CN101966158A - Bendamustine hydrochloride freeze-dried powder injection for injection and preparation method thereof - Google Patents
Bendamustine hydrochloride freeze-dried powder injection for injection and preparation method thereof Download PDFInfo
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- CN101966158A CN101966158A CN 201010295570 CN201010295570A CN101966158A CN 101966158 A CN101966158 A CN 101966158A CN 201010295570 CN201010295570 CN 201010295570 CN 201010295570 A CN201010295570 A CN 201010295570A CN 101966158 A CN101966158 A CN 101966158A
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Abstract
The invention relates to the technical field of medicinal preparations. Bendamustine hydrochloride is easy to degrade in the preparation process, so in order to prevent degradation products from generating, the aqueous solution of tertiary butanol with certain concentration is used as a solvent; therefore, medicaments and relevant auxiliary materials are dissolved, and the dissolved mixture is subjected to freeze-drying so as to obtain the bendamustine hydrochloride; however, the tertiary butanol is harmful to human bodies when inhaled or orally taken, the conventional literature indicates that the tertiary butanol can cause the oxidative injury of deoxyribonucleic acid (DNA), and experiments of rats and mice prove that the tertiary butanol has the carcinogenicity. The invention provides a bendamustine hydrochloride freeze-dried powder injection for injection and a preparation method thereof. In the preparation method, an organic solvent and particularly the tertiary butanol are not added in the processes of preparation and freeze-drying, so the safety of production and clinical medication is improved greatly. The bendamustine hydrochloride freeze-dried powder injection for the injection has the high stability and water solubility, has the characteristics of stability, controlled quality, safety and reliability, and particularly does not have organic solvent residues.
Description
Technical field
The present invention relates to medical technical field, be specifically related to a kind of organic solvent that do not contain, particularly do not contain hydrochloride for injection bendamustine freeze-dried powder injection of the tert-butyl alcohol and preparation method thereof.
Background technology
Bendamustine hydrochloride (Bendamustine Hydrochloride) early than the initial stage sixties 19th century by Ozegowski and its colleague microbiological test association development at Jena, Germany, be a kind of dual-functional group alkylating agent, external have cytotoxicity to human ovarian cancer and breast carcinoma.Its pharmacological action of bendamustine hydrochloride is to make dna single chain and double-stranded crosslinked by alkanisation, disturbs the function of DNA and synthesizing of DNA, thus the performance antitumor action.Be mainly used in separately or and treat following malignant tumor: Hodgkin, non Hodgkin lymphoma, plasmocytoma (multiple myeloma), chronic lymphocytic leukemia (CLL), breast carcinoma etc. with other antitumor drug drug combination.
[structural formula]:
[molecular formula]: C
16H
21Cl
2N
3O
2HCl
[relative molecular mass]: 394.72
[Chinese named]: 4-[5-[pair-(2-chloroethyl) amino]-1-methyl-2-benzimidazolyl] the butyrate hydrochlorate
[English name]: 4-[5-[bis (2-chloroethyl) amino]-1-methylbenzimidazol-2-yl] butanoic acid ydrochloride.
Bendamustine belongs to the nitrogen mustards alkylating agent, and big to Weishang epidermis cell toxicity, the oral organism-absorbing utilization rate is low, and therapeutic effect is not good.In addition, bendamustine hydrochloride character instability, illumination, being heated all to make its degraded, produces the degradation impurity cause toxic and side effects.For this reason, it is prepared into the injection freeze-dried powder, has both improved stability of drug, improved bioavailability again.
Because bendamustine hydrochloride is very easily degraded in process for preparation, people are dissolved medicine and relevant auxiliary materials as solvent with certain density tert-butyl alcohol aqueous solution for fear of the generation of catabolite, and lyophilizing forms then.For example: Chinese patent application CN200910181696.1, denomination of invention is the claim 6 of the prospectus (CN 101606934A) of " bendamustine hydrochloride compound ", in 7, requiring has the tert-butyl alcohol in the lyophilizing liquid, and 15 embodiment of this patent all use the tert-butyl alcohol; Chinese patent application CN200910033895.8, denomination of invention is in the claim 1 of prospectus (CN 101584668A) of " bendamustine hydrochloride freeze-dried powder injection ", requiring has the tert-butyl alcohol in the lyophilizing liquid, and 10 embodiment of this patent all use the tert-butyl alcohol; The claim 21-24 of PCT patent application WO2006/07662, in 39,40,48,53, requiring the used organic solvent of lyophilizing is the tert-butyl alcohol, dissolvent residual is the tert-butyl alcohol in the medicine; In the specification digest of U.S. Patent application US 20060159713, require organic solvent in the 0030th, 0037,0047 joint, and optimum is the tert-butyl alcohol.
