CN105726472B - 苯达莫司汀药剂组合物及应用 - Google Patents
苯达莫司汀药剂组合物及应用 Download PDFInfo
- Publication number
- CN105726472B CN105726472B CN201610179590.8A CN201610179590A CN105726472B CN 105726472 B CN105726472 B CN 105726472B CN 201610179590 A CN201610179590 A CN 201610179590A CN 105726472 B CN105726472 B CN 105726472B
- Authority
- CN
- China
- Prior art keywords
- bendamustine
- bendamustine hydrochloride
- injection
- filtering
- filter membrane
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 229960002707 bendamustine Drugs 0.000 title claims abstract description 29
- 239000000203 mixture Substances 0.000 title claims abstract description 9
- 239000003814 drug Substances 0.000 title abstract description 13
- ZHSKUOZOLHMKEA-UHFFFAOYSA-N 4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoic acid;hydron;chloride Chemical compound Cl.ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 ZHSKUOZOLHMKEA-UHFFFAOYSA-N 0.000 claims abstract description 34
- 229960001215 bendamustine hydrochloride Drugs 0.000 claims abstract description 31
- 239000003381 stabilizer Substances 0.000 claims abstract description 11
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 29
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 27
- 238000001914 filtration Methods 0.000 claims description 20
- 239000012528 membrane Substances 0.000 claims description 20
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 238000002156 mixing Methods 0.000 claims description 11
- 241000894006 Bacteria Species 0.000 claims description 10
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 claims description 8
- 229940035024 thioglycerol Drugs 0.000 claims description 8
- 230000001502 supplementing effect Effects 0.000 claims description 7
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 6
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000007924 injection Substances 0.000 abstract description 13
- 238000002347 injection Methods 0.000 abstract description 13
- 150000002148 esters Chemical class 0.000 abstract description 3
- 239000007788 liquid Substances 0.000 abstract description 3
- 150000003839 salts Chemical class 0.000 abstract description 3
- 239000012453 solvate Substances 0.000 abstract description 3
- 238000013112 stability test Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 9
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 8
