CN108883125A - 受控释放和层状的环糊精包合物媒介物 - Google Patents
受控释放和层状的环糊精包合物媒介物 Download PDFInfo
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- CN108883125A CN108883125A CN201780017946.0A CN201780017946A CN108883125A CN 108883125 A CN108883125 A CN 108883125A CN 201780017946 A CN201780017946 A CN 201780017946A CN 108883125 A CN108883125 A CN 108883125A
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- cyclodextrin
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- inclusion compound
- acid
- enzyme
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Abstract
本发明提供了环糊精包合物递送媒介物,其中所述环糊精包合物与具有能够消化环糊精的环糊精降解活性酶一起提供,使得在所述媒介物递送至靶标时,所述酶被激活并从环糊精的腔中释放客分子。在可选的方面,这些环糊精包合物递送媒介物以例如下述形式提供:药物、食品成分、医疗食品成分、营养补充剂成分、膳食补充剂成分、除草剂、杀虫剂、杀真菌剂、动物驱避剂、信息素、植物生长调节剂、芳香剂、织物或包装材料。
Description
相关申请
本申请要求于2016年2月4日递交的第62/291,202号美国临时申请;2016年8月9日递交的第15/232,647号美国非临时申请;2016年10月4日递交的第15/285,264号美国非临时申请;和2017年1月9日递交的第62/444,036号美国临时申请的优先权权益,其内容通过引用并入本文中。
发明领域
本发明属于用于递送生物活性试剂的生物化学构建体领域,包括递送媒介物,其包含在环糊精内作为包合物携带的分子,其与所选择的具有环糊精降解活性的酶一起递送。
发明背景
环糊精为非还原性环状葡萄糖寡糖,通常为环麦芽糖糊精葡聚糖转移酶(E.C.2.4.1.19;CGTase)催化淀粉降解的产物。环糊精可具有多种结构(参见Saenger etal.,Chem.Rev.98(1998)1787-1802),包括具有通过α-1,4糖苷键连接成环的6、7或8个D-吡喃葡萄糖酸残基的三种常见的环糊精(分别为α-环糊精、β-环糊精和γ-环糊精)。环糊精的截头圆锥形形状形成空腔或内腔,所述腔根据葡萄糖单元的数目而具有不同的直径。选定环糊精(CD)结构的大小列出于表1中。还可能是较大的环糊精如环状麦芽九糖(δ-CD)和环状麦芽十糖(ε-CD),以及各种基于环糊精的超分子结构(参见Zhang and Ma,Adv DrugDeliv Rev.2013 Aug;65(9):1215-33)。
表1:环糊精结构
环糊精通常为两亲性的,其内腔的较宽边缘显示2-OH和3-OH基团,而较窄边缘显示6-OH。因此,这些亲水性的羟基位于内腔的外侧,而内表面通常为疏水性的,且排列有异头氧原子以及C3-H和C5-H氢原子。在水溶液中,该疏水性内腔可含有水分子,例如约3个(α-CD)、7个(β-CD)或9个(γ-CD)不稳定容纳但低熵,因此相对容易被置换的水分子。因此,亲水性环糊精在所述CD内腔内或部分地在所述CD内腔内可以结合保留一种或多种大小合适的分子,形成环糊精包含体或复合物。例如,可以结合非极性的脂肪族和芳香族化合物,包括药物如亲脂性药物,从而增加正常情况下疏水性的化合物的水溶性,或者将某些食品添加剂中不希望的性质如气味或味道最小化。因此,环糊精包含物被广泛应用于药物、食品和化妆品领域(参见Hedges,Chem.Rev.98(1998)2035-2044)。例如,环糊精已被应用于各种缓释药物制剂中,如用于医用化合物与疏水性环糊精衍生物的包合物(第4,869,904号美国专利)。
环糊精可以以多种方式进行化学修饰。例如,为了改变环糊精的包含特异性、物理和化学特性。例如,可以将CD羟基衍生化。例如,两种经修饰的CD已被用于多种药物产品:SBE-β-CD或Captisol(β-CD的一种聚阴离子可变取代的磺丁基醚),和HP-β-CD(一种由Janssen商业化开发的经修饰的CD)。其他的CD衍生物包括舒更葡糖(sugammadex)或Org-25969(其中γ-CD上的6-羟基被羧基硫代乙酸醚键取代),以及羟丁烯基-β-CD。环糊精的可选形式包括:2,6-二-O-甲基-β-CD(DIMEB)、2-羟丙基-β-环糊精(HP-β-CD)、随机甲基化-β-环糊精(RAMEB)、磺丁基醚β-环糊精(SBE-β-CD)和磺丁基醚-γ-环糊精(SBEγCD)、磺丁基化的β-环糊精钠盐、磺丁基化的β-环糊精钠盐、(2-羟丙基)-α-环糊精、(2-羟丙基)-β-环糊精、(2-羟丙基)-γ-环糊精、DIMEB-50七(2,6-二-O-甲基)-β-环糊精、TRIMEB七(2,3,6-三-O-甲基)-β-环糊精、甲基-β-环糊精、八(6-脱氧-6-碘)-γ-环糊精,和八(6-脱氧-6-溴)-γ-环糊精。尽管诸如这些的CD已被开发为具有良好的药理学和毒理学特性,但是仍然存在这样的可能性,即在给药后,残留的CD可能干扰药物的药代动力学特性,包括共同给药的药物,特别是在肠胃外给药后(参见Stellaand He,Toxicol Pathol 2008年1月,vol.36,no.130-42)。
关于来自治疗性CD包合物的残留CD的生理学效应的关注,源自CD如α-CD和β-CD耐受胃酸和唾液及胰酶消化,γ-CD仅在GIT中被淀粉酶部分消化的观察结果。通常认为仅相对少量的经口CD被吸收,并且所吸收的CD被认为在尿液中排泄而未经过有意义的代谢。未吸收的CD被认为由肠道微生物发酵。
环糊精对酶促消化的敏感性存在差异。例如,γ-CD相对容易被α-淀粉酶水解,而α-环糊精更不容易被水解。基于CD的治疗通常取决于内源性淀粉酶消化CD的活性。然而,患者之间的淀粉酶活性存在显著差异。例如,患有胰功能不全、囊性纤维化、乳糜泻或克罗恩病的患者可能缺少正常量的淀粉酶。类似地,患者,特别是衰老患者,可能存在胃酸产生不足,因而不能在十二指肠中产生适当低pH的条件来适当引发胰淀粉酶的释放。增加的抗酸剂、组胺-2阻滞剂、质子泵抑制剂或替代性酸阻断剂的常规使用增加可能产生类似的影响。
已鉴定了多种微生物环糊精消化酶。CD降解酶包括环麦芽糖糊精酶(或环糊精酶,或CDase,EC 3.2.1.54)、麦芽糖淀粉酶(EC 3.2.1.133)、新普鲁兰酶(EC 3.2.1.135),其已被报导道能够水解CD,并且在一些情况下,能够水解其他的底物如普鲁兰糖和淀粉。环糊精酶(CDase)催化CD水解形成α-1,4-键的线性寡糖,并因此其可以从CD包合物中释放底物。在1968年报道了来自浸麻芽孢杆菌(Bacillus macerans)的CDase,并且此后已表征了许多来自细菌的CDases,如来自芽孢杆菌属(Bacillus sp.)、嗜热厌氧乙醇杆菌(Thermoanaerobacter ethanolicus)菌株39E、黄杆菌属(Flavobacterium sp.)和产酸克雷伯杆菌(Klebsiella oxytoca)菌株M5a1的酶。已通过闪烁古生球菌(Archaeoglobusfulgidus)、嗜热球菌(Thermococcus sp.)B1001、嗜热球菌(Thermococcus sp.)CL1、依赖热丝菌(Thermofilum pendens),和激烈火球菌(Pyrococcus furiosus)表征了古细菌CDase。来自黄杆菌属CDase的结构已被详细表征(参见Sun et al.,Archaea,卷2015(2015),文章编号397924,报道了编码来自Thermococcus kodakarensis KOD1(CDase-Tk)的环糊精酶的基因鉴定)。
附图简述
图1为基于912睡眠周期示出了对象的典型基线睡眠周期模式图。
图2为示出了给予无淀粉酶的大麻油环糊精包合物制剂后对象的睡眠周期,其显示相比给予具有淀粉酶的大麻油环糊精包合物制剂后对象的睡眠模式明显更少的深度睡眠。
图3为示出了给予具有淀粉酶的大麻油环糊精包合物制剂后对象的睡眠周期,其显示相比对象的基线睡眠周期模式明显更多的深度睡眠模式。
