CN102198100B - Carmustine injectable powder and preparation technology - Google Patents
Carmustine injectable powder and preparation technology Download PDFInfo
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- CN102198100B CN102198100B CN201110130214.7A CN201110130214A CN102198100B CN 102198100 B CN102198100 B CN 102198100B CN 201110130214 A CN201110130214 A CN 201110130214A CN 102198100 B CN102198100 B CN 102198100B
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- carmustine
- soybean phospholipid
- injectable powder
- powder
- mannitol
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Abstract
The present invention relates to a kind of carmustine injectable powder and preparation technology of pro-liposome form.This carmustine injectable powder is Main Ingredients and Appearance by carmustine, soybean phospholipid, cholesterol and crystallization of mannitol powder.Wherein the weight percentage ranges of each component is, carmustine: 1.5-3%; Soybean phospholipid: 15-20%; Cholesterol: 4-6%; Mannitol: 71.1-79.5%.In soybean phospholipid used, phosphatidylcholine weight content is 65% ~ 70%, and PHOSPHATIDYL ETHANOLAMINE weight content is 14%-20%.The made carmustine injectable powder feature of this technique is that envelop rate can reach 100%, and be easy to be scattered in water, particle diameter is little, and stability is better, and toxic and side effects is little, safer, stores also more convenient.
Description
Technical field:
The present invention relates to a kind of carmustine is medicine, forms injectable powder prescription and the preparation technology of pro-liposome form.
Background technology:
Carmustine (Canmustin), (molecular formula is C also to claim carmustine
5h
9cl
2n
3o
2), being called for short CBNU, is broad-spectrum anticarcinogen, there is fat-solubility, easily by blood brain barrier, be the drug of first choice of cerebroma, for malignant brain tumor, the marrowbrain transfer of malignant tumor, leukemia is better with the patient's curative effect invading nervus centralis, and its anticancer mechanism is and archaeal dna polymerase effect, suppresses the synthesis of RNA and DNA, have stronger lethal effect to Tumor cells, its effect is similar with alkylating agent.BCNU also kills and wounds normal cell while suppression Tumor cells, mainly acts on medulla hematopoietic system, obvious to leukocyte, hematoblastic suppression.Usually after medication, in 3---5 week, occur during administration, there is the digestive tract reaction such as Nausea and vomiting, loss of appetite, also can produce liver stomach toxicity reaction time heavy dose of, pigmentation or dermatitis can be occurred with contact skin.
Common carmustine injection is the less stable of aseptic Aqueous Solutions of Polyethylene Glycol, carmustine, and long-time storage is easy to decompose in aqueous.In order to reduce the toxic and side effects of BCNU, enhanced stability, improving curative effect, adopting liposome as the carrier of BCNU.
Liposome (Liposomem abridge L) is a kind of artificial class biomembrane, the closed microcapsule be made up of one or more layers lipoids bilayer.Its film is fat phase, can wrap up fat-soluble medicine; Remainder is aqueous phase, can coated water-soluble medicine.Liposome has the potential of very large drug coated, and fat-soluble strong or that water solublity is strong two class medicines are the optimum medicine of liposome bag quilt.BCNU is strong lipophilic substance, can be wrapped in lipid bilayer, and may obtain high encapsulation rate, therefore liposome may be the carrier of BCNU the best.The film material (phospholipid and steroid) of composition liposome is similar to the membrane substance of mammalian cell, is easy to be degraded, has biocompatibility, non-immunogenicity and toxicity in body.Carmustine is wrapped in the duplicature of liposome, substantially reduces its toxic and side effects to human body, can to patient's continuous use.But carmustin liposome still also exists unstability under solution state, as seepage, the problem such as aggregation of particles and phospholipid oxidation in the liquid state, hydrolysis of medicine, its practical application is affected.
Pro-liposome is with certain crystalline powder for proppant, is coated on by lipid film on this crystalline powder by rights, stores with this solid-state form, is just adding disperse medium before use, i.e. redispersible formation liposome.This way solves the physical instability of liposomal dispersion, as the seepage of medicine, aggregation of particles and phospholipid oxidation in the liquid state, hydrolysis etc.And be convenient to transport, storage, be also applicable to commercial production.
Namely carmustine injectable powder is be encapsulated in the duplicature of liposome by carmustine, is then coated on a kind of crystalline powder by this lipid film, thus forms low, the good stability of toxicity, is easy to store the novel form of transport.
Author of the present invention is once in patent " carmustine injectable powder and preparation method ", the patent No. is the prescription and the preparation method that describe carmustine pro-liposome injectable powder in CN98113958.2, the feature of the method is first encapsulated into by carmustine in bilayer lipid membrane that phospholipid and sterin formed, again this lipid film is coated on crystallization of mannitol powder, define carmustine injectable powder, during use, water mixes with injectable powder, forms carmustin liposome injection.Because carmustine is encapsulated in liposome tunic, substantially reduce the toxic and side effects of carmustine to human body, to patient's continuous use, curative effect can be ensure that.Meanwhile, because dosage form is pressed powder for this reason, effectively can avoid the hydrolysis of carmustine, substantially increase product stability and convenient transport.
