CN101309688B - 持续释放β-丙氨酸的组合物和方法 - Google Patents
持续释放β-丙氨酸的组合物和方法 Download PDFInfo
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- CN101309688B CN101309688B CN200680026773.0A CN200680026773A CN101309688B CN 101309688 B CN101309688 B CN 101309688B CN 200680026773 A CN200680026773 A CN 200680026773A CN 101309688 B CN101309688 B CN 101309688B
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- alanine
- beta
- dietary supplement
- free beta
- sustained release
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Abstract
本发明提供用于增加肌肉和其它组织的无氧工作能力的方法和组合物。还提供配制成能用于持续释放游离β-丙氨酸的组合物。
Description
技术领域
本申请总体涉及药学和生理学领域,更具体来讲涉及持续释放游离β-丙氨酸的组合物和方法。
背景
天然食品补充剂通常设计成能够用于补偿现代人和动物膳食中营养素水平的降低。具体来讲,消耗有益的补充剂可增强组织的功能。特别重要的是补充其日常膳食中可能缺乏只来自肉和动物制品的营养素的人和特殊种类动物(如素食者及其它食草动物)的膳食。
另外,在喜好体育和运动的人群中,特别用于改善运动能力的天然食品补充剂越来越重要,如用于休闲或职业目的的促进或增强体格能力的补充剂。另一种实例是,无氧(如乳酸产生)应激可导致疲劳和不适的出现,随年龄增加越来越明显。无氧应激还可由于长时间接近极限等长运动引起,此时肌内压增加(如攀岩过程中)导致局部循环部分或完全闭塞,或者由涉及憋气时间延长(如自由式潜水或花样游泳)的运动引起。过量乳酸的产生可导致细胞内环境酸化。
现有研究证明给予β-丙氨酸或β-丙氨酸生物源(如肌肽)补充剂后肌肉内肌肽明显增加。虽然给药方案已经优选这样给药(即每天8次),但存在依从性问题和感觉异常的难题。因此,需要含游离β-丙氨酸或其生物源的改良补充剂的持续释放制剂,以增加依从性和减少感觉异常事件。
概述
给予单次大剂量(bolus)2-6克游离β-丙氨酸(或化学上等量的β-丙氨酸生物源的化合物,如肌肽)导致感觉异常,是重要的不良反应,症状包括异常感觉如烧灼感、刺痛感或“发麻”感。直接或者从充当β-丙氨酸生物源的化合物中持续释放游离β-丙氨酸可通过减弱β-丙氨酸血浆浓度的增加,避免严重不良反应,提供无氧活动时安全和有效地增加肌肉内肌肽生物合成并且减弱代谢性酸中毒和肌肉疲劳的方法。
本文提供持续释放游离β-丙氨酸或其生物源的组合物和方法。在一个实施方案中,组合物是包含游离β-丙氨酸或其生物源以及可接受的载体的药用组合物,其中组合物配制成能用于持续释放游离β-丙氨酸。在另一个实施方案中,组合物是包含游离β-丙氨酸或其生物源的膳食补充剂。
还提供增加肌肉及其它组织无氧工作能力的方法。此类方法包括提供配制成能用于持续释放游离β-丙氨酸的组合物,给予有效量的游离β-丙氨酸或其生物源以增加肌肉或其它组织中肌肽合成。
提供配制成能用于持续释放游离β-丙氨酸的含游离β-丙氨酸或其生物源及药学上可接受的载体的药用组合物。在一个实施方案中,药用组合物是可口服给药的片剂、胶囊剂或微珠。在另一个实施方案中,药用组合物是配制成能用于持续释放游离β-丙氨酸的皮肤贴剂或局部皮肤病化合物。可将药用组合物配制成能用于人。
提供包含游离β-丙氨酸或其生物源的膳食补充剂。在一个实施方案中,膳食补充剂是能量棒、食用混悬液或其它食品。可将膳食补充剂配制成能用于人。
药用组合物可包含约0.1-200.0、约1.0-9.0、约2.0-8.0、约3.0-7.0或约4.0-6.0克(g)游离β-丙氨酸或其等量生物源。可将药用组合物配制成能用于人,可包含约0.1-200.0、约1.0-9.0、约2.0-8.0、约3.0-7.0或约4.0-6.0g游离β-丙氨酸或其等量生物源。
膳食补充剂可包含约0.1-200.0、约1.0-9.0、约2.0-8.0、约3.0-7.0或约4.0-6.0g游离β-丙氨酸或其等量生物源。可将膳食补充剂配制成能用于人,可包含约0.1-200.0、约1.0-9.0、约2.0-8.0、约3.0-7.0或约4.0-6.0g游离β-丙氨酸或其等量生物源。在一个实施方案中,膳食补充剂是能量棒、食用混悬液或食品。在一方面,膳食补充剂包含多份,每份含0.1-10.0gβ-丙氨酸或其等量生物源。膳食补充剂包含的游离β-丙氨酸或其等量生物源的总量可以为约0.1-200,0、约1.0-8.0、约3.0-7.0或约4.0-6.0g游离β-丙氨酸或其等量生物源。
