CN114630658A - 包含超细化合物的组合物及其生产 - Google Patents
包含超细化合物的组合物及其生产 Download PDFInfo
- Publication number
- CN114630658A CN114630658A CN202080073887.0A CN202080073887A CN114630658A CN 114630658 A CN114630658 A CN 114630658A CN 202080073887 A CN202080073887 A CN 202080073887A CN 114630658 A CN114630658 A CN 114630658A
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- Prior art keywords
- cyclodextrin
- inhalable
- soluble
- edible
- degradable
- 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.)
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Abstract
本发明提供了稳定、不可降解可食用、可吸入、可溶和可饮用的组合物,其包含具有99%纯度和增加200%的生物利用度的高生物利用度药物级超细活性药物成分,及其生产方法。
Description
相关申请的交叉引用
本申请要求2019年10月21日提交的美国临时申请第62/923,726号和2019年11月1日提交的美国临时申请第62/929,455号的优先权,其内容以全文引用的方式并入。
技术领域
本申请涉及药物级高生物利用度的超细环糊精包封的活性药物成分、包含所公开的环糊精包封的活性药物成分的稳定且不可降解的可食用、可吸入、可溶和可饮用的组合物,以及制造超细环糊精包封的活性药物成分的方法。
背景技术
亲脂性活性药物成分(API)难溶于水,并且其提取和精制是耗时过程,需要提取、馏出物生产和精制。这些工艺涉及使用有害溶剂,并且通常产生稳定性低和缺乏功效的产品。此外,所得API产品缺乏药物级纯度并且具有低生物利用度。
大麻素(Cannabinoid)是亲脂性API,其在一年生植物大麻(Cannabis sativa)、印度大麻(Cannabis indica)、莠草大麻(Cannabis ruderalis)及其杂种中天然产生。四氢大麻酚(Tetrahydrocannabinol,THC)是最有活性的天然存在的大麻素,有益于治疗广泛的医学病症,包括青光眼、AIDS消瘦、神经性疼痛,治疗与多发性硬化相关的痉挛、纤维肌痛、呕吐和化疗引起的恶心。大麻二酚(Cannabidiol,CBD)不具有精神作用,并且其被FDA批准用于治疗癫痫。大麻酚(Cannabinol,CBN)是一种有效的镇静剂和炎症缓解剂。通常对大麻素,特别是对用于娱乐用途的THC、CBD和CBN的需求日益增加。精神药物,例如迷幻剂(psychedelic),也因其对意识状态的影响而有需求。然而,这些API在水中的溶解度是有限的。例如,目前可用的大麻二酚(CBD)分离物在水中的溶解度仅为0.0126mg/ml。
大麻素来源于前体大麻萜酚酸(cannabigerolic acid,CBGA),或其类似物次大麻萜酚酸(cannabigerovaric acid,CBGVA)。CBGA的酶促转化产生多种大麻素,包括(-)-反式-Δ9-四氢大麻酚(Δ9-THC)、(-)-反式-Δ9-庚基延伸四氢大麻酚(trans-Δ9-tetrahydrocannabiphorolol,Δ9-THCP)、大麻萜酚(cannabigerol,CBG)、大麻环萜酚(cannabichromene,CBC)、大麻环酚(cannabicyclol,CBL)、大麻二酚(CBD)、脱氢大麻二酚(cannabinodiol,CBND)和大麻酚(CBN)。CBGVA的酶促转化产生Δ9-四氢次大麻酚(Δ9-tetrahydrocannabivarin,Δ9-THCV)、次大麻酚(cannabivarin,CBV)、次大麻二酚(cannabidivarin,CBDV)和次大麻环萜酚(cannabichromevarin,CBCV)。