In patent CN98113958.2, the envelop rate of BCNU in liposome is generally about 90%, still has about 10% free BCNU in system.It disperses to form liposome in water, and the particle diameter of more than 99% is less than 5 μm.For improving safety and the stability of product further, we improve product.
Summary of the invention:
On the former working foundation of the present invention, prescription and technique are improved further, a kind of particle diameter reducing liposome is provided, improves prescription of the pro-liposome carmustine injectable powder of BCNU envelop rate and preparation method thereof, make 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 realizes as follows:
Carmustine: 1.5-3%;
Soybean phospholipid: 15-20%;
Cholesterol: 4-6%;
Mannitol: 71.1-79.5%.
The mixture that soybean phospholipid used in this invention is is Main Ingredients and Appearance with phosphatidylcholine (also claiming lecithin) and PHOSPHATIDYL ETHANOLAMINE (also claiming cephalin), what this was through certain technique separating-purifying is mainly used in intravenous Refined Soybean phospholipid, require that phosphatidylcholine weight content is wherein 65% ~ 70%, PHOSPHATIDYL ETHANOLAMINE weight content is 14%-20%.In prescription, Refined Soybean phospholipid and cholesterol form the liposome membrane with closed microcapsule, compared with the liposome formed with cholesterol with other single phospholipid (as lecithin), this liposome membrane has better film-strength and covering property, effectively can improve the envelop rate of carmustine, and it is dispersed to make liposome be easier to, form the dispersion that particle diameter is less.Experiment proves, in the forming process of liposome, adds a certain amount of cephalin in lecithin, and than being used alone, the liposome membrane that lecithin formed is more tough and tensile, and hole is less, and its dispersibility in water is better.This Refined Soybean phospholipid being Main Ingredients and Appearance with lecithin and cephalin is better than other phospholipid.
Crystalline powder in this invention mainly plays proppant effect, and lipid film can be coated on this crystalline powder surface, makes it to preserve in the solid state, prevents the seepage of medicine, oxidation, hydrolysis etc., improves stability and the safety of medicine.This crystalline powder with the effect of mannitol for the best.In CN98113958.2, the content of crystalline powder is 55-71%; But in the system for liposome Main Components with Refined Soybean phospholipid and cholesterol, the content of mannitol is good with 71.1-79.5%.The carmustin liposome precursor formed, its envelop rate can reach 100%, and this injectable powder is very easily scattered in water, usually can be soluble in water at about 5 minutes, and the liposome particles formed is more tiny, evenly the particle diameter of more than 99% is all less than 2 μm.
The preparation method of carmustine injectable powder of the present invention is: the composition dissolution with solvents such as carmustine, Refined Soybean phospholipid, cholesterol are become solution.Solvent generally adopts ether, ethanol.This course of dissolution requires to make dissolving by the shake mixing of same direction.Joining dissolving the gradation of gained solution in the crystallization of mannitol powder constantly stirred, after mix homogeneously, through vacuum drying recycling design, making loose carmustine injectable powder.Product subpackage is filled nitrogen, sealing.All operations of the present invention all need operate under 4-6 DEG C and aseptic condition.
We have studied its granularity and distribution thereof with Ku Ertefa (Coulter), TA--II type Ku Erte (Coulter) instrument is used to measure, result shows: carmustine injectable powder to be scattered in water form liposome, maximum particle diameter is no more than 10 μm, the particle that particle diameter is greater than 5 μm is no more than 0.2 ‰, and the particle diameter of more than 99% is less than 2 μm.Meet the regulation of 2000 in China pharmacopeia about liposome particle size.
Adopt ultraviolet spectrophotometry to measure the content of BCNU, remove free BCNU with gel chromatographic columns (model Sephadex G-50) sieve method, measure envelop rate.Result shows, does not detect free BCNU in system, and the envelop rate of BCNU is 100%.
Product was through 4-6 DEG C of storage 18 months, and timing detects, and observed change, the change of jitter time, the liposome particle size of formation and the change of distribution thereof of the appearance luster of product, content and envelop rate.Result shows, in the storage of 18 months, content does not have change substantially, envelop rate is still 100%, and within granularity carmustine injectable powder being distributed to the liposome formed in water is 5 μm substantially, the granularity within 2 μm is still more than 99%, appearance luster is still faint yellow, granule has caking phenomenon, but does not affect and disperse in water, and jitter time is usually at 5-8 minute.Show that this carmustine injectable powder is more stable.
