CN104666261B - A kind of tablet of everolimus - Google Patents
A kind of tablet of everolimus Download PDFInfo
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- CN104666261B CN104666261B CN201510055759.4A CN201510055759A CN104666261B CN 104666261 B CN104666261 B CN 104666261B CN 201510055759 A CN201510055759 A CN 201510055759A CN 104666261 B CN104666261 B CN 104666261B
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- everolimus
- tablet
- hydroxypropyl cellulose
- aerosil
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Abstract
The invention belongs to field of pharmaceutical preparations, in particular a kind of tablet of everolimus.The everolimus tablet, contain everolimus, hydroxypropyl cellulose, aerosil, everolimus, hydroxypropyl cellulose are dissolved in TC, add aerosil absorption, then it is well mixed with pharmaceutically acceptable auxiliary material, is formed using the compacting of direct tablet compressing technique.Compared with prior art, drug-eluting speed is fast, and technique is simple, it is not necessary to adds surfactant, it is not required that micronization processes by the present invention.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, in particular a kind of tablet of everolimus.
Background technology
Everolimus (everolimus) is sirolimus (Sirolimus, also known as rapamycin, i.e. rapamycin)
Derivative, therefore everolimus is also known as 40-O- (the light ethyls of 2-)-rapamycin, or 40-O- (the light ethyls of 2-)-sirolimus.
Everolimus, molecular formula：C53H83NO14, molecular weight：958.22 structural formula is as follows：
Everolimus is a kind of mTOR inhibitor (rapamycin mammal target point), the one of PI3K/AKT passage downstreams
Kind serine threonine kinases.Everolimus is developed at first by Novartis Co., Ltd of Switzerland (NovartiS), trade name
Certican, listed first in Sweden within 2003, European market was captured comprehensively in 2006.
FDA ratifies it and is used for the patient of Sutent or Sorafenib treatment advanced renal cell cancer failure, according to the research of Novartis,
Everolimus can slow down the growth of kidney cancer cell, reduce by 67% death rate.By suppressing growth and the propagation of tumour cell,
Directly act on tumour cell；By suppressing angiogenesis, tumor vessel distribution is caused to reduce and play indirectly-acting (by having
Effect suppresses the propagation of the endothelial cell of tumour cell VEGF generation and VEGF inductions).
2010, everolimus was approved for preventing the organ rejection of heart and renal transplant recipients.In addition, except kidney is thin
Rejection after born of the same parents' cancer and organ transplant, everolimus also carrying out to neuroendocrine tumor, lymthoma, other cancers and
The research of tuberous sclerosis, unitary agent can be used as or shared with existing cancer treatment method.
Everolimus is white to micro-yellow powder, lipophilicity, and solubility is less than 0.01% (g/ml) in water at 25 DEG C, because
This improves its dissolution rate and is particularly important.
Chinese invention patent CN102138903A discloses a kind of Everolimus solid oral medicinal composition, including according to dimension
The not composition of department or derivatives thereof and excipient composition, the pH value of the aqueous solution of the composition is 4~7, the Yi Weimo
The percentage by weight that department or derivatives thereof accounts for the composition is 0.05~5%, and main ingredient is carried out by fluid bed technique for packing
It is dispersed.Its shortcoming is preparation technology complexity, and production operation difficulty is big, and cost is high；Water or other is used in preparation process
Solvent and need to heat, cause the impurity of the drug for preparing big, stability is poor.
The A of Chinese invention patent CN 103610646 disclose a kind of preparation method of the solid dispersions containing everolimus,
This method is after everolimus and a kind of polymer support HPMC are dissolved in into organic solvent, to be made through centrifugal spray drying.It is lacked
Point is that the use of organic solvent can or can not have an impact and the residue problem of organic solvent to everolimus and excipient, if
Standby problem, human users' safety problem, test problems of residual solvent etc., can not only increase the complexity of operating procedure, also deposit
In potential safety hazard, while add cost.
At present, Novartis has listed the tablet and dispersible tablet of everolimus, but wherein contains BHT.Two uncles
Butyl paracresol is a kind of oil-soluble organic compound, because it can produce chemical reaction with free radical, and is slowed down in food
The speed of redox reaction, it is possible thereby to keep the color of food, aroma and flavor, mainly it is used as in food additives
Antioxidant.Because BHT has hypotoxicity, and make moist or illumination can all cause it is rotten, Japan, Romania,
All forbid adding in food in the ground such as Sweden, Australia, the U.S..Antioxidant di-t-butyl is with the addition of in the listing preparation of Novartis to first
Phenol, influences the property of product, and safety risks are brought to patient medication.
The content of the invention
In view of the shortcomings of the prior art, the invention provides a kind of everolimus tablet of Fast Stripping.Inventor will consolidate
Body dispersion technology is combined with solubilizer and adsorbent, prepares solid dispersions solubilising medicine first, and the dispersion of medicine is molten
Liquid is adsorbed with aerosil, then is well mixed with pharmaceutically acceptable auxiliary material, tabletting, and gained tablet dissolution is rapid.