发明概述
提供了环糊精包合物递送媒介物,其中所述环糊精具有腔,其中生物活性分子作为客分子至少部分保留于所述腔中,形成环糊精包合物。可以提供生物可接受载体用于所述环糊精包合物,使得所述客分子被所述环糊精稳定地保留于生物可接受载体内。还可以在所述媒介物中提供酶,其具有环糊精降解活性,能够消化保留所述客分子的环糊精。所述酶可配制使得环糊精降解活性在所述媒介物递送至靶标时被激活,从而从所述环糊精腔中释放所述客分子。
在所述递送媒介物的可选的方面,所述酶可以与所述环糊精包合物共同配制,或者所述酶可以与所述环糊精包合物共同包装于所述递送媒介物中。当所述酶被共包装时,所述递送媒介物还可包含用于所述酶的生化可接受载体。
例如,所述靶标可以为宿主生物,如人类患者,或者所述靶标可以为无生命环境,如织物或包装材料。
所述酶例如,可以为淀粉酶、环糊精酶、麦芽糖淀粉酶或新普鲁兰酶。淀粉酶例如,可以为哺乳动物唾液淀粉酶或胰淀粉酶,或者真菌或细菌来源的淀粉酶。环糊精酶例如,可以为微生物环糊精酶。
所述环糊精例如,可以为CD衍生物,如疏水性的烷基化环糊精或混合的甲基化/乙基化环糊精。
所述环糊精与所述客分子的比例可以为,例如5:1、4:1、3:1、2:1、1:1、1:2、1:3、1:4或1:5,尽管对于该参数,还有可能是各种不同的可选值,包括非整数比例。
所述环糊精例如,可以为α环糊精、β环糊精或γ环糊精,同样地,可以使用各种不同的可选CD结构。
在选择的实施方案中,所述客分子例如,可以为药物或前药,如黄酮类(槲黄素)、大麻素或抗炎剂(包括对乙酰氨基酚)。在该情况下,所述生物可接受载体可有利地为药学可接受载体。这类递送媒介物可被配制用于例如,通过以下途径递送:肠胃外、静脉内、皮内、皮下、肌内、颅内、眶内、经眼、心室内、囊内、脊柱内、鞘内、脑池内、腹膜内、鼻内、吸入、喷雾、局部、瘤内、舌下或经口。类似地,所述递送媒介物可被配制用于所述药物或前药的缓释。
在可选的方面,所述递送媒介物可以包括客分子,即除草剂、杀虫剂、杀真菌剂、动物趋避剂、信息素或植物生长调节剂。在其他的可选方案中,所述客分子例如,可以为芳香分子。
以这种方式,本发明提供了可选实施方案,其中CD递送媒介物可以用作药剂、食品成分、医疗食品成分、营养补充剂成分、膳食补充剂成分、芳香剂、织物或包装材料,或者用于农业环境作为除草剂、杀虫剂、杀真菌剂、动物趋避剂、信息素或植物生长调节剂。
因此,在不同的方面,所述递送媒介物与有效量的具有CD降解活性的酶一起提供了CD包合物,从而促进所述客分子以可预测的方式从所述CD释放。
在选择的实施方案中,在所述递送媒介物中的所述药物或前药可以为短链脂肪酸或其酯衍生物,例如丁(丁烷)酸、丙酸、乙酸或其酯衍生物,如甘油酯。当提供甘油酯形式时,例如,可以将脂肪酶包含于所述递送媒介物中。这类制剂可以用于治疗胃肠病症,如结肠炎、憩室炎、克罗恩病、炎性肠病、肠易激综合症、与造瘘术造口相关的炎症或与造瘘术造口相关的肉芽。
客分子可以包含多种氨基酸,如L-苯丙氨酸、N-乙酰-半胱氨酸(和L-半胱氨酸)、L-甲硫氨酸、L-异亮氨酸和L-色氨酸。在选择的实施方案中,N-乙酰-半胱氨酸例如,可以与对乙酰氨基酚组合,例如在保肝制剂中。例如,可选的保肝客分子可以来源于水飞蓟素、姜黄素或四氢姜黄素提取物。
提供了用于配制环糊精包合物递送媒介物的方法,包括:提供具有腔的环糊精;提供作为客分子至少部分保留于所述环糊精的腔内的生物活性分子,形成环糊精包合物;提供用于所述环糊精包合物的生物可接受载体,其中所述客分子由所述环糊精稳定保留于所述生物可接受载体内;以及,可选地,提供具有环糊精降解活性的酶,其能够消化保留所述客分子的环糊精,其中所述酶与所述环糊精包合物共同配制,使得所述环糊精降解活性在所述媒介物递送至靶标时被激活,从而从所述环糊精的腔中释放所述客分子。
还提供了多组分层状环糊精包合物,例如,其包含:具有腔的环糊精;氨基酸,其作为第一客分子保留于所述环糊精的腔内;以及生物可接受脂质,其作为第二客分子至少部分保留于所述环糊精的腔内。在选择的实施方案中,例如,多组分层状环糊精包合物可以包含N-乙酰-半胱氨酸(作为第一客分子至少部分保留于所述环糊精的腔内),和对乙酰氨基酚(作为第二客分子同样至少部分保留于在所述环糊精的腔内)。在这些层状包合物中,所述客分子可以以任何顺序存在,使得所述CD的腔为截头圆锥形,即具有设置于所述腔的相对端的较大直径开口和较小直径开口时,所述第一体分子可以靠近所述较小开口,且所述第二客分子可以靠近所述较大开口(或者反之亦然)。
提供了治疗患有自闭症谱系病症的患者的方法,包括给予有效量的短链脂肪酸环糊精包合物。类似地,这类方法可用于调节患有神经疾病的患者的微生物群。例如,所述短链脂肪酸可以为丁酸,并且在一些实施方案中,治疗还可以包括给予乙酸(任选地作为包合物)。
发明详述
各种不同的生物活性化合物可以包含于本发明的递送媒介物中,例如以药物组合物的形式,如:多西他赛(美国专利出版物20140336149、20130296268);卡巴咪嗪(美国专利出版物20140080812);利福平(美国专利第7001893号);强心苷,特别是地高辛(美国专利第4555504号)、黄体酮(参见Zoppetti et al.,Journal of Inclusion Phenomena andMacrocyclic Chemistry,2007年4月,第57卷,第1期,283-288页);阿苯达唑、甲苯咪唑、阿苯达唑亚砜(Ricobendazole)、非诺洛芬、酮洛芬、可卡因、格列齐特、洋地黄毒苷、大环化合物(MCCs)、异丁普生、普鲁氯-米近(Prochloro-methazine)、DY-9760e、NSC-639829、ETH-615、吡罗昔康、左依莫帕米HCl、甲磺酸齐拉西酮、苏灵大、甲苯咪唑、舒林大、酚酞、达那唑(参见Challa et al.,2005,AAPS PharmSciTech 2005;6(2)第43条);伊曲康唑、甲磺酸奈非那韦、替米沙坦、5-氟尿嘧啶和其他核苷类似物、喜树碱或黄酮类。
类似地,在农业化学品领域,可以提供包含具有各种不同活性的客分子的递送媒介物,如除草剂、杀虫剂、杀真菌剂、驱避剂、信息素和生长调节剂。
本发明的环糊精递送媒介物还可以包含在纺织品或织物或包装材料中具有芳香或其他生物活性分子的环糊精包合物(参见Wang and Chen,2005,Journal of IndustrialTextiles,Vol.34,No.3,157-166;美国专利出版物:20150375521、20150217896、20150150256、20140315780、20130251926)。例如,可以将环糊精消化酶掺入纺织品中,随后可以将环糊精包合物施加至含酶的织物上以形成递送媒介物。相反,可以将CD包合物掺入纺织品中,随后将酶施加至织物以形成所述递送媒介物。类似地,CD包合物和酶均可以在制造期间掺入纺织品中。酶可以例如通过涉及分层组件和/或纳米涂层的固定化而掺入至纺织品中,其中酶附着于纺织品基质以使其保持催化活性(类似于例如,通过固定溶菌酶而实现羊毛抗菌功能化的方法,如Wang et al.,2009,Bioprocess Biosyst Eng 32:633-639中描述,以及如Nierstrasz and Cavaco-Pauloeds.Advances in Textile Biotechnology,Elsevier,2010综述的)。
除了CD和CD衍生物之外,多种基于环糊精的超分子系统可用于递送上述范围的生物活性分子(如Zhangand Ma,Adv Drug Deliv Rev.2013Aug;65(9):1215-33中综述)。因此,基于环糊精的递送媒介物的方面包括已被表征为基于环糊精的纳米海绵(nanosponges)的实施方案。这些系统可以例如在本发明的上下文中适用于生物活性分子如药物的受控递送。
在选择的实施方案中,媒介物中提供的酶可配制使得环糊精降解活性在媒介物递送至靶标时被激活,从而从环糊精的腔中释放客分子。例如,酶激活可以在例如用于经口递送的药物,在干燥剂型如胶囊或片剂中完成,其中所述酶为混合的,使得酶直到被宿主胃肠道中的水分激活才会有活性。类似地,已知多种限时释放基质和制剂,其可适合用于CD递送媒介物,使得在递送至靶标时协调CD降解酶的适当激活。
