CN111840215A - 一种氟比洛芬注射液与容器的组合 - Google Patents
一种氟比洛芬注射液与容器的组合 Download PDFInfo
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- 229960002390 flurbiprofen Drugs 0.000 title claims abstract description 85
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 title claims abstract description 83
- 238000002347 injection Methods 0.000 title claims abstract description 44
- 239000007924 injection Substances 0.000 title claims abstract description 44
- 239000011521 glass Substances 0.000 claims abstract description 79
- 229910000272 alkali metal oxide Inorganic materials 0.000 claims abstract description 15
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910052593 corundum Inorganic materials 0.000 claims abstract description 11
- 229910001845 yogo sapphire Inorganic materials 0.000 claims abstract description 11
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- 238000003860 storage Methods 0.000 claims description 9
- 150000001413 amino acids Chemical class 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- SYTBZMRGLBWNTM-SNVBAGLBSA-N (R)-flurbiprofen Chemical compound FC1=CC([C@H](C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-SNVBAGLBSA-N 0.000 claims description 4
- SYTBZMRGLBWNTM-JTQLQIEISA-N (S)-flurbiprofen Chemical compound FC1=CC([C@@H](C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-JTQLQIEISA-N 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- 239000004615 ingredient Substances 0.000 abstract description 3
- 229910052681 coesite Inorganic materials 0.000 abstract 1
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- 239000000377 silicon dioxide Substances 0.000 abstract 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 abstract 1
- 229910052682 stishovite Inorganic materials 0.000 abstract 1
- 229910052905 tridymite Inorganic materials 0.000 abstract 1
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- 238000002156 mixing Methods 0.000 description 20
- 238000003756 stirring Methods 0.000 description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 14