The tert-butyl alcohol belongs to organic solvent, and is inflammable and explosive, brings potential safety hazard to production, needs to use supporting explosion-proof type ventilating system and equipment, and organic solvent very easily causes damage to vacuum pump in freeze-drying process, has increased production cost greatly; In addition, in freeze-drying process, can't avoid the tert-butyl alcohol residual in freeze-dried powder, bibliographical information, the tert-butyl alcohol sucks or is oral harmful to health, poisoning manifestations can have headache, nauseating, dizzy, make as solvent and inevitably to have residual organic solvent (WO2006/07662 spells out as the PCT patent application, have in the freeze-drying prods tert-butyl alcohol residual) in the freeze-drying prods.The genotoxicity of the tert-butyl alcohol studies show that the tert-butyl alcohol can cause the oxidative damage of DNA, and confirms its carcinogenecity in big mouse test, and the oral carcinogenic amount (CPFo) that environmental health hazards assessment offices (OEHHA) calculate is 3 * 10
-3(mg/kg-day)
-1(referring to document: John D.Budroe, Acute toxicity and cancer risk assessment values for tert-butyl acetate, Regulatory Toxicology and Pharmacology, Volume 40, Issue 2, November 2004, Pages 168-176; S.Acharya, Administration of subtoxic doses of t-butyl alcohol and trichloroacetic acid to male Wistar rats to study the interactive toxicity, Toxicology Letters, Volume 80, Issues 1-3, October1995, Pages 97-104).Test shows, adopts tert-butyl alcohol aqueous solution as the prepared freeze-dried powder of preparation solvent, and muffin is more coarse after the lyophilizing, and powder body is easily cracked, and the outward appearance of product is relatively poor.Difficult the redissolution needs the jolting of long period when redissolving with water for injection, after redissolving sometimes turbid phenomenon arranged.So in lyophilized formulations, adopt the tert-butyl alcohol as solvent, not only production proposed special requirement, and brought potential safety hazard to clinical application.
Summary of the invention
The purpose of this invention is to provide a kind of the preparation and freeze-drying process in do not add organic solvent, particularly do not add tert-butyl alcohol hydrochloride for injection bendamustine freeze-dried powder injection, and preparation method thereof.
The inventor is in research process, unexpectedly find, adopt the preparation technology who provides among the present invention after removing the tert-butyl alcohol, prepared do not contain organic solvent, the hydrochloride for injection bendamustine freeze-dried powder injection that does not particularly contain the tert-butyl alcohol, the fine and smooth homogeneous of outward appearance, powder body is complete, not easily broken and redissolve with water for injection after clarification fully, the more important thing is that organic solvent-free is residual in the lyophilized injectable powder of the present invention, improved clinical application safety greatly, and, because the situation of dissociating of organic solvent influence medicine, medicine is the form with salt, still with the form of free alkali, therefore, and be that the prepared lyophilized injectable powder of solvent has in essence different with the t-butanol solution.
The invention provides a kind of organic solvent that do not contain, particularly do not contain the hydrochloride for injection bendamustine freeze-dried powder injection of the tert-butyl alcohol, adopt following preparation method to prepare:
Take by weighing lyophilizing proppant 1-20% (grams per milliliter), stirring and dissolving is in temperature is 2-20 ℃ an amount of water for injection; Add bendamustine hydrochloride 0.1-5% (grams per milliliter), stirring and dissolving; Be settled to full dose with water for injection; An amount of with the pH regulator agent, the adjusting pH value is 1.5-4.5; Filter, reduce phlegm and internal heat former, packing, lyophilizing, seal, promptly get hydrochloride for injection bendamustine freeze-dried powder injection.
Above-mentioned lyophilizing proppant is selected from but is not limited to mannitol, dextran, sucrose, sodium chloride, glucose, lactose, trehalose, xylitol, maltose, sorbitol, albumin etc. and is used alone or as a mixture, and consumption is 1-20% (grams per milliliter); Preferred mannitol, dextran, sucrose are used alone or as a mixture the preferred 2-8% of consumption (grams per milliliter).
Above-mentioned water for injection temperature is 2-20 ℃, preferred 5-15 ℃.
Above-mentioned bendamustine hydrochloride consumption is 0.1-5% (grams per milliliter), preferred 0.5-3% (grams per milliliter).
Above-mentioned pH regulator agent is selected from but is not limited to citric acid, tartaric acid, lactic acid, hydrochloric acid, glacial acetic acid etc., and the adjusting pH value is 1.5-4.5.
Above-mentioned filter method adopts but is not limited to microporous filter membrane, sand filtration rod, sintered filter funnel or filter press device, preferred microporous filter membrane.
The above-mentioned former method of reducing phlegm and internal heat adopts but is not limited to activated carbon adsorption, ultrafiltration membrance filter, and wherein activated carbon dosage is 0.1-1% (grams per milliliter); Wherein the molecular weight of ultrafilter membrane is 3000-150000.
