CN102198100A - Carmustine powder injection and preparation technology thereof - Google Patents
Carmustine powder injection and preparation technology thereof Download PDFInfo
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- CN102198100A CN102198100A CN2011101302147A CN201110130214A CN102198100A CN 102198100 A CN102198100 A CN 102198100A CN 2011101302147 A CN2011101302147 A CN 2011101302147A CN 201110130214 A CN201110130214 A CN 201110130214A CN 102198100 A CN102198100 A CN 102198100A
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- carmustine
- soybean phospholipid
- liposome
- injectable powder
- powder
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Abstract
The invention relates to a pro-liposome carmustine powder injection and a preparation process thereof. The carmustine powder injection mainly comprises, by weight, 1.5 to 3 % of carmustine, 15 to 20% of granulesten, 4 to 6% of cholesterol and 71.1 to 79.5% of mannitol crystalline powders, wherein the granulesten comprises, by weight, 65 to 70% of phosphatidylcholine and 14 to 20% of phosphatidylethanolamine. The carmustine powder injection prepared by the preparation process is easy to disperse in water and convenient in storage, and has an entrapment rate of 100%, a small particle size, improved stability, small toxic and side effects and enhanced safety.
Description
Technical field:
The present invention relates to a kind of carmustine is medicine, forms the injectable powder prescription and the preparation technology of pro-liposome form.
Background technology:
Carmustine (Canmustin) claims that also (molecular formula is C to carmustine
5H
9Cl
2N
3O
2), be called for short CBNU, be the broad-spectrum anticarcinogen, has fat-solubility,, be the drug of first choice of cerebroma, easily for malignant brain tumor by blood brain barrier, the marrowbrain of malignant tumor shifts, leukemia is better with patient's curative effect of invading nervus centralis, and its anticancer mechanism is and the archaeal dna polymerase effect to suppress the synthetic of RNA and DNA, the cerebroma cell is had stronger lethal effect, and its effect is similar with alkylating agent.BCNU also kills and wounds normal cell when suppressing the cerebroma cell, mainly be to act on medulla hematopoietic system, and is apparent in view to leukocyte, hematoblastic inhibition.Usually 3---5 occurred in week after medication, and digestive tract reactions such as nauseating, vomiting, loss of appetite are arranged during the administration, also can produce the reaction of liver stomach toxicity when heavy dose of, pigmentation or dermatitis can occur with contact skin.
Common carmustine injection is aseptic Polyethylene Glycol aqueous solution, the less stable of carmustine, and long-time the storage is easy to decompose in aqueous solution.In order to reduce the toxic and side effects of BCNU, enhanced stability improves curative effect, adopts the carrier of liposome as BCNU.
Liposome (Liposomem abridge L) is a kind of artificial class biomembrane, the sealing microcapsule of being made up of one or more layers lipoids bilayer.Its film is the fat phase, can wrap up fat-soluble medicine; Remainder is a water, but the coated water-soluble medicine.Liposome has the potential of very big drug coated, and fat-soluble strong or two strong class medicines of water solublity are the optimum medicine of liposome bag quilt.BCNU is strong lipophilic substance, can be wrapped in the lipid bilayer, and may obtain high envelop rate, so liposome may be the carrier of BCNU the best.The film material (phospholipid and steroid) of forming liposome is similar to the membrane substance of mammalian cell, is easy to be degraded in body, has biocompatibility, non-immunogenicity and toxicity.Carmustine is wrapped in the duplicature of liposome, has reduced its toxic and side effects to human body greatly, can be to patient's continuous use.But the carmustine liposome still exists unstability under solution state, as problems such as the oxidation under liquid state of seepage, aggregation of particles and the phospholipid of medicine, hydrolysis, its practical application is affected.
Pro-liposome is to be proppant with certain crystalline powder, and lipid film is coated on this crystalline powder by rights, stores with this solid-state form, is just facing with preceding adding disperse medium promptly redispersible formation liposome.This way has solved the physical instability of liposome disperse system, as the oxidation under liquid state of seepage, aggregation of particles and the phospholipid of medicine, hydrolysis etc.And be convenient to transportation, storage, also be applicable to commercial production.
The carmustine injectable powder promptly is that carmustine is encapsulated in the duplicature of liposome, then this lipid film is coated on a kind of crystalline powder, thereby forms that toxicity is low, good stability, be easy to store the novel form of transportation.
