CN103893134A - Anticancer drug sustained-release preparation - Google Patents
Anticancer drug sustained-release preparation Download PDFInfo
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- CN103893134A CN103893134A CN201210580333.7A CN201210580333A CN103893134A CN 103893134 A CN103893134 A CN 103893134A CN 201210580333 A CN201210580333 A CN 201210580333A CN 103893134 A CN103893134 A CN 103893134A
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- paclitaxel
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Abstract
The invention discloses an anticancer drug sustained-release preparation using chitosan as a carrier; a paclitaxel drug sustained-release microsphere is developed, the continuous degradation character of the chitosan in vivo is used to prolong the drug acting time; and the drug sustained-release microsphere is locally and slowly released at a focus by controlling of the particle size of the microsphere. The invention also discloses necessary components of the paclitaxel drug sustained-release microsphere and a preparation method of the paclitaxel drug sustained-release microsphere. A first necessary component is paclitaxel, a second necessary component is the chitosan and a third necessary component is calcium sulfate. Taking the weight of a lyophilized product as the reference, the necessary components comprises 5-30% of the paclitaxel, 50-40% of the chitosan and 45-30% of the calcium sulfate. By a suitable method the paclitaxel drug sustained-release microsphere with an average particle diameter of 300-500nm is made.
Description
Technical field
The invention belongs to medical technical field, relate to a kind of anti-cancer medicine slow release preparation and preparation method thereof.
Background technology
Paclitaxel (paclitaxel) is a kind of cancer therapy drug extracting from the trunk of Ramulus et folium taxi cuspidatae and bark, can promote microtubule dimer to be assembled into microtubule, thereby block cell division suppresses tumor growth, be after adriamycin and Platinol cisplatin the 3rd generation antitumor drug, Chang Zuowei treats the first-line drug of newborn breast carcinoma, pulmonary carcinoma, ovum groove cancer clinically.Paclitaxel has good active anticancer and unique mechanism of action.
Developed country of U.S. has occupied the first place of kinds of tumor, and in the crowd of city, China's Coastal Areas, the sickness rate of pulmonary carcinoma has the trend rising steadily.Paclitaxel is become the first-line drug for the treatment of nonsmall-cell lung cancer at present by U.S. FDA approval, but when clinical injection is used, there are the dose dependent toxicity such as (neutrality) granulocytopenia, the untoward reaction such as bone marrow depression, heart ventricle arrhythmia, and can cause serious anaphylaxis.Because taxol soluble is poor, the cosolvent polyoxyethylene castor oil (cremophor EL) containing in paclitaxel injection also has very strong untoward reaction, therefore in the time of clinical use, is subject to certain restrictions in addition.Satisfied administering mode is that the modern preparation technique of application makes medicine directly act on cancer target tissue and produces the effect discharging of controlling,, to improve the concentration of medicine in local organization, reduce the drug level in blood and hetero-organization thereof.
Chitosan is the deacetylation product of chitin, has good biocompatibility and biodegradability, is the unique natural alkaline polysaccharide of finding up to now, has no side effect, and has great superiority as the carrier of medicine.
Summary of the invention
This research, taking chitosan as carrier, is developed a kind of taxol drug sustained-release micro-spheres, the characteristic of utilizing chitosan constantly to degrade in vivo, the time of prolong drug effect; By controlling its size, make medicament slow-release microsphere discharge medicine in focus local slow.
Taxol drug sustained-release micro-spheres of the present invention, its key component is: as the first necessary component is paclitaxel; The chitosan that is of the second necessary component; The calcium sulfate that is of the 3rd necessary component.
Taxol drug sustained-release micro-spheres, is characterized in that, its key component percentage by weight is counted taking taxol drug sustained-release micro-spheres freeze-drying prods: paclitaxel is as 5～30%, and chitosan is 50～40%; Sulphuric acid Ca45～30%.
Taxol slow release microballoons preparation method is as follows:
A. first get appropriate carboxymethyl chitosan and be dissolved in distilled water, make concentration expressed in percentage by weight and be 0.5～2.0% carboxymethyl chitosan sugar aqueous solution;
B. separately the paclitaxel of recipe quantity is dissolved in appropriate 30%～50%, slowly adds in above-mentioned carboxymethyl chitosan sugar aqueous solution, make to be uniformly dissolved.
c.the calcium sulfate of recipe quantity is dissolved in distilled water, make concentration expressed in percentage by weight and be 10%～15% aqueous solution, under room temperature, stirring condition, slowly add in b item drug solution according to prescription ratio, stir 60 minutes～120 minutes (500 revs/min～2000 revs/min), make mean diameter 300～500nm taxol drug sustained-release micro-spheres.