The invention provides a kind of hydrochloride for injection bendamustine freeze-dried powder injection and preparation method thereof, is not add organic solvent in preparation and freeze-drying process, does not particularly add the tert-butyl alcohol.The hydrochloride for injection bendamustine freeze-dried powder injection that the present invention is prepared, have good stable and water solublity, can directly be dissolved in water for injection, 5%, 10% glucose or 0.9% sodium chloride injection posterior vein and instil, have stable, quality controllable, safe and reliable characteristics.The present invention be that the prepared lyophilized injectable powder of solvent has in essence different with the t-butanol solution, the resulting lyophilized injectable powder of the present invention has the advantages that production technology is simple, cost is low, organic solvent-free is residual, quality controllable, has overcome effectively to add a series of deficiencies that the tert-butyl alcohol brings.
The specific embodiment
Describe the present invention below in conjunction with embodiment, but enforcement of the present invention is not limited only to this.
Embodiment 1 hydrochloride for injection bendamustine freeze-dried powder injection
Take by weighing mannitol 2.5 grams, stirring and dissolving is in 80 milliliters of waters for injection of 5 ℃; Add bendamustine hydrochloride 1.5 grams, stirring and dissolving; Be settled to 100 milliliters with water for injection; With 0.22 μ m filtering with microporous membrane, it is former that this filtrate is reduced phlegm and internal heat through the ultrafiltration membrance filter of 10000 molecular weight, packing, lyophilizing, seals, and promptly gets hydrochloride for injection bendamustine freeze-dried powder injection.
By measuring, after this lyophilized injectable powder redissolved with water for injection, the solution clarification; Indicating content is 100.2%.
Embodiment 2 hydrochloride for injection bendamustine freeze-dried powder injections
Take by weighing mannitol 3 grams, stirring and dissolving is in 80 milliliters of waters for injection of 7 ℃; Add bendamustine hydrochloride 2 grams, stirring and dissolving; Be settled to 100 milliliters with water for injection; With 0.45 μ m filtering with microporous membrane, it is former that this filtrate is reduced phlegm and internal heat through the ultrafiltration membrance filter of 5000 molecular weight, packing, lyophilizing, seals, and promptly gets hydrochloride for injection bendamustine freeze-dried powder injection.
By measuring, after this lyophilized injectable powder redissolved with water for injection, the solution clarification; Indicating content is 99.4%.
Embodiment 3 hydrochloride for injection bendamustine freeze-dried powder injections
Take by weighing mannitol 4 grams, stirring and dissolving is in 80 milliliters of waters for injection of 3 ℃; Add bendamustine hydrochloride 1 gram, stirring and dissolving; Be settled to 100 milliliters with water for injection; With 0.45 μ m filtering with microporous membrane, it is former that this filtrate is reduced phlegm and internal heat through the ultrafiltration membrance filter of 10000 molecular weight, packing, lyophilizing, seals, and promptly gets hydrochloride for injection bendamustine freeze-dried powder injection.
By measuring, after this lyophilized injectable powder redissolved with water for injection, the solution clarification; Indicating content is 99.8%.
Embodiment 4 hydrochloride for injection bendamustine freeze-dried powder injections
Take by weighing mannitol 15 grams, stirring and dissolving is in 160 milliliters of waters for injection of 6 ℃; Add bendamustine hydrochloride 6 grams, stirring and dissolving; Be settled to 200 milliliters with water for injection; With 0.45 μ m filtering with microporous membrane, it is former that this filtrate is reduced phlegm and internal heat through the ultrafiltration membrance filter of 20000 molecular weight, packing, lyophilizing, seals, and promptly gets hydrochloride for injection bendamustine freeze-dried powder injection.
By measuring, after this lyophilized injectable powder redissolved with water for injection, the solution clarification; Indicating content is 99.2%.
Embodiment 5 hydrochloride for injection bendamustine freeze-dried powder injections
Take by weighing mannitol 18 grams, stirring and dissolving is in 160 milliliters of waters for injection of 10 ℃; Add bendamustine hydrochloride 7 grams, stirring and dissolving; Be settled to 200 milliliters with water for injection; With 0.22 μ m filtering with microporous membrane, it is former that this filtrate is reduced phlegm and internal heat through the ultrafiltration membrance filter of 10000 molecular weight, packing, lyophilizing, seals, and promptly gets hydrochloride for injection bendamustine freeze-dried powder injection.
By measuring, after this lyophilized injectable powder redissolved with water for injection, the solution clarification; Indicating content is 98.7%.