Author of the present invention is once in patent " carmustine injectable powder and preparation method ", the patent No. is prescription and a preparation method of having introduced carmustine pro-liposome injectable powder among the CN98113958.2, the characteristics of this method are earlier carmustine to be encapsulated in phospholipid and the formed bilayer lipid membrane of sterin, again this lipid film is coated on the crystallization of mannitol powder, formed the carmustine injectable powder, water mixes with injectable powder during use, forms the carmustine lipidosome injection.Because carmustine is encapsulated in the liposome tunic, has reduced the toxic and side effects of carmustine to human body greatly, can guarantee curative effect to patient's continuous use.Simultaneously,, the hydrolysis of carmustine be can effectively avoid, product stability and convenient transportation improved greatly because this dosage form is a pressed powder.
In patent CN98113958.2, the envelop rate of BCNU in liposome is generally about 90%, still has about 10% free BCNU in the system.It disperses to form liposome in water, and the particle diameter more than 99% is less than 5 μ m.For further improving security of products and stability, we improve product.
Summary of the invention:
On the former working foundation of the present invention, prescription and technology are further improved, a kind of particle diameter that reduces liposome is provided, and prescription of the pro-liposome carmustine injectable powder of raising BCNU envelop rate and preparation method thereof makes carmustine injectable powder product more stablize safer.
Carmustine injectable powder prescription of the present invention and preparation method thereof: include BCNU, soybean phospholipid, cholesterol, manna crystalline powder in its prescription.In the prescription of this invention, the percentage by weight of each component is realized as follows:
Carmustine: 1.5-3%;
Soybean phospholipid: 15-20%;
Cholesterol: 4-6%;
Mannitol: 71.1-79.5%.
Used soybean phospholipid is to be the mixture of Main Ingredients and Appearance with phosphatidylcholine (also claiming lecithin) and PHOSPHATIDYL ETHANOLAMINE (also claiming cephalin) in this invention, this is to separate the intravenous refining soybean phospholipid that is mainly used in of purifying and forming through certain technology, requiring phosphatidylcholine weight content wherein is 65%～70%, and the PHOSPHATIDYL ETHANOLAMINE weight content is 14%-20%.Refining soybean phospholipid and cholesterol form the liposome membrane with sealing microcapsule in prescription, compare with the liposome that cholesterol forms with other single phospholipid (as lecithin), this liposome membrane has better film-strength and covering property, can effectively improve the envelop rate of carmustine, and make liposome be easier to homodisperse, form the littler dispersion of particle diameter.Experiment showed, that in the forming process of liposome add a certain amount of cephalin in lecithin, more tough and tensile than the formed liposome membrane of independent use lecithin, hole is littler, and its dispersibility in water is better.This is that the refining soybean phospholipid of Main Ingredients and Appearance is better than other phospholipid with lecithin and cephalin.
Crystalline powder in this invention mainly plays the proppant effect, and lipid film can be coated on this crystalline powder surface, makes it to preserve down solid-state, prevents the seepage, oxidation, hydrolysis of medicine etc., improves stability of drug and safety.This crystalline powder is the best with the effect of mannitol.In CN98113958.2, the content of crystalline powder is 55-71%; But, be in the system of the main component of liposome with refining soybean phospholipid and cholesterol, the content of mannitol is good with 71.1-79.5%.Formed carmustine liposome precursor, its envelop rate can reach 100%, and this injectable powder very easily is scattered in water, usually can be soluble in water about 5 minutes, formed liposome particles is more tiny, and is more even, and the particle diameter more than 99% is all less than 2 μ m.
The preparation method of carmustine injectable powder of the present invention is: compositions such as carmustine, refining soybean phospholipid, cholesterol are become solution with dissolution with solvents.Solvent generally adopts ether, ethanol.This course of dissolution requires to shake mixing by same direction and makes dissolving.The gradation of dissolving gained solution is joined in the crystallization of mannitol powder of continuous stirring, behind the mix homogeneously, reclaim solvent, make loose carmustine injectable powder through vacuum drying.With the product packing and fill nitrogen, seal.All operations of the present invention all needs to operate under 4-6 ℃ and aseptic condition.
We have studied its granularity and distribution thereof with Ku Ertefa (Coulter), use TA--II type Ku Erte (Coulter) instrument to measure, the result shows: the carmustine injectable powder is scattered in the liposome that forms in the water, maximum particle diameter is no more than 10 μ m, particle diameter is no more than 0.2 ‰ greater than the particle of 5 μ m, and the particle diameter more than 99% is less than 2 μ m.The regulation that meets China's relevant liposome particle size of pharmacopeia in 2000.
Adopt ultraviolet spectrophotometry to measure the content of BCNU, remove free BCNU, measure envelop rate with gel chromatographic columns (model Sephadex G-50) sieve method.The result shows, does not detect free BCNU in the system, and the envelop rate of BCNU is 100%.