本文还提供持续释放包含在药用组合物中的游离β-丙氨酸或其等量生物源的制剂。在一方面,将含游离β-丙氨酸或其等量生物源的药用组合物配制成能用于持续释放,可以片剂、凝胶剂或微珠形式口服给药。在另一方面,药用组合物是局部皮肤病制剂如水凝胶,配制成能用于透过皮肤持续释放游离β-丙氨酸。
尽管不受任何具体作用机制的约束,但本文提供的是增加肌肉及其它组织无氧工作能力的方法和组合物。本文公开的方法和组合物通过利用β-丙氨酸使机体组织内肌肽蓄积。所述方法包括进食或输注配制成能用于持续释放入体内的含游离β-丙氨酸或其生物源的组合物。在一方面,组合物是能够增加人和动物组织中β-丙氨酰组氨酸肽(如肌肽)蓄积的化合物混合物。当引入体内时,组合物可诱导人或动物体内β-丙氨酰组氨酸肽的合成和蓄积。
本文提供的组合物可用于制备膳食补充剂(包括如饮料、食用混悬液或食物)或者用于人或动物的药用组合物。本发明的组合物可用于本发明的任何方法。
在一方面,提供增加组织的无氧工作能力的方法。所述方法包括将有效量增加组织内肌肽合成的游离β-丙氨酸提供入血液或血浆中。本文所指的组织可以是骨骼肌。
因此,在举例方面,本文提供持续释放包含在药用组合物或膳食补充剂中的游离β-丙氨酸的组合物和方法,通过增加肌肽生物合成,增加肌肉组织的无氧工作能力。
除非另外限定,否则本文使用的全部专业和科学术语都具有本发明所属领域技术人员通常理解的相同含义。虽然与本文的描述类似或等同的方法和材料可用于实施或检验本发明,但下文描述的是优选方法和材料。另外,材料、方法和实施例只用于举例说明,并非限制性。本文提及的所有出版物、专利申请、专利及其它参考文献都通过引用完全结合到本文中。在有冲突的情况下,将对照本说明书,包括定义。
在下述附图和详述中列出了本发明的一个或多个实施方案的细节。根据附图和详细描述以及权利要求,本发明的其它特征、目的和优点将显而易见。
附图简述
图1显示摄入β-丙氨酸饮料或β-丙氨酸持续释放胶囊后个体的血浆β-丙氨酸水平。
图2显示摄入两种不同的持续释放β-丙氨酸制剂后个体的血浆β-丙氨酸水平。
不同附图中同样的参考标志表示同样的成分。
详述
本文提供持续释放游离β-丙氨酸的组合物。本文还提供通过将有效增加组织合成β-丙氨酰组氨酸肽特别是肌肽量的游离β-丙氨酸提供给血液或血浆,增加组织无氧工作能力的的方法。β-丙氨酰组氨酸肽可包括β-丙氨酸的肽,如肌肽、鹅肌肽和鲸肌肽。预期持续释放游离β-丙氨酸可预防不需要的不良副作用如感觉异常。
可将本文公开的任何含β-丙氨酸组合物配制为组合物中唯一的药用活性成分,或者可将β-丙氨酸与其它活性成分组合和/或联合给药。例如,另一种活性成分可以是本领域已知的另一种药物,通过增加肌肽生物合成以延缓无氧运动时疲劳的出现,从而具有减弱高强度运动时产生的代谢性酸中毒。此外,优选与肌酸组合,因为可增强制剂的机能增进效应。而且,还可将活性材料与其它不削弱所需作用的活性材料混合,或者与补充所需作用的材料如制酸剂、H2阻滞剂和利尿剂混合。
用于本文的联合给药指在协同治疗过程中给予一种以上治疗剂,以获得改善的临床效果。这种联合给药还可以是同延的;也就是说在重叠时间段发生。
A.β-丙氨酸和肌肉
β-丙氨酸和L-组氨酸及其甲基化类似物在人或动物体内形成二肽。由β-丙氨酸和组氨酸产生的二肽包括肌肽(β-丙氨酰-L-组氨酸)、鹅肌肽(β-丙氨酰-L-1-甲基组氨酸)或鲸肌肽(β-丙氨酰-L-3-甲基组氨酸)(本文统称为“β-丙氨酰组氨酸肽”)。β-丙氨酰组氨酸肽涉及调节肌肉收缩时细胞内的pH稳态,因此,涉及肌肉疲劳的出现。β-丙氨酰组氨酸肽提供pH敏感性组氨酸残基蓄积在细胞内的有效途径。因此,肌肉β-丙氨酰组氨酸肽浓度的变化影响肌肉的无氧工作能力,增加肌肉内β-丙氨酰组氨酸肽的量有利于工作能力和肌肉可完成的工作量。
β-丙氨酸和L-组氨酸可在体内产生或者从膳食中获得。在体内,β-丙氨酸被转运至组织如肌肉中。因为处于典型进食状态,肌肉内β-丙氨酸的浓度低于L-组氨酸浓度,β-丙氨酸浓度可能是合成β-丙氨酰组氨酸肽的限制因素。通过增加β-丙氨酸的血液或血浆浓度,增加β-丙氨酸和肌酸的血液或血浆浓度,或者增加β-丙氨酸、L-组氨酸和肌酸(即N-(氨基亚氨基甲基)-N-甘氨酸、N-脒基肌氨酸、N-甲基-N-脒基甘氨酸或甲基胍基乙酸)的血液或血浆浓度,可增加人或动物体内β-丙氨酰组氨酸肽的合成和蓄积。
在持续强烈运动或者在局部缺氧条件下持续运动时,糖酵解形成的水合氢离子的蓄积和无氧代谢引起乳酸的蓄积可严重降低细胞内pH。pH降低可危害肌酸-磷酰肌酸系统的功能。细胞内pH的下降还影响细胞内其它功能如肌纤维内收缩蛋白的功能。将β-丙氨酸给予个体可提高肌肉β-丙氨酰组氨酸肽水平,增加肌肉的总体工作能力。另外,长期膳食补充β-丙氨酸可增加肌肉β-丙氨酰组氨酸肽浓度,从而增加肌肉内缓冲能力。