Embodiment 6 hydrochloride for injection bendamustine freeze-dried powder injections
Take by weighing dextran 16 grams, stirring and dissolving is in 160 milliliters of waters for injection of 9 ℃; Add bendamustine hydrochloride 5 grams, stirring and dissolving; Be settled to 200 milliliters with water for injection; With 0.45 μ m filtering with microporous membrane, it is former that this filtrate is reduced phlegm and internal heat through the ultrafiltration membrance filter of 30000 molecular weight, packing, lyophilizing, seals, and promptly gets hydrochloride for injection bendamustine freeze-dried powder injection.
By measuring, this is frozen after injectable powder redissolves with water for injection the solution clarification; Indicating content is 99.3%.
Embodiment 7 hydrochloride for injection bendamustine freeze-dried powder injections
Take by weighing sucrose 5 grams, stirring and dissolving is in 400 milliliters of waters for injection of 12 ℃; Add bendamustine hydrochloride 2 grams, stirring and dissolving; Be settled to 500 milliliters with water for injection; With citron acid for adjusting pH to 4.5; With 0.45 μ m filtering with microporous membrane, it is former that this filtrate is reduced phlegm and internal heat through the ultrafiltration membrance filter of 30000 molecular weight, packing, lyophilizing, seals, and promptly gets hydrochloride for injection bendamustine freeze-dried powder injection.
By measuring, after this lyophilized injectable powder redissolved with water for injection, the solution clarification; Indicating content is 98.8%.
Embodiment 8 hydrochloride for injection bendamustine freeze-dried powder injections
Take by weighing trehalose 8 grams, maltose 2 grams, sorbitol 5 grams, stirring and dissolving is in 400 milliliters of waters for injection of 15 ℃; Add bendamustine hydrochloride 1 gram, stirring and dissolving; Be settled to 500 milliliters with water for injection; With winestone acid for adjusting pH to 3.5; With 0.22 μ m filtering with microporous membrane, it is former that this filtrate is reduced phlegm and internal heat through the ultrafiltration membrance filter of 10000 molecular weight, packing, lyophilizing, seals, and promptly gets hydrochloride for injection bendamustine freeze-dried powder injection.
By measuring, after this lyophilized injectable powder redissolved with water for injection, the solution clarification; Indicating content is 98.6%.
Embodiment 9 hydrochloride for injection bendamustine freeze-dried powder injections
Take by weighing glucose 10 grams, lactose 5 grams, xylitol 5 grams, stirring and dissolving is in 400 milliliters of waters for injection of 14 ℃; Add bendamustine hydrochloride 1 gram, stirring and dissolving; Be settled to 500 milliliters with water for injection; With winestone acid for adjusting pH to 4.0; With 0.22 μ m filtering with microporous membrane, it is former that this filtrate is reduced phlegm and internal heat through the ultrafiltration membrance filter of 10000 molecular weight, packing, lyophilizing, seals, and promptly gets hydrochloride for injection bendamustine freeze-dried powder injection.
By measuring, after this lyophilized injectable powder redissolved with water for injection, the solution clarification; Indicating content is 98.6%.
Embodiment 10 hydrochloride for injection bendamustine freeze-dried powder injections
Take by weighing mannitol 80 grams, stirring and dissolving is in 800 milliliters of waters for injection of 2 ℃; Add bendamustine hydrochloride 18 grams, stirring and dissolving; Be settled to 1000 milliliters with water for injection; With 0.45 μ m filtering with microporous membrane, it is former that this filtrate is reduced phlegm and internal heat through the ultrafiltration membrance filter of 20000 molecular weight, packing, lyophilizing, seals, and promptly gets hydrochloride for injection bendamustine freeze-dried powder injection.
By measuring, after this lyophilized injectable powder redissolved with water for injection, the solution clarification; Indicating content is 99.5%.
Embodiment 11 hydrochloride for injection bendamustine freeze-dried powder injections
Take by weighing mannitol 100 grams, stirring and dissolving is in 800 milliliters of waters for injection of 5 ℃; Add bendamustine hydrochloride 14 grams, stirring and dissolving; Be settled to 1000 milliliters with water for injection; With 0.22 μ m filtering with microporous membrane, it is former that this filtrate is reduced phlegm and internal heat through the ultrafiltration membrance filter of 10000 molecular weight, packing, lyophilizing, seals, and promptly gets hydrochloride for injection bendamustine freeze-dried powder injection.
By measuring, after this lyophilized injectable powder redissolved with water for injection, the solution clarification; Indicating content is 99.9%.
Embodiment 12 hydrochloride for injection bendamustine freeze-dried powder injections
Take by weighing mannitol 70 grams, stirring and dissolving is in 800 milliliters of waters for injection of 8 ℃; Add bendamustine hydrochloride 10 grams, stirring and dissolving; Be settled to 1000 milliliters with water for injection; With 0.45 μ m filtering with microporous membrane, it is former that this filtrate is reduced phlegm and internal heat through the ultrafiltration membrance filter of 5000 molecular weight, packing, lyophilizing, seals, and promptly gets hydrochloride for injection bendamustine freeze-dried powder injection.