Specifically, the present invention is realized by following technology：
The invention provides a kind of everolimus tablet, containing everolimus, hydroxypropyl cellulose, aerosil,
TC and other pharmaceutically acceptable auxiliary materials.Described everolimus tablet, everolimus and diethyl two
The weight ratio of alcohol list ethylether is 1:6~11.Preferably, weight ratio is 1:9.
Described everolimus tablet is prepared by the following method：Everolimus is dissolved in TC
In, add hydroxypropyl cellulose, be stirred to dissolve, add aerosil absorption, then with it is pharmaceutically acceptable auxiliary
Material is well mixed, is formed using the compacting of direct tablet compressing technique.
The weight ratio of described everolimus tablet, everolimus and hydroxypropyl cellulose is 1:5~6.
The weight ratio of described everolimus tablet, everolimus and aerosil is 1:15~22.Preferably, weight
Amount is than being 1:20.
Described pharmaceutically acceptable auxiliary material is filler, disintegrant, lubricant.
One or more of the described filler in microcrystalline cellulose, lactose, mannitol, starch and dextrin；It is described
Disintegrant in sodium carboxymethyl starch, Ac-Di-Sol, PVPP and low-substituted hydroxypropyl cellulose
One or more；The one kind of described lubricant in magnesium stearate, sodium stearyl fumarate, talcum powder and silica
It is or a variety of.Preferably, described filler is microcrystalline cellulose；Described disintegrant is PVPP；Described lubricant
For magnesium stearate.
Compared with prior art, drug-eluting speed is fast, and technique is simple by the present invention, it is not necessary to surfactant is added,
Micronization processes are not needed.
Embodiment
Following examples further describe beneficial effects of the present invention, and embodiment is only used for the purpose of illustration, do not limit this
The scope of invention, while obvious change and modification that those of ordinary skill in the art are made according to the present invention are also contained in
Within the scope of the invention.
Embodiment 1
Preparation technology：
Everolimus is dissolved in TC, is added hydroxypropyl cellulose, is stirred to dissolve, adds place
The aerosil absorption just measured, is then well mixed with lactose, sodium carboxymethyl starch, magnesium stearate, using direct tablet compressing
Technique compacting forms.
Embodiment 2
Preparation technology：
Everolimus is dissolved in TC, is added hydroxypropyl cellulose, is stirred to dissolve, adds place
The aerosil absorption just measured, is then well mixed with microcrystalline cellulose, PVPP, magnesium stearate, using direct
Tablet forming technique compacting forms.
Embodiment 3
Preparation technology：
Everolimus is dissolved in TC, is added hydroxypropyl cellulose, is stirred to dissolve, adds place
The aerosil absorption just measured, is then well mixed with microcrystalline cellulose, PVPP, magnesium stearate, using direct
Tablet forming technique compacting forms.
Embodiment 4
Preparation technology：
Everolimus is dissolved in TC, is added hydroxypropyl cellulose, is stirred to dissolve, adds place
The aerosil absorption just measured, is then well mixed with starch, low-substituted hydroxypropyl cellulose, talcum powder, using direct
Tablet forming technique compacting forms.
Embodiment 5
Preparation technology：
Everolimus air-flow crushing, particle diameter D90=10.8, add hydroxypropyl cellulose, the gas phase titanium dioxide of recipe quantity
Silicon, microcrystalline cellulose, PVPP are well mixed, and are added TC, granulation, are then added magnesium stearate,
It is well mixed, formed using the compacting of direct tablet compressing technique.
Embodiment 6
Preparation technology：
Everolimus air-flow crushing, particle diameter D90=10.8, add hydroxypropyl cellulose, the gas phase titanium dioxide of recipe quantity
Silicon, microcrystalline cellulose, PVPP are well mixed, and are added TC, granulation, are then added magnesium stearate,
It is well mixed, formed using the compacting of direct tablet compressing technique.
Embodiment 7
Preparation technology：
The everolimus and microcrystalline cellulose for weighing recipe quantity are well mixed.Everolimus microcrystalline cellulose mixt is added
Enter to crush 3 minutes in pulverizer, then the aerosil with recipe quantity, hydroxypropyl cellulose, crosslinking carboxylic PVP, mix
Uniformly, TC is added, granulation, then adds magnesium stearate, is well mixed, is suppressed using direct tablet compressing technique
Form.
Direct tablet compressing obtains everolimus piece.
Comparative example 1
Preparation technology：
Everolimus is dissolved in TC, adds the aerosil absorption of recipe quantity, then
It is well mixed with microcrystalline cellulose, PVPP, magnesium stearate, is formed using the compacting of direct tablet compressing technique.
Comparative example 2
Preparation technology：
Everolimus air-flow crushing, D90=10.3 microns, then mixed with microcrystalline cellulose, PVPP, magnesium stearate
Close uniformly, formed using the compacting of direct tablet compressing technique.