提供β-丙氨酸或作为β-丙氨酸生物源的化合物(如肌肽、鹅肌肽或鲸肌肽及其盐和化学衍生物)是可行性方法,通过增加β-丙氨酰组氨酸肽生物合成减弱高强度运动时产生的代谢性酸中毒,从而延缓无氧运动时疲劳的出现。本文定义的作为β-丙氨酸生物源的化合物是这样一种化合物,当以任何途径(如胃肠外、口服或局部)给予机体时,通过一种或多种化学-或酶-催化的反应步骤被转化为β-丙氨酸,然后β-丙氨酸出现在血液、血浆或血清中,被有效吸收入肌肉及其它组织内。
组合物包含的游离β-丙氨酸可以β-丙氨酸的任何活性形式或其类似物(如酯或盐)形式存在。组合物包含的游离β-丙氨酸在掺入药用组合物之前可进行微粉化处理(如破碎、磨粉、粉碎等),以便所得组合物的结构不会呈不合格的“砂样”。
B.药用组合物
本文提供的组合物包含配制成能用于持续释放的与药学上可接受的载体组合的游离β-丙氨酸或其生物源。虽然口服是一种递药方式,但可使用本发明组合物的其它递药方式。这些方式包括粘膜递药、鼻部递药、眼部递药、经皮递药、胃肠外递药、阴道递药、直肠递药和子宫内递药。组合物可采用液体、半液体或固体形式,可按照适合预期给药途径的方式配制。
通常,可用本领域熟知的工艺和操作将含本文描述的游离β-丙氨酸或其生物源的组合物配制成药用组合物。参阅如Ansel,IntroductiontoPharmaceuticalDosageForms,第4版,1985,126页。适合给予游离β-丙氨酸或其生物源的药用载体或溶媒包括本领域技术人员已知适合具体给药途径的任何此类载体。
包含合适量β-丙氨酸或其生物源的制剂包括,例如胶囊剂、片剂、丸剂、粉剂、粒剂、无菌注射液或混悬液、口服溶液或混悬液、油水乳液以及植入和微囊递药系统,以及生物可降解、生物相容性聚合物如胶原、乙烯乙酸乙烯酯、聚酐、聚乙醇酸、聚原酸酯和聚乳酸。本领域技术人员已知这些组合物的制备方法。
口服递药的制剂可包括,例如片剂、胶囊剂、粒剂和整装散剂。口服片剂类型包括压制的咀嚼锭剂以及可以是肠溶衣、糖衣或薄膜包衣的片剂。胶囊剂可以是硬或软明胶胶囊剂,粒剂和散剂可以是与本领域技术人员已知的其它成分组合的非泡腾剂或泡腾剂形式。例如,可使游离β-丙氨酸或其生物源悬浮于如碳酸丙烯、植物油或甘油三酯中并包裹在胶囊剂内。此类溶液及其制备和包囊公开于如美国专利号4,328,245、4,409,239和4,410,545。
例如,肠溶衣片由于存在肠溶衣,可耐受胃酸作用,在中性或碱性肠道内溶解或分解;糖衣片是其上涂覆有不同层的药学上可接受的物质的压制片;薄膜包衣片是已经涂布聚合物或其它合适包衣的压制片;多重压制片是用前述药学上可接受的物质通过不止一次压制循环制备的压制片。任何这些片剂制剂都适合递送β-丙氨酸或其生物源。
游离β-丙氨酸或其生物源可采用液体形式口服给药。口服递药的液体制剂包括水溶液(如酏剂和糖浆剂)、乳液、混悬液、溶液和/或混悬液。酏剂是澄清的甜味水醇制剂,用于酏剂的药学上可接受的载体通常包括溶剂。糖浆剂是糖如蔗糖的浓缩水溶液,可含有防腐剂。乳液是两相系统,其中一种液体以小球形式分散遍及另一种液体。用于乳液的药学上可接受的载体是非水液体、乳化剂和防腐剂。混悬液使用药学上可接受的悬浮剂和防腐剂。
在制备溶液或混悬液时,可能使用如水或生理学上可接受的有机溶剂如醇(如乙醇、丙醇、异丙醇、1,2-丙二醇、聚乙二醇及其衍生物、脂肪醇、甘油偏酯)、油类(如花生油、橄榄油、芝麻油、杏仁油、向日葵油、豆油或蓖麻油)、石蜡、二甲基亚砜、甘油三酯等。在液体制剂的情况下,可用下列物质作为稳定剂或增溶剂:含2-4个碳原子的低级脂族单价和多价醇如乙醇、正丙醇、甘油、分子量为200-600的聚乙二醇(如1-40%水溶液)、阿拉伯胶、瓜尔胶或其它选自水胶体的悬浮剂。
除了口服递药的液体制剂之外,用于非口服递药(如胃肠外、皮内、皮下或局部)的溶液或混悬液可包含下列任何组分:无菌稀释剂如水、盐水溶液、非挥发油、聚乙二醇、甘油、丙二醇、二甲基乙酰胺或其它合成溶剂;抗微生物剂如苄醇和羟苯甲酯;抗氧化剂如抗坏血酸和亚硫酸氢钠;螯合剂如乙二胺四乙酸(EDTA);缓冲剂如乙酸盐、枸橼酸盐和磷酸盐;和张力调节剂如氯化钠或右旋糖。可将胃肠外制剂包装在安瓿、一次性使用注射器或者由玻璃、塑料或其它合适材料制成的单剂量或多剂量小瓶内。
在游离β-丙氨酸或其生物源出现溶解度不足的情况下,可用增加游离β-丙氨酸或其生物源溶解的方法。本领域技术人员已知这样的方法,包括但不限于用共溶剂如二甲基亚砜(DMSO)、二甲基乙酰胺,用表面活性剂如TWEEN,或者使β-丙氨酸溶于碳酸氢钠水溶液中。
在一个实施方案中,可将β-丙氨酸或其生物源配制在脂质体混悬液(如组织定向脂质体)中递药至人或动物。可根据本领域技术人员已知的方法制备脂质体混悬液。参阅如美国专利号4,522,811。简而言之,可通过使卵磷脂酰胆碱和脑磷脂酰丝氨酸(如以7∶3摩尔比值)在烧瓶内壁干燥,形成脂质体如多室脂质体(MLV′s)。加入β-丙氨酸或其生物源在无二价阳离子的磷酸缓冲盐水中的溶液,振荡烧瓶直至脂质薄膜分散。洗涤所得小囊泡以除去未包封的β-丙氨酸,离心沉淀,然后再悬浮于PBS中。