By measuring, after this lyophilized injectable powder redissolved with water for injection, the solution clarification; Indicating content is 100.5%.
Embodiment 13 hydrochloride for injection bendamustine freeze-dried powder injections
Take by weighing mannitol 120 grams, stirring and dissolving is in 1600 milliliters of waters for injection of 3 ℃; Add bendamustine hydrochloride 3 grams, stirring and dissolving; Be settled to 2000 milliliters with water for injection; Regulate pH to 2.0 with lactic acid; With 0.22 μ m filtering with microporous membrane, it is former that this filtrate is reduced phlegm and internal heat through the ultrafiltration membrance filter of 10000 molecular weight, packing, lyophilizing, seals, and promptly gets hydrochloride for injection bendamustine freeze-dried powder injection.
By measuring, after this lyophilized injectable powder redissolved with water for injection, the solution clarification; Indicating content is 99.1%.
Embodiment 14 hydrochloride for injection bendamustine freeze-dried powder injections
Take by weighing mannitol 150 grams, stirring and dissolving is in 1600 milliliters of waters for injection of 9 ℃; Add bendamustine hydrochloride 5 grams, stirring and dissolving; Be settled to 2000 milliliters with water for injection; Regulate pH to 3.0 with glacial acetic acid; Filter with sand filtration rod, it is former that this filtrate is reduced phlegm and internal heat through the ultrafiltration membrance filter of 20000 molecular weight, packing, lyophilizing, seals, and promptly gets hydrochloride for injection bendamustine freeze-dried powder injection.
By measuring, after this lyophilized injectable powder redissolved with water for injection, the solution clarification; Indicating content is 99.6%.
Embodiment 15 hydrochloride for injection bendamustine freeze-dried powder injections
Take by weighing mannitol 160 grams, stirring and dissolving is in 1600 milliliters of waters for injection of 11 ℃; Add bendamustine hydrochloride 2 grams, stirring and dissolving; Be settled to 2000 milliliters with water for injection; Regulate pH to 1.5 with hydrochloric acid; With 0.22 μ m filtering with microporous membrane, it is former that this filtrate is reduced phlegm and internal heat through the ultrafiltration membrance filter of 10000 molecular weight, packing, lyophilizing, seals, and promptly gets hydrochloride for injection bendamustine freeze-dried powder injection.
By measuring, after this lyophilized injectable powder redissolved with water for injection, the solution clarification; Indicating content is 99.7%.
Embodiment 16 hydrochloride for injection bendamustine freeze-dried powder injections
Take by weighing sucrose 1000 grams, stirring and dissolving is in 3500 milliliters of waters for injection of 13 ℃; Add bendamustine hydrochloride 300 grams, stirring and dissolving; Be settled to 5000 milliliters with water for injection; Filter with sintered filter funnel, will add 5 gram active carbons, filter and reduce phlegm and internal heat formerly, packing, lyophilizing, seal, promptly get hydrochloride for injection bendamustine freeze-dried powder injection to this filtrate.
By measuring, after this lyophilized injectable powder redissolved with water for injection, the solution clarification; Indicating content is 100.7%.
Embodiment 17 hydrochloride for injection bendamustine freeze-dried powder injections
Take by weighing trehalose 500 grams, glucose 200 grams, stirring and dissolving is in 3000 milliliters of waters for injection of 17 ℃; Add bendamustine hydrochloride 250 grams, stirring and dissolving; Be settled to 5000 milliliters with water for injection; Filter with sintered filter funnel, will add 25 gram active carbons, filter and reduce phlegm and internal heat formerly, packing, lyophilizing, seal, promptly get hydrochloride for injection bendamustine freeze-dried powder injection to this filtrate.
By measuring, after this lyophilized injectable powder redissolved with water for injection, the solution clarification; Indicating content is 100.4%.
Embodiment 18 hydrochloride for injection bendamustine freeze-dried powder injections
Take by weighing dextran 300 grams, albumin 200 grams, stirring and dissolving is in 3000 milliliters of waters for injection of 20 ℃; Add bendamustine hydrochloride 100 grams, stirring and dissolving; Be settled to 5000 milliliters with water for injection; With 1.0 μ m filtering with microporous membranes, it is former that this filtrate is reduced phlegm and internal heat through the ultrafiltration membrance filter of 40000 molecular weight, packing, lyophilizing, seals, and promptly gets hydrochloride for injection bendamustine freeze-dried powder injection.
By measuring, after this lyophilized injectable powder redissolved with water for injection, the solution clarification; Indicating content is 100.4%.