本领域需要有效和安全地生产稳定的、不可降解的组合物,该组合物包含药物级、可吸入、可溶和高生物利用度的API。
发明内容
本申请通过提供包含药物级高生物可利用度的超细环糊精包封的活性药物成分的稳定、不可降解、可食用、可吸入、可溶或可饮用的组合物和生产药物级纯度的高生物可利用度的超细环糊精包封的活性药物成分的快速、节省成本并且容易规模化的工艺,提供了上述挑战的解决方案。所公开的工艺不需要使用有机溶剂,并且因此满足最具限制性的健康指南要求。所得超细药物活性成分可以用于肺部和口服递送、食品生产以及药物和医疗应用。
本文提供了稳定、不可降解、可食用、可吸入、可溶或可饮用的组合物,其包含药物级环糊精包封的活性药物成分(API)和药学上可接受的载体、赋形剂和/或粘合剂,所述环糊精包封的活性药物成分具有99.9%纯度和与非环糊精包封的活性药物成分制剂相比增加200%的生物利用度。
合适的活性药物成分包括但不限于大麻素、迷幻剂、镇痛剂、麻醉剂、抗炎剂、抗菌剂、抗病毒剂、抗凝剂、抗惊厥剂、抗抑郁剂和肌肉松弛剂。
在一些实施例中,药物级环糊精包封的活性药物成分为纳米颗粒形式,其平均粒径在100nm与40μm之间并且粒径分布在平均粒径的1%和50%内。
在一些实施例中,药物级环糊精包封的活性药物成分为超细干粉形式,其平均粒径在100nm与5μm之间。
在一些实施例中,药物级环糊精包封的活性药物成分为可溶的或可饮用的溶液或悬浮液的形式。
在一些实施例中,API被包封在一种或多种乙酰化环糊精中。合适的乙酰化环糊精包括但不限于乙酰化α-环糊精、乙酰化β-环糊精、乙酰化γ-环糊精或其任何混合物。
在一些实施例中,API被包封在一种或多种乙酰化环糊精和一种或多种亲水性环糊精中。合适的乙酰化环糊精包括但不限于乙酰化α-环糊精、乙酰化β-环糊精、乙酰化γ-环糊精或其任何混合物。合适的亲水性环糊精包括但不限于亲水性α-环糊精、亲水性β-环糊精、亲水性γ-环糊精或其任何混合物。
在一些实施例中,API和一种或多种乙酰化环糊精的API:乙酰化环糊精摩尔比范围为1:0.5至1:10。在一些实施例中,API:乙酰化环糊精摩尔比为1:0.5、1:0.75、1:1、1:1.5、1:2、1:2.5、1:3、1:3.5、1:4、1:4.5、1:5、1:5.5、1:6、1:6.5、1:7、1:7.5、1:8、1:8.5、1:9、1:9.5或1:10。
在一些实施例中,API被包封在一种或多种亲水性环糊精中。合适的亲水性环糊精包括但不限于亲水性α-环糊精、亲水性β-环糊精、亲水性γ-环糊精或其任何混合物。
在一些实施例中,药物级环糊精包封的活性药物成分是迷幻剂,例如脱磷酸裸盖菇素(psilocin)或裸盖菇素(psilocybin)。
在一些实施例中,药物级环糊精包封的活性药物成分是大麻素,例如大麻萜酚酸(CBGA)、次大麻萜酚酸(CBGVA)、四氢大麻酚酸(cannabigerovaric acid,THCA)、大麻环萜酚酸(cannabichromene acid,CBCA)、大麻二酚酸(cannabidiolic acid,CBDA)、四氢次大麻酚酸(tetrahydrocannabivarinic acid,THCVA)、次大麻环萜酚酸(cannabichromevarinic acid,CBCVA)、次大麻二酚酸(cannabidivarinic acid,CBDVA)、(-)-反式-Δ9-四氢大麻酚(Δ9-THC)、反式-Δ9-庚基延伸四氢大麻酚(Δ9-THCP)、大麻萜酚(CBG)、大麻环萜酚(CBC)、大麻环酚(CBL)、大麻二酚(CBD)、脱氢大麻二酚(CBND)和大麻酚(CBN)中的一种或多种。