本领域已知药学上可接受的载体,通常根据预期递药途径选择。用于本文提供的组合物和方法的固体和水分散体的载体实例包括,但不限于水溶性聚合物如瓜尔胶、葡甘露聚糖、洋车前子、阿拉伯胶、聚乙二醇、聚乙烯吡咯烷酮、羟丙基甲基纤维素及其它纤维素醚如甲基纤维素和羧甲基纤维素钠。液体组合物的其它载体包括,如水、盐水、含水右旋糖、甘油、二醇类、乙醇等。
连同β-丙氨酸或其生物源一起,组合物可包含任何数目的附加组分。例如,含β-丙氨酸的组合物还可包含:稀释剂如乳糖、蔗糖、磷酸二钙或羧甲基纤维素;润滑剂如硬脂酸镁、硬脂酸钙和滑石;和/或粘合剂如淀粉、天然树胶如阿拉伯胶明胶、葡萄糖、糖蜜、聚乙烯吡咯烷酮、纤维素及其衍生物、聚维酮、交聚维酮及其它本领域技术人员已知的此类粘合剂。本发明组合物还可包含崩解剂、着色剂(如任何批准合格的水溶性FD&C染料)、调味剂和湿润剂。可使用调味剂和甜味剂,以及防腐剂、稳定剂、缓冲剂和抗氧化剂。
本文公开的药用组合物还可包含更多物质如乳化剂、增溶剂、pH缓冲剂等(如乙酸盐、枸橼酸钠、环糊精衍生物、单月桂酸脱水山梨醇酯、三乙醇胺乙酸钠、油酸三乙醇胺酯及其它此类药物)。溶剂包括甘油、山梨醇、乙醇和糖浆;防腐剂的实例包括甘油、对羟甲酯和对羟丙酯、苯甲酸、苯甲酸钠和醇;用于乳剂的非水液体的实例包括矿物油和棉籽油;乳化剂的实例包括明胶、阿拉伯胶、西黄蓍胶、膨润土,和表面活性剂如聚氧乙烯单油酸脱水山梨醇酯;悬浮剂包括羧甲基纤维素钠、果胶、西黄蓍胶、硅酸镁铝和阿拉伯胶;甜味剂包括蔗糖、糖浆、甘油和人工甜味剂如糖精;湿润剂包括单硬脂酸丙二醇酯、单油酸脱水山梨醇酯、单月桂酸二甘醇酯和聚氧乙烯月桂醚。
可如下制备药学上可给药的液体组合物,例如通过使游离β-丙氨酸或其生物源和任选的药用佐剂溶解、分散于载体中或者以其他混合方式在载体中混合,所述载体如水、盐水、右旋糖水溶液、甘油、二醇类、乙醇等,从而形成溶液或混悬液。另外,可按照本领域技术人员所知将片剂和胶囊制剂包衣,以调节或维持活性成分的溶解。因此,例如可用常规包衣如水杨酸苯酯、蜡类和邻苯二甲酸乙酸纤维素或者用另一种肠溶衣包衣,所述肠溶衣在胃内维持其完整性,持续释放β-丙氨酸。本领域技术人员已知或者将清楚制备药用组合物的方法。参阅如Remington′sPharmaceuticalSciences,MackPublishingCompany,Easton,Pa.,第15版,1975。
C.持续释放制剂
优选本文公开的含游离β-丙氨酸或其生物源的组合物的制剂是持续释放制剂。用于本发明时,可将下列术语视为基本等同于“持续释放”:连续释放、控制释放、延缓释放、贮备、逐渐释放、长期释放、程序释放、延长释放、成比例释放、拖延释放、贮藏、迟缓、缓慢释放、间隔释放、定时包衣、定时释放、延缓作用、延长作用、分时作用、长效、延效、反复作用、缓慢作用、持续作用、持续作用给药和延长释放。这些术语的更多讨论可参阅LesczekKrowczynski,Extended-ReleaseDosageForms,1987(CRCPress,Inc.)。
在本文公开的组合物中游离β-丙氨酸或其生物源的浓度,通过将有效增加肌肉及其它组织合成β-丙氨酰组氨酸肽(特别是肌肽)量的游离β-丙氨酸提供给血液或血浆,可有效增加组织的无氧工作能力。给予β-丙氨酸的持续释放制剂,其给药量有效减弱高强度运动时遇到的代谢性酸中毒,从而延缓无氧运动时疲劳的发生,并且不引起感觉异常的症状。
在药周组合物中游离β-丙氨酸或其生物源的浓度将取决于具体制剂、吸收率、β-丙氨酸的灭活和排泄率、β-丙氨酸的物理化学特征和剂量计划表以及本领域技术人员已知的其它因素。然而,预期所述组合物可包含0.001%-100%游离β-丙氨酸或其生物源(如0.1-85%或75-95%)。
将游离β-丙氨酸或其生物源包含在药学上可接受的载体中,其量足够发挥治疗有效作用,而且没有不良副作用。可通过在体外和体内系统(如本文描述)中测试一定量β-丙氨酸,然后外推人体剂量,从经验上确定治疗有效浓度。
通常,治疗有效剂量应该在肌肉或其它组织产生约0.1μg/ml至约50-100μg/mlβ-丙氨酸或其等量生物源的血液、血浆或血清浓度。药用组合物通常应提供剂量为每天每kg体重约0.001mg至约2000mgβ-丙氨酸。制备的药用剂量单位形式可提供每剂量单位形式约1mg至约10,000mg(如约10至约5,000mg)β-丙氨酸。
游离β-丙氨酸剂量可为每公斤(kg)体重约1毫克(mg)至约200mg,或者其生物源(如β-丙氨酸的肽(如肌肽))的剂量可以为每kg体重约2.5mg至约500mg。例如,在80kg的人体合适的控制释放剂量可以是每天0.08克-16.0克游离β-丙氨酸或等量β-丙氨酸生物源。在一方面,控制释放剂量中给予人的游离β-丙氨酸总量可以为每天至少200mg、200mg-5g、5g-10g或5g-16g或更多。可将单剂量活性成分如游离β-丙氨酸或其生物源配制成约200、400、800、1600、3200、6400mg或更多的量。