Embodiment 19 hydrochloride for injection bendamustine freeze-dried powder injections
Take by weighing sodium chloride 1000 grams, lactose 400 grams, stirring and dissolving is in 7000 milliliters of waters for injection of 8 ℃; Add bendamustine hydrochloride 1000 grams, stirring and dissolving; Be settled to 10000 milliliters with water for injection; With 1.0 μ m filtering with microporous membranes, it is former that this filtrate is reduced phlegm and internal heat through the ultrafiltration membrance filter of 50000 molecular weight, packing, lyophilizing, seals, and promptly gets hydrochloride for injection bendamustine freeze-dried powder injection.
By measuring, after this lyophilized injectable powder redissolved with water for injection, the solution clarification; Indicating content is 98.4%.
Embodiment 20 hydrochloride for injection bendamustine freeze-dried powder injections
Take by weighing mannitol 500 grams, dextran 300 grams, stirring and dissolving is in 7000 milliliters of waters for injection of 15 ℃; Add bendamustine hydrochloride 700 grams, stirring and dissolving; Be settled to 10000 milliliters with water for injection; With 0.45 μ m filtering with microporous membrane, it is former that this filtrate is reduced phlegm and internal heat through the ultrafiltration membrance filter of 60000 molecular weight, packing, lyophilizing, seals, and promptly gets hydrochloride for injection bendamustine freeze-dried powder injection.
By measuring, after this lyophilized injectable powder redissolved with water for injection, the solution clarification; Indicating content is 98.5%.
Embodiment 21 hydrochloride for injection bendamustine freeze-dried powder injections
Take by weighing sucrose 1200 grams, xylitol 200 grams, stirring and dissolving is in 7000 milliliters of waters for injection of 10 ℃; Add bendamustine hydrochloride 350 grams, stirring and dissolving; Be settled to 10000 milliliters with water for injection; With 1.0 μ m filtering with microporous membranes, it is former that this filtrate is reduced phlegm and internal heat through the ultrafiltration membrance filter of 100000 molecular weight, packing, lyophilizing, seals, and promptly gets hydrochloride for injection bendamustine freeze-dried powder injection.
By measuring, after this lyophilized injectable powder redissolved with water for injection, the solution clarification; Indicating content is 98.8%.
Embodiment 22 hydrochloride for injection bendamustine freeze-dried powder injections
Take by weighing mannitol 1500 grams,, stirring and dissolving is in 16000 milliliters of waters for injection of 9 ℃; Add bendamustine hydrochloride 600 grams, stirring and dissolving; Be settled to 20000 milliliters with water for injection; Filter with the filter press device, it is former that this filtrate is reduced phlegm and internal heat through the ultrafiltration membrance filter of 120000 molecular weight, packing, lyophilizing, seals, and promptly gets hydrochloride for injection bendamustine freeze-dried powder injection.
By measuring, after this lyophilized injectable powder redissolved with water for injection, the solution clarification; Indicating content is 101.5%.
Embodiment 23 hydrochloride for injection bendamustine freeze-dried powder injections
Take by weighing sucrose 2000 grams,, stirring and dissolving is in 16000 milliliters of waters for injection of 10 ℃; Add bendamustine hydrochloride 700 grams, stirring and dissolving; Be settled to 20000 milliliters with water for injection; Filter with the filter press device, in this filtrate, add 200 gram active carbons, filter and reduce phlegm and internal heat formerly, packing, lyophilizing, seal, promptly get hydrochloride for injection bendamustine freeze-dried powder injection.
By measuring, after this lyophilized injectable powder redissolved with water for injection, the solution clarification; Indicating content is 100.7%.
Embodiment 24 hydrochloride for injection bendamustine freeze-dried powder injections
Take by weighing sucrose 2500 grams,, stirring and dissolving is in 16000 milliliters of waters for injection of 15 ℃; Add bendamustine hydrochloride 800 grams, stirring and dissolving; Be settled to 20000 milliliters with water for injection; With 0.45 μ m filtering with microporous membrane, it is former that this filtrate is reduced phlegm and internal heat through the ultrafiltration membrance filter of 150000 molecular weight, packing, lyophilizing, seals, and promptly gets hydrochloride for injection bendamustine freeze-dried powder injection.
By measuring, after this lyophilized injectable powder redissolved with water for injection, the solution clarification; Indicating content is 98.3%.
Embodiment 25 the present invention and the contrast that contains the embodiment of the tert-butyl alcohol
In order to further specify superiority of the present invention, we will contain the tert-butyl alcohol and do contrast with the outward appearance that does not contain the prepared bendamustine freeze-dried powder injection of the tert-butyl alcohol, redissolution clarity, medicament contg.
