CN101612121A - The preparation of microemulsion containing paclitaxel method - Google Patents
The preparation of microemulsion containing paclitaxel method Download PDFInfo
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- CN101612121A CN101612121A CN200910074954A CN200910074954A CN101612121A CN 101612121 A CN101612121 A CN 101612121A CN 200910074954 A CN200910074954 A CN 200910074954A CN 200910074954 A CN200910074954 A CN 200910074954A CN 101612121 A CN101612121 A CN 101612121A
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Abstract
The preparation method of paclitaxel and derivant microemulsion thereof belongs to technical field of medicine.With a kind of in refined maize oil, soybean oil, the olive oil or wherein two kinds mixture be oil phase, a kind of in lecithin, the poloxamer or the mixture of the two are emulsifying agent, a kind of in dehydrated alcohol, the propylene glycol or the mixture of the two are co-emulsifier, water is water, is prepared into the self-emulsifying micro-emulsion of paclitaxel or its derivant.This microemulsion is the medicine carrying body of paclitaxel or its derivant; be intermediate products; steady quality; the toxicity and the sensitization that do not have Cremophor EL; have targeting, the oral administration biaavailability height, preparation condition is simple; be suitable for industrialization, large-scale production, can further be prepared into acceptable clinically various dosage forms.
Description
Technical field
The invention belongs to technical field of medicine, be specifically related to the self emulsifying preparation method of medicine carrying body microemulsion, particularly the preparation method of paclitaxel and derivant microemulsion thereof.
Background technology
Paclitaxel, paclitaxel injection have recorded in existing American Pharmacopeia and China national drug standard, are used for the treatment of transitivity ovarian cancer and breast carcinoma, pulmonary carcinoma, the esophageal carcinoma.American Pharmacopeia and China national drug standard regulation, paclitaxel is a white crystalline powder, and odorless is tasteless, and its English name is Paclitaxel, and molecular formula is C
47H
51NO
14, molecular weight is 853.92.Paclitaxel injection is a kind of water white transparency or slightly yellowy viscosity solution, contains 6mg paclitaxel, 527mg Cremophor EL and 49.7% dehydrated alcohol in every milliliter of paclitaxel injection.
During the clinical practice paclitaxel injection,, treated preceding 12 hours and 6 hours oral dexamethasones, treat and gave diphenhydramine, quiet notes cimetidine 300mg or ranitidine 50mg in preceding 30～60 minutes at paclitaxel injection in order to prevent to take place anaphylaxis.Paclitaxel injection list pharmaceutical quantities is 135～200mg/m
2, under granulocyte colony-stimulating factor was supported, dosage can reach 250mg/m
2, it is 0.3～1.2mg/mL that paclitaxel injection is diluted to final concentration with normal saline or 5% glucose saline, after the microporous membrane that is no more than 0.22 μ m through diameter filters, quiet 3 hours; Drug combination dosage is 135～175mg/m
2, 3～4 weeks repeated.
There are many problems in present paclitaxel injection, mainly contains: the 1. toxicity of solvent and sensitization: mainly be the anaphylaxis that causes of adjuvant Cremophor EL and cause bronchospasm, rapid breathing, tired, hypotension etc.; Syringe, transfusion bag in container and the clinical practice contacts with Cremophor EL and can leach a large amount of plasticizer phthalic acid diethyl ethyl phosphonate in process of production in addition, causes anaphylaxis.2. paclitaxel injection dilution back is unstable: when said preparation is diluted to 0.3～1.2mg/mL, if surpass 24h, the graininess precipitation can occur, the analysis showed that this precipitation is not a paclitaxel, use filter when therefore recommending quiet in transfusion device.3. compatibility changes: clinical 60 kinds of medicines commonly used can cause that with the paclitaxel injection compatibility transfusion is muddy, and some drugs and paclitaxel are competed and combined plasma protein and can make the toxicity increase.
Because the paclitaxel bioavailability is very low, therefore, also there is not the paclitaxel oral formulations of industrialization at present.