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- 238000004806 packaging method and process Methods 0.000 description 10
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- 235000001014 amino acid Nutrition 0.000 description 5
- ZLKQQDFLPVWFDT-UHFFFAOYSA-N 1-(3-fluoro-4-phenylphenyl)ethanone Chemical group FC1=CC(C(=O)C)=CC=C1C1=CC=CC=C1 ZLKQQDFLPVWFDT-UHFFFAOYSA-N 0.000 description 4
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 4
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
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- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- ALIVXCSEERJYHU-UHFFFAOYSA-N Flurbiprofen axetil Chemical compound FC1=CC(C(C)C(=O)OC(OC(C)=O)C)=CC=C1C1=CC=CC=C1 ALIVXCSEERJYHU-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
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- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000005263 alkylenediamine group Chemical group 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000001760 anti-analgesic effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000009697 arginine Nutrition 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
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- 238000002474 experimental method Methods 0.000 description 1
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- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 235000014304 histidine Nutrition 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
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- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- XMYQHJDBLRZMLW-UHFFFAOYSA-N methanolamine Chemical compound NCO XMYQHJDBLRZMLW-UHFFFAOYSA-N 0.000 description 1
- 229940087646 methanolamine Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 238000009512 pharmaceutical packaging Methods 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
- A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
本发明提供一种氟比洛芬注射液与容器的组合。其中,容器的材料为玻璃,且玻璃中包含SiO2 70‑80%,B2O3 5‑20%,Al2O3 1‑10%,碱金属氧化物 1‑10%。优选地,玻璃中包含B2O3 7.5‑11.5%,Al2O3 3‑7%,碱金属氧化物3‑10%。本发明提供的组合能够获得储存中始终维持澄清、透明的物理状态稳定的氟比洛芬注射液,同时也能够维持多种处方下氟比洛芬注射液中有效成分氟比洛芬的稳定。