对于人和动物,本文公开的组合物可以是,例如(a)1%-99%重量的游离β-丙氨酸或其生物源和0%-98%重量的水;(b)1%-98%重量的游离β-丙氨酸或其生物源和0%-97%重量的水;(c)1%-20%重量的游离β-丙氨酸或其生物源、9%-99%重量的葡萄糖或其它简单碳水化合物和0%-60%重量的水或(d)1%-20%重量的游离β-丙氨酸或1%-20%重量的β-丙氨酸肽、9%-99%重量的葡萄糖或其它简单碳水化合物和0%-60%重量的水。
可将特定剂量的β-丙氨酸以单次剂量给药,或者可分成许多较小剂量以特定时间间隔给药。应注意浓度和剂量值还可根据待减轻的疾病的严重度改变。还应理解对于任何特定患者,应随时间的推移根据个体需要和管理或指导组合物给药的人的专业判断改变特定剂量方案,本文列出的浓度范围只用于举例,并非有意限制要求的组合物的范围或实施。
通常将药学治疗活性的游离β-丙氨酸、β-丙氨酸生物源及其衍生物、类似物或轭合物配制为单位剂型或多剂型给药。用于本文的单位剂型指适合人和受试动物并且按照本领域已知分别包装的物理分离单位。每单位剂量包含足够产生所需治疗效应的预定量的治疗活性β-丙氨酸以及所需的药用载体、溶媒或稀释剂。可分成几份或多次给予单位剂型。多剂型通常是包装在单一容器内以分离的单位剂型给药的许多完全相同的单位剂型。单位剂型的实例包括安瓿和注射器和分装片剂或胶囊剂,多剂型的实例包括片剂或胶囊剂的管形瓶、瓶和品脱或加仑瓶。
用于本文时,持续释放可指多种延长释放剂型中的任何一种。各种持续释放工艺涵盖非常广泛的药物剂型。持续释放工艺包括但不限于物理系统以及化学系统。
物理系统包括但不限于含速率控制膜的贮备系统如包囊(如微-和大-)和膜系统;不含速率控制膜的贮备系统如中空纤维、超微孔三乙酸纤维素和多孔聚合底物和泡沫;单片系统,包括物理溶解于无孔性聚合体或弹性体基质(如非侵蚀性、可侵蚀性、环境因素侵袭和可降解)的系统和物理分散于非多孔性聚合物或弹性体基质(如非侵蚀性、可侵蚀性、环境因素侵袭和可降解)的材料;层状结构,包括化学上与外控制层相似或不同的贮备层;及其它物理方法,如渗透泵或吸附在离子交换树脂上。
化学系统包括但不限于化学侵蚀聚合物基质(如不均匀或均匀侵蚀)或生物侵蚀聚合物基质(如不均匀或均匀)。还可用水凝胶,如描述于“ControlledReleaseSystems:FabricationTechnology”,第II卷,第3章;41-60页;“GelsForDrugDelivery”,Hsieh,D.编辑。
已经开发多种持续释放药物制剂。这些制剂包括但不限于微囊粉剂;渗透压控制胃肠道递药系统;流体压控制胃肠道递药系统;膜渗透控制胃肠道递药系统,其中包含微孔膜渗透控制胃肠道递药装置;凝胶扩散控制胃肠道递药系统;和离子交换控制胃肠道递药系统,其中包含阳离子和阴离子药物。在一个实施方案中,持续释放系统可以是可与液体混合并可作为混合饮料饮用的油微囊化持续释放散剂。还参阅RohmHass研制的持续释放制剂(Philadelphia,PA),以及公开持续释放制剂的代表性美国专利(如美国专利号6,696,500、6,756,049、6,919,372、6,992,065和7,048,947)。
而且,当许多常规药用粘合剂、赋形剂和添加剂足量使用时,可充当控制释放聚合物,产生持续释放效应。这些包括但不限于明胶、天然糖(如粗糖或乳糖)、卵磷脂、胶浆、植物胶、果胶或果胶衍生物、海藻多糖、葡甘露聚糖、琼脂和木质素、瓜尔胶、刺槐豆胶、阿拉伯胶、黄原胶、角叉菜胶、梧桐胶、西黄蓍胶、茄替胶、淀粉(如玉米淀粉或直链淀粉)、葡聚糖、聚乙烯吡咯烷酮、聚乙酸乙烯酯、阿拉伯胶、海藻酸、羟乙基纤维素、滑石粉、石松粉、硅胶(如胶体)、纤维素和纤维素衍生物(如纤维素醚、其中纤维素羟基被低饱和脂族醇和/或低级饱和的脂族氧基醇(oxyalcohols)偏酯化的纤维素醚:如甲氧基丙基纤维素、甲基纤维素、羟丙基甲基纤维素、邻苯二甲酸羟丙基甲基纤维素、交联羧甲基纤维素钠、交联羟丙基纤维素、高分子量羟甲基丙基纤维素、羧甲基纤维素、低分子量羟丙基甲基纤维素、中度粘性羟丙基甲基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、烷基纤维素、乙基纤维素、乙酸纤维素、丙酸纤维素(低、中或高分子量)、丙酸乙酸纤维素、丁酸乙酸纤维素、三乙酸纤维素、甲基纤维素、羟丙基纤维素或羟丙基甲基纤维素)、脂肪酸以及含12-22个碳原子的脂肪酸特别是饱和脂肪酸的镁、钙或铝盐(如硬脂酸盐如硬脂酸镁)、聚羧酸、乳化剂、油类和脂肪特别是植物油(如花生油、蓖麻油、橄榄油、芝麻油、棉子油、玉米油、麦胚芽油、向日葵子油、鱼肝油,各自还任选是水合的);饱和脂肪酸(如C12H24O2-C18H36O2)的甘油酯和聚甘油酯及其混合物,甘油羟基可能被完全也可能只是部分酯化(如甘油单酯、甘油二酯和甘油三酯);适合微囊化的高熔点氢化植物油;药学上可接受的单价或多价醇和聚二醇如聚乙二醇及其衍生物,脂族饱和或不饱和脂肪酸(如2-22个碳原子,如10-18个碳原子)与单价脂族醇(如1-20个碳原子)或可任选被酯化的多价醇(如二醇类、甘油、二甘醇、季戊四醇、山梨醇、甘露醇等)的酯,枸橼酸与伯醇的酯、乙酸、尿素、苯甲酸苄酯、二氧戊烷、甘油甲醛、四氢糠醇、与C1-C12醇的聚二醇醚、二甲基乙酰胺、乳酰胺、乳酸盐、碳酸乙酯、硅酮(如中度粘性聚二甲基硅氧烷)、碳酸钙、碳酸钠、磷酸钙、磷酸钠、碳酸镁等。