For overcoming the above problems, the medicament scholar mainly is conceived to eliminate the untoward reaction that Cremophor EL causes, increases dissolubility, the stability of paclitaxel, reduces toxicity, increase bioavailability and launch research, simultaneously can industrialization also quite become the bottleneck in the pharmaceutical engineering.Mainly contain prodrug method, emulsion process at present and make methods such as micelle, liposome, nanoparticle, microemulsion, microsphere, cyclodextrin clathrate and topical, wherein promising is to make microemulsion, can eliminate the untoward reaction that Cremophor EL causes on the one hand, increase dissolubility, the stability of paclitaxel, reduce toxicity, can improve the bioavailability of oral formulations on the other hand.Yet, present yew alcohol micro-emulsion also rests on laboratory stage, some has strict demand to manufacturing machine equipment, particularly need high-pressure emulsification or need high temperature emulsifying or need high-speed stirred emulsifying, as Chinese patent 02153674.0 disclosed " a kind of cancer therapy drug novel formulation-yew alcohol micro-emulsion ", it at first with paclitaxel chloroformic solution decompression film forming, adds the Semen Maydis oil through the aquation supersound process then, uses the high pressure homogenisers microemulsified again after supersound process.This method complex process, the cost height is unfavorable for industrialization.
Chinese patent 200810084683.8 disclosed " supersaturation self-microemulsion oral preparation of a kind of paclitaxel and derivant thereof " and Chinese patent 200610135060.x disclosed " many rare paclitaxel submicron emulsion injections and preparation method thereof ", though adopted comparatively simple production technology, but its raw material still contains Cremophor EL, does not fundamentally eliminate the untoward reaction that Cremophor EL causes.
The 24th the 4th phase of volume of publishing " Chinese new drug and clinical " in April, 2005 has been delivered people's such as Zhang Xuenong research paper " preparation of taxol self-emulsifying microemulsion and in its pharmacokinetics in rats ", this research is oil phase with tricaprylin-tributyrin (1: 1), the paclitaxel self-microemulsion that dehydrated alcohol is done the co-emulsifier preparation forms stable microemulsion after the normal saline dilution, mean diameter is (16 ± 3) nm; The shortcoming of this research is that tributyrin has very strong biological activity.
Summary of the invention
The purpose of this invention is to provide a kind of preparation of microemulsion containing paclitaxel method, contain Cremophor EL and the toxicity and the sensitization that produce with the paclitaxel injection that solves present clinical use, the paclitaxel injection that solves present clinical use is diluted to behind 0.3～1.2mg/mL unstable, solves problems such as oral formulation for paclitaxel bioavailability is low.
Preparation of microemulsion containing paclitaxel method of the present invention is characterized in that always measuring paclitaxel 0.2-0.3 gram by preparation 100ml yew alcohol micro-emulsion; The oil phase 30-50ml that constitutes by the arbitrary proportion compositions of any one or two kinds of oil products in refined maize oil, soybean oil or the olive oil; The emulsifying agent 15-35 that is made of lecithin and/or poloxamer restrains; The co-emulsifier 10-30ml that constitutes by dehydrated alcohol and/or propylene glycol; Surplus is a water;
Operating procedure: paclitaxel, oil phase, emulsifying agent, co-emulsifier are mixed and stir evenly; Then, add entry while stirring,, form microemulsion, add water to full dose, promptly get yew alcohol micro-emulsion until clear and bright.
Described preparation of microemulsion containing paclitaxel method is characterized in that described microemulsion is that thermodynamically stable, homogeneous, particle diameter are the clear liquid of 10nm～100nm, is O/W type self-emulsifying micro-emulsion.
Described preparation of microemulsion containing paclitaxel method, the content that it is characterized in that lecithin in the emulsifying agent is 50-100%, the content of poloxamer is 0-50%; Dehydrated alcohol content is 50-100% in the co-emulsifier, and the content of propylene glycol is 0-50%.