在不同的方面,CD递送媒介物可以具有与环糊精包合物共同配制的酶,例如如上所述的,或者可以将酶与环糊精包合物共同包装于递送媒介物中。在共同包装的情况下,所述递送媒介物例如可以包含用于酶的生化可接受载体——不同于用于CD包合物的载体。例如,递送媒介物可以具有包含CD包合物和CD降解酶的分离的隔室,使得递送载体由与CD降解酶隔室连接的CD包合物隔室组成。可以提供用于CD包合物和CD降解酶从递送载体中的各自隔室组合释放的机构。例如,可以提供具有这种不同隔室的注射器,其通过共同排出机构排出,如通过协同移动每个隔室中的活塞以排出等分的CD包合物和CD降解酶的机构,使得随后可以将酶和配合物混合以激活客分子从所述CD中的酶促释放。这种媒介物可以例如用于分配局部用乳膏剂或其他表面活化制剂。多种这类的递送载体可以由已知的用于分配双组分组合物如环氧树脂、双组分药物或牙科制剂的装置改造,例如,如第4538920号、第8100295号、第8308340号、第8875947号、第8499976号美国专利,以及国际专利出版物WO2007041266和WO2000021842中公开的。
有多种可用于制备CD包合物的技术,例如,如Chaudhary&Patel,IJPSR,2013;Vol.4(1):68-76;美国专利出版物US20090029020;第5,070,081号、第5,552,378号和第8,658,692号美国专利中所描述的。一种常见的方法被称为捏合方法,其包括将CD与水或含水酒精混合来提供糊状物。然后可以将生物活性分子添加至糊状物中,并揉捏特定的时间。然后可以将揉捏的混合物干燥,并根据需要过筛。其他已知的制备CD包含物的方法包括冻干、微波辐照和超临界流体抗溶剂技术。
本发明的CD递送载体可以在载体如脂质体、佐剂或者任何药学或生物可接受载体的存在下单独提供或与其他化合物(例如,核酸分子、小分子、肽或肽类似物)组合提供。选择的实施方案包括适合给予动物宿主如哺乳类(例如人)的形式的药物。如本文中使用的“药学可接受载体”或“赋形剂”包括生理上相容的任何及所有的溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂等。所述载体可以适合任何适当的给药形式,包括局部、皮下、皮内、静脉内、肠胃外、腹膜内、肌内、舌下、吸入、瘤内或经口给药。药学可接受载体包括无菌水溶液或分散液以及用于临时制备无菌可注射溶液或分散液的无菌粉末。这类介质和试剂用于药物活性物质的用途为本领域所熟知。除非任何常规介质或试剂与所述生物活性化合物达到不兼容的程度,否则考虑将其用于本发明的药物组合物中。补充性活性化合物也可以掺入组合物中。
可以采用常规的药学实践来提供合适的制剂或组合物,以将递送媒介物给予对象。可以采用任何合适的给药途径,例如,肠胃外、静脉内、皮内、皮下、肌内、颅内、眶内、经眼、心室内、囊内、脊柱内、鞘内、脑池内、腹膜内、鼻内、吸入、喷雾、局部、瘤内、舌下或经口给药。治疗剂可以为液体溶液或悬浮液的形式;对于经口给药,制剂可以为片剂或胶囊剂的形式;对于鼻内制剂,为粉末、滴鼻剂或气雾剂的形式;对于舌下制剂,为滴剂、气雾剂或片剂的形式。
环糊精降解或消化酶可以例如配制用于经口递送。例如,可以提供肠溶酶制剂,如通过乳液溶剂蒸发制备的亚微米颗粒制剂(Sharma et al.,Pharm Dev Technol.2013May-Jun;18(3):560-9)。类似地,递送媒介物可以配制为水凝胶(参见美国专利出版物20140094433),或药用树胶(参见美国专利出版物20130022652)。
本领域熟知用于制备制剂的方法可以在例如“Remington’s PharmaceuticalSciences”(第20版),ed.A.Gennaro,2000,Mack Publishing Company,Easton,PA中找到。用于肠胃外给药的制剂可以例如包含赋形剂、无菌水或盐水、聚亚烷基二醇如聚乙二醇、植物油或氢化萘。生物相容且可生物降解的丙交酯聚合物、丙交酯/乙交酯共聚物,或聚氧乙烯-聚氧丙烯共聚物可用于控制所述化合物的释放。其他可能有用的肠胃外递送系统包括乙烯-乙酸乙烯酯共聚物颗粒、渗透泵、植入式输注系统和脂质体。用于吸入的制剂可以包含赋形剂如乳糖,或者可以为包含例如聚氧乙烯-9-十二烷基醚、甘胆酸盐和脱氧胆酸盐的水溶液,或者可以为用于以滴鼻剂形式或作为凝胶给药的油性溶液。
本发明的药物组合物可以为允许将所述组合物给予患者的任何形式。例如,所述组合物可以为固体、液体或气体(气雾剂)形式。典型的给药途径包括但不限于:经口、局部、肠胃外、舌下、经直肠、经阴道和鼻内。如本文中使用的术语“肠胃外”包括皮下注射、静脉内、肌内、硬膜外、胸骨内注射或输注技术。本发明的药物组合物经配制使得在将所述组合物给予患者后,能够允许其中包含的活性成分为生物可利用的。将给予患者的组合物采用一个或多个剂量单位的形式,例如,其中片剂、胶囊或扁胶囊(cachet)可以为单剂量单位,并且气雾剂形式的化合物的容器可以容纳多个剂量单位。
用于制备药物组合物的材料应当为药学上纯的,且在使用的量下是无毒的。本发明的组合物可以包含一种或多种已知具有特定期望作用的化合物(活性成分)。对本领域普通技术人员显而易见的是,药物组合物中活性成分的最佳剂量取决于多种因素。相关的因素包括但不限于,对象的类型(例如,人)、活性成分的特定形式、给药方式和所用的组合物。
通常,所述药物组合物包含混合有一种或多种载体的如本文中描述的本发明的递送媒介物。所述载体可以为颗粒,因而所述组合物为例如,片剂或粉末形式。所述载体可以是液体,其中所述组合物为例如,口服糖浆或可注射液体。另外,所述载体可以是气体,以便提供可用于例如,吸入给药的气雾剂组合物。
当期望用于经口给药时,所述组合物优选为固体或液体形式,其中半固体、半液体、悬浮液和凝胶形式包含在本文所认为的固体或液体形式中。
作为用于经口给药的固体组合物,可以将所述组合物配制成粉末、颗粒、压缩片剂、丸剂、胶囊、扁胶囊、咀嚼胶、薄片、锭剂等形式。这样的固体组合物通常包含一种或多种惰性稀释剂或可食用载体。此外,可存在以下一种或多种佐剂:粘合剂如糖浆、阿拉伯树胶、山梨醇、聚乙烯吡咯烷酮、羧甲基纤维素、乙基纤维素、微晶纤维素、黄蓍胶或明胶,以及以上物质的混合物;赋形剂如淀粉、乳糖或糊精;崩解剂如海藻酸、海藻酸钠、Primogel、玉米淀粉等;润滑剂,如硬脂酸镁或Sterotex;填充剂如乳糖、甘露醇、淀粉、磷酸钙、山梨醇、甲基纤维素,和以上物质的混合物;润滑剂如硬脂酸镁、高分子量聚合物如聚乙二醇、高分子量脂肪酸如硬脂酸,二氧化硅,润湿剂如十二烷基硫酸钠、助流剂如胶体二氧化硅;甜味剂如蔗糖或糖精、增味剂如薄荷、水杨酸甲酯或橙香精(orange flavoring)和着色剂。
当所述组合物为胶囊形式,例如明胶胶囊时,除了上述类型的材料外,其还可包含液体载体如聚乙二醇或脂肪油。
所述组合物可以是液体形式,例如酏剂、糖浆、溶液、水性或油性乳剂或悬浮剂,或者甚至是干粉末,其可以在使用前用水和/或其它液体介质复溶。作为两个实例,所述液体可以用于经口给药或通过注射递送。当打算用于经口给药时,优选的组合物除了包含本发明的合成物外,还含有一种或多种甜味剂、增稠剂、防腐剂(例如,对羟基苯甲酸烷基酯)、染色剂/着色剂和增味剂(增香剂)。在打算通过注射给药的组合物中,可以包含一种或多种表面活性剂、防腐剂(例如,对羟基苯甲酸烷基酯)、润湿剂、分散剂、悬浮剂(例如,山梨醇、葡萄糖或其他糖浆)、缓冲剂、稳定剂和等渗剂。所述乳化剂可选自卵磷脂或山梨醇单油酸酯。
本发明的液体药物组合物,无论其为溶液、悬浮液或其他类似形式,均可包含以下佐剂中的一种或多种:无菌稀释液,如注射用水、盐溶液,优选生理盐水、林格氏溶液、等渗氯化钠,不挥发性油,如可作为溶剂或悬浮介质的合成的甘油单酯或甘油二酯,聚乙二醇、甘油、丙二醇或其他溶剂;抗菌剂如苄醇或对羟基苯甲酸甲酯;抗氧化剂如抗坏血酸或亚硫酸氢钠;螯合剂如乙二胺四乙酸;缓冲剂如乙酸盐、柠檬酸盐或磷酸盐,以及调节渗透压的试剂,如氯化钠或葡萄糖。肠胃外制剂可以封装于由玻璃或塑料制成的安瓿瓶、一次性注射器或多剂量小瓶中。生理盐水是优选的佐剂。可注射药物组合物优选是无菌的。
所述药物组合物可用于局部给药,在这种情况下,所述载体可适当地包含溶液、乳液、软膏、乳膏或凝胶基质。所述基质,例如,可包含以下物质中的一种或多种:矿脂、羊毛脂、聚乙二醇、蜂蜡、矿物油、稀释剂如水和醇,以及乳化剂和稳定剂。在药物组合物中可以存在增稠剂,以用于局部给药。如果打算用于透皮给药,所述组合物可包含透皮贴剂或离子电渗疗法装置。局部制剂可包含约0.1%至约25%w/v(重量/单位体积)的生物活性化合物浓度。
所述组合物可用于直肠给药,例如以在直肠中融化并释放所述药物的栓剂的形式。用于直肠给药的组合物可以包含油性基质作为合适的无刺激性赋形剂。这样的基质包括但不限于羊毛脂、可可油和聚乙二醇。优选将低熔点蜡用于制备栓剂,其中脂肪酸甘油酯和/或可可油的混合物是合适的蜡。可以将所述蜡融化,并通过搅拌将氨基环己基醚化合物均匀分散在其中。然后将融化的均匀混合物倒入方便大小的模具中,使其冷却并凝固。