- 238000001802 infusion Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 235000006708 antioxidants Nutrition 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000008354 sodium chloride injection Substances 0.000 description 5
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 235000012000 cholesterol Nutrition 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 239000000787 lecithin Substances 0.000 description 4
- 229940067606 lecithin Drugs 0.000 description 4
- 235000010445 lecithin Nutrition 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 229960004641 rituximab Drugs 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000008215 water for injection Substances 0.000 description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 3
- 235000010262 sodium metabisulphite Nutrition 0.000 description 3
- XKJMBINCVNINCA-UHFFFAOYSA-N Alfalone Chemical compound CON(C)C(=O)NC1=CC=C(Cl)C(Cl)=C1 XKJMBINCVNINCA-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000021023 sodium intake Nutrition 0.000 description 2
- 229940001584 sodium metabisulfite Drugs 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 208000028564 B-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000011821 Indolent B-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- AGBQKNBQESQNJD-UHFFFAOYSA-M lipoate Chemical compound [O-]C(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-M 0.000 description 1
- 235000019136 lipoic acid Nutrition 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229940044519 poloxamer 188 Drugs 0.000 description 1
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229940001607 sodium bisulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229940001482 sodium sulfite Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 229940001474 sodium thiosulfate Drugs 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- FGCSIJPPCNCQJB-FAOVPRGRSA-M sodium;(2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;chloride Chemical compound [Na+].[Cl-].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O FGCSIJPPCNCQJB-FAOVPRGRSA-M 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960002663 thioctic acid Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
Abstract
本发明公开一种苯达莫司汀药剂组合物包含：1.5％‑5％苯达莫司汀或其可药用的盐或酯或溶剂化物、0％‑20％稳定剂、0.05％‑2％抗氧剂、0％‑0.008％pH调节剂、余量的专属溶剂。临床使用时，可根据患者给药剂量，采用10‑100mL注射液稀释成最终浓度为0.1mg/mL‑10mg/mL的盐酸苯达莫司汀使用，且初步稳定试验表明，本发明经过稀释后在25℃或5℃条件下，放置48小时是稳定的，与市售冻干制剂相比，所用稀释液体积减少(现有冻干制剂需要500mL注射液复溶)，稀释后药液稳定性提高，病人顺应性好，解决了现有临床问题。