D. by centrifugal above-mentioned product, lyophilization obtains taxol drug sustained-release micro-spheres.
E. taxol drug sustained-release micro-spheres dried frozen aquatic products is dissolved in the sterilizing phosphoric acid buffer of appropriate pH7.4, subpackage, makes taxol drug sustained-release microspheres injection.
advantage of the present invention:
According to different clinical applications, taxol drug sustained-release micro-spheres prepared by the present invention is for cancer or easily local injection or the implantation of metastasis site.Therefore its advantage is the localized sustained that easily shifts, recurs in cancer or cancer, slow Slow release, can make focus topical remedy assemble, being more suitable for treatment of cancer needs local drug concentration high, and the persistent period is long, reduces and avoid the needs of the systemic side effects of cancer therapy drug.Pharmaceutical carrier chitosan used is nontoxic, have no side effect, and has good biocompatibility and biodegradable performance.Avoid ordinary preparation easily to cause the drawback of systemic side effects, be more superior to general macromolecular material and do slow releasing pharmaceutical carrier metabolism difficulty, easily caused the shortcomings such as thrombosis.
Following examples are used for further illustrating the present invention, and it consists of optimizing prescriptions, but are never restriction on its scope.
Detailed description of the invention
embodiment 1:
The preparation of taxol drug sustained-release micro-spheres.
A. take 0.5 gram of carboxymethyl chitosan and be dissolved in 50ml distilled water, make concentration expressed in percentage by weight and be 1.0% carboxymethyl chitosan sugar aqueous solution;
B. separately 0.05 gram of paclitaxel is dissolved in 10.0ml50% ethanol, is slowly added dropwise in above-mentioned carboxymethyl chitosan sugar aqueous solution, make to be uniformly dissolved.
C. take 0.45g calcium sulfate and be dissolved in 45ml distilled water and dissolve, under room temperature, stirring condition, slowly add in b item drug solution according to prescription ratio, 500 revs/min are stirred 120 minutes, make mean diameter 500nm taxol drug sustained-release micro-spheres.
D. by centrifugal above-mentioned product, lyophilization obtains taxol drug sustained-release micro-spheres.
E. by 1 gram of taxol drug sustained-release micro-spheres dried frozen aquatic products, be dissolved in the sterilizing phosphate buffer solution of 100 milliliters of pH 7, subpackage, makes taxol drug sustained-release microspheres injection.
embodiment 2:
The preparation of taxol drug sustained-release micro-spheres.
A. take 0.45 gram of carboxymethyl chitosan and be dissolved in 45ml distilled water, make concentration expressed in percentage by weight and be 1.0% carboxymethyl chitosan sugar aqueous solution;
B. separately 0.15 gram of paclitaxel is dissolved in 15.0ml50% ethanol, is slowly added dropwise in above-mentioned carboxymethyl chitosan sugar aqueous solution, make to be uniformly dissolved.
C. take 0.40g calcium sulfate and be dissolved in 40ml distilled water and dissolve, under room temperature, stirring condition, slowly add in b item drug solution according to prescription ratio, 1000 revs/min are stirred 90 minutes, make mean diameter 450nm taxol drug sustained-release micro-spheres.
D. by centrifugal above-mentioned product, lyophilization, aseptic subpackaged, must implant and use taxol drug sustained-release micro-spheres.
embodiment 3:
The preparation of taxol drug sustained-release micro-spheres.
A. take 0.4 gram of carboxymethyl chitosan and be dissolved in 40ml distilled water, make concentration expressed in percentage by weight and be 1.0% carboxymethyl chitosan sugar aqueous solution;
B. separately 0.3 gram of paclitaxel is dissolved in 20.0ml50% ethanol, is slowly added dropwise in above-mentioned carboxymethyl chitosan sugar aqueous solution, make to be uniformly dissolved.
C. take 0.3g calcium sulfate and be dissolved in 30ml distilled water and dissolve, under room temperature, stirring condition, slowly add in b item drug solution according to prescription ratio, 2000 revs/min are stirred 60 minutes, make mean diameter 300nm taxol drug sustained-release micro-spheres.