所述组合物可以包含改变固体或液体剂量单位的物理形式的各种材料。例如,所述组合物可以包含在所述活性成分周围形成包衣壳的材料。形成包衣壳的材料通常是惰性的,并且可以选自例如,糖、虫胶和其他肠溶包衣剂。可选地,可将所述活性成分包裹在明胶胶囊或扁胶囊中。
本发明的药物组合物可以由气体剂量单位组成,例如,其可以为气雾剂的形式。术语“气雾剂”用于表示多种系统,范围从具有胶体性质的那些至由加压包装组成的系统。可以通过液化或压缩气体,或者通过分配活性成分的合适泵系统进行递送。本发明化合物的气雾剂可以以单相、双相或三相系统递送,以便递送所述活性成分。所述气雾剂的递送包括必要的容器、活化剂、阀门、子容器等,它们一起可以形成试剂盒。
所述生物活性化合物可以为游离碱的形式或药学可接受盐的形式,如盐酸盐、硫酸盐、磷酸盐、柠檬酸盐、富马酸盐、甲磺酸盐、乙酸盐、酒石酸盐、马来酸盐、乳酸盐、扁桃酸盐、水杨酸盐、琥珀酸盐和本领域已知的其他盐。可以选择合适的盐来提高化合物的生物可利用性或稳定性,以获得合适的应用方式(例如,经口或肠胃外给药途径)。
打算通过通过注射施用的组合物可以通过将本发明的递送媒介物与水,并且优选与缓冲剂组合来形成溶液而制备。所述水优选为无菌无热原水。可以添加表面活性剂来促进形成均相溶液或悬浮液。表面活性剂为与氨基环己基醚化合物非共价相互作用的化合物,从而促进所述氨基环己基醚化合物在含水递送系统中的溶解或均匀悬浮。在本发明的含水组合物中最好存在表面活性剂,因为根据本发明的氨基环己基醚化合物可能为疏水性的。其他注射用载体包括但不限于无菌无过氧化物的油酸乙酯、脱水醇、丙二醇,以及它们的混合物。
用于注射溶液的合适的药物佐剂包括稳定剂、增溶剂、缓冲剂和粘度调节剂。这些佐剂的实例包括乙醇、乙二胺四乙酸(EDTA)、酒石酸盐缓冲剂、柠檬酸盐缓冲剂和高分子量聚氧化乙烷粘度调节剂。这些药物制剂可以经肌内、硬膜外、腹膜内或静脉内注射。
本发明还提供了包含药物组合物的试剂盒,所述药物组合物包含一种或多种递送媒介物。所述试剂盒还包含使用该药物的说明书。优选地,商业包装将包含一个或多个单位剂量的药物组合物。例如,这样的单位剂量可以为足以制备静脉内注射的量。对本领域普通技术人员显而易见的是,光敏和/或气敏的化合物可能需要特殊的包装材料和/或制剂。例如,包装材料可以使用避光和/或密闭而避免接触环境空气,和/或配制有合适的包衣或赋形剂。
根据本发明的CD包合物递送媒介物的“有效量”包括治疗有效量或预防有效量。“治疗有效量”是指在必要的剂量和时间段内有效实现预期治疗结果的量。递送媒介物的治疗有效量根据诸如个体的疾病阶段、年龄、性别和体重,以及所述化合物引起个体预期反应的能力等因素可能存在差异。可以调整给药方案来提供最佳的治疗反应。治疗有效量也可能为递送媒介物或活性化合物的治疗有益效应超过其任何毒性或有害效应的量。“预防有效量”是指在必要的剂量和时间段内有效实现预期预防效果的量。通常,将预防性剂量在疾病之前或在疾病的较早阶段用于对象,这样预防有效量可能小于治疗有效量。对于任何特定的对象,治疗的时间和剂量可以根据个体需要和给药或监督组合物给药的人的专业判断随时间进行调整(例如,时间可能为每天、每隔一天、每周、每月)。
在选择的实施方案中,本发明提供了包含与药学可接受载体、稀释剂或赋形剂组合的一种或多种生物活性分子的组合物或药剂,所述生物活性分子选自:生物活性化合物或溶剂化物、药学可接受的盐、酯、酰胺、络合物、螯合物、立体异构体、立体异构体混合物、几何异构体、晶体或非结晶形式、代谢物、代谢前体其或前药,包括其分离的对映体、非对映异构体和几何异构体,以及以上物质的混合物,并且还提供了用于制备这种组合物或药剂的方法。
尽管在本文中公开了本发明的不同实施方案,可以根据本领域技术人员的一般常识在本发明的范围内进行许多调整和修改。这样的修改包括为了以基本上相同的方式达到相同的结果,对本发明的任何方面进行已知等同物的取代。数字范围包括限定范围的数字。本文中使用的词语“包括”为开放性术语,基本上等同于短语“包括但不限于”,并且词语“包含”具有相应的含义。除非上下文明确指出,如本文中所用的单数形式“一个/一种”和“所述”包括复数指示物,。因此,例如,提及“一种物质”包括多于一种这样的物质。
本文中参考文献的引用并非承认这样的参考文献为本发明的现有技术。任何优先权文件和所有出版物,包括但不限于本说明说中引用的专利和专利申请,均通过引用并入本文中。在本文引用的文件中引用或参考的所有文件以及本文或通过引用并入本文中的任何文件中提及的任何产品的任何厂商指导、描述、产品说明书和产品表,均在此通过引用并入本文中,并且可以用于实施本发明。更具体地,所有参考文件通过引用以相同的程度并入本文中,就像明确地和单独地提及每个单独的出版物通过引用并入本文中,以及就像在本文中完整描述。本发明包括基本上如上文中描述且参考实施例和附图的所有实施方案和变体。
在一些实施方案中,本发明不包括涉及医学或手术治疗的步骤。
实施例
实施例1:棕属(Serenoa)和李属(Prunus)提取物
使用从锯叶棕榈(Serenoa repens)纯化的种子提取物(Indena,Italy)和非洲李(Prunus Africana)树皮提取物(Indena,France),以2:1的比例采用捏合方法制备了γ环糊精(GCD,Wacker Chemi,Germany)包合物。所述棕属提取物富含脂肪酸和植物甾醇。例如,棕属提取物可以包含三甘油酯和/或游离脂肪酸,如:油酸、月桂酸、辛酸、癸酸、十三烷酸、肉豆蔻酸、十五烷酸、棕榈酸、棕榈油酸、十七烷酸、硬脂酸、异油酸、亚油酸、亚麻酸、花生酸、二十碳-11-烯酸、二十二烷酸、二十四烷酸。例如,棕属提取物中的植物甾醇可以包含:菜油甾醇、β-谷甾醇和豆甾醇。类似地,所述李属提取物包含多种这样的这类化合物,例如,其可以包括:N-丁基苯磺酰胺、阿彻瑞克酸(atraric acid)、β-谷甾醇、β-谷甾酮(β-sitostenone),以及脂肪酸,如亚油酸、棕榈酸、油酸、硬脂酸、亚麻酸、月桂酸和肉豆蔻酸、二十二烷醇、山嵛酸、熊果酸、二十四烷酸、阿魏酸和无羁萜(friedelin)。
棕属提取油呈琥珀色,而李属提取物类似于“焦油球”,包含可以用手揉捏的几乎黑色的硬化提取物。两种提取物都具有几乎令人愉悦的较浓的水果气味(deep fruitodor),当被包含于环糊精包合物中时该气味几乎完全消失。
在干燥和研磨后,测定了包合物样品对草本提取物的酶促释放敏感性。在该测定中,在容器1中将1g包合物与20ml蒸馏水混合,并在容器2中将等量的1g包合物和20ml蒸馏水,连同20mg未稀释的淀粉酶粉末(Enzyme Development Corporation,New York)混合。将两个容器均加热至37℃,每5分钟搅拌一次。
在测定的第20分钟时间点,容器2中的颜色变化开始变得明显,并且在第30分钟时间点时非常显著。相反,在没有添加所述酶的容器1中保持灰白色(在以后的整个5小时内保持一致)。在淀粉酶消化GCD包合物时,容器2的内容物明显变得更暗。30分钟后,由于GCD的保护性包膜被酶破坏,原料成分再次可见,容器2显示出提取物的一些天然颜色。另外,在30分钟后,在容器2而非容器1中,两种成分的气味再次变得明显。在第30分钟时,在容器1中没有成分分离,这可通过无脂质存在来证明,该容器的内容物仍然为包合物颗粒。然而,在容器2中,在30分钟时,包合物的破坏较明显,不仅表现在溶液主体上,还出现了棕属和李属提取物作为脂质物在容器周围形成了油状平滑环,且在容器2的白色陶瓷表面上可以看到油滴。
本实施例说明脂肪酸和植物甾醇能够从配制为CD包合物的植物提取物中有效释放。因此,本实施方案为包含诸如以下一种或多种脂肪酸和/或植物甾醇的包合物示例:油酸、月桂酸、辛酸、癸酸、十三烷酸、肉豆蔻酸、十五烷酸、棕榈酸、棕榈油酸、十七烷酸、硬脂酸、异油酸、亚油酸、亚麻酸、花生酸、巨头鲸鱼酸、二十二烷酸、二十四烷酸、菜油甾醇、β-谷甾醇;豆甾醇;N-丁基苯磺酰胺、阿彻瑞克酸、β-谷甾酮、二十二烷醇、山嵛酸、熊果酸、二十四烷酸、阿魏酸和无羁萜。
实施例2:丁酸
利用捏合方法,制备了含有丁酸(Vigon,USA)的α环糊精(ACD,Wacker Chemi,Germany)包合物。丁酸是一种脂肪酸(也称为丁烷酸),其在室温下为澄清的轻质油,有一些令人作呕的气味,在包入环糊精包合物中该气味几乎完全消失。在大于10ppm的浓度时,丁酸气味可以通过人鼻子闻到,且会对皮肤、眼睛和呼吸系统造成刺激。
在干燥和研磨后,测定了包合物样品对丁酸酶促释放的敏感性。在该测定中,在容器1中将1g包合物与20ml蒸馏水混合,在容器2中将等量的1g包合物和20ml蒸馏水以及20mg未稀释的淀粉酶粉末(Enzyme Development Corporation,New York)混合。将两个容器均加热至37℃,并每5分钟搅拌一次。
