CN112107537A - 一种普瑞巴林口服溶液及其制备方法 - Google Patents
一种普瑞巴林口服溶液及其制备方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title abstract description 13
- 229940015656 pregabalin oral solution Drugs 0.000 title description 3
- 239000000203 mixture Substances 0.000 claims abstract description 42
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 claims abstract description 37
- 229960001233 pregabalin Drugs 0.000 claims abstract description 35
- 239000007788 liquid Substances 0.000 claims abstract description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000003756 stirring Methods 0.000 claims abstract description 15
- 239000008213 purified water Substances 0.000 claims abstract description 14
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims abstract description 5
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- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 12
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- 235000013355 food flavoring agent Nutrition 0.000 claims description 10
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 8
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- FJJCIZWZNKZHII-UHFFFAOYSA-N [4,6-bis(cyanoamino)-1,3,5-triazin-2-yl]cyanamide Chemical compound N#CNC1=NC(NC#N)=NC(NC#N)=N1 FJJCIZWZNKZHII-UHFFFAOYSA-N 0.000 claims description 6
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- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 6
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Classifications
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- 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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- 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
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Health & Medical Sciences (AREA)
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- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Inorganic Chemistry (AREA)
- Rheumatology (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明涉及一种普瑞巴林口服液及其制备方法,属于医药技术领域。所述普瑞巴林口服液,其包括:含普瑞巴林1.0‑5.0g、防腐剂0.01‑0.10g、磷酸盐0.01‑5.0g、矫味剂0.10‑5.00g、食用香精0.01‑1.0g和纯化水。制备该口服液的工艺为:(1)将处方量矫味剂和防腐剂加入新沸的纯化水中,搅拌使完全溶解,得混合物一。(2)向混合物一中加入将处方量pH调节剂,溶解后得混合物二。(3)将处方量普瑞巴林加入60摄氏度水溶剂中,搅拌使其溶解,得混合物三。(4)将混合物三,在搅拌状态下缓慢加入混合物二,混合均匀,并加入处方量香精,混合均匀,在40‑50℃下保温15min,得混合物四。(5)将混合物四灌装、压盖、包装。采用本发明制得的口服液为澄明液体,尤其适用于服药困难的糖尿病性神经痛和带状疱疹神经痛及治疗成年人局部发作性癫痫患者,也能够有效防止病人藏药、吐药等服药不配合行为。