1. sample preparation
A. supply test preparation:
According to the prepared hydrochloride for injection bendamustine freeze-dried powder injection of embodiment 1, as this contrast test for test preparation;
B. Comparative formulation:
Take by weighing mannitol 2.5 grams, stirring and dissolving is in 80 milliliter of 30% t-butanol solution of 5 ℃; Add bendamustine hydrochloride 1.5 grams, stirring and dissolving; Be settled to 100 milliliters with 30% t-butanol solution; With 0.22 μ m filtering with microporous membrane, it is former that this filtrate is reduced phlegm and internal heat through the ultrafiltration membrance filter of 10000 molecular weight, packing, lyophilizing, seals, and promptly gets the hydrochloride for injection bendamustine freeze-dried powder injection that contains the tert-butyl alcohol, as a comparison preparation.
2. evaluation methodology
The uniformity of perusal powder body and sponginess after the lyophilizing; To redissolve with water for injection respectively for examination and Comparative formulation, make into the solution of 5mg/mL, then in the clarity of observing under the lamp inspection instrument after redissolving; To redissolve with water for injection respectively for examination and Comparative formulation, make into the solution of 5mg/mL, this solution will be crossed the filter membrane of 0.22 μ m, measure the medicament contg in the filtrate, and calculate and indicate percentage composition, thus whether complete when determining to redissolve.
3. result
5 bottles of the parallel samplings of each evaluation index, result of the test such as following table.
4. interpretation of result
The prepared hydrochloride for injection bendamustine freeze-dried powder outward appearance of the present invention is evenly loose, shake non-friablely, redissolves the back clarification, and medicine sign content meets quality standard at 98-101%; And the Comparative formulation outward appearance that contains the tert-butyl alcohol is coarse, shakes frangiblely, and redissolving the rear section has insoluble muddiness, and medicine indicates content and drops to 70%, in use has potential safety hazard.By contrast test, fully proved the superiority of the hydrochloride for injection bendamustine freeze-dried powder of the present invention's preparation.
Claims (12)
1. the preparation method of a hydrochloride for injection bendamustine freeze-dried powder injection is characterized in that it is made up of following proportioning and step:
Take by weighing lyophilizing proppant 1-20% grams per milliliter, stirring and dissolving is in temperature is 2-20 ℃ an amount of water for injection; Add bendamustine hydrochloride 0.1-5% grams per milliliter, stirring and dissolving; Be settled to full dose with water for injection; An amount of with the pH regulator agent, the adjusting pH value is 1.5-4.5; Filter, reduce phlegm and internal heat former, packing, lyophilizing, seal, promptly get hydrochloride for injection bendamustine freeze-dried powder injection.
2. the preparation method of hydrochloride for injection bendamustine freeze-dried powder injection according to claim 1 is characterized in that described lyophilizing proppant is selected from mannitol, dextran, sucrose, sodium chloride, glucose, lactose, trehalose, xylitol, maltose, sorbitol, albumin and is used alone or as a mixture.
3. the preparation method of hydrochloride for injection bendamustine freeze-dried powder injection according to claim 1 and 2 is characterized in that described lyophilizing proppant consumption is the 2-8% grams per milliliter.
4. the preparation method of hydrochloride for injection bendamustine freeze-dried powder injection according to claim 1 and 2 is characterized in that described water for injection temperature is 5-15 ℃.
5. the preparation method of hydrochloride for injection bendamustine freeze-dried powder injection according to claim 1 and 2 is characterized in that described bendamustine hydrochloride consumption is the 0.5-3% grams per milliliter.
6. the preparation method of hydrochloride for injection bendamustine freeze-dried powder injection according to claim 1 and 2 is characterized in that described pH regulator agent is citric acid, tartaric acid, lactic acid, hydrochloric acid or glacial acetic acid.
7. the preparation method of hydrochloride for injection bendamustine freeze-dried powder injection according to claim 1 and 2 is characterized in that described filter method is microporous filter membrane, sand filtration rod, sintered filter funnel or filter press device.
8. the preparation method of hydrochloride for injection bendamustine freeze-dried powder injection according to claim 1 and 2 is characterized in that the described former method of reducing phlegm and internal heat is activated carbon adsorption or ultrafiltration membrance filter.
9. the preparation method of hydrochloride for injection bendamustine freeze-dried powder injection according to claim 8 is characterized in that activated carbon dosage wherein is the 0.1-1% grams per milliliter.
10. the preparation method of hydrochloride for injection bendamustine freeze-dried powder injection according to claim 8, the molecular weight that it is characterized in that ultrafilter membrane wherein is 3000-150000.
11. hydrochloride for injection bendamustine freeze-dried powder injection preparation method according to claim 1 is characterized in that it is made up of following proportioning and step:
Take by weighing mannitol 2.5 grams, stirring and dissolving is in 80 milliliters of waters for injection of 5 ℃; Add bendamustine hydrochloride 1.5 grams, stirring and dissolving; Be settled to 100 milliliters with water for injection; With 0.22 μ m filtering with microporous membrane, it is former that this filtrate is reduced phlegm and internal heat through the ultrafiltration membrance filter of 10000 molecular weight, packing, lyophilizing, seals, and promptly gets hydrochloride for injection bendamustine freeze-dried powder injection.