D. by centrifugal above-mentioned product, lyophilization, aseptic subpackaged, must implant and use taxol drug sustained-release micro-spheres.
embodiment 4:tablets in vitro test
The taxol drug sustained-release micro-spheres of test drug: embodiment 1,2,3 preparations.
Take the taxol drug sustained-release micro-spheres 5mg of embodiment 1,2,3 preparations of lyophilizing, be dissolved in respectively the phosphate buffer of 1 ml pH 7. 4, being placed in bag filter seals, be suspended in 25ml tool plug in vitro, in pipe, add the phosphate buffer 20ml of pH 7. 4, be placed in 37 DEG C of water-baths, get PBS liquid 2ml outside Dialysis tubing every day and measure its A value at 227 nm places, supplement synthermal fresh medium 2ml simultaneously.Calculate its cumulative release amount.
Be respectively 7 days, 5 days, 4 days the release time that the taxol drug sustained-release micro-spheres sample cumulative release amount of result: embodiment 1,2,3 preparations reaches more than 80%.Illustrate that this product has reached desirable slow release effect.
embodiment 4: preliminaryanimal pharmacodynamics test
Get at random 4 ~ 5 week age, g) 30 of rats of body weight 15 ~ 20, (being provided by the pharmacology of Shanghai Pharmaceutical Inst., Chinese Academy of Sciences the first research department).Every Mus back subcutaneous vaccination S-180 cell suspension, animal random packet,, treats that gross tumor volume reaches 100 mm by 10 every group
3time, begin treatment.Positive controls intraperitoneal injection of saline respectively, the taxol drug sustained-release microspheres injection that treatment group is prepared respectively at locally injected into tumor (20mgkg-1) paclitaxel injection and embodiment 1.
After inoculation, treat and put to death animal on the 10th day, the complete Subcutaneous tumor graft of peeling off, weighs, and calculates tumour inhibiting rate according to formula: tumour inhibiting rate=(1-treatment group tumor weight/matched group tumor weight) × 100%, and carry out statistical procedures.
Result: taxol drug sustained-release microspheres injection compared with common paclitaxel injection, tumor-inhibiting action be significantly increased (P<0.01).
Claims (6)
1. anti-cancer medicine slow release preparation of the present invention, its key component is: as the first necessary component is paclitaxel; The chitosan that is of the second necessary component; The calcium sulfate that is of the 3rd necessary component.
2. according to anti-cancer medicine slow release preparation claimed in claim 1, it is characterized in that, its key component percentage by weight is counted taking taxol drug sustained-release micro-spheres freeze-drying prods: paclitaxel is as 5～30%, and chitosan is 50～40%; Sulphuric acid Ca45～30%.
3. according to the anti-cancer medicine slow release preparation described in claim 1～2, it is characterized in that, described paclitaxel is yew tree or/and the extract of bark, synthetic or semisynthetic paclitaxel.
4. the preparation method of the taxol drug sustained-release micro-spheres described in claim 1～3, is characterized in that adopting following steps:
First get appropriate carboxymethyl chitosan and be dissolved in distilled water, make concentration expressed in percentage by weight and be 0.5～2.0% carboxymethyl chitosan sugar aqueous solution;
Separately the paclitaxel of recipe quantity is dissolved in 30%～50% appropriate alcoholic solution, slowly adds in above-mentioned carboxymethyl chitosan sugar aqueous solution, make to be uniformly dissolved.
5. calcium sulfate is dissolved in distilled water, make concentration expressed in percentage by weight and be 10%～15% aqueous solution, under room temperature, stirring condition, slowly add in b item drug solution according to prescription ratio, stir 60 minutes～120 minutes (500 revs/min～2000 revs/min), make the taxol drug sustained-release micro-spheres of mean diameter 300～500nm.
6. by centrifugal above-mentioned product, lyophilization obtains taxol drug sustained-release micro-spheres.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210580333.7A CN103893134A (en) | 2012-12-28 | 2012-12-28 | Anticancer drug sustained-release preparation |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210580333.7A CN103893134A (en) | 2012-12-28 | 2012-12-28 | Anticancer drug sustained-release preparation |
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| CN103893134A true CN103893134A (en) | 2014-07-02 |
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| CN201210580333.7A Pending CN103893134A (en) | 2012-12-28 | 2012-12-28 | Anticancer drug sustained-release preparation |
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Application publication date: 20140702 |