Verify embodiment
Dissolution determination.This product is taken, according to dissolution method (two methods of annex XC the 3rd of Chinese Pharmacopoeia version in 2010), with
0.4% lauryl sodium sulfate aqueous solution 500ml is dissolution medium, and rotating speed is 50 turns per minute, is operated in accordance with the law, during through 5 minutes,
Take solution appropriate, filter, take subsequent filtrate as need testing solution.Another precision weighs everolimus reference substance about 12.5mg, is placed in
In 50ml measuring bottles, first plus second eyeball 5ml makes its dissolving, then solubilization go out medium to scale, shakes up, precision measures lml and is placed in
In 50ml measuring bottles, solubilization goes out medium to scale, shakes up, as reference substance solution.By the chromatographic condition under assay item,
Precision measures each 100 microlitres of above two solution, injects liquid chromatograph, chromatogram is recorded, by external standard method with main peak and isomery
Body peak area sum calculates the stripping quantity of every.
Each embodiment measurement result
| Embodiment | 0 day result (%) | 40 DEG C, result (%) after 75%RH accelerates 6 months |
| Embodiment 1 | 99.3 | 99.1 |
| Embodiment 2 | 99.3 | 98.9 |
| Embodiment 3 | 100.1 | 99.9 |
| Embodiment 4 | 99.2 | 99.1 |
| Embodiment 5 | 77.5 | 76.9 |
| Embodiment 6 | 76.8 | 76.4 |
| Embodiment 7 | 75.6 | 74.3 |
| Comparative example 1 | 50.1 | 49.2 |
| Comparative example 2 | 64.3 | 63.9 |
As seen from the table, the dissolution of the embodiment of the present invention 1~4 is rapid, and dissolution is substantially unchanged after acceleration；Embodiment 5~7,
Pelletized with TC, because raw material can not be substantially dissolved in solvent, therefore dissolution is slightly slow；Comparative example 1,
Hydroxypropyl cellulose is not added in solvent, when dissolution determines, medicine separates out, therefore dissolution is unhappy；Comparative example 2, raw material micro mist
Change is handled, and dissolution is more of the invention slow.
Claims (8)
- A kind of 1. everolimus tablet, it is characterised in that containing everolimus, hydroxypropyl cellulose, aerosil and its His pharmaceutically acceptable auxiliary material；The weight ratio of the everolimus and TC is 1:6~11；By such as lower section Method is prepared：Everolimus is dissolved in TC, is added hydroxypropyl cellulose, is stirred to dissolve, then is added Enter aerosil absorption, be then well mixed with pharmaceutically acceptable auxiliary material, formed using the compacting of direct tablet compressing technique.
- 2. everolimus tablet according to claim 1, it is characterised in that everolimus and TC Weight ratio is 1:9.
- 3. everolimus tablet according to claim 1, it is characterised in that the weight of everolimus and hydroxypropyl cellulose Than for 1:5~6.
- 4. everolimus tablet according to claim 1, it is characterised in that the weight of everolimus and aerosil Than for 1:15~22.
- 5. everolimus tablet according to claim 1, it is characterised in that the weight of everolimus and aerosil Than for 1:20.
- 6. everolimus tablet according to claim 1, it is characterised in that pharmaceutically acceptable auxiliary material be filler, Disintegrant, lubricant.
- 7. everolimus tablet according to claim 6, it is characterised in that described filler be selected from microcrystalline cellulose, One or more in lactose, mannitol, starch and dextrin；Described disintegrant is selected from sodium carboxymethyl starch, cross-linked carboxymethyl One or more in sodium cellulosate, PVPP and low-substituted hydroxypropyl cellulose；Described lubricant is selected from stearic acid One or more in magnesium, sodium stearyl fumarate, talcum powder and silica.
- 8. everolimus tablet according to claim 6, it is characterised in that described filler is microcrystalline cellulose；Institute The disintegrant stated is PVPP；Described lubricant is magnesium stearate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510055759.4A CN104666261B (en) | 2015-02-03 | 2015-02-03 | A kind of tablet of everolimus |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510055759.4A CN104666261B (en) | 2015-02-03 | 2015-02-03 | A kind of tablet of everolimus |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104666261A CN104666261A (en) | 2015-06-03 |
| CN104666261B true CN104666261B (en) | 2017-11-10 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510055759.4A Active CN104666261B (en) | 2015-02-03 | 2015-02-03 | A kind of tablet of everolimus |
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Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4782695B2 (en) * | 2004-10-25 | 2011-09-28 | 日本たばこ産業株式会社 | Solid preparation with improved solubility and stability and method for producing the same |
| CN101366715A (en) * | 2007-08-15 | 2009-02-18 | 上海医药工业研究院 | Rapamycin composition and preparation thereof |
| CN103099790B (en) * | 2011-11-11 | 2015-09-02 | 山东新时代药业有限公司 | A kind of tablet containing everolimus and preparation method thereof |
| CN103585122B (en) * | 2012-08-17 | 2017-12-05 | 山东新时代药业有限公司 | A kind of tablet containing everolimus and preparation method thereof |
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