Described preparation of microemulsion containing paclitaxel method is characterized in that described lecithin preferably soya lecithin; The preferred poloxamer 188 of poloxamer.
According to the yew alcohol micro-emulsion of preparation of microemulsion containing paclitaxel method preparation of the present invention, be the medicine carrying body of a kind of paclitaxel and derivant thereof, be thermodynamically stable liquid; Wherein do not contain Cremophor EL, just do not have corresponding toxicity and sensitization certainly yet; This yew alcohol micro-emulsion has targeting; Improved the oral administration biaavailability of paclitaxel and derivant thereof.
Preparation of microemulsion containing paclitaxel method provided by the invention, preparation condition is simple, is suitable for industrialization, large-scale production.
Preparation of microemulsion containing paclitaxel method of the present invention, the yew alcohol micro-emulsion that adopts this method preparation has been carried out accelerated stability test, yew alcohol micro-emulsion (containing paclitaxel 2.02mg/mL) is packaged in the 100mL glass infusion bottle, put into constant temperature and humidity incubator (40 ± 2 ℃ of temperature, relative humidity 75% ± 5%) in, respectively at 1,2,3, the every quality index of sampling and measuring in June, and with result of the test and comparison in 0 month, its character, clarity, pH value, microemulsion particle diameter, content of taxol change not obvious, and quality is more stable.
With yew alcohol micro-emulsion (containing paclitaxel 2.02mg/mL) with 10 times of medical preparation dilute with waters that meet the ejection preparation standard after, be packaged in the 100mL glass infusion bottle, carried out accelerated stability test, put into constant temperature and humidity incubator (40 ± 2 ℃ of temperature, relative humidity 75% ± 5%) in, respectively at 1,2,3, the every quality index of sampling and measuring in June, and with result of the test and comparison in 0 month, its character, clarity, pH value, microemulsion particle diameter, content of taxol do not have significant change, and quality is also more stable.
Yew alcohol micro-emulsion of the present invention, effective ingredient wherein comprises paclitaxel and derivant thereof, it is the medicine carrying body of paclitaxel and derivative formulations thereof, be intermediate products, can make acceptable clinically various dosage forms further, include but are not limited to dosage forms such as injection, oral formulations, external preparation.Thereby the final paclitaxel injection that solves present clinical use of realizing contains Cremophor EL and the problem of toxigenicity and sensitization; The paclitaxel injection that has solved present clinical use is diluted to problem of unstable behind 0.3～1.2mg/mL; Problems such as oral formulation for paclitaxel bioavailability is low have been solved.
The specific embodiment
Embodiment 1
1) raw material: prepare following raw material by 100 milliliters of preparation amounts:
Paclitaxel (purity 99.5%): 0.2g; Refined maize oil: 40mL;
Soybean lecithin: 20g; Poloxamer 188:5g; Dehydrated alcohol: 20mL; Water: an amount of;
Above-mentioned each composition is all taken from the commercially available product that meets China national medicine preparation standard.
2) operating procedure:, mix and stir evenly with above-mentioned prescription paclitaxel, refined maize oil, soybean lecithin, poloxamer 188, dehydrated alcohol are mixed; Then, add entry while stirring,, add water to full dose again, promptly get the 100mL yew alcohol micro-emulsion until clear and bright.Measure the microemulsion particle diameter and be about 24nm.
Attention: in the aforesaid operations step, add entry while stirring,, when forming microemulsion,, can suitably add some water again and make water excessive more stable to guarantee microemulsion if amount of water has has met or exceeded full dose until clear and bright.This product can be by further dilution of explanation when clinical use.
Embodiment 2
1) raw material: prepare following raw material by 100 milliliters of preparation amounts:
Paclitaxel (purity 99.5%): 0.3g; Refined maize oil and olive oil: each 25mL;
Soybean lecithin: 25g; Poloxamer 188:10g; Dehydrated alcohol: 30mL; Water: an amount of;
Above-mentioned each composition is all taken from the commercially available product that meets China national medicine preparation standard.