12. hydrochloride for injection bendamustine freeze-dried powder injection for preparing as the arbitrary claim method of claim 1-11.
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| CN103989641A (en) * | 2014-05-29 | 2014-08-20 | 四川汇宇制药有限公司 | Preparation method of bendamustine hydrochloride composition for injection |
| CN104173300A (en) * | 2014-08-29 | 2014-12-03 | 四川汇宇制药有限公司 | Preparation method of bendamustine hydrochloride freeze-dried injection |
| ITMI20131013A1 (en) * | 2013-06-19 | 2014-12-20 | Chemi Spa | LYOPHILIZED FORMULATIONS OF BENDAMUSTINA CHLORIDRATE |
| US8987469B2 (en) | 2012-07-24 | 2015-03-24 | Heyl Chemisch-Pharmazeutische Fabrik Gmbh & Co. Kg | Process for the preparation of bendamustine |
| US9149464B2 (en) * | 2012-11-12 | 2015-10-06 | Ignyta, Inc. | Bendamustine derivatives and methods of using same |
| WO2017067474A1 (en) * | 2015-10-20 | 2017-04-27 | 杭州民生药物研究院有限公司 | Pharmaceutical composition and preparation method therefor |
| CN111166722A (en) * | 2019-12-07 | 2020-05-19 | 四川汇宇制药有限公司 | Bendamustine hydrochloride pre-freeze-drying liquid medicine for injection and preparation method thereof |
| CN111166721A (en) * | 2019-12-07 | 2020-05-19 | 四川汇宇制药有限公司 | Stable bendamustine hydrochloride for injection and preparation method thereof |
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| CN101836962A (en) * | 2009-03-20 | 2010-09-22 | 北京本草天源药物研究院 | Method for preparing bendamustine hydrochloride freeze-dried powder injection |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US8987469B2 (en) | 2012-07-24 | 2015-03-24 | Heyl Chemisch-Pharmazeutische Fabrik Gmbh & Co. Kg | Process for the preparation of bendamustine |
| US9452988B2 (en) | 2012-11-12 | 2016-09-27 | Ignyta, Inc. | Bendamustine derivatives and methods of using same |
| US9630926B2 (en) | 2012-11-12 | 2017-04-25 | Ignyta, Inc. | Bendamustine derivatives and methods of using same |
| US9913827B2 (en) | 2012-11-12 | 2018-03-13 | Ignyta, Inc. | Bendamustine derivatives and methods of using same |
| US9150517B2 (en) | 2012-11-12 | 2015-10-06 | Ignyta, Inc. | Bendamustine derivatives and methods of using same |
| US9149464B2 (en) * | 2012-11-12 | 2015-10-06 | Ignyta, Inc. | Bendamustine derivatives and methods of using same |
| ITMI20131013A1 (en) * | 2013-06-19 | 2014-12-20 | Chemi Spa | LYOPHILIZED FORMULATIONS OF BENDAMUSTINA CHLORIDRATE |
| US9308174B2 (en) | 2013-06-19 | 2016-04-12 | Chemi S.P.A. | Lyophilized formulations of bendamustine hydrochloride |
| WO2014202553A1 (en) | 2013-06-19 | 2014-12-24 | Chemi S.P.A. | Lyophilized formulations of bendamustine hydrochloride |
| RU2679614C2 (en) * | 2013-06-19 | 2019-02-12 | Кеми С.П.А. | Lyophilised formulations of bendamustine hydrochloride |
| CN103989641A (en) * | 2014-05-29 | 2014-08-20 | 四川汇宇制药有限公司 | Preparation method of bendamustine hydrochloride composition for injection |
| CN104173300A (en) * | 2014-08-29 | 2014-12-03 | 四川汇宇制药有限公司 | Preparation method of bendamustine hydrochloride freeze-dried injection |
| WO2017067474A1 (en) * | 2015-10-20 | 2017-04-27 | 杭州民生药物研究院有限公司 | Pharmaceutical composition and preparation method therefor |
| CN111166722A (en) * | 2019-12-07 | 2020-05-19 | 四川汇宇制药有限公司 | Bendamustine hydrochloride pre-freeze-drying liquid medicine for injection and preparation method thereof |
| CN111166721A (en) * | 2019-12-07 | 2020-05-19 | 四川汇宇制药有限公司 | Stable bendamustine hydrochloride for injection and preparation method thereof |
| CN111166721B (en) * | 2019-12-07 | 2022-03-29 | 四川汇宇制药股份有限公司 | Stable bendamustine hydrochloride for injection and preparation method thereof |
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