Description
技术领域
本申请属于医药技术领域,具体涉及一种普瑞巴林口服液及其制备方法。
背景技术
神经病理性疼痛是指由于神经系统受到损伤或产生病变而导致的疼痛,以钝痛、灼热、刺痛为主要特征。癫痫-神经系统常见疾病之一,是一种慢性、反复发作的短暂脑功能失调综合征,无论在发达国家还是发展中国家,癫痫都是一项重要的公共卫生问题。带状疱疹是一种急性皮肤黏膜感染的疾病,是由水痘-带状疱疹病毒引起,导致皮肤水泡簇集,易溃烂感染,而带状疱疹后神经痛是带状疱疹最严重的并发症,发作时伴有撕裂,针刺样疼痛,使患者寝食难安,而且多伴有抑郁或焦虑症状。紧张性头痛是最常见的一种头痛类型,患病率较高,患者通常感觉到钝痛,可并发失眠、抑郁及其他颅内并发症,多伴有烦躁、情绪
低落等症状。上述疾病严重影响患者的身心健康和生活质量,在工作、生活上常常不能发挥正常功能。
普瑞巴林由辉瑞公司于2004年7月6日获欧洲药物管理局(EMA)批准上市,之后于2004年12月30日获美国食品药品管理局(FDA)批准作为治疗糖尿病性神经痛和带状疱疹神经痛的药物上市。普瑞巴林是美国和欧洲认可的第一个同时适用于治疗上述两种疼痛的药物。2005年6月,普瑞巴林获批用于辅助治疗成年人局部发作性癫痫,之后陆续批准治疗广泛性焦虑障碍及纤维肌痛综合征等等。新型钙离子通道调节剂普瑞巴林能够有效治疗上述疾病,改善患者的疼痛,提高睡眠质量,缓解疲劳等症状。
普瑞巴林目前已在多个国家和地区上市,上市剂型主要有胶囊剂由辉瑞公司于2004年7月6日获欧洲药物管理局(EMA)批准上市,FDA批准辉瑞制药有限公司、Vega Baja,PR 00694生产的普瑞巴林胶囊(规格:25,50,75,100,150,200,225和300毫克)上市,商品名为Lyrica®/,口崩片(商品名为“乐瑞卡”,LYRICA®)和口服液有美国辉瑞公司Kalamazoo,MI 49001生产(规格20 mg/mL)上市。
本专利所制普瑞巴林口服溶液制剂,为吞咽困难或者不能吞咽的患者提供了一种重要的新选择。同时增加了患者用药的顺应性。
发明内容
本发明的目的是解决现有普瑞巴林制剂技术中原料难溶于水,液体制剂存在质量隐患;片剂等常规剂型不适合部分局部发作性癫痫患者服用,容易造成服药不配合甚至吐药的问题。
本发明所述普瑞巴林口服液,其特征在于,各成分按制剂总重量计:
本发明所述一种普瑞巴林口服液,该制剂中含有普瑞巴林、防腐剂、缓冲剂、矫味剂、芳香剂、纯化水,其特征在于,各成分按制剂总重量计:
普瑞巴林 1.00-5.00g
防腐剂 0.01-0.10g、
磷酸盐 0.01-5.00g、
矫味剂 0.10-5.00g、
食用香精 0.01-1.00g
纯化水 补足至100ml
本发明所述如权利要求2所述的普瑞巴林口服液,其特征在于,优选的各成分按制剂总重量计:
普瑞巴林 1.00-4.00g
防腐剂 0.01-0.15g、
磷酸盐 0.01-5.50g、
矫味剂 0.10-6.00g、
食用香精 0.01-1.50g
纯化水 补足至100ml
本发明所述如权利要求1~2所述的口服液,其特征在于,该口服液的pH范围为5.5~6.0。
本发明所述如权利要求1~2所述的口服液,其特征在于,该药物制剂中的缓冲剂指磷酸
氢二钠-磷酸二氢钠缓冲溶液、磷酸氢二钾-磷酸二氢钾缓冲溶液、磷酸氢二钠-磷酸二氢钾缓冲溶液,其用量应控制在能使口服溶液的pH值在5.5~6.0间。
本发明所述该药物制剂中的矫味剂含有甜味剂和香精,其中矫味剂选自蔗糖、葡萄糖、乳糖、果糖、木糖醇、甘露醇、山梨醇、赤藓糖醇、三氯蔗糖、安赛蜜、阿斯巴甜和甜菊糖中一种或几种的混合物,优选三氯蔗糖、阿斯巴甜、木糖醇、山梨醇、安赛蜜。香精选自香蕉香精、桔子香精、柠檬香精、水蜜桃香精、奶油香精、巧克力香精、草莓香精、菠萝香精、苹果香精、猕猴桃香精、葡萄香精、西瓜香精、哈密瓜香精中的一种或几种的混合物,优选桔子香精水蜜桃香精、草莓香精、哈密瓜香精;
本发明所述该药物制剂中的防腐剂选自羟苯甲酯、羟苯乙酯、羟苯丙酯、羟苯丁酯、苯甲酸、尼泊金、山梨酸及其盐类,优选羟苯甲酯、羟苯丙酯。
本发明所述提供一种普瑞巴林口服液的制备方法,具体操作为:
(1)将处方量矫味剂和防腐剂加入新沸的纯化水中,搅拌使完全溶解,得混合物一。
(2)向混合物一中加入将处方量pH调节剂,溶解后得混合物二。
(3) 将处方量普瑞巴林加入60摄氏度水溶剂中,搅拌使其溶解,得混合物三。
(4)将混合物三在搅拌状态下缓慢加入混合物二,混合均匀,并加入处方量香精,混合均匀,在40-50℃下保温15min,得混合物四。
(5)将混合物四灌装、压盖、包装。
由于口服溶液的pH值会影响样品的稳定性及服药顺应性,通过以下实验说明调整口服液pH值对药物稳定性的有益效果。
在制备过程中,通过加入不同pH调节剂,考察不同pH值的普瑞巴林口服液在高温60℃及光照5000±500lx 10天的外观性状、pH值、有关物质的变化。结果见表1。