另外,可将包衣剂用于产生或增强药用组合物的持续释放特性。例如,可用作包衣剂的增塑剂包括但不限于枸橼酸和酒石酸酯(枸橼酸乙酰基三乙酯、枸橼酸乙酰基三丁酯、枸橼酸三丁酯、枸橼酸三乙酯);甘油和甘油酯(二乙酸甘油酯、三乙酸甘油酯、乙酰甘油单酯、蓖麻油);邻苯二甲酸酯(邻苯二甲酸二丁酯、邻苯二甲酸二戊酯、邻苯二甲酸二乙酯、邻苯二甲酸二甲酯、邻苯二甲酸二丙酯)、二-(2-甲氧基-或2-乙氧基乙基)-邻苯二甲酸酯、邻苯二甲酰乙醇酸乙酯、邻苯二甲酰乙基乙醇酸丁酯和乙醇酸丁酯;醇类(丙二醇、各种链长的聚乙二醇);己二酸酯(己二酸二乙酯、二(2-甲氧基-或2-乙氧基乙基)-己二酸酯);二苯甲酮;癸二酸二乙酯和癸二酸二丁酯;琥珀酸二丁酯;酒石酸二丁酯;二丙酸二甘醇酯;二乙酸乙二醇酯、二丁酸乙二醇酯、二丙酸乙二醇酯;磷酸三丁酯、三丁酸甘油酯;聚乙二醇单油酸脱水山梨醇酯;聚山梨酯如Polysorbar50;和单油酸脱水山梨醇酯。
本领域已知制备持续释放药用组合物的方法。例如,可将包衣剂如乙基纤维素和羟丙基甲基纤维素混合一起,在流化床制粒机中喷在β-丙氨酸或其生物源上。另一种制备持续释放药用组合物的方法应用高温熔化的植物油(如具有约5的最大碘值和约145°F的熔点)和纤维素醚如乙基纤维素的混合物。这种合并可在加套的垂直或水平高强度混合器或搅拌器中进行,以便让热水浴在混合器周围循环,使油温升高至熔点。然后使粉状β-丙氨酸或其生物源与熔化的油混合,直至达到完全覆盖(约5-10分钟),冷却,将乙基纤维素喷洒在颗粒上。终产物是具有延长释放曲线图的微囊化、自由流动的持续释放粉剂。还参阅美国专利号6,835,397、6,013,286和5,190,775描述的控制释放包囊化生物活性物质的方法。
在组合物中,使有效浓度的游离β-丙氨酸或其生物源与合适的药用载体或溶媒混合。如本领域所知,可在配制前将游离β-丙氨酸或其生物源衍生为相应的盐、酯、烯醇醚或酯、酸、碱、溶剂合物、水合物或前药。
D.膳食补充剂
提供配制成能用于持续释放游离β-丙氨酸或其生物源的膳食补充剂。膳食补充剂可包括食品或液体制品。
1.固体食品
配制为食品的膳食补充剂可以是固体或食用混悬液。固体食品可包括咀嚼或食用棒、饼干、苏打饼干、糖锭、口香糖或食用混悬液。在一个实施方案中,含游离-β丙氨酸或其生物源的膳食补充剂是含半乳糖的高能量多糖食用棒形式的固体食品。
在一个实施方案中,食用食物棒包含糖类组分(包括3-37%重量/重量(w/w)半乳糖、0.1-75%w/w游离β-丙氨酸或其生物源)和任选更多选自氨基酸、碳水化合物、纤维和脂肪的成分,以及其它成分如肌酸和β-丙氨酰组氨酸肽(如肌肽、鹅肌肽和/或鲸肌肽)。半乳糖的量可以是例如5-20%w/w(如5-15%w/w)。糖类组分也可包括葡萄糖。在一个实施方案中,提供等量葡萄糖和半乳糖。在另一个实施方案中,半乳糖的量大于葡萄糖的量。
本发明总体包括将游离β-丙氨酸或其生物源与其它成分掺杂,得到低糖和具有低升糖指数的棒、饮料或其它类型食物。使用半乳糖具有几个优点。例如,半乳糖并非胰岛素原性;也就是说,半乳糖本身不诱发胰岛素反应。因此,其使用伴随的胰岛素反应小于相等质量的葡萄糖。本发明的产物可用于糖尿病或不耐受乳糖的人。半乳糖可迅速被肝脏用来合成糖原或葡萄糖,与其它糖类相比引起牙侵蚀的可能性较小。
一些含游离β-丙氨酸的固体食品组合物的实施方案加入0.1-50%游离β-丙氨酸或其生物源。为了预防不需要的有害副作用,优选从食品内持续或延缓释放游离β-丙氨酸或其生物源。例如,可将游离β-丙氨酸或其生物源包含在食品内并与任何潮湿成分分离(如通过分层制剂)。或者,可将游离β-丙氨酸或其生物源包埋在食物本身的基质内,其中基质的性质延缓食物在胃内溶解。另外,可将β-丙氨酸包封在干燥不渗水的壳中(如微囊化)作为粒剂或散剂并用于食品。这样,通过溶解可在胃内缓慢释放游离β-丙氨酸。
食品(如能量棒)中使用纤维是有利的,因为不同的纤维制品影响糖的释放,影响各种组分的结合,有利于延缓消化。可将0-5%(或更多)w/w量的糖用于含β-丙氨酸或其生物源的食品。而且,在制备食品之前,可将含β-丙氨酸或其生物源的组合物吸附在纤维上。这样,可延迟β-丙氨酸吸收入体内。
在分层排列中,可用坚硬的干糖层覆盖游离β-丙氨酸粉剂或聚集物。或者或除此之外,可用含巧克力层作为防潮层。可将含游离β-丙氨酸层作为置于棒内的薄片状圆柱层提供为内层。或者或除此之外,可将成分如纤维、坚果和干果铺在含游离β-丙氨酸层上以形成薄片。这样的层可掺入糖浆以便形成混合型层。
在备选食品中,可将β-丙氨酸粉剂或聚集物用硬糖混合物、巧克力或两种都用来覆盖,形成质量为100-500mg的颗粒。可将这些颗粒与其余成分合并,在基质内形成分散单位,如作为饼干内的巧克力条。可将这样的包囊化排列掺入前述各层。
2.食用混悬液