Product was stored regularly detection, variation, the variation of jitter time, the liposome particle size of formation and the variation of distribution thereof of appearance luster, content and the envelop rate of observation product 18 months through 4-6 ℃.The result shows, in 18 months storage, content does not have variation substantially, envelop rate still is 100%, and the granularity that the carmustine injectable powder is distributed to the liposome that forms in the water is in the 5 μ m substantially, and 2 μ m still are more than 99% with interior granularity, appearance luster still is faint yellow, granule has caking phenomenon, does not disperse but do not influence in water, and jitter time is usually at 5-8 minute.Show that this carmustine injectable powder is more stable.
The animal acute toxicity test result of study: the LD50=188.15 ± 27.48mg/kg of carmustine injectable powder, and the LD50=45.20 ± 8.47mg/kg of common BCNU injection, its toxicity reduces by 4.2 times.
With the made carmustine injectable powder of the present invention, malignant tumor chemotherapy in the brain has been carried out clinical research, implement case 66 examples, total effective rate 64%, produce effects 21%.In 6 months treatment, CT follow-up investigations result, tumor is dwindled obviously, toxic and side effects such as bone marrow depression do not occur, compares better efficacy with common water-soluble grease plastid.But because of lacking clinical service time, the clinical case data statistics is still incomplete.
The specific embodiment
Further specify the present invention below in conjunction with embodiment.All operations is all operated under 4-6 ℃ and aseptic condition among the embodiment.
Embodiment 1,
Soybean phospholipid 100g, cholesterol 25g, carmustine 12.5g, mannitol 412.5g are made with extra care in weighing, are solvent with the ether, and same direction is shaken to make and is dissolved to clear and brightly, places, and filters, and gradation is sprayed on the crystallization of mannitol powder of continuous stirring, mixing.With the 0.75-0.1Mpa vacuum drying, reclaim ether.Ether content must not detect in the products obtained therefrom.Be distributed into 100 and charge into 99.99% high pure nitrogen, seal.Wherein in refining soybean phospholipid, the phosphatidylcholine weight content is 66%, and the PHOSPHATIDYL ETHANOLAMINE weight content is 20%.
Embodiment 2
Soybean phospholipid 108g, cholesterol 30.5g, carmustine 14.6g, mannitol 396.9g are made with extra care in weighing, are solvent with the ether, and same direction is shaken and made dissolving fully, places, and filters, and gradation is sprayed on the crystallization of mannitol powder of continuous stirring, mixing.With the 0.75-0.1Mpa vacuum drying, reclaim ether.Product is detected, qualified back packing, and charge into 99.99% high pure nitrogen, seal.Wherein in refining soybean phospholipid, the phosphatidylcholine weight content is 70%, and the PHOSPHATIDYL ETHANOLAMINE weight content is 14.3%.
Embodiment 3
Soybean phospholipid 91.6g, cholesterol 22.9g, carmustine 10.5g, mannitol 425g are made with extra care in weighing, are solvent with the ether, and same direction is shaken and made dissolving fully, places, and filters, and gradation is sprayed on the crystallization of mannitol powder of continuous stirring, mixing.Vacuum drying reclaims ether.Be distributed into 100 bottles after the products obtained therefrom detection is qualified, and charge into 99.99% high pure nitrogen, seal.Wherein in refining soybean phospholipid, the phosphatidylcholine weight content is 67.6%, and the PHOSPHATIDYL ETHANOLAMINE weight content is 17.1%.
Get a certain amount of the foregoing description products obtained therefrom, the carmustine injection that obtains soluble in water detects wherein free BCNU content, envelop rate, particle diameter and jitter time etc., and testing result is as follows:
Carmustine injectable powder testing result
| Free BCNU content | Envelop rate (%) | Particle diameter＞5 μ m | Particle diameter≤2 μ m | Jitter time (min) | |
| Embodiment 1 | Do not detect | 100 | 0 | 99.6％ | 5.2 |
| Embodiment 2 | Do not detect | 100 | 0.12‰ | 99.1％ | 5.8 |
| Embodiment 3 | Do not detect | 100 | 0.08‰ | 99.3％ | 5.3 |
Claims (4)
1. carmustine injectable powder, the percentage by weight of each component is as follows:
Carmustine: 1.5-3%;
Soybean phospholipid: 15-20%;
Cholesterol: 4-6%;
Mannitol: 71.1-79.5%.