2) operating procedure: the paclitaxel of above-mentioned raw materials, refined maize oil, olive oil, soybean lecithin, poloxamer 188, dehydrated alcohol are mixed, mix and stir evenly; Then, add entry while stirring,, add water to full dose again, promptly get the 100mL yew alcohol micro-emulsion until clear and bright.Measure the microemulsion particle diameter and be about 50nm.
Embodiment 3
1) raw material: prepare following raw material by 100 milliliters of preparation amounts:
Paclitaxel and derivant thereof (purity 99.5%): 0.25g; Soybean oil: 30mL;
Soybean lecithin: 20g; Dehydrated alcohol: 15mL; Water: an amount of;
Above-mentioned each composition is all taken from the commercially available product that meets China national medicine preparation standard.
2) operating procedure: the paclitaxel of above-mentioned raw materials, soybean oil, soybean lecithin, dehydrated alcohol are mixed, mix and stir evenly; Then, add entry while stirring,, add water to full dose again, promptly get the 100mL yew alcohol micro-emulsion until clear and bright.Measure the microemulsion particle diameter and be about 100nm.
Embodiment 4
1) raw material: prepare following raw material by 100 milliliters of preparation amounts:
Paclitaxel and derivant thereof (purity 99.5%): 0.2g; Refined maize oil and olive oil: each 15mL;
Soybean lecithin: 10g; Poloxamer: 10g; Dehydrated alcohol and propylene glycol: each 10mL;
Water: an amount of;
Above-mentioned each composition is all taken from the commercially available product that meets China national medicine preparation standard.
2) operating procedure: above-mentioned raw materials is mixed and stir evenly; Then, add entry while stirring,, add water to full dose again, promptly get the 100mL yew alcohol micro-emulsion until clear and bright.Measure the microemulsion particle diameter and be about 10nm.
Embodiment 5
1) raw material: prepare following raw material by 100 milliliters of preparation amounts:
Paclitaxel and derivant thereof (purity 99.5%): 0.2g; Refined maize oil: 35mL;
Soybean lecithin: 15g; Dehydrated alcohol: 10mL; Water: an amount of;
Above-mentioned each composition is all taken from the commercially available product that meets China national medicine preparation standard.
2) operating procedure: above-mentioned raw materials is mixed and stir evenly; Then, add entry while stirring,, and then add water to full dose, promptly get the 100mL yew alcohol micro-emulsion until clear and bright.Measure the microemulsion particle diameter and be about 10nm.
Claims (4)
1, preparation of microemulsion containing paclitaxel method is characterized in that always measuring paclitaxel 0.2-0.3 gram by preparation 100ml yew alcohol micro-emulsion; The oil phase 30-50ml that constitutes by the arbitrary proportion compositions of any one or two kinds of oil products in refined maize oil, soybean oil or the olive oil; The emulsifying agent 15-35 that is made of lecithin and/or poloxamer restrains; The co-emulsifier 10-30ml that constitutes by dehydrated alcohol and/or propylene glycol; Surplus is a water;
Operating procedure: paclitaxel, oil phase, emulsifying agent, co-emulsifier are mixed and stir evenly; Then, add entry while stirring,, form microemulsion, add water to full dose, promptly get yew alcohol micro-emulsion until clear and bright.
2, according to the preparation of microemulsion containing paclitaxel method of claim 1, it is characterized in that described microemulsion is that thermodynamically stable, homogeneous, particle diameter are the clear liquid of 10nm～100nm, be O/W type self-emulsifying micro-emulsion.
3, according to the preparation of microemulsion containing paclitaxel method of claim 1, the content that it is characterized in that lecithin in the emulsifying agent is 50-100%, and the content of poloxamer is 0-50%; Dehydrated alcohol content is 50-100% in the co-emulsifier, and the content of propylene glycol is 0-50%.