Description
技术领域
本发明涉及药物技术领域,具体涉及一种稳定的氟比洛芬注射液与容器的组合。
背景技术
氟比洛芬,化学名称为(±)-2-(2-氟-4-联苯基)-丙酸,是一种非甾体类解热、消炎、镇痛药物,其作用机制为抑制前列腺素环氧酶,阻断前列腺素的生物合成,从而发挥疗效,其消炎镇痛能力强于阿司匹林和氟比洛芬,并且副作用较小,具有良好的耐受性,广泛用于治疗类风湿性关节炎和其他风湿性疾病。
由于氟比洛芬几乎不溶于水的特性,目前尚无氟比洛芬静脉给药制剂上市。氟比洛芬的前药氟比洛芬酯被制备为脂肪乳注射液用于静脉注射,临床上用于术后及癌症的镇痛。专利ZL201210064288.X提供了一种氟比洛芬与碱性氨基酸的药物组合物水溶液。
一般来说,直接与药品接触的容器必须是药学上可接受的。直接接触药品的包装材料和容器是药品不可分割的一部分,伴随药品的生产、流通和使用的全过程。对于注射液来说,在制备过程中通常需要进行灭菌,灭菌过程中的高温高压环境可能造成药品包装材料的降解,降解出来的物质可能与药物组合物中的成分发生反应,也有可能造成药物组合物中的成分在包材中的过多吸附。除此之外,药物在长期储存中,光照和温度等外部环境的变化,也有导致包材的变化以及药品中有效成分的降解。无论何种改变,都有可能造成制剂稳定性降低,对临床上的使用带来安全隐患。
现有技术中未认为不同包材的选择会导致氟比洛芬注射液在灭菌或储存过程中质量发生变化。对此,本发明解决的技术问题是提供一种稳定的氟比洛芬注射液与容器的组合,能够获得储存中始终维持澄清、透明的物理状态稳定的氟比洛芬注射液,同时也能够维持多种处方下氟比洛芬注射液中有效成分氟比洛芬的稳定。
发明内容
本发明提供一种氟比洛芬注射液和容器的组合,所述容器的材料为玻璃。
所述的玻璃包含:SiO2 70-80%,B2O3 5-20%,Al2O3 1-10%,碱金属氧化物1-10%。优选地,所述的玻璃包含:B2O3 7.5-11.5%,Al2O3 3-7%,碱金属氧化物3-10%。
所述的氟比洛芬注射液包含氟比洛芬和注射用水。
上述氟比洛芬注射液中,还包含氨基酸、氨基多元醇和磷酸盐或者其组合。
根据本发明目的的一个方面,本发明提供的氟比洛芬注射液和容器的组合,能够避免氟比洛芬注射液在低温光照储存中氟比洛芬晶体的产生,获得一种物理性质更加稳定的氟比洛芬注射液。
在本发明的一些实施方案中,所述的氟比洛芬注射液包含氟比洛芬、氨基酸和注射用水。氨基酸与氟比洛芬的摩尔比的范围为0.1-10:1,其中0.1-10包含0.1-10之间的任一数值,比如0.1:1、0.25:1、0.5:1、1:1、2:1、5:1、10:1等。氨基酸包括,但不限于精氨酸、赖氨酸、组氨酸或者其组合,所述的氨基酸可以为L型或D型。
在另一实施方案中,所述的氟比洛芬注射液包含氟比洛芬、氨基多元醇和注射用水。氨基多元醇与氟比洛芬的摩尔比的范围为0.1-10:1,其中0.1-10包含0.1-10之间的任一数值,比如0.1:1、0.25:1、0.5:1、1:1、2:1、5:1、10:1等。其中,氨基多元醇包括,但不限于氨丁三醇、葡甲胺、甲醇胺、单乙醇胺、二乙醇胺、丙醇胺、亚烷基二胺或其组合;优选为氨丁三醇和/或葡甲胺。
在另一实施方案中,所述的氟比洛芬注射液包含氟比洛芬、磷酸盐和注射用水。磷酸盐与氟比洛芬的摩尔比的范围为0.1-10:1,其中0.1-10包含0.1-10之间的任一数值,比如0.1:1、0.25:1、0.5:1、1:1、2:1、5:1、10:1等。其中,磷酸盐包括,但不限于磷酸钠、磷酸钾、磷酸氢二钠、磷酸氢二钾、磷酸二氢钠、磷酸二氢钾或者其组合,优选为磷酸氢二钠。
根据本发明目的的另一个方面,本发明提供的氟比洛芬注射液和容器的组合,能够避免氟比洛芬注射液中的有效成分氟比洛芬在热压灭菌以及长期储存中的降解,降低降解杂质的产生。
所述的容器具有用于储存药物组合物的闭合装置。
所述的氟比洛芬选自(RS)-氟比洛芬或其衍生物、R-氟比洛芬或其衍生物、S-氟比洛芬或其衍生物或者R-氟比洛芬或其衍生物与S-氟比洛芬或其衍生物的任意比例的组合。
所述的氟比洛芬注射液中,氟比洛芬的浓度为0.1~50mg/ml,氟比洛芬浓度可为该浓度范围内的任一浓度值(例如0.25mg/ml、0.375mg/ml、0.5mg/ml、5mg/ml、7.5mg/ml、10mg/ml)及任选的浓度范围,优选的浓度范围为0.25~10mg/ml。
所述的容器的容积范围为1ml~250ml,容积可为该容积范围内的任一容积或任选的容积范围,优选的容积范围为5ml~100ml。
本发明所述的降解杂质4-乙酰基-2-氟联苯结构如下所示:
令人惊讶的是,针对氟比洛芬注射液的不同处方,本申请的氟比洛芬注射液和容器的组合均能够保证在高温高压灭菌前后以及长期储存中,氟比洛芬注射液物理状态的稳定(储存中不析出氟比洛芬晶体),以及能够降低氟比洛芬注射液中有效成分氟比洛芬的降解。
具体实施方式
实施例1
处方:
制备方法:
(1)将处方量L-精氨酸、氯化钠加入注射用水中,搅拌并混合均匀;
(2)将处方量氟比洛芬加入步骤(1)混合物中,搅拌并混合均匀;
(3)调节pH值为7.0-7.5;
(4)将所得溶液分别包装在玻璃型号1、玻璃型号2、玻璃型号3、玻璃型号4和玻璃型号5制成的容器中,规格为10ml;
(5)121℃,12min灭菌,即得。
实施例2
处方:
制备方法:
(1)将处方量L-赖氨酸、氯化钠加入注射用水中,搅拌并混合均匀;
(2)将处方量氟比洛芬加入步骤(1)混合物中,搅拌并混合均匀;
(3)调节pH值为7.0-7.5;
(4)将所得溶液分别包装在玻璃型号1、玻璃型号2、玻璃型号3、玻璃型号4和玻璃型号5制成的容器中,规格为10ml;
(5)121℃,12min灭菌,即得。
实施例3
处方:
制备方法:
(1)将处方量氨丁三醇、氯化钠加入注射用水中,搅拌并混合均匀;
(2)将处方量氟比洛芬加入步骤(1)混合物中,搅拌并混合均匀;
(3)使用氢氧化钠/盐酸调节pH值为7.0-7.5;
(4)将所得溶液分别包装在玻璃型号1、玻璃型号2、玻璃型号3、玻璃型号4和玻璃型号5制成的容器中,规格为10ml;
(5)121℃,12min灭菌,即得。
实施例4
处方:
制备方法:
(1)将处方量葡甲胺、氯化钠加入注射用水中,搅拌并混合均匀;
(2)将处方量氟比洛芬加入步骤(1)混合物中,搅拌并混合均匀;
(3)使用氢氧化钠/盐酸调节pH值为7.0-7.5;
(4)将所得溶液分别包装在玻璃型号1、玻璃型号2、玻璃型号3、玻璃型号4和玻璃型号5制成的容器中,规格为10ml;
(5)121℃,12min灭菌,即得。
实施例5
处方:
制备方法:
(1)将处方量磷酸氢二钠、氯化钠加入注射用水中,搅拌并混合均匀;
(2)将处方量氟比洛芬加入步骤(1)混合物中,搅拌并混合均匀;
(3)使用氢氧化钠/盐酸调节pH值为7.0-7.5;
(4)将所得溶液分别包装在玻璃型号1、玻璃型号2、玻璃型号3、玻璃型号4和玻璃型号5制成的容器中,规格为10ml;
(5)121℃,12min灭菌,即得。
本发明所使用的不同型号玻璃瓶玻璃材料中的成分如下所示:
玻璃型号1:SiO2 75.3%,B2O3 3.5%,Al2O3 5.3%,碱金属氧化物6.5%。
玻璃型号2:SiO2 74.4%,B2O36.4%,Al2O3 5.7%,碱金属氧化物6.6%。
玻璃型号3:SiO2 76.2%,B2O3 7.5%,Al2O3 6.1%,碱金属氧化物6.1%。
玻璃型号4:SiO2 75.8%,B2O3 11.2%,Al2O3 6.2%,碱金属氧化物6.3%。
玻璃型号5:SiO2 75.1%,B2O3 7.6%,Al2O3 5.7%,碱金属氧化物12.3%。
测试例1在不同温度及光照条件下的样品稳定性考察。
将实施例1-5的样品在4℃,光照4500±500lx条件下放置,分别于0天、5天、10天、30天观察样品情况。结果如下表1所示:
表1 4℃,4500±500lx不同时间点观察结果
将实施例1-5的样品在室温,光照4500±500lx条件下放置,分别于0天、5天、10天、30天观察样品情况。结果如下表2所示:
表2室温,4500±500lx不同时间点观察结果
将实施例1-5的样品在4℃条件下,避光放置,分别于0天、5天、10天、30天观察样品情况。结果如下表3所示:
表3 4℃,避光不同时间点观察结果
根据上述实验结果可以发现,采用玻璃材料型号1-5制备的玻璃瓶作为容器时,在室温光照下以及低温避光下保存所获得的氟比洛芬注射液稳定性都较好,能维持澄清、无色的状态。但是,只有采用各组分在本发明范围内的玻璃材料作为容器时(玻璃型号2-4作为容器),所制备的氟比洛芬注射液在低温光照实验中能保持稳定。采用玻璃型号1(B2O3含量为3.5%)以及玻璃型号5(碱金属氧化物含量为12.3%)所制得的玻璃瓶中保存的氟比洛芬注射液在低温光照下氟比洛芬容易析出,制剂的物理状态不稳定。
测试例2
将实施例1-5的样品在40℃,4500±500lx条件下放置,分别于高温灭菌后、3个月、6个月取样品,采用高效液相色谱法对降解杂质4-乙酰基-2-氟联苯的含量进行检测,结果如下表所示:
表3氟比洛芬降解杂质4-乙酰基-2-氟联苯的含量
根据上述检测结果可以发现,实施例1-5样品在采用玻璃型号1和玻璃型号5的玻璃材料制备的玻璃容器中,高温灭菌后以及储存过程中降解杂质4-乙酰基-2-氟联苯的含量增高明显,尤其在6个月时已超过0.1%。而采用玻璃型号2、3、4的玻璃材料制备的玻璃容器包装的样品,其降解杂质含量明显处于较低水平,且其中采用玻璃型号3和玻璃型号4玻璃容器包装的氟比洛芬注射液中有效成分氟比洛芬更为稳定。