实验结果由表1可知,pH值分别为4.0、4.5的样品在进行pH值调节过程中产生乳白色絮状沉淀,因此未将其进行影响因素放样。①有关物质:在高温60℃及光照5000±500lx条件下放置10天后,各样品的有关物质均略有增长,其中, pH5.0样品增长最为明显,而pH5.5和pH6.0的增长趋势较缓慢。②外观性状: pH5.0及pH5.5样品在高温60℃条件下放置10天后其颜色与0天相比明显变深,其余样品均无明显变化。综合有关物质及外观性状的结果,初步说明样品在pH5.5-6.0之间质量稳定。
具体实施方式:
以下通过实施例形式的具体实施方式,对本发明的上述内容再做进一步的详细说明。但本发明不局限于这些例子。
实施例1
普瑞巴林 2.00g
磷酸二氢钠 2.70g
磷酸氢二钠 0.05g、
羟苯甲酯 0.015g
羟苯丙酯 0.002g
安赛蜜 1.00g
哈密瓜香精 0.20g
纯化水 补足至100ml
制备方法
1)将处方量安赛蜜和羟苯甲酯、羟苯丙酯加入新沸的纯化水中,搅拌使完全溶解,得混合物一。
(2)向混合物一中加入将处方量磷酸二氢钠、磷酸氢二钠,溶解后得混合物二。
(3) 将处方量普瑞巴林加入60摄氏度水溶剂中,搅拌使其溶解,得混合物三。
(4)将混合物三在搅拌状态下缓慢加入混合物二,混合均匀,并加入处方量哈密瓜香精,混合均匀,在40-50℃下保温15min,得混合物四。
(5)将混合物四灌装、压盖、包装。
实施例2
普瑞巴林 2.00g
磷酸二氢钠 2.60g
磷酸氢二钠 0.04g、
羟苯甲酯 0.013g
羟苯丙酯 0.002g
三氯蔗糖 0.50g
草莓香精 0.20g
纯化水 补足至100ml
制备方法
1)将处方量三氯蔗糖和羟苯甲酯、羟苯丙酯加入新沸的纯化水中,搅拌使完全溶解,得混合物一。
(2)向混合物一中加入将处方量磷酸二氢钠、磷酸氢二钠,溶解后得混合物二。
(3) 将处方量普瑞巴林加入60摄氏度水溶剂中,搅拌使其溶解,得混合物三。
(4)将混合物三在搅拌状态下缓慢加入混合物二,混合均匀,并加入处方量草莓香精,混合均匀,在40-50℃下保温15min,得混合物四。
(5)将混合物四灌装、压盖、包装。
微生物限度检测方法:
试验条件:环境洁净度10000级下的局部洁净度100级的单向流空气域内,全过程应严格遵守无菌操作。
检查方法:取口服液10ml,采用薄膜过滤法(800ml冲洗)检查细菌、霉菌和酵母菌,用薄膜过滤法(800ml冲洗)检查控制菌:大肠埃希菌。
加速试验方法:
将包装后的样品置药物稳定性考察试验箱中,设定考察条件为温度40℃,相对湿度75%,分别于1月、2月、3月和6月取样,检测性状、pH值、微生物限度、含量和有关物质。
实施例1加速试验结果:
实施例2加速试验结果:
由上两表可知,实施例1、2的样品在加速实验条件下放置6个月,性状、pH值、微生物限度和含量均无明显变化,有关物质略有增加趋势,但仍明显低于限度要求,表明样品稳定性良好。
Claims (5)
1.一种普瑞巴林口服液,该制剂中含有普瑞巴林、防腐剂、缓冲剂、矫味剂、芳香剂、纯化水,其特征在于,各成分按制剂总重量计:
普瑞巴林 1.00-5.00g
防腐剂 0.01-0.10g、
磷酸盐 0.01-5.00g、
矫味剂 0.10-5.00g、
食用香精 0.01-1.00g
纯化水 补足至100ml。
2.如权利要求2所述的普瑞巴林口服液,其特征在于,优选的各成分按制剂总重量计:
普瑞巴林 1.00-4.00g
防腐剂 0.01-0.15g、
磷酸盐 0.01-5.50g、
矫味剂 0.10-6.00g、
食用香精 0.01-1.50g
纯化水 补足至100ml。
3.如权利要求1~2所述的口服液,其特征在于,该口服液的pH范围为5.5~6.0。
4.如权利要求1~2所述的口服液,其特征在于,该药物制剂中的缓冲剂指磷酸氢二钠-磷酸二氢钠缓冲溶液、磷酸氢二钾-磷酸二氢钾缓冲溶液、磷酸氢二钠-磷酸二氢钾缓冲溶液,其用量应控制在能使口服溶液的pH值在5.5~6.0间;
该药物制剂中的矫味剂含有甜味剂和香精,其中矫味剂选自蔗糖、葡萄糖、乳糖、果糖、木糖醇、甘露醇、山梨醇、赤藓糖醇、三氯蔗糖、安赛蜜、阿斯巴甜和甜菊糖中一种或几种的混合物,优选三氯蔗糖、阿斯巴甜、木糖醇、山梨醇、安赛蜜;
香精选自香蕉香精、桔子香精、柠檬香精、水蜜桃香精、奶油香精、巧克力香精、草莓香精、菠萝香精、苹果香精、猕猴桃香精、葡萄香精、西瓜香精、哈密瓜香精中的一种或几种的混合物,优选桔子香精水蜜桃香精、草莓香精、哈密瓜香精;
该药物制剂中的防腐剂选自羟苯甲酯、羟苯乙酯、羟苯丙酯、羟苯丁酯、苯甲酸、尼泊金、山梨酸及其盐类,优选羟苯甲酯、羟苯丙酯。
5.制备权利要求1~5中任何一项的口服液的方法,其特征在于,该方法包括如下步骤:
(1)将处方量矫味剂和防腐剂加入新沸的纯化水中,搅拌使完全溶解,得混合物一;
(2)向混合物一中加入将处方量pH调节剂,溶解后得混合物二;
(3) 将处方量普瑞巴林加入60摄氏度水溶剂中,搅拌使其溶解,得混合物三;
(4)将混合物三在搅拌状态下缓慢加入混合物二,混合均匀,并加入处方量香精,混合均匀,在40-50℃下保温15min,得混合物四;
(5)将混合物四灌装、压盖、包装。
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