Description
技术领域
本发明涉及肿瘤性疾病和自身免疫性疾病的药物组合物的领域，特别是氮芥苯达莫司汀，例如盐酸苯达莫司汀或其可药用的酯、盐或溶剂化物的新型药剂组合物。
背景技术
苯达莫司汀(Bendamustine)，化学名：4-{5-[二(2-氯乙基)氨基]-1-甲基-2-苯并咪唑基}丁酸，结构式为：
苯达莫司汀最初合成于1963年德意志民主共和国(GDR)，1971年到1992年以的商品名由耶拿制药公司生产，从1993年后，被ribosepharm GmbH公司以的商品名上市销售。2008年，美国Cephalon公司生产的注射剂盐酸苯达莫司汀(Bendamustine Hydrochloride)在美国上市，商品名为用于治疗使用利妥昔单抗无效的复发难治性B细胞非何杰金氏淋巴瘤。同年3月，美国FDA首先批准盐酸苯达莫司汀用于治疗慢性淋巴细胞性白血病(CLL)。同年10月，FDA又批准了该药的第2个适应症，即在利妥昔单抗(美罗华)或含利妥昔单抗方案治疗过程中，或者治疗6个月内，病情仍然进展的惰性B细胞非霍奇金淋巴瘤(NHL)患者。苯达莫司汀冻干粉针呈白色至灰白色，规格为100mg/支、20mg/支，其中含有盐酸苯达莫司汀和甘露醇，该药储存温度不应超过30℃，避光保存，使用前临时配制。
由于苯达莫司汀在水溶液中降解(与其它氮芥类似，氮芥由于其在水溶液中的高度反应性，难以配制成药品，以冻干的形式供应给药)，冻干品需要在给药前由熟练的医院工作人员进行复溶。产品用20mL的无菌注射用水复溶，溶解时间一般不超过5分钟，在溶解后30分钟之内，根据需要抽取适量苯达莫司汀水溶液，转移至500mL氯化钠注射液(0.9％)或葡萄糖氯化钠注射液(2.5％/0.45％)中，并确保苯达莫司汀在注射液中的最终浓度在0.2～0.6mg/ml之间，静脉输注，30-60分钟内使用完。临床使用中的问题是：现有苯达莫司汀冻干粉末复溶困难，临床报道显示，复溶需要至少15分钟，并可能需要长达30分钟。除了对于复溶该产品的健康护理专业人士来说麻烦和费时之外，由于水对该产品的水解作用，复溶过程中苯达莫司汀在水中过长时间的暴露增加了失效和杂质形成的可能性。其次，为避免水解，本品一旦配置完成，需要在30-60分钟内静脉注射完，造成患者适应性差。再者，高输液量和更长的输液时间与很多副作用相关联，例如：目前使用苯达莫司汀治疗时，需要输入大剂量的含钠注射液，对于心脏疾病(充血性心脏衰竭和/或肾功能衰竭)患者是禁忌，原本可以受益于苯达莫司汀治疗的患者不能服用此药，或者在没有替代疗法的条件下，患者被迫接受由于注射大量含钠注射液所导致的显著物理伤害。并且，高输液量对患者的患病器官包括心脏和肾脏造成不健康的压力。
因此，临床上需要新的苯达莫司汀制剂，该制剂要便于配置，并且可经更少的输液体积、在较短时间给予患者，同时，这对于输液量和钠摄入限制患者也是最有利的。
发明内容
本发明的目的在于针对苯达莫司汀临床治疗问题，尤其是对输液量和钠摄入限制患者，提供一种苯达莫司汀新型药物制剂组合物，通过提高产品稳定性、患者顺应性来满足治疗需求。
本发明提供的苯达莫司汀药剂组合物包含：1.5％-5％苯达莫司汀或其可药用的盐或酯或溶剂化物、0％-20％稳定剂、0.05％-2％抗氧剂、0％-0.008％pH调节剂、余量的专属溶剂。临床使用时，可根据患者给药剂量，采用10-100mL注射液稀释成最终浓度为0.1mg/mL-10mg/mL的盐酸苯达莫司汀使用。
本发明是通过以下技术方案实现的：
盐酸苯达莫司汀作为主要活性物质，加入稳定剂、抗氧剂，混合均匀、溶解，再将其溶于专属溶剂，调节pH至所需范围，加入活性炭，搅拌，0.45μm滤膜过滤除碳，0.22μm滤膜过滤除菌，按每瓶1-5mL分装于安瓿瓶中，其浓度为1-50mg/mL，即得。临用前使用10-100mL注射液稀释成最终浓度为0.1mg/mL-10mg/mL的盐酸苯达莫司汀。
上述方法的具体步骤如下：
步骤A：取1.5％-5％的盐酸苯达莫司汀，加入0％-20％的稳定剂，混合均匀或溶解后，再加入0.05％-2％的抗氧剂，搅拌溶解；
步骤B：取专属溶剂，将步骤1配制的溶液定容至所需体积，搅拌均匀，调节pH值至所需范围；
步骤C：加入所需体积0.05-1％的药用活性炭，搅拌30-60min，过0.45μm滤膜过滤除碳，滤液继续过0.22μm滤膜除菌，使盐酸苯达莫司汀浓度为1-50mg/mL，最后按每瓶1-10mL分装于安瓿瓶中。
步骤A中，所述的稳定剂包括：卵磷脂、胆固醇、丙二醇、甘油、PEG3000-5000-PLA2000-5000、PEG3000-5000-PLA2000-5000-PEG3000-5000、聚乙二醇400、泊洛沙姆188、PLGA(50:50)；
步骤A中，所述的加入稳定剂后混合均匀或溶解的方法包括：直接搅拌溶解、将稳定剂和药物通过逆向蒸发法溶解中的任意一种；
步骤A中，所述的抗氧剂包括：焦亚硫酸钠、亚硫酸氢钠、亚硫酸钠、硫代甘油、硫代硫酸钠、硫辛酸中的任意一种或两种；
步骤B中，所述的pH值范围：2-3；
步骤B中，所述的专属溶剂包含：注射用水、聚乙二醇400、丙二醇、甘油、二甲基乙酰胺。
该新型苯达莫司汀制剂可减少临床配伍所需的注射液体积，缩短输液时间，大大提高盐酸苯达莫司汀的稳定性。而且，使其在制备、运输和贮存过程中具有更好的稳定性，避免了因药物降解带来的疗效降低和降解产生杂质给患者用药安全带来的隐患。