在第25分钟时间点,容器2中的丁酸气味开始变得明显,并且在第35分时间点变得更加明显。相反,没有添加所述酶的容器1在以后的5小时内保持相同的微弱气味且不增加。
实施例3:大麻油提取物
利用捏合方法以纯化的大麻油提取物(CV Sciences,USA)制备了γ环糊精(GCD,Wacker Chemi,Germany)包合物。大麻油通常含有多种脂肪酸、植物甾醇和生理活性成分,如:亚油酸、α-亚麻酸、油酸、β-谷甾醇、菜油甾醇、植醇、环阿屯醇、γ-生育酚和大麻二酚,以及较小比例的萜烯类物质,在本文中引用标注为“大麻精油”,如下文所述。
在干燥和研磨后,测定了包合物样品对大麻油提取物体内酶促释放的敏感性。在该测定中,将390mg的包合物包封在0号胶囊中。制备第二组胶囊,其包含390mg的包合物以及10mg未稀释的淀粉酶粉末(Enzyme Development Corporation,New York)。
以一名身体状况良好、有912个晚上睡眠周期记录的43岁男性为对象,在不同的日子,在他晚上11点的标准就寝时间之前30分钟,给予2粒每种制剂胶囊,给药时间在晚餐后很久,因此没有食物来诱导唾液淀粉酶。
图1显示了对象的典型睡眠模式,包括深度睡眠的持续时间和水平。图2显示了服用无任何添加淀粉酶的包合物后的睡眠模式,其示出了相比于典型基线具有稍微更深睡眠的睡眠模式,其中对象报告了在其评级中的平均睡眠。图3显著地显示了对象描述的“其多年来最安静的睡眠”。除了起床短暂地使用卫生间,并快速恢复睡眠之外,整个睡眠模式达到了之前未达到的睡眠深度和深度睡眠时间。
本实施例阐明了利用添加到包合物制剂中的淀粉酶从包合物体内释放出生理活性成分。本实施例的一个方面显示了所述制剂的独立性,其释放活性成分对唾液或消化性淀粉酶没有任何依赖性。
在示例性的实施方案中,可选的制剂可以包括多种来源于大麻或大麻属植物的生物活性分子,例如各种大麻素如大麻萜酚(CBG)、大麻色原烯(CBC)、四氢次大麻酚(THCV)、四氢大麻酚(THC)、大麻二醇(CBD)和大麻醇(CBN)的环糊精包合物。
实施例4:青光眼
本实施例中的对象是加利福尼亚医学博士,其自1996年以来具有使用医用大麻的经验。该对象自己服用按实施例3中所述制备的胶囊,其包含390mg大麻油包合物和10mg淀粉酶粉末。在连续使用几天后,对象的青光眼有明显的改善,使用包合物的效果优于对象在过去使用分离的大麻二醇或标准化产品任何组合的效果。
实施例5:层状包合物
本实施例涉及CD包合物混合物的生产,其中多种可选的客分子与多种可选的环糊精形成了包合物,其中每种客分子的大小和/或亲和力与对应的环糊精相匹配,所述环糊精具有大小合适的或适于稳定保留客分子的腔。以这种方式,可以配制独特的,例如大小不同的生物活性分子的包合物混合物,从而得到层状包合物混合物。
在示例性的实施方案中,以α和β环糊精按顺序配制了大麻精油(百分比比例见表2)。首先将一些大麻精油加入到α环糊精和水的浆料中,进行揉捏一段时间后形成尺寸上适合α环糊精腔室的客分子包合物。接下来,向具有较大腔的环糊精——β环糊精加入额外的水,并进行揉捏,以通过形成太大而不能契合α环糊精的腔的客分子包合物来获得一定大小的层状包含物混合物。通过首先与具有较小的腔的环糊精形成包合物,并接着与具有较大的腔的环糊精形成包合物,该过程提供了一种包合物混合物,其中客分子被封装于环糊精中,并与之形成了最稳定的包合物,避免了较大CD对小分子的次优捕获。这一过程可以是重复的,其中一系列较大的或不同修饰的CD被用于形成复合的层状包合物,其中客分子被依次保留在化学或立体结构匹配的环糊精中。
表2:大麻精油分析
可以配制层状包合物的合成混合物,以提供与制备包合物的初始混合物相比具有不同的生物活性分子比例。为了采用上述示例性实施方案,可以将来自一系列大麻精油的α环糊精包合物样品合并,然后可以向该合并的α环糊精制剂加入单个等分试样的β环糊精包合物,从而相比原来的组合物亚麻精油,以包合物的形式提供富含较小生物活性分子的制剂。可选地,如上文所述,可以制备层状包合物的合成混合物,以便重现选定的起始材料中生物活性分子的相对丰度。在示例性的实施方案中,这通过使用α环糊精与β环糊精的比例为4:1来实现,反映了这一事实,即约80%的大麻精油样品由契合α环糊精的生物活性分子组成,而剩下的20%契合β环糊精包合物。
示例性的实施方案提供了层状包合物的合成混合物,其包含比例可调的如来自于大麻属(Cannabis)或大麻样品或提取物的大麻素和萜烯。这些混合物可以包括不同大麻素的包合物,所述大麻素如大麻萜酚(CBG)、大麻色原烯(CBC)、四氢次大麻酚(THCV)、四氢大麻酚(THC)、大麻二醇(CBD)和大麻醇(CBN)。这些混合物中的萜烯(类异戊二烯)例如可以包括:α-蒎烯、罗勒烯、石竹烯(β-石竹烯)、莰烯、莰酮、桉叶油醇(eucatyptol)、蛇麻烯(α-蛇麻烯)、月桂烯、γ-萜品烯、顺式-橙花叔醇(nerolidoI)、蒈烯(carene)、萜品油烯、松油醇、反式-橙花叔醇、伞花烃(对-伞花烃)、芳樟醇、水芹烯、愈创木醇(guaiol)、柠檬烯、异-长叶薄荷醇(iso-pulegol)、石竹烯-氧化物(cary-oxide)、α-萜品烯、香叶醇、朱栾倍半萜、葑醇、茨醇(异茨醇)、叶绿醇、桧烯、薄荷醇、雪松烯、橙花叔醇、异蒲勒醇、乙酸香叶酯、长叶薄荷酮和没药醇。
层状包合物可配制成与一种或多种酶一起递送,所述酶具有环糊精降解活性可消化环糊精而保留客分子。在选择的实施方案中,例如,酶可选自那些对混合物中的环糊精亚类具有优先或专一活性的酶。可以此方式对层状环糊精包合物递送载体进行调整,以使其含有两种或更多种独特的酶,并且所述独特的酶经配制后具有独特的环糊精降解活性,其在将载体递送至两个或更多个独特的靶标,例如胃肠道的两个不同的部位时被激活。
实施例6:短链脂肪酸包合物
本实施例涉及药物、膳食补充剂、食品或医疗食品制剂,其包含单个或组合的短链脂肪酸(SCFA)与疏水性的或亲水性环糊精(包括α、β或γCD,以及改性的CD如乙基化CD)的包合物。SCFA可以以酯的形式存在,如甘油酯(单、双或三甘油酯)、盐或另外的药学上可接受的衍生物。SCFA包合物可以与具有环糊精降解活性的酶一起以剂量的形式提供,所述酶能够消化CD而保留SCFA客分子,例如α、β或γ淀粉酶的。类似地,可以将脂肪酶加入到所述制剂中从而可将SCFA从油脂中释放出来,例如,作用于SCFA的酯,如甘油酯。这些制剂可以配制为速释剂量或食品形式,或者缓释剂量或食品形式。在缓释剂量形式中,一种或多种组合物的溶解和释放可以以受控速率维持或延迟,包括SCFA医药成分、CD和/或淀粉酶。例如,有或没有CD包合物的淀粉酶可以配制成包被于各种各样的缓释包衣或树脂形式中的微粒或颗粒的形式。类似地,特别是当脂肪酶被包含于所述制剂中时,可以在基质上提供甘油酯如甘油三酯,例如在纤维素基质上喷雾干燥,例如与脂肪酶混合。例如,这些制剂可以进行调整以将医药化合物或其代谢物,如SCFA的血液浓度控制或维持在比无缓释载体的情形下具有更长时间的有效水平。
这些制剂的一个方面是向如人或哺乳类的对象的小肠和大肠提供SCFA剂量形式的应用。例如,所述制剂可用于胃肠病症如结肠炎、憩室炎、克罗恩病、炎性肠病或肠易激综合症(IBS)治疗中的辅助或治疗目的。另一方面,这些制剂可用于提供胃肠道的肿瘤性疾病如结肠癌的预防性或治疗性治疗。又一方面,这些制剂可用于提供糖尿病胰岛素敏感性的预防性或治疗性治疗。又一方面,这些制剂可用于提供提高产热活动和后续体重减轻的预防性或治疗性治疗。
在选择的实施方案中,这些制剂提供了一种药物制剂,其包含由至少一种SCFA组成的包合物,所述SCFA作为活性成分,能够作为包合物与至少一种疏水性的环糊精复合。在特定的实施方案中,例如,所述SCFA可以为丁(丁烷)酸、丙酸或乙酸中的一种或多种。例如,可以以选定的比例提供多种SCFA,例如从9:1至1:9。例如,选择的SCFA可被配制于最优的制剂中,例如包含75%-95%的丁酸、1%-20%的丙酸和1%-10%的乙酸,例如约85%的丁酸、10%的丙酸和5%的乙酸。
实施例7:采用丁酸制剂进行胃肠道治疗
本实施例涉及一般性胃肠道功能失调的治疗。让一名具有反复和长期临床上不同的胃肠道功能失调症状的48岁女性服用30mg按实施例2所述制备的丁酸包合物胶囊,每天4粒,给药3次。开始治疗3周后,其医生报告了治疗功效的临床相关证据,并且在4年内该患者第一次显示出正常GI功能的特征。
实施例8:采用SCFA制剂进行胃肠道治疗