实施例6
处方:
制备方法:
(1)将处方量L-精氨酸、氯化钠加入注射用水中,搅拌并混合均匀;
(2)将处方量氟比洛芬加入步骤(1)混合物中,搅拌并混合均匀;
(3)调节pH值为7.0-7.5;
(4)将所得溶液分别包装在玻璃型号1、玻璃型号2、玻璃型号3、玻璃型号4和玻璃型号5制成的容器中,规格为100ml;
(5)121℃,12min灭菌,即得。
实施例7
制备方法:
(1)将处方量L-赖氨酸、氯化钠加入注射用水中,搅拌并混合均匀;
(2)将处方量氟比洛芬加入步骤(1)混合物中,搅拌并混合均匀;
(3)调节pH值为7.0-7.5;
(4)将所得溶液分别包装在玻璃型号1、玻璃型号2、玻璃型号3、玻璃型号4和玻璃型号5制成的容器中,规格为100ml;
(5)121℃,12min灭菌,即得。
实施例8
处方:
制备方法:
(1)将处方量氨丁三醇、氯化钠加入注射用水中,搅拌并混合均匀;
(2)将处方量氟比洛芬加入步骤(1)混合物中,搅拌并混合均匀;
(3)使用氢氧化钠/盐酸调节pH值为7.0-7.5;
(4)将所得溶液分别包装在玻璃型号1、玻璃型号2、玻璃型号3、玻璃型号4和玻璃型号5制成的容器中,规格为100ml;
(5)121℃,12min灭菌,即得。
实施例9
处方:
制备方法:
(1)将处方量葡甲胺、氯化钠加入注射用水中,搅拌并混合均匀;
(2)将处方量氟比洛芬加入步骤(1)混合物中,搅拌并混合均匀;
(3)使用氢氧化钠/盐酸调节pH值为7.0-7.5;
(4)将所得溶液分别包装在玻璃型号1、玻璃型号2、玻璃型号3、玻璃型号4和玻璃型号5制成的容器中,规格为100ml;
(5)121℃,12min灭菌,即得。
实施例10
处方:
制备方法:
(1)将处方量磷酸氢二钠、氯化钠加入注射用水中,搅拌并混合均匀;
(2)将处方量氟比洛芬加入步骤(1)混合物中,搅拌并混合均匀;
(3)使用氢氧化钠/盐酸调节pH值为7.0-7.5;
(4)将所得溶液分别包装在玻璃型号1、玻璃型号2、玻璃型号3、玻璃型号4和玻璃型号5制成的容器中,规格为100ml;
(5)121℃,12min灭菌,即得。
将实施例6-10的样品采用上述测试例1-2的试验方法进行相关检测,所得结果与相应的实施例1-5检测结果能够得出相同结论。
上详细描述了本发明的优选实施方式。但是,本发明并不限于上述实施方式中的具体细节,在本发明的技术构思范围内,可以对本发明的技术方案进行多种简单变型。这些简单变型均属于本发明的保护范围。
另外需要说明的是,在上述具体实施方式中所描述的各个具体技术特征,在不矛盾的情况下,可以通过任何方式进行组合。为了避免不必要的重复,本发明对各种可能的组合方式不再另行说明。采用本发明所述的三种氟比洛芬组合物的不同氟比洛芬浓度以及不同的氟比洛芬与辅料的比例,根据测试例1和测试例2的方法进行检测,均能够得到相同结论。
此外,本发明的各种不同的实施方式之间也可以进行任意组合,只要不违背本发明的思想,其同样应当视为本发明所公开的内容。
Claims (10)
1.一种氟比洛芬注射液与容器的组合,其特征在于,所述的容器的材料为玻璃。
2.根据权利要求1所述的氟比洛芬注射液与容器的组合,其特征在于,所述的玻璃包含:SiO2 70-80%,B2O3 5-20%,Al2O3 1-10%,碱金属氧化物 1-10%。
3.根据权利要求2所述的氟比洛芬注射液与容器的组合,其特征在于,所述的玻璃包含:B2O3 7.5-11.5%,Al2O3 3-7%,碱金属氧化物3-10%。
4.根据权利要求1所述的氟比洛芬注射液与容器的组合,其特征在于,所述的氟比洛芬注射液包含氟比洛芬和注射用水。
5.根据权利要求4所述的氟比洛芬注射液与容器的组合,其特征在于,所述的氟比洛芬注射液中还包含氨基酸、氨基多元醇、磷酸盐或者其组合。
6.根据权利要求1所述的氟比洛芬注射液与容器的组合,其特征在于,所述的容器具有用于储存药物组合物的闭合装置。
7.根据权利要求1所述的氟比洛芬注射液与容器的组合,其特征在于,所述的氟比洛芬选自(RS)-氟比洛芬或其衍生物、R-氟比洛芬或其衍生物、S-氟比洛芬或其衍生物或者R-氟比洛芬或其衍生物与S-氟比洛芬或其衍生物的任意比例的组合。
8.根据权利要求1所述的氟比洛芬注射液与容器的组合,其特征在于,所述的氟比洛芬的浓度为0.1 ~ 50mg/ml,优选为0.25 ~ 10mg/ml。
9.根据权利要求1所述的氟比洛芬注射液与容器的组合,其特征在于,所述的容器的容积为1ml-250ml,优选为5ml-100ml。
10.根据权利要求1-9任一所述的氟比洛芬注射液与容器的组合,其特征在于,所述的容器能够保证氟比洛芬注射液储存中的稳定性。
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