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 carmustine injectable powder that the present invention is made, clinical research is carried out to malignant tumor chemotherapy in brain, implemented case 66 example, total effective rate 64%, effective 21%.In the treatment of 6 months, CT follow-up investigations result, tumor regression is obvious, does not occur the toxic and side effects such as bone marrow depression, compared with common water-soluble grease plastid, better efficacy.But because the Clinical practice time is short, clinical case data statistics is still incomplete.
Detailed description of the invention
The present invention is further illustrated below in conjunction with embodiment.In embodiment, all operations all operates under 4-6 DEG C and aseptic condition.
Embodiment 1,
Weighing Refined Soybean phosphatidase 1 00g, cholesterol 25g, carmustine 12.5g, mannitol 412.5g, take ether as solvent, and the shake of same direction makes to be dissolved to clear and bright, places, filters, and gradation is sprayed on the crystallization of mannitol powder that constantly stirs, mixing.With 0.75-0.1Mpa vacuum drying, reclaim ether.In products obtained therefrom, ether content must not detect.Be distributed into 100 and be filled with 99.99% high pure nitrogen, sealing.Wherein in Refined Soybean phospholipid, phosphatidylcholine weight content is 66%, and PHOSPHATIDYL ETHANOLAMINE weight content is 20%.
Embodiment 2
Weighing Refined Soybean phosphatidase 1 08g, cholesterol 30.5g, carmustine 14.6g, mannitol 396.9g, take ether as solvent, and the shake of same direction makes to dissolve completely, places, and filters, and gradation is sprayed on the continuous crystallization of mannitol powder stirred, mixing.With 0.75-0.1Mpa vacuum drying, reclaim ether.Product is detected, qualified rear subpackage, and be filled with 99.99% high pure nitrogen, sealing.Wherein in Refined Soybean phospholipid, phosphatidylcholine weight content is 70%, and PHOSPHATIDYL ETHANOLAMINE weight content is 14.3%.
Embodiment 3
Weighing Refined Soybean phospholipid 91.6g, cholesterol 22.9g, carmustine 10.5g, mannitol 425g, take ether as solvent, and the shake of same direction makes to dissolve completely, places, and filters, and gradation is sprayed on the continuous crystallization of mannitol powder stirred, mixing.Vacuum drying, reclaims ether.Be distributed into 100 bottles after products obtained therefrom detection is qualified, and be filled with 99.99% high pure nitrogen, sealing.Wherein in Refined Soybean phospholipid, phosphatidylcholine weight content is 67.6%, and PHOSPHATIDYL ETHANOLAMINE weight content is 17.1%.
Get a certain amount of above-described embodiment products obtained therefrom, soluble in waterly obtain carmustine injection, detect wherein free BCNU content, envelop rate, particle diameter and jitter time etc., testing result is as follows:
Carmustine injectable powder testing result
| Free BCNU content | Envelop rate (%) | Particle diameter > 5 μm | Particle diameter≤2 μm | 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 (2)
1. a 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%;
The Refined Soybean phospholipid that described soybean phospholipid is phosphatidylcholine weight content is 65% ~ 70%, PHOSPHATIDYL ETHANOLAMINE weight content is 14%-20%.
2. a preparation method for carmustine injectable powder is that carmustine, soybean phospholipid, cholesterol composition dissolution with solvents are become solution, and this course of dissolution requires to make it dissolve by the shake mixing of same direction; The percentage by weight of each component is carmustine 1.5-3%, soybean phospholipid 15-20%, cholesterol 4-6%, mannitol 71.1-79.5%; Solvent adopts ether or ethanol; The gradation of dissolving gained solution is sprayed onto on crystallization of mannitol powder, after mix homogeneously, through vacuum drying recycling design, makes loose carmustine injectable powder; The Refined Soybean phospholipid that described soybean phospholipid is phosphatidylcholine weight content is 65% ~ 70%, PHOSPHATIDYL ETHANOLAMINE weight content is 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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| 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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| CN102198100A CN102198100A (en) | 2011-09-28 |
| CN102198100B true CN102198100B (en) | 2015-10-07 |
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| CN201110130214.7A Expired - Fee Related CN102198100B (en) | 2011-05-19 | 2011-05-19 | Carmustine injectable powder and preparation technology |
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Families Citing this family (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 |
| CA3044636C (en) * | 2016-11-25 | 2023-10-03 | Emcure Pharmaceuticals Limited | Lipid formulations of carmustine |
| CA3109440A1 (en) | 2018-09-05 | 2020-03-12 | 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 not_active Expired - Fee Related
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 (3)
| Title |
|---|
| 卡氮芥脂质体注射液的研究;马淑贤等;《中国药学杂志》;19950630;第30卷(第6期);第345-348页 * |
| 注射用大豆磷脂的精制工艺的研究及其在医药上的应用;梁玉屏;《粮食与油脂》;19881231(第4期);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》.1994,(第12期),45-46. * |
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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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