在另一个实施方案中,含游离-β丙氨酸或β-丙氨酸生物源的膳食补充剂是食品,其中使游离β-丙氨酸或β-丙氨酸生物源悬浮于食用支持基质中,以形成食用混悬液。术语“混悬液”意思是指本文提供的含游离β-丙氨酸或β-丙氨酸生物源的组合物,它包含固体形式的游离β-丙氨酸(如晶体、粉末等),分布在食用粘稠液或半固体或者固体支持基质中,这样通常抑制或防止固体β-丙氨酸的沉降(在重力影响下)。
可提供固体、液体或半液体形式(如饮料、汤或酸奶)的组合物。优选游离β-丙氨酸基本均匀分布遍及支持基质各处(通过一些方式匀化,如通过搅拌、混合等),可手工(如由消费者)和/或在制备组合物时机械完成。
方便地,所述食品是补充游离β-丙氨酸或β-丙氨酸生物源以致β-丙氨酸悬浮于食品中的其它常规食品。可代表适用于本发明组合物的支持基质的食品实例包括可涂开的固体如涂抹型奶酪或乳酪、麦淇淋、肉和鱼酱等。其它方便的支持基质是含糖或其它碳水化合物的基质,如液体(“流动”)或固体(“固定”)蜂蜜、糖蜜、糖浆(如玉米糖浆、葡萄糖糖浆)、蜜糖或任何性状的凝胶剂,通过冷却制备的粘性食物如冰淇淋,以及通过烹饪和烘焙制备的粘性食物如松饼、馅饼、挞、蛋糕、饼干和谷物片。
如果需要,可通过加入增粘剂、胶凝剂等增加食用基质和/或整个组合物的粘度。此类组分在食品工业众所周知,包括例如植物衍生的多糖、树胶等,如半乳甘露聚糖、葡聚糖、瓜尔胶、槐树豆胶等。如果需要,此类增粘剂、凝胶剂等可形成支持基质。一种代表性食用基质可包含用浓缩芦荟提取物制备的凝胶剂:一种光滑的奶油状糊剂,例如可包装在可挤压的管内。
组合物可包含一种或多种更多组分以改善其可口性、稳定性、味道或营养质量。这些更多组分可包括电解质、维生素(如维生素E、维生素C、硫胺素、核黄素、烟酸、维生素B6、叶酸、维生素B12、生物素和泛酸)、脂质、碳水化合物(如淀粉和/或糖类,如葡萄糖、果糖、蔗糖和麦芽糖)、氨基酸、微量元素、着色剂、调味剂、人造甜味剂、天然健康改善物质、抗氧化剂、稳定剂、防腐剂和缓冲剂。组合物可以无味道或者具有基质的正常味道。或者,可加入一种或多种味道(如水果、奶酪或鱼味)。
可包含在本发明公开的持续释放β-丙氨酸的组合物中的其它成分可包括例如抗氧化剂、α-硫辛酸、生育三烯酚类、N-乙酰半胱氨酸、辅酶Q-10、迷迭香提取物如鼠尾草酚、植物抗氧化剂(如绿茶多酚、葡萄籽提取物)、COX-1型抑制剂(如白藜芦醇、银杏和大蒜提取物)。可加入其它氨基酸如L-半胱氨酸或L-瓜氨酸。可能需要与乙酰胆碱前体如氯化胆碱或磷脂酰胆碱联合,例如用于增强血管舒张。应理解此类联合疗法构成本文提供的组合物和治疗方法的又一方面。
可使用的人造甜味剂包括阿司帕坦、乙酰舒泛K、糖精和环己氨磺酸。可加入几乎任何需要的调味剂,如水果(如草莓、柠檬、橙、木瓜和葡萄柚)味。可用枸橼酸作为酸化剂,用枸橼酸盐(如枸橼酸钠)作为缓冲剂。而且,可加入生理学活性量的其它天然健康改善物质如PanD′Arco茶、人参、Suma茶、银杏、花粉和没药。可包含防腐剂如苯甲酸钾和/或山梨酸钾。可包含着色剂如冷的水溶性着色剂如β-胡萝卜素。然而,本领域技术人员将清楚其它合适的着色剂。如果需要,可将混浊剂包含在组合物中以改善组合物的外观。
还可加入适合人消费的任何类型或形式的矿物和微量元素。方便地提供其葡糖酸盐、磷酸盐或磷酸氢盐形式的钙和钾、氧化物或碳酸盐形式的镁、吡啶甲酸铬形式的铬、亚硒酸钠或硒酸钠形式的硒和葡萄糖酸锌形式的锌。代表性的量包括400mg/L钠、100mg/L钙、600mg/L氯、200mg/L钾、75mg/L镁和50mg/L磷、125μg/L铬、125μg/L硒和15mg/L锌。
根据本发明,可应用本技术领域范围内的常规分子生物学、微生物学、生物化学和重组DNA技术。此类技术在文献中有详细解释。在下列实施例中将进一步描述本发明,所述实施例不限制权利要求描述的本发明范围。
实施例
实施例1-持续释放游离β-丙氨酸的食用凝胶制剂
为了制备含游离β-丙氨酸的食用凝胶剂,将两包市售获得的草莓味明胶凝胶剂内容物溶于200ml沸水中。继续搅拌内容物,直至凝胶完全溶解。加入小、袋(sachet)明胶胶囊剂再强化凝胶。向其内加入80g游离β-丙氨酸(终体积约300ml)。将浓缩的凝胶溶液倾入12×12cm平模中,深度约2cm,让其在4℃形成硬的凝胶。一片方形凝胶(大小约2×2×2cm)包含约2gβ-丙氨酸。
当摄入含2gβ-丙氨酸的凝胶片(或者作为两个半片)时,在接着的20分钟内有轻度感觉异常症状,一些受试者可能根本没有察觉。相反,在摄入溶于水的2g游离β-丙氨酸的受试者中出现感觉异常症状。因此持续释放游离β-丙氨酸可减轻以等量单次大剂量给药时感觉到的感觉异常症状。
实施例2-β-丙氨酸胶囊剂的溶出
样品。用β-丙氨酸的脂质包衣颗粒填充BalchemEncapsulates制备的β-丙氨酸胶囊剂(NewHampton,NY;参阅如美国专利号6,835,397)。基于β-丙氨酸的量计,将样品确定为RIA-174360%、70%、80%、90%和RIA-174460%、70%、80%、90%。