具体实施方式
下面结合本发明的实施例对本发明的实施作详细说明，以下实施例是在以本发明方案为前提下进行实施，给出了详细的实施方式和具体的操作过程，但本发明的保护范围不限于下述的实施例。
实施例一：
取6％-9％卵磷脂、4％-6％胆固醇于圆底烧瓶中，逆向蒸发，加入2％-3％的盐酸苯达莫司汀的10％-20％丙二醇溶液，混合均匀，加入0.5％焦亚硫酸钠，补加注射用水至足量，调pH至2-3，盐酸苯达莫司汀浓度为25mg/mL，加入活性炭，搅拌，0.45μm滤膜过滤除碳，0.22μm滤膜过滤除菌，分装即得。
实施例二：
取6％-9％卵磷脂、4％-6％胆固醇于圆底烧瓶中，逆向蒸发，加入2％-3％的盐酸苯达莫司汀的5％-10％甘油溶液，混合均匀，加入0.5％焦亚硫酸钠，补加注射用水至足量，调节pH至2-3，盐酸苯达莫司汀浓度为25mg/mL，加入活性炭，搅拌，0.45μm滤膜过滤除碳，0.22μm滤膜过滤除菌，分装即得。
实施例三：
取6％-9％卵磷脂、4％-6％胆固醇于圆底烧瓶中，逆向蒸发，加入2％-3％的盐酸苯达莫司汀的10％-20％丙二醇溶液、0.1％-0.5％硫代甘油，混合均匀，加入表中不同的抗氧剂，补加注射用水至足量，调节pH至2-3，盐酸苯达莫司汀浓度为25mg/mL，加入活性炭，搅拌，0.45μm滤膜过滤除碳，0.22μm滤膜过滤除菌，分装即得。
实施例四：
取2％-5％的盐酸苯达莫司汀、1％-10％表中的不同稳定剂，加入5％-15％丙二醇，直接搅拌混合均匀，加入0.5％硫代甘油，补加PEG400至足量，调节pH至2-3，盐酸苯达莫司汀浓度为25mg/mL，加入活性炭，搅拌，0.45μm滤膜过滤除碳，0.22μm滤膜过滤除菌，分装即得。
实施例五：
取2％-5％的盐酸苯达莫司汀、表中的不同稳定剂，直接搅拌混合均匀，加入0.5％硫代甘油，补加PEG400或二甲基乙酰胺至足量，使盐酸苯达莫司汀浓度为25mg/mL，加入活性炭，搅拌，0.45μm滤膜过滤除碳，0.22μm滤膜过滤除菌，分装即得。
实施例六：
取2％-5％的盐酸苯达莫司汀、表中不同的稳定剂，直接搅拌混合均匀，加入0.5％硫代甘油，补加PEG400或二甲基乙酰胺或丙二醇至足量，使盐酸苯达莫司汀浓度为25mg/mL，加入活性炭，搅拌，0.45μm滤膜过滤除碳，0.22μm滤膜过滤除菌，分装即得。
实施例七：
取上述处方，分别于25℃和40℃考察10天加速稳定性，结果如下表所以：
结果表明，本发明公开的苯达莫司汀药剂组合物，在25℃和40℃下放置10天，稳定性较好，总杂没有超出限度要求，通过加速稳定性试验表明新剂型在25℃和5℃下至少可以放置15个月。
实施例八：
取上述处方，分别用50mL、100mL0.9％氯化钠注射液稀释，于25℃和40℃考察12h、48h的稳定性，结果如下表所以：
50mL0.9％氯化钠注射液稀释
100mL0.9％氯化钠注射液稀释
结果表明，本发明公开的苯达莫司汀药剂组合物，临用前使用10-100mL注射液稀释后，在25℃或5℃条件下，放置48小时是稳定的，符合临床治疗需求。与现有制剂相比，所用稀释液体积减少(现有冻干制剂需要500mL注射液复溶)，稀释后稳定性提高，因此，减少了输液量，同时降低输液时间，提高病人顺应性。
Claims (2)
1.苯达莫司汀药剂组合物，包含以下浓度百分比的组分：2％-5％盐酸苯达莫司汀、作为稳定剂的1％-10％甘油和1％-10％丙二醇、作为抗氧剂的0.5％硫代甘油以及余量的专属溶剂PEG400；
所述组合物的制备方法包括以下步骤：取2％-5％的盐酸苯达莫司汀、1％-10％甘油和1％-10％丙二醇，直接搅拌混合均匀，加入0.5％硫代甘油，补加PEG400至足量，使盐酸苯达莫司汀浓度为25mg/mL，加入活性炭，搅拌，0.45μm滤膜过滤除碳，0.22μm滤膜过滤除菌，分装即得。
2.根据权利要求1所述的苯达莫司汀药剂组合物的制备方法，其特征在于：取2％-5％的盐酸苯达莫司汀、1％-10％甘油和1％-10％丙二醇，直接搅拌混合均匀，加入0.5％硫代甘油，补加PEG400至足量，使盐酸苯达莫司汀浓度为25mg/mL，加入活性炭，搅拌，0.45μm滤膜过滤除碳，0.22μm滤膜过滤除菌，分装即得。
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911109940.3A CN110772480B (zh) | 2016-03-25 | 2016-03-25 | 苯达莫司汀药剂组合物及应用 |
| CN201610179590.8A CN105726472B (zh) | 2016-03-25 | 2016-03-25 | 苯达莫司汀药剂组合物及应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610179590.8A CN105726472B (zh) | 2016-03-25 | 2016-03-25 | 苯达莫司汀药剂组合物及应用 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911109940.3A Division CN110772480B (zh) | 2016-03-25 | 2016-03-25 | 苯达莫司汀药剂组合物及应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105726472A CN105726472A (zh) | 2016-07-06 |