2. as the said carmustine injectable powder of claim 1, its feature exists: soybean phospholipid is for the phosphatidylcholine weight content is 65%～70%, the PHOSPHATIDYL ETHANOLAMINE weight content is the refining soybean phospholipid of 14%-20%.
3. the preparation method of a carmustine injectable powder is that compositions such as carmustine, soybean phospholipid, cholesterol are become solution with dissolution with solvents, and this course of dissolution requires to shake mixing by same direction and makes its dissolving; The percentage by weight of each component is carmustine 1.5-3%, uses soybean phospholipid 15-20%, cholesterol 4-6%, mannitol 71.1-79.5%; Solvent adopts ether or ethanol; To dissolve the gradation of gained solution and be sprayed onto on the crystallization of mannitol powder, behind the mix homogeneously, reclaim solvent, make loose carmustine injectable powder through vacuum drying.
4. as the preparation method of the said carmustine injectable powder of claim 3, its feature exists: soybean phospholipid is for the phosphatidylcholine weight content is 65%～70%, the PHOSPHATIDYL ETHANOLAMINE weight content is the refining soybean phospholipid of 14%-20%.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110130214.7A CN102198100B (en) | 2011-05-19 | 2011-05-19 | Carmustine injectable powder and preparation technology |
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|---|---|---|---|
| CN201110130214.7A CN102198100B (en) | 2011-05-19 | 2011-05-19 | Carmustine injectable powder and preparation technology |
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| CN102198100A true CN102198100A (en) | 2011-09-28 |
| CN102198100B CN102198100B (en) | 2015-10-07 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103989636A (en) * | 2014-06-12 | 2014-08-20 | 东南大学 | Nitrogen mustard liposome and preparation method thereof |
| US20190298671A1 (en) * | 2016-11-25 | 2019-10-03 | Emcure Pharmaceuticals Limited | Lipid formulations of carmustine |
| US11865206B2 (en) | 2018-09-05 | 2024-01-09 | Emcure Pharmaceuticals Ltd | Stable ready-to-use carmustine pharmaceutical composition |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1198930A (en) * | 1998-04-30 | 1998-11-18 | 大连市医药科学研究所 | Carmustinum powder injection and its preparation method |
| CN1520808A (en) * | 2003-02-09 | 2004-08-18 | 谷松兰 | Carmustine precursor liposome powder injection formulation and process for preparing |
-
2011
- 2011-05-19 CN CN201110130214.7A patent/CN102198100B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1198930A (en) * | 1998-04-30 | 1998-11-18 | 大连市医药科学研究所 | Carmustinum powder injection and its preparation method |
| CN1520808A (en) * | 2003-02-09 | 2004-08-18 | 谷松兰 | Carmustine precursor liposome powder injection formulation and process for preparing |
Non-Patent Citations (4)
| Title |
|---|
| 中华人民共和国卫生部药政局: "《新药品种资料汇编》", 31 December 1998, article "精制卵磷脂", pages: 370 * |
| 梁玉屏: "注射用大豆磷脂的精制工艺的研究及其在医药上的应用", 《粮食与油脂》, no. 4, 31 December 1988 (1988-12-31), pages 33 - 37 * |
| 陆文达等: "大豆磷脂（供注射用）在国内已能批量生产", 《上海医药》, no. 12, 31 December 1994 (1994-12-31), pages 45 - 46 * |
| 马淑贤等: "卡氮芥脂质体注射液的研究", 《中国药学杂志》, vol. 30, no. 6, 30 June 1995 (1995-06-30), pages 345 - 348 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103989636A (en) * | 2014-06-12 | 2014-08-20 | 东南大学 | Nitrogen mustard liposome and preparation method thereof |
| US20190298671A1 (en) * | 2016-11-25 | 2019-10-03 | Emcure Pharmaceuticals Limited | Lipid formulations of carmustine |
| US10583101B2 (en) * | 2016-11-25 | 2020-03-10 | Emcure Pharmaceuticals Limited | Lipid formulations of carmustine |
| US11865206B2 (en) | 2018-09-05 | 2024-01-09 | Emcure Pharmaceuticals Ltd | Stable ready-to-use carmustine pharmaceutical composition |
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| Publication number | Publication date |
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| CN102198100B (en) | 2015-10-07 |
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Effective date of registration: 20171030 Address after: 300000 Tianjin city temple town Xiqing District of outer ring road and friendship road junction Southwest Forestry Xiyuan 37-3-102-2 Patentee after: Tianjin nuoli science and Technology Co Ltd Address before: 116021 Liaoning Province, Dalian city Zhongshan District Wuhan Street No. 42 4-3 Co-patentee before: Zhou Honghai Patentee before: Ma Shuxian |
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