4,, it is characterized in that described lecithin preferably soya lecithin according to the preparation of microemulsion containing paclitaxel method of claim 3; The preferred poloxamer 188 of poloxamer.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011113301A1 (en) * | 2010-03-16 | 2011-09-22 | 北京银谷世纪药业有限公司 | Self-emulsifying formulation of taxanes and preparation method thereof |
| CN102309445A (en) * | 2010-07-06 | 2012-01-11 | 上海现代药物制剂工程研究中心有限公司 | Docetaxel intravenous injection composition and preparation method thereof |
| CN102670504A (en) * | 2012-05-22 | 2012-09-19 | 北京大学 | CLA (conjugated linoleic acid)-PTX (paclitaxel) containing micro-emulsion preparation |
| CN103720654A (en) * | 2014-01-10 | 2014-04-16 | 无锡万全医药技术有限公司 | Aripiprazole micro-emulsion preparation and preparation method thereof |
| CN105123990A (en) * | 2015-10-08 | 2015-12-09 | 河南工业大学 | Method for preparing stable type sesamol microemulsion |
| CN105166908A (en) * | 2015-10-10 | 2015-12-23 | 付强 | Micro-capsule powder rich in omega-3 fatty acid and preparation method thereof |
| CN105638666A (en) * | 2016-03-23 | 2016-06-08 | 江苏省中国科学院植物研究所 | Agricultural ovum killing bacterial agent containing paclitaxel or paclitaxel derivatives and application of agricultural ovum killing bacterial agent |
| CN106805069A (en) * | 2017-01-24 | 2017-06-09 | 中国林业科学研究院资源昆虫研究所 | A kind of high triacontanol microemulsion and preparation method thereof |
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2009
- 2009-07-22 CN CN200910074954A patent/CN101612121A/en active Pending
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011113301A1 (en) * | 2010-03-16 | 2011-09-22 | 北京银谷世纪药业有限公司 | Self-emulsifying formulation of taxanes and preparation method thereof |
| CN102309445A (en) * | 2010-07-06 | 2012-01-11 | 上海现代药物制剂工程研究中心有限公司 | Docetaxel intravenous injection composition and preparation method thereof |
| CN102309445B (en) * | 2010-07-06 | 2013-03-27 | 上海现代药物制剂工程研究中心有限公司 | Docetaxel intravenous injection composition and preparation method thereof |
| CN102670504A (en) * | 2012-05-22 | 2012-09-19 | 北京大学 | CLA (conjugated linoleic acid)-PTX (paclitaxel) containing micro-emulsion preparation |
| CN102670504B (en) * | 2012-05-22 | 2015-04-15 | 北京大学 | CLA (conjugated linoleic acid)-PTX (paclitaxel) containing micro-emulsion preparation |
| CN103720654A (en) * | 2014-01-10 | 2014-04-16 | 无锡万全医药技术有限公司 | Aripiprazole micro-emulsion preparation and preparation method thereof |
| CN105123990A (en) * | 2015-10-08 | 2015-12-09 | 河南工业大学 | Method for preparing stable type sesamol microemulsion |
| CN105123990B (en) * | 2015-10-08 | 2021-08-06 | 河南工业大学 | Method for preparing stable sesamol microemulsion |
| CN105166908A (en) * | 2015-10-10 | 2015-12-23 | 付强 | Micro-capsule powder rich in omega-3 fatty acid and preparation method thereof |
| CN105638666A (en) * | 2016-03-23 | 2016-06-08 | 江苏省中国科学院植物研究所 | Agricultural ovum killing bacterial agent containing paclitaxel or paclitaxel derivatives and application of agricultural ovum killing bacterial agent |
| CN106805069A (en) * | 2017-01-24 | 2017-06-09 | 中国林业科学研究院资源昆虫研究所 | A kind of high triacontanol microemulsion and preparation method thereof |
| CN106805069B (en) * | 2017-01-24 | 2021-03-09 | 中国林业科学研究院资源昆虫研究所 | High-grade alkanol microemulsion and preparation method thereof |
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Open date: 20091230 |