| CN105726472B true CN105726472B (zh) | 2019-12-13 |
Family
ID=56252042
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610179590.8A Active CN105726472B (zh) | 2016-03-25 | 2016-03-25 | 苯达莫司汀药剂组合物及应用 |
| CN201911109940.3A Active CN110772480B (zh) | 2016-03-25 | 2016-03-25 | 苯达莫司汀药剂组合物及应用 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911109940.3A Active CN110772480B (zh) | 2016-03-25 | 2016-03-25 | 苯达莫司汀药剂组合物及应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (2) | CN105726472B (zh) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2019099557A (ja) * | 2017-11-28 | 2019-06-24 | 日本化薬株式会社 | ベンダムスチンを含有する溶液製剤 |
| CN110123747A (zh) * | 2019-04-26 | 2019-08-16 | 嘉兴市爵拓科技有限公司 | 苯达莫司汀的制剂 |
| CN111557904A (zh) * | 2020-04-09 | 2020-08-21 | 比卡生物科技（广州）有限公司 | 苯达莫司汀组合物及其用途 |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101584668A (zh) * | 2009-06-19 | 2009-11-25 | 江苏奥赛康药业有限公司 | 盐酸苯达莫司汀冻干粉针剂 |
| CN102164579A (zh) * | 2008-09-25 | 2011-08-24 | 赛福伦公司 | 苯达莫司汀的液体配制品 |
| CN102413816A (zh) * | 2009-04-28 | 2012-04-11 | 赛福伦公司 | 苯达莫司汀的口服制剂 |
| CN103037852A (zh) * | 2010-06-02 | 2013-04-10 | 安斯泰来德国有限公司 | 苯达莫司汀的口服剂型及其治疗用途 |
| CN104203235A (zh) * | 2012-02-14 | 2014-12-10 | 鹰制药股份有限公司 | 苯达莫司汀的制剂 |
| WO2015104720A2 (en) * | 2014-01-13 | 2015-07-16 | Hetero Research Foundation | Parenteral compositions of bendamustine |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10306724A1 (de) * | 2002-02-28 | 2003-09-18 | G O T Therapeutics Gmbh | Vesikuläre Verkapselung von Bendamustin |
| CN101219112A (zh) * | 2008-01-28 | 2008-07-16 | 济南帅华医药科技有限公司 | 一种含苯达莫司汀的复方抗癌缓释注射剂 |
| DK2827862T3 (da) * | 2012-03-20 | 2024-02-12 | Eagle Pharmaceuticals Inc | Formuleringer af bendamustin |
| CN103989641A (zh) * | 2014-05-29 | 2014-08-20 | 四川汇宇制药有限公司 | 一种注射用盐酸苯达莫司汀组合物的制备方法 |
-
2016
- 2016-03-25 CN CN201610179590.8A patent/CN105726472B/zh active Active
- 2016-03-25 CN CN201911109940.3A patent/CN110772480B/zh active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102164579A (zh) * | 2008-09-25 | 2011-08-24 | 赛福伦公司 | 苯达莫司汀的液体配制品 |
| CN102413816A (zh) * | 2009-04-28 | 2012-04-11 | 赛福伦公司 | 苯达莫司汀的口服制剂 |
| CN101584668A (zh) * | 2009-06-19 | 2009-11-25 | 江苏奥赛康药业有限公司 | 盐酸苯达莫司汀冻干粉针剂 |
| CN103037852A (zh) * | 2010-06-02 | 2013-04-10 | 安斯泰来德国有限公司 | 苯达莫司汀的口服剂型及其治疗用途 |
| CN104203235A (zh) * | 2012-02-14 | 2014-12-10 | 鹰制药股份有限公司 | 苯达莫司汀的制剂 |