本实施例说明了以包含SCFA混合物的制剂治疗特定胃肠道症状。对象是一名65岁的男性,具有间歇性液体腹泻,在早上喝完咖啡后(特别是早上吃完柑橘后),或者在吃完丰盛的晚餐后有可预测的症状性爆发。服用SCFA包合物开始治疗,其是包含丁酸(27mg)、丙酸(2.5mg)和乙酸(2.5mg)与α环糊精的包合物的胶囊。初始治疗方案为4粒胶囊,每天3次。随后降低为每天两次。在首次服药的24小时内,液体腹泻停止,且在整个5周的治疗期期间未复发。在治疗期间,该患者报告大便开始完全一致,且排便量明显减少。该患者还能在饭后和睡前停止常规的抗酸治疗,并报告说对适量饮酒的耐受性有所改善。
实施例9:采用丁酸制剂进行IBD治疗
本实施例说明了对慢性肠易激病(IBD)症状的缓和。患者是一名52岁女性,患慢性IBD 30年,每天接受2-4次剂量的洛哌丁胺症状治疗。以实施例2所述的丁酸制剂开始治疗,3粒,每天2次,在IBD发作期间开始,采用丁酸包合物制剂的7天治疗期间无伴随性洛哌丁胺治疗。在48小时内,所有腹泻停止。该患者还报告在7天的治疗后明显的食欲抑制。因此,本实施例证明了治疗IBD的治疗功效,以及SCFA包合物制剂作为食欲抑制剂的用途。
实施例10:造瘘术炎症
本实施例说明了与造瘘术相关症状的治疗,包括炎症和肉芽。这是一例有3年造瘘术炎症和感染复发史的医生病历。在以丁酸盐CD制剂治疗前,该患者的病史如下:
·1971年由于溃疡性结肠炎进行了结肠切除术;
·2012年11月–2014年1月持续未知的葡萄穗霉属(Stachybotrys)感染;
·葡萄穗霉属感染后继发的免疫系统功能失调;
·从01/13–06/15,反复的结肠袋炎以及肠皮肤瘘发作,对多剂量的环丙沙星和甲硝哒唑均无响应;在该段时间进行了5次剖腹术以减少损伤;最后取下肠贮袋(reservoir)替换为标准的布鲁克回肠造瘘(Brooke Ileosomy);
·由于未愈合的皮肤伤口进行了两次手术来清除并最终移除了回肠造瘘;
·造口周围持续存在肉芽组织,对两次联合他克莫司乳膏的类固醇注射给药无反应。
以根据实施例2制备的丁酸制剂开始口服治疗,8粒胶囊,每天两次。所述胶囊为30mg的净丁酸与具有淀粉酶的缓释CD配制而成。当治疗停止时,炎症的愈合逐渐趋于稳定。在停止丁酸盐CD治疗1周内,病灶开始破裂并再次生长。病灶持续恶化2周。在重新开始丁酸CD治疗后,再次开始愈合。
实施例11:骨髓纤维化
本实施例说明了与骨髓纤维化相关症状的治疗。以槲黄素CD制剂治疗一名患有骨髓纤维化的患者。该制剂由槲黄素(Glanbia Nutritionals)粉末制成,与γ环糊精形成包合物,干燥并与淀粉酶粉末混合。在开始槲黄素CD治疗时,该患者约每10天需要进行输血。在开始槲黄素CD治疗后,该患者能够将输血间隔时间增加至20天。监管医生自1984年开始实践使用槲黄素,据其陈述,该患者在标准的槲黄素补充疗法后并没有达到这一效果。
本实施例说明了本发明的递送载体可用于提供具有优势的类黄酮的递送,包括槲皮素等生物类黄酮。
实施例12:自闭症
本实施例包括使用混合淀粉酶的丁酸α-环糊精包合物对3名儿童自闭症谱系障碍(ASD)的治疗病历。
对1名确诊为ASD的5岁男孩,O,采用以捏合方法制备且混合有淀粉酶的丁酸α-环糊精包合物进行口服治疗。给药为30mg净丁酸,每天两次。在10天内,精神病学评估发现ASD症状有大幅改善。这与护理人员对生活质量有很大改善的评估是一致的。
对1名确诊为自闭症谱系的6岁男孩,M,采用以捏合方法制备且混合有淀粉酶的丁酸α-环糊精包合物以每天1/4茶匙的量进行治疗。M以前在与人(即使是他的母亲)说话时通常不能进行目光接触,且不能自己系鞋带。开始丁酸盐CD治疗后24小时,在2次剂量后,M自己系鞋带且在表达其取得成就的自豪时与他母亲进行直接目光接触。
对1名确诊为自闭症非语言谱系的17岁女孩,采用3粒,每天两次的丁酸α-环糊精包合物进行治疗,所述包合物以捏合方法制备且混合有淀粉酶,180mg净丁酸盐。在3天内,该患者表现了较好的目光接触,变得平静,且现在能够主动指出并辨认图画书中的动物和图片,甚至说出特定人物的名字。
自闭症与多种胃肠道症状有关,且研究已发现了闭症患者肠道微生物群系具有独特特征的证据,以及丁酸盐有益作用的相关证据。因此,本发明在一个方面提供了丁酸环糊精包合物制剂用于神经系统疾病患者肠道菌群的调节。
实施例13:低过敏性的膳食替代制剂和基本饮食制剂
本实施例涉及CD包合物混合物的制备,其中单个氨基酸或氨基酸组与环糊精形成包合物,例如,以掩蔽味道和提高不易溶解氨基酸的溶解性。
在示例性的实施方案中,可以从已知苦味的或硫占优势的单个氨基酸形成CD包合物,如:L-苯丙氨酸、N乙酰-半胱氨酸(和L半胱氨酸)、L-甲硫氨酸、L-异亮氨酸和L-色氨酸。在一个实例中,利用捏合方法将这些氨基酸以等摩尔比的比例单独包入β环糊精中。第二组通过捏合方法,以等摩尔比的比例包入γ环糊精中。然后将这些材料干燥并磨碎。加入自来水后,发现这些包合物完全溶解,且与基质材料相比可以相当好地掩蔽了令人讨厌的味道。
在另一个实施方案中,将相同的氨基酸(L-苯丙氨酸、N乙酰-半胱氨酸(和L-半胱氨酸)、L-甲硫氨酸、L-异亮氨酸和L-色氨酸)预混后作为一组氨基酸,然后利用捏合方法,以等摩尔比值的比例包入β环糊精中。第二组通过捏合方法,以等摩尔比的比例包入γ环糊精中。然后将材料干燥并磨碎。加入自来水后,发现这些组合的包含物完全溶解且相当好地掩蔽了令人讨厌的味道。
因此,这些方法可用于天然存在或合成的单个或组合氨基酸。在一些情况下,β环糊精包合物可能具有严格的剂量要求,例如限定为每天通过口服相对较小的量。因此,对于特定氨基酸小剂量给药的制剂,β环糊精可能是用于包合物的合适选择(其相比α或γ环糊精,从成本角度考虑更为有利)。或者,在大小允许时,可以将氨基酸包入α环糊精包合物中。
已有可用于胃肠道训练的商业化膳食替代品,如VivonexTMPlus,其为氨基酸、大豆油(用于必要的脂肪)、麦芽糖糊精/玉米淀粉(碳水化合物来源),以及基本的维生素和矿物质及防腐剂的预包装产品。味道为苦味或硫占优势的5种氨基酸(L-苯丙氨酸、N乙酰-半胱氨酸(和L半胱氨酸)、L-甲硫氨酸、L-异亮氨酸和L-色氨酸)可被认为使这类产品不可口。这类产品的成分,以及本发明中相应的含有以CD包合物形式存在的一个或多个氨基酸的产品,例如可以包括:麦芽糖糊精(来自玉米)、L-谷氨酰胺、改性玉米淀粉、L-亮氨酸、L-精氨酸醋酸盐、大豆油和少于2%的葡萄糖酸镁、L-赖氨酸醋酸盐、甘油磷酸钙、L-异亮氨酸、L-缬氨酸、L-苯丙氨酸、柠檬酸钠、L-苏氨酸、柠檬酸钾、L-半胱氨酸盐酸盐、柠檬酸、L-甲硫氨酸、L-酪氨酸、L-组氨酸盐酸盐、L-天冬氨酸、L-脯氨酸、L-色氨酸、磷酸二钠、氯化钾、胆碱酒石酸盐、L-丝氨酸、L-丙氨酸、甘氨酸、抗坏血酸、脂肪酸的聚甘油酯、牛磺酸、L-肉毒碱、α-生育酚乙酸酯、硫酸锌、山梨酸钾以及bha和bht及生育酚(以保持新鲜)、硫酸亚铁、烟酰胺、维生素a棕榈酸酯、泛酸钙、葡萄糖酸铜、维生素D3、盐酸吡哆醇、硫酸锰、核黄素、盐酸硫胺、叶酸、氯化铬、生物素、碘化钾、钼酸钠、亚硒酸钠、植物甲萘醌、维生素B12。
例如,这些膳食替代品和基本饮食制剂可以以约79.4g的份量配制来提供:蛋白(作为氨基酸)13.5g;脂肪2g;碳水化合物57g;维生素、矿物质和其他成分6.9g。
可选地,膳食替代制剂可提供模拟天然蛋白质来源,如鸡蛋的氨基酸比例。
在一个示例性的实施方案中,利用捏合方法,以等摩尔比例将菜籽油(一种脂肪酸来源)包入γ环糊精包合物中。然后将材料干燥并磨碎,作为预混物加入到膳食替代制剂中。所包含的预混物一份的量以克表示为:菜籽油2.0;来自γ环糊精的碳水化合物10.5。在本实施方案中,将氨基酸L-苯丙氨酸、N乙酰-半胱氨酸、L-甲硫氨酸L-异亮氨酸和L-色氨酸预混成为一组氨基酸,然后利用捏合方法,以等摩尔比例包入γ环糊精中。然后将材料干燥并磨碎,作为预混物加入到膳食替代制剂中。一份量的所包含预混物的比例以克表示为:
氨基酸:
来自γ环糊精的碳水化合物…26.8
然后将该材料加入以克计的以下氨基酸量:
混合物中存在的氨基酸的总量为18.21g。混合物中γ环糊精的总量为37.3g。混合物中菜籽油的总量为2g。
制备了材料的干燥混合物并加入以下物质:
大米麦芽糖糊精……..19.7g
氯化钠………366mg
制剂可以含有各种各样的维生素和矿物质。例如,可以加入含有高度可吸收的生物活性成分的多维生素矿物质预混物,总共约3g,并且可以包含:
维生素A(2,00IU来自β胡萝卜素和1,000IU作为棕榈酸酯)3,000IU。
维生素C(以抗坏血酸)50mg。
维生素D(以维生素D3)200IU。
维生素E(以d-α生育酚)40IU.
