperature room temperature, the condition of 40 DEG C, 60 DEG C respectively, detection is sampled respectively in the 5th day, the 10th day,, for Buddhist nun's content related substance contrast with 0 day data investigate the stability of preparation to temperature for paper examines index with outward appearance, dissolution, gram azoles.The results are shown in Table 1.
Table 1 temperature influence factor tests
*: represent white particle
Illumination effect factorial experiments test method: sample thief 1 batch, removing outer package, place 10 days under being placed in the condition of indoor, 45001x ± 5001x illumination respectively, detection is sampled respectively in the 5th day, the 10th day,, for Buddhist nun's content, related substance contrast with 0 day data investigate the stability of preparation to temperature for paper examines index with outward appearance, dissolution, gram azoles.
The factorial experiments of table 2 illumination effect
*: represent white particle
Result shows: this product is stablized 40 DEG C of high temperature, 60 DEG C of high temperature, 45001x intense light irradiations, all performance, and character, gram azoles are for Buddhist nun's content and 0 day more equal no significant difference.
Accelerated test test method: sample thief 3 batches, by listing packaging, put that temperature is 40 DEG C ± 2 DEG C, relative humidity is in the medicine stability test case of 75% ± 5%, place 6 months, the 1st, 2,3,6 the end of month, sampling detects, for paper examines index, preparation accelerated stability is investigated with 0 month Data Comparison for Buddhist nun's content, related substance with outward appearance, dissolution, gram azoles.The results are shown in Table 3.
Table 3 accelerated stability test
*: represent white capsule
Result shows: this product 40 DEG C is accelerated 6 months, and character, dissolution, related substance, gram azoles all conform with the regulations for Buddhist nun's content, and compared no significant difference with 0 month.
Long term test test method: sample thief 3 batches, by listing packaging, place 36 months under temperature 25 DEG C ± 2 DEG C, relative humidity 60% ± 10% condition, detect respectively at sampling at the 3rd, 6,9 the end of month, for paper examines index, preparation long-time stability are investigated with 0 month Data Comparison for Buddhist nun's content with character, dissolution, related substance, gram azoles.Result is as shown in table 5.
Long-term stable experiment
*: represent white particle
Result shows: this product 25 DEG C is long-term 9 months, and character, dissolution, related substance, gram azoles all conform with the regulations for Buddhist nun's content, and compared no significant difference with 0 month.
Claims (7)
1. the invention provides a kind of gram azoles for Buddhist nun's capsule and preparation method, described gram of azoles comprises gram azoles for Buddhist nun, microcrystalline Cellulose, calcium phosphate dibasic anhydrous for Buddhist nun's capsule, carboxymethylstach sodium, micropowder silica gel, magnesium stearate, hard capsule composition, described gram of azoles is that 200mg and 250mg: every supplementary product consumption is respectively microcrystalline Cellulose 30 ~ 100mg, calcium phosphate dibasic anhydrous 50 ~ 200mg, carboxymethylstach sodium 20 ~ 50mg, micropowder silica gel 5 ~ 25mg, magnesium stearate 1 ~ 10mg for Buddhist nun's capule size.Preparation method is fluid-bed marumerization, mixing, fill capsule.
2. according to claim 1 gram of azoles is for Buddhist nun's capsule and preparation method, and its principal character is: gram azoles comprises gram azoles for Buddhist nun, microcrystalline Cellulose, calcium phosphate dibasic anhydrous for Buddhist nun's capsule, carboxymethylstach sodium, micropowder silica gel, magnesium stearate.
3. according to claim 1 gram of azoles is for Buddhist nun's capsule and preparation method, and its principal character is: filler microcrystalline Cellulose consumption 30 ~ 100mg, and further optimizing consumption is 50 ~ 70mg.
4. according to claim 1 gram of azoles is for Buddhist nun's capsule and preparation method, and its principal character is: calcium phosphate dibasic anhydrous consumption 50 ~ 200mg, and further optimizing consumption is 80 ~ 120mg.
5. according to claim 1 gram of azoles is for Buddhist nun's capsule and preparation method, and its principal character is: carboxymethylstach sodium consumption 20 ~ 50mg, and further optimizing consumption is 30mg.
6. according to claim 1 gram of azoles is for Buddhist nun's capsule and preparation method, and its principal character is: this fluidized bed granulation is included in mixing in fluid bed, granulates, dry.
7. according to claim 7 gram of azoles is for Buddhist nun's capsule and preparation method, and its principal character is: this fluidized bed granulation wetting agent used is 80% alcoholic solution.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201410154688.9A CN104971054A (en) | 2014-04-11 | 2014-04-11 | Crizotinib capsule and preparation method thereof |
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| CN201410154688.9A CN104971054A (en) | 2014-04-11 | 2014-04-11 | Crizotinib capsule and preparation method thereof |
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| CN104971054A true CN104971054A (en) | 2015-10-14 |
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| CN201410154688.9A Pending CN104971054A (en) | 2014-04-11 | 2014-04-11 | Crizotinib capsule and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108721243A (en) * | 2017-04-25 | 2018-11-02 | 正大天晴药业集团股份有限公司 | Gram azoles is for Buddhist nun's pharmaceutical composition and preparation method thereof |
| CN115887406A (en) * | 2022-12-24 | 2023-04-04 | 山东理工职业学院 | Preparation method of crizotinib capsule |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101321527A (en) * | 2005-12-05 | 2008-12-10 | 辉瑞产品公司 | Method of treating abnormal cell growth |
| EP2620140A1 (en) * | 2012-01-26 | 2013-07-31 | ratiopharm GmbH | Crizotinib containing compositions |
-
2014
- 2014-04-11 CN CN201410154688.9A patent/CN104971054A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101321527A (en) * | 2005-12-05 | 2008-12-10 | 辉瑞产品公司 | Method of treating abnormal cell growth |
| EP2620140A1 (en) * | 2012-01-26 | 2013-07-31 | ratiopharm GmbH | Crizotinib containing compositions |
Non-Patent Citations (2)
| Title |
|---|
| PFIZER: "HIGHLIGHTS OF PRESCRIBING INFORMATION FOR XALKORI", 《HIGHLIGHTS OF PRESCRIBING INFORMATION FOR XALKORI》 * |
| 林宁: "《药剂学》", 31 January 2008, 湖北科学技术出版社 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108721243A (en) * | 2017-04-25 | 2018-11-02 | 正大天晴药业集团股份有限公司 | Gram azoles is for Buddhist nun's pharmaceutical composition and preparation method thereof |
| CN108721243B (en) * | 2017-04-25 | 2022-07-08 | 正大天晴药业集团股份有限公司 | Crizotinib pharmaceutical composition and preparation method thereof |
| CN115887406A (en) * | 2022-12-24 | 2023-04-04 | 山东理工职业学院 | Preparation method of crizotinib capsule |
| CN115887406B (en) * | 2022-12-24 | 2024-02-13 | 山东理工职业学院 | Preparation method of crizotinib capsule |
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