| WO2015104720A2 (en) * | 2014-01-13 | 2015-07-16 | Hetero Research Foundation | Parenteral compositions of bendamustine |
Non-Patent Citations (1)
| Title |
|---|
| 苯达莫司汀的药理与临床研究;陈祥峰，等;《中国新药杂志》;20111231;第20卷(第8期);第665-668页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110772480A (zh) | 2020-02-11 |
| CN110772480B (zh) | 2022-05-17 |
| CN105726472A (zh) | 2016-07-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10052385B2 (en) | Formulations of bendamustine | |
| CN105726472B (zh) | 苯达莫司汀药剂组合物及应用 | |
| JP6159567B2 (ja) | 既製のゲムシタビン注入溶液 | |
| KR102656841B1 (ko) | 레파뮬린의 주사가능한 약제학적 제형 | |
| US20210275500A1 (en) | Liquid bendamustine pharmaceutical compositions | |
| US8969414B2 (en) | Intrathecal baclofen pharmaceutical dosage forms with fewer degradation products | |
| RU2493824C2 (ru) | Концентрат эсмолола | |
| US20230310384A1 (en) | Stable pharmaceutical compositions of bendamustine | |
| US8426467B2 (en) | Colored esmolol concentrate | |
| US20230107569A1 (en) | Methocarbamol compositions and related methods | |
| CN102274194B (zh) | 一种含托烷司琼化合物的药物组合物及其制备方法 | |
| US11642358B1 (en) | Stable pharmaceutical formulation | |
| KR20100022992A (ko) | 벤질 알코올을 갖는 다중 투여 농축 에스몰올 | |
| US20230241218A1 (en) | Formulations of bendamustine | |
| EP3192509B1 (en) | Remifentanil injection | |
| EP2976063A1 (en) | Parenteral formulation of fluoroquinolone antibacterial agent and method for preparation thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20220406 Address after: 210000 Room 401, building E2, No. 9, Weidi Road, Xianlin University City, Xianlin street, Qixia District, Nanjing, Jiangsu Province Patentee after: Nanjing Baijin Enterprise Management Consulting Co.,Ltd. Address before: 210000 Nanjing, Jiangsu Province room ao102, building 28, No. 699-18, Xuanwu Avenue, Xuanwu District, Nanjing, Jiangsu Province Patentee before: NANJING KANGBOSI PHARMACEUTICAL TECHNOLOGY Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20231007 Address after: Room 415, 4th Floor, No. 371 Taiping South Road, Qinhuai District, Nanjing City, Jiangsu Province, 210000 Patentee after: NANJING BAIXINYU MEDICINE Co.,Ltd. Address before: 210000 Room 401, building E2, No. 9, Weidi Road, Xianlin University City, Xianlin street, Qixia District, Nanjing, Jiangsu Province Patentee before: Nanjing Baijin Enterprise Management Consulting Co.,Ltd. |
|
| TR01 | Transfer of patent right |