硫胺(以硫胺HCl)5mg。
核黄素(以核黄素5'-磷酸钠)2mg。
烟酸(20mg以烟酰胺和5mg作为烟酸)25mg。
维生素B6(以吡哆醛5'-磷酸盐)2mg。
叶酸(200mcg以来自L-5-甲基四氢叶酸,氨基葡萄糖盐的L-5-甲基四氢叶酸盐)200mcg。
维生素B12(10mcg以腺苷钴胺素和10mcg甲基钴胺素)20mcg。
生物素100mcg。
泛酸(以泛酸钙)20mg。
胆碱(以柠檬酸盐)100mg。
钙(120mg以柠檬酸钙和90mg苹果酸钙)210mg。
铁(以吡啶甲酸铁)3mg。
碘(以碘化钾)225mcg。
镁(60mg以柠檬酸镁和30mg苹果酸镁)90mg。
锌(以吡啶甲酸锌)3mg。
硒(以L-硒基甲硫氨酸)40mcg。
铜(以吡啶甲酸铜)0.3mg。
锰(以吡啶甲酸锰)3mg。
铬(铬占替诺烟酸盐甘氨酸盐螯合物)*40mcg。
钼(以为吡啶甲酸钼)20mcg。
钾(30mg以柠檬酸钾和30mg苹果酸钾)60mg。
硼(以吡啶甲酸硼)0.5mg。
钒(以吡啶甲酸钒)20mcg。
根据上述实施方案,提供了约80g的总份量。这产生了美味的、低致敏的、维沃(Vivonex)类型的膳食替代制剂,没有典型的无法忍受的苦味或硫氨基酸残基的味道。还提供了可选的份量、成分和成分比例。例如,另外的或可选的成分,例如,可以含有烟酰胺核苷、丁酸和乙酸。
在另一个实施方案中,利用捏合方法,以等摩尔比例,将氨基酸L-苯丙氨酸和L-色氨酸分别包入γ环糊精包合物中。然后将每种材料干燥并磨碎,加入到预混物中并进一步加入到膳食替代制剂。重复了另一种预混和包含这两种氨基酸的方案,得到相同的结果。随后,利用捏合方法,以等摩尔比例将氨基酸N乙酰-半胱氨酸、L-甲硫氨酸和L-异亮氨酸分别包入γ环糊精包合物中。也可以将油加入到最终产品中,例如,以在最终的制剂中占用较少的空间。为达到本实施例的目的,在每个过程中通过捏合将与氨基酸相同量的菜籽油加入到每种氨基酸包含物中。用0.85克菜籽油配制L-苯丙氨酸,0.5克菜籽油配制N乙酰半胱氨酸,以及0.5克菜籽油配制L-甲硫氨酸。令人吃惊的是,以这些量加入时,油被明显地包入到γ环糊精包合物中。因此,不仅环糊精允许氨基酸进入腔,掩蔽氨基酸的刺激性味道,而且CD也允许至少一部分的菜籽油三甘油酯进入,在油脂在CD的腔中形成类似插头(notionalplug)的结构,锁定CD中的氨基酸。因此,本发明提供了这种类型的与油脂相组合的制剂,其提供了可溶的、掩蔽风味的氨基酸。以单独的脂肪酸——癸酸代替菜籽油重复了本实施例,取得了相同的令人吃惊的结果。这在单个环糊精内形成了层状双包合物。然后将每种经菜籽油处理的材料干燥并磨碎,以加入到预混物并进一步加入到膳食替代制剂中。重复了这3种相同氨基酸的预混和包含的另一种方案,随后加入菜籽油,得到最相同的最终结果。
如上所述,本实施例涉及含有CD的适口性的基本饮食制剂(有和没有酶来促进CD的分解)。在这种情形下,有一些证据表明基本饮食可造成一些患者的胰腺酶分泌减少,并且对于存在这种情形的患者,使用本发明的制剂中的一种或多种酶可能是特别有利的。
氨基酸补充剂也可提供为有和没有酶来促进CD分解的CD包合物。
例如,这对于支链氨基酸,如亮氨酸、异亮氨酸和缬氨酸可能是特别有利的。因此,在本实施例中,亮氨酸和缬氨酸配制于美味的αCD包合物中,并将异亮氨酸配制于美味的γCD包合物中。
实施例14:对乙酰氨基酚包合物
一方面,本实施例涉及CD包合物混合物的制备,其中抗炎剂或疼痛缓解物质与环糊精形成包合物,从而掩蔽味道并增加作为单独包含物时的溶解性。在可选的实施方案中,可以在包合物中包含其他物质。这些实施方案可配制成有和没有一种或多种酶来促进CD分解。
在示例性的实施方案中,利用捏合方法,以等摩尔比例将对乙酰氨基酚包入α环糊精包合物中。利用捏合方法,以等摩尔比例将第二种量包入β环糊精中。利用捏合方法,以等摩尔比例将第三种量包入γ环糊精中。然后将每种材料干燥并磨碎。加入自来水后,发现这些包含物完全溶解且相当好地掩蔽掉令人讨厌的味道。
在另一个实施方案中,利用捏合方法,以等摩尔比例将如上述实施例13中的N-乙酰-半胱氨酸包入γ环糊精中。然后将材料干燥和磨碎。加入自来水后,发现包含物完全溶解且极大地掩蔽了通常令人讨厌的味道和气味。
然后制备了对乙酰氨基酚/γ-环糊精和N-乙酰-半胱氨酸/γ环糊精干燥粉末的预混物。在与自来水混合后,其提供治疗剂量的对乙酰氨基酚,以及N-乙酰-半胱氨酸的保肝功效。两种成分(以包含物)的组合不仅提供了因溶解性增加而更容易递送对乙酰氨基酚的媒介物,还提供了气味和令人讨厌味道显著减少的N-乙酰-半胱氨酸的递送形式。例如,可以添加少量风味剂和甜味剂化合物来增强这类制剂,例如以粉剂形式或掺入到其他标准剂型中,如胶囊或片剂,包括缓释形式,有和没有酶来促进CD的分解。
实施例15:保肝剂
本实施例涉及CD包合物混合物的制备,其中保肝物质以单独的包含物或加入至其他也为包合物的物质的形式与环糊精形成包合物,例如,以掩蔽味道和改善溶解性。
在示例性的实施方案中,利用捏合方法,以等摩尔比例将如实施例13中的N-乙酰-半胱氨酸包入γ环糊精中。然后将材料干燥并磨碎。加入自来水后,发现包含物完全溶解并非常好地掩蔽了令人讨厌的味道。
利用捏合方法,以等摩尔比例,将水飞蓟素提取物(Indena SPA)包入γ环糊精中。然后将材料干燥并磨碎。加入自来水后,发现包含物完全溶解并相当好地掩蔽了令人讨厌的味道。
利用捏合方法,以等摩尔比例,将姜黄素提取物(Sabinsa)包入γ环糊精中。然后将材料干燥并磨碎。加入自来水后,发现包含物完全溶解且相当好地掩蔽了令人讨厌的味道。
利用捏合方法,以1:2摩尔比的比例,将姜黄素提取物(Sabinsa)包入γ环糊精中。然后将材料干燥并磨碎。加入自来水后,发现包含物完全溶解且相当好地掩蔽了令人讨厌的味道。
利用捏合方法,以等摩尔比例将四氢姜黄素(Sabina)包入γ环糊精。然后将材料干燥并磨碎。加入自来水后,发现包含物完全溶解且相当好地掩蔽了令人讨厌的味道。
利用捏合方法,以1:2摩尔比的比例,将四氢姜黄素(Sabina)包入γ环糊精中。然后将材料干燥并磨碎。加入自来水后,发现包含物完全溶解且相当好地掩蔽了令人讨厌的味道。
N-乙酰-半胱氨酸,例如,商品名为Mucomyst,在急诊室中针对对乙酰氨基酚过量而使用的药物,例如用于根据毒性水平Rumack-Matthew诺模图确定的具有肝毒性风险的患者。当前大多数ER通过静脉注射给药,这是由于N-乙酰-半胱氨酸具有极度令人讨厌的味道和气味。因此,一个实施方案是提供有或没有CD降解酶,如淀粉酶的包含N-乙酰-半胱氨酸的混合物,例如配制成与水或果汁一起向患者给药,以作为对乙酰氨基酚中毒的一种抢救策略。这些制剂也可以作为预防性的,例如与每天或高剂量的对乙酰氨基酚一起使用。类似地,可以提供其他的保肝剂,包括水飞蓟素、姜黄素和其他已知的保肝剂,包括但不限于葡萄柚、柚皮苷、柚皮素、蓝莓、蔓越莓、黄酮类、儿茶素、表儿茶素、花青素、原花青素、白藜芦醇、仙人掌果实、洋甘菊、螺旋藻、蜂胶和β葡聚糖。
在另一方面,对乙酰氨基酚自身可与氨基酸CD包合物一起配制,以及有和没有酶来促进CD的分解。例如,可以配制N-乙酰-半胱氨酸CD包含物,特别是用作儿科制剂,从而防止肝损伤。在可选的实施方案中,例如可以以多层多组分包合物的形式将对乙酰氨基酚包入到与N-乙酰-半胱氨酸相同的CD中,例如以对乙酰氨基酚作为初始包含物,而所述氨基酸作为第二包含物,或者反之亦然。在选择的实施方案中,利用γ环糊精,可以将对乙酰氨基酚和N-乙酰-半胱氨酸均包含在CD的腔内。
两种或更多种成分(以包含物形式)的组合,提供了一种由于溶解性增加而更容易递送所述成分的载体,并且提供了一种具有显著减少的气味和令人讨厌味道的递送形式,这可以通过添加少量粉末剂型的调味剂和甜味剂或者并入到其他标准剂型,如胶囊或片剂,包括缓释形式,来容易地进行调节。
实施例16:层状包合物
本实施例涉及CD包合物混合物的制备,其中底物与环糊精形成包合物来掩蔽味道,改善层状包含物的溶解性。在示例性的实施方案中,利用捏合方法,以等摩尔比例在γ环糊精中掺入如实施例13中的N-乙酰-半胱氨酸。将对乙酰氨基酚以等摩尔比例添加至N-乙酰-半胱氨酸包含物中,形成层状包含物。然后将材料干燥并磨碎。加入自来水后,发现包合物完全溶解且相当好地掩蔽了异味。在选择实施方案中,可以配制层状包合物,以便将多种化合物并入至单个环糊精中,例如以减少产品剂量的体积。
Claims (57)
1.环糊精包合物递送媒介物,其包含:
具有腔的环糊精;
生物活性分子,其作为客分子至少部分保留于所述环糊精的腔内,形成环糊精包合物;
用于所述环糊精包合物的生物可接受载体,其中所述客分子由所述环糊精稳定保留于所述生物可接受载体内;以及