实验测试。用LoganInstrumentsDISSOIII,3型USP测试装置由NaturalAlternativeInc.’sResearch&DevelopmentLaboratory进行测试。在0.1N盐酸中溶出6小时。在1、2、3和6小时采集样品。
第一次分析在顶和底盖用单个大小为40目的滤网。第二次分析RIA-1744在顶和底盖用两个目筛:一个40目筛和第二目筛(孔径稍大)组合。目筛组合的作用是将颗粒包含在往复式圆柱体中。胶囊壳崩解后从胶囊内释放颗粒。用蒸发光散射检测HPLC分析进行定量。
结果。表1和2显示用单个大小为40目的筛网的结果,表3显示用双目筛分析RIA-1744。数据显示RIA-1743和RIA-1744两种制剂的80%和90%样品几乎不表现持续释放特征。RIA-174460%和70%制剂在两次分析中都表现持续释放特征。60%制剂在6小时结束时甚至更少β-丙氨酸溶出。
表1
表2
表3
实施例3-与非持续释放制剂相比的持续释放制剂
将1.75g溶于水的β-丙氨酸(配制为饮料)或5粒各自含0.35gβ-丙氨酸的胶囊延缓释放制剂给予两个受试者。给予含1.75gβ-丙氨酸的饮料的受试者报告感觉异常症状,累及面部、头皮、颈、手臂、手和臀部,但给予1.75g延缓释放胶囊制剂的受试者则无。结果(均数±SE)在图1显示。
实施例4-持续释放制剂
将β-丙氨酸的含量同为400mg但处方组成不同的胶囊剂给予受试者,所述胶囊剂的处方组成为100%、90%、80%、70%和60%β-丙氨酸与延缓溶出的包含脂质混合物的其余物质。用两种不同的脂质混合物,本文称为混合物“A”和“B”。
图2显示含最高β-丙氨酸浓度的未记录到感觉异常症状的组合物“A”和“B”。图中各列表示(从顶至底):受试者编号;性别;体重(kg);和摄入的400mg胶囊剂数。
即使胶囊剂完全(即100%)是β-丙氨酸时,受试者1-6也没有记录感觉异常症状。受试者1-4摄入5粒每剂量的胶囊,受试者5-6摄入4粒每剂量的胶囊。受试者7-10摄入稍低%的β-丙氨酸后,感觉异常症状完全消失,与摄入混合物“A”相比,当摄入混合物“B”时更是如此。受试者7-10各自摄入4粒每剂量的胶囊。受试者11-14对β-丙氨酸的感觉异常效应比其它受试者更敏感,在100%β-丙氨酸时记录最高级别症状。摄入含60%β-丙氨酸的混合物“A”或“B”时,受试者11不出现感觉异常症状。摄入含60%β-丙氨酸的两种混合物时,受试者12-13仍出现轻度感觉异常症状,因此,预期两种混合物各含50%β-丙氨酸时无症状。受试者13和14只摄入3粒每剂量的胶囊剂。
其它实施方案
应理解虽然已经结合详细叙述描述了本发明,但以上叙述只用于举例说明,不限制本发明的范围,所述范围由附属权利要求的范围限定。其它方面、优点和修饰在以下权利要求的范围之内。
Claims (14)
1.一种膳食补充剂,其为包含游离β-丙氨酸并配制成能用于在包含0.1g至10.0g游离β-丙氨酸的单份中持续释放游离β-丙氨酸的食用凝胶。
2.权利要求1的膳食补充剂,其中所述补充剂配制成单份并包含:
(a)1.0g至10.0g游离β-丙氨酸;
(b)2.0g至8.0g游离β-丙氨酸;
(c)3.0g至7.0g游离β-丙氨酸;或
(d)4.0g至6.0g游离β-丙氨酸。
3.权利要求1的膳食补充剂,其中所述补充剂在食品中。
4.权利要求1-3中任一项的膳食补充剂,还包含一种或多种选自下列的附加组分:维生素、脂质、碳水化合物、氨基酸、微量元素、着色剂、调味剂、稳定剂和缓冲剂。
5.权利要求4的膳食补充剂,还包含一种或多种来自下列的附加组分:PauD’Arco茶、人参、Suma茶、银杏、花粉和没药。
6.权利要求3的膳食补充剂,其中所述游离β-丙氨酸包含在与食品其它成分分离的层内。
7.权利要求3的膳食补充剂,其中所述食品包含悬浮于配制成能用于持续释放β-丙氨酸的食用支持基质中的游离β-丙氨酸。
8.权利要求7的膳食补充剂,还包含一种或多种选自下列的附加组分:维生素、脂质、碳水化合物、氨基酸、微量元素、着色剂、调味剂、稳定剂和缓冲剂。
9.权利要求8的膳食补充剂,还包含一种或多种来自下列的附加组分:PauD’Arco茶、人参、Suma茶、银杏、花粉和没药。
10.权利要求7的膳食补充剂,其中食用支持基质包含选自蜂蜜、糖浆、糖蜜、蜜糖和浓缩芦荟凝胶的成分。
11.游离β-丙氨酸在制备用于增加组织无氧工作能力的持续释放膳食补充剂中的用途,所述膳食补充剂在持续释放的制剂中向血液或血浆提供游离β-丙氨酸,其中所述膳食补充剂包含有效增加组织内β-丙氨酰组氨酸肽合成的量的游离β-丙氨酸,且其中所述膳食补充剂是在单份中包含0.1g至10.0g游离β-丙氨酸的明胶凝胶制剂。
12.权利要求4或8的膳食补充剂,其包含抗氧化剂。
13.权利要求4或8的膳食补充剂,其包含防腐剂。
14.权利要求4或8的膳食补充剂,其包含人造甜味剂。
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