具有环糊精降解活性的酶,其能够消化保留所述客分子的环糊精,其中所述酶被配制使得环糊精降解活性在所述媒介物递送至靶标时被激活,从而从所述环糊精腔中释放所述客分子。
2.如权利要求1所述的递送媒介物,其中所述酶与所述环糊精包合物共同配制。
3.如权利要求1所述的递送媒介物,其中所述酶与所述环糊精包合物共同包装于所述递送载体中,所述递送载体还包含用于所述酶的生化可接受载体。
4.如权利要求1-3中任一项所述的递送媒介物,其中所述靶标为宿主生物。
5.如权利要求1-3中任一项所述的递送媒介物,其中所述靶标为无生命环境。
6.如权利要求1-4中任一项所述的递送媒介物,其中所述酶为淀粉酶、环糊精酶、麦芽糖淀粉酶或新普鲁兰酶。
7.如权利要求6所述的递送媒介物,其中所述淀粉酶为哺乳动物唾液淀粉酶、哺乳动物胰淀粉酶或微生物淀粉酶。
8.如权利要求6所述的递送媒介物,其中所述环糊精酶为微生物环糊精酶。
9.如权利要求1-8中任一项所述的递送媒介物,其中所述环糊精为疏水性烷基化环糊精。
10.如权利要求1-9中任一项所述的递送媒介物,其中所述环糊精为混合的甲基化/乙基化环糊精。
11.如权利要求1-10中任一项所述的递送媒介物,其中所述环糊精与所述客分子的比例为5:1至1:5。
12.如权利要求1-11中任一项所述的递送媒介物,其中所述环糊精为α环糊精、β环糊精或γ环糊精。
13.如权利要求1-12中任一项所述的递送媒介物,其中客分子为药物或前药,并且所述生物可接受载体为药学可接受载体。
14.如权利要求13所述的递送媒介物,其中所述递送媒介物被配制用于通过以下途径递送:肠胃外、静脉内、皮内、皮下、肌内、颅内、眶内、经眼、心室内、囊内、脊柱内、鞘内、脑池内、腹膜内、鼻内、吸入、喷雾、局部、瘤内、舌下或经口。
15.如权利要求13或14所述的递送媒介物,其中所述递送媒介物被配制用于所述药物或前药的缓释。
16.如权利要求13、14或15所述的递送媒介物,其中所述药物或前药为短链脂肪酸或其酯衍生物。
17.如权利要求16所述的递送媒介物,其中所述短链脂肪酸为以下的一种或多种:丁(丁烷)酸、丙酸或乙酸。
18.如权利要求16或17所述的递送媒介物,其中所述酯衍生物为甘油酯。
19.如权利要求18所述的递送媒介物,其还包含脂肪酶。
20.如权利要求13或14所述的递送媒介物,其中所述药物为槲黄素。
21.如权利要求20所述的递送媒介物,其中所述环糊精为γ环糊精。
22.如权利要求20或21所述的递送媒介物,其中所述环糊精降解酶为淀粉酶。
23.如权利要求1-12中任一项所述的递送媒介物,其中所述客分子为N-乙酰半胱氨酸,其中所述生物可接受载体为药学可接受载体,并且所述递送媒介物还包含对乙酰氨基酚。
24.治疗胃肠病症的方法,包括给予有需要的对象有效量的权利要求16-19中任一项所述的递送媒介物。
25.如权利要求24所述的方法,其中所述对象为人类患者,所述递送途径为经口,并且所述病症为结肠炎、憩室炎、克罗恩病、炎性肠病、肠易激综合症、与造瘘术造口相关的炎症或与造瘘术造口相关的肉芽。
26.如权利要求25所述的方法,其中短链脂肪酸为丁酸。
27.如权利要求1-12中任一项所述的递送媒介物,其中所述客分子为除草剂、杀虫剂、杀真菌剂、动物趋避剂、信息素或植物生长调节剂。
28.如权利要求1-12中任一项所述的递送媒介物,其中所述客分子为芳香分子。
29.权利要求1-19中任一项所述的递送媒介物作为药剂的用途。
30.权利要求1-19中任一项所述的递送媒介物作为食品成分、医疗食品、营养补充剂或膳食补充剂的用途。
31.权利要求27所述的递送媒介物作为除草剂、杀虫剂、杀真菌剂、动物趋避剂、信息素或植物生长调节剂的用途。
32.权利要求28所述的递送媒介物作为芳香剂的用途。
33.如权利要求1-12中任一项所述的递送媒介物作为织物或包装材料的用途。
34.配制环糊精包合物递送媒介物的方法,包括:
提供具有腔的环糊精;
提供生物活性分子,其作为客分子至少部分保留于所述环糊精的腔内,形成环糊精包合物;
提供用于所述环糊精包合物的生物可接受载体,其中所述客分子由所述环糊精稳定保留于所述生物可接受载体内;以及
提供具有环糊精降解活性的酶,其能够消化保留所述客分子的环糊精,其中所述酶与所述环糊精包合物共同配制,使得环糊精降解活性在所述媒介物递送至靶标时被激活,从而从所述环糊精腔中释放所述客分子。
35.药物制剂,其包含在药学可接受载体中的对乙酰氨基酚和N-乙酰半胱氨酸环糊精包合物。
36.如权利要求35所述的制剂,其中所述环糊精为β环糊精或γ环糊精。
37.如权利要求35或36所述的制剂,其还包含具有环糊精降解活性的酶,其能够消化所述环糊精。
38.配制对乙酰氨基酚的方法,包括将对乙酰氨基酚和N-乙酰半胱氨酸环糊精包合物在药学可接受载体中组合。
39.如权利要求1-12中任一项所述的递送媒介物,其中客分子为氨基酸,并且所述生物可接受载体为药学可接受载体。
40.如权利要求39所述的递送媒介物,其中所述氨基酸为以下中的一种或多种:L-苯丙氨酸、N-乙酰-半胱氨酸、L-半胱氨酸、L-甲硫氨酸、L-异亮氨酸或L-色氨酸。
41.如权利要求39或40所述的递送媒介物,其中所述递送媒介物被配制用于通过以下途径递送:肠胃外、静脉内、皮内、皮下、肌内、颅内、眶内、经眼、心室内、囊内、脊柱内、鞘内、脑池内、腹膜内、鼻内、吸入、喷雾、局部、瘤内、舌下或经口。
42.膳食替代制剂或要素饮食制剂,其包含在环糊精包合物中的氨基酸,其中所述氨基酸为以下中的一种或多种:L-苯丙氨酸、N-乙酰-半胱氨酸、L-半胱氨酸、L-甲硫氨酸、L-异亮氨酸或L-色氨酸。
43.如权利要求42所述的膳食替代制剂或要素饮食制剂,其中所述制剂包含以下中的至少10种:麦芽糖糊精、L-谷氨酰胺、改性玉米淀粉、L-亮氨酸、L-精氨酸醋酸盐、大豆油、葡萄糖酸镁、L-赖氨酸醋酸盐、甘油磷酸钙、L-异亮氨酸、L-缬氨酸、L-苯丙氨酸、柠檬酸钠、L-苏氨酸、柠檬酸钾、L-半胱氨酸盐酸盐、柠檬酸、L-甲硫氨酸、L-酪氨酸、L-组氨酸盐酸盐、L-天冬氨酸、L-脯氨酸、L-色氨酸、磷酸二钠、氯化钾、胆碱酒石酸盐、L-丝氨酸、L-丙氨酸、甘氨酸、抗坏血酸、脂肪酸聚甘油酯、牛磺酸、L-肉毒碱、α-生育酚乙酸酯、硫酸锌、硫酸亚铁、烟酰胺、维生素A棕榈酸酯、泛酸钙、葡萄糖酸铜、维生素D3、盐酸吡哆醇、硫酸锰、核黄素、盐酸硫胺、叶酸、氯化铬、生物素、碘化钾、钼酸钠、亚硒酸钠、植物甲萘醌、维生素B12。
44.多组分层状环糊精包合物,其包含:
具有腔的环糊精;
氨基酸,其作为第一客分子保留于所述环糊精的腔内;和
生物可接受脂质,其作为第二客分子至少部分保留于所述环糊精的腔内。
45.多组分层状环糊精包合物,其包含:
具有腔的环糊精;
N-乙酰半胱氨酸,其作为第一客分子至少部分保留于所述环糊精的腔内;和
对乙酰氨基酚,其作为第二客分子至少部分保留于所述环糊精的腔内。
46.如权利要求45所述的环糊精包合物,其中所述腔为截头圆锥形的,具有设置于所述腔的相对端的较大直径开口和较小直径开口;其中所述第一客分子靠近所述较小开口,且所述第二客分子靠近所述较大开口。
47.如权利要求45所述的环糊精包合物,其中所述腔为截头圆锥形,具有设置于所述腔的相对端的较大直径开口和较小直径开口;其中所述第一客分子靠近所述较大开口,且所述第二客分子靠近所述较小开口。
48.如权利要求44-47中任一项所述的多组分层状环糊精包合物,其还包含具有环糊精降解活性的酶,其能够消化保留所述第一客分子和第二客分子的环糊精,其中所述酶被配制使得环糊精降解活性在所述媒介物递送至靶标时被激活,从而从所述环糊精腔中释放所述客分子。
49.用于治疗患有自闭症谱系病症的患者的方法,包括给予所述患者有效量的短链脂肪酸环糊精包合物。
50.用于调节患有神经疾病的患者的微生物群的方法,包括给予所述患者有效量的短链脂肪酸环糊精包合物。
51.如权利要求49或50所述的方法,其中所述短链脂肪酸为丁酸。
52.如权利要求49-51中任一项所述的方法,其中所述环糊精为α-环糊精。
53.如权利要求49-52中任一项所述的方法,还包含给予所述患者有效量的乙酸。
54.如权利要求53所述的方法,其中所述乙酸被配制于所述短链脂肪酸环糊精包合物中。
55.如权利要求49-54中任一项所述的方法,其中所述环糊精包合物在包含酶的制剂中提供,所述酶具有环糊精降解活性,其能够消化保留丁酸的所述环糊精。
56.如权利要求55所述的方法,其中所述酶为淀粉酶。
57.如权利要求13、14或15所述的递送媒介物,其中所述药物或前药为大麻素。
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