在一些实施例中,大麻素是大麻二酚(CBD)。在一些实施例中,大麻素是四氢大麻酚(THC)。在一些实施例中,一种或多种大麻素是大麻二酚(CBD)和四氢大麻酚(THC)。在一些实施例中,大麻素是大麻酚(CBN)。在一些实施例中,大麻素是庚基延伸四氢大麻酚(THCP)。
可以用于所公开的组合物中的合适的药学上可接受的载体、赋形剂和粘合剂包括但不限于柠檬酸钠、磷酸二钙、淀粉、乳糖、蔗糖、葡萄糖、甘露醇、硅酸、羧甲基纤维素、藻酸盐、明胶、卵磷脂、聚乙烯吡咯烷酮、蔗糖、阿拉伯胶、湿润剂、增溶剂、乳化剂、崩解剂、溶液阻滞剂、吸收促进剂、润湿剂、吸收剂、润滑剂、油、佐剂、甜味剂、调味剂、芳香剂、缓冲剂及其任何混合物。
在一些实施例中,所公开的组合物为吸入器、胶囊、片剂、丸剂、粉末、珠粒、锭剂、糖锭剂、颗粒剂、膳食组合物、食品、饮料、乳液、溶液、悬浮液、乳膏、凝胶、防晒霜、洗发剂、牙膏、经皮贴片、膏药、植入物、糖浆、酏剂、注射剂或输注剂的形式。
在一些实施例中,所公开的组合物被配制成立即释放形式、持续释放形式或控制释放形式。
在一些实施例中,所公开的组合物进一步包含包衣。合适的包衣包括但不限于肠溶包衣、延长释放包衣、持续释放包衣、延迟释放包衣和立即释放包衣。
所公开的组合物可以配制成用于口服、粘膜、肺部、局部、肠胃外、经皮或粘膜下给药。
在一些实施例中,所公开的组合物为食品形式。合适的食品包括但不限于面包、饼干、汤、谷物、沙拉、三明治、豆芽、蔬菜和糖果。
在一些实施例中,所公开的组合物为饮料形式。合适的饮料包括但不限于茶、果汁、糖浆、苏打水、发酵饮料、酒精饮料、非酒精饮料、蒸馏饮料和酿造饮料。
本公开的前述和其它特征将从以下参考附图进行的详细描述中变得更加明显。
附图说明
并入并构成本说明书的一部分的附图绘示了实施例的一个或多个实例,并且与实例实施例的描述一起用于解释实施例的原理和实施方案。
图1A示出了加工前的CBD分离物。CBD分离物具有结晶形态和大颗粒之间的大量附聚。
图1B示出了在3500psi的压力和40℃的温度下加工后的CBD馏出物。所得馏出物颗粒示出球形的无定形形态和在100nm与40μm之间的粒径。
图2A示出了通过所公开的方法生产的以1:2.5w/w的大麻素:环糊精摩尔比与α-环糊精复合的纯化CBD纳米颗粒的32X放大图(250mg的CBD与100mg的α-环糊精复合)。CBD纳米颗粒具有球形形态和在100nm与40μm之间的粒径。
图2B示出了通过所公开的方法生产的以1:2.5w/w的大麻素:环糊精摩尔比与α-环糊精复合的纯化CBD纳米颗粒的200X放大图(250mg的CBD与100mg的α-环糊精复合)。CBD纳米颗粒具有球形形态和在100nm与40μm之间的粒径。
图3示出了加工前的CBD分离物的晶体。晶体不溶于酸和水。
图4示出了加工后在水中的纯化的CBD纳米颗粒。CBD纳米颗粒完全溶解在水中。
图5示出了加工后在类似于胃条件的酸性溶剂中的纯化的CBD纳米颗粒。CBD纳米颗粒完全溶解在酸性溶液中并且溶液是澄清的。
图6是用于超临界溶液快速膨胀的设备的示意图。罐1,其含有溶剂流体,例如CO2(99.0%);入口阀2打开并控制流向HPLC泵3的入口的流量;出口阀4打开并控制高压溶剂向提取容器8的流动;压力计5指示入口管线和提取容器8中溶剂的压力;温度计6指示提取容器8的内部温度;加热带7调节提取容器8的内部热量;提取容器8含有待混合并溶解在超临界流体中的溶质;喷雾阀9将提取容器中的超临界溶液通过喷雾嘴11分配到沉淀/收集室10中,在该沉淀/收集室中进行该工艺并收集最终产物;压力反应阀或排气口12降低沉淀/收集室10中的压力。
图7示出了用于本文提供的工艺的一些实施例的简化设备。将API和一种或多种乙酰化环糊精通过进料阀插入加热的加压容器1。然后将超临界、亚临界、高压气体或液体二氧化碳从CO2罐中通过进料阀5释放,在冷却室3中冷却,并用泵4通过入口阀6泵送到加热的加压容器1中以将API和乙酰化环糊精溶解到环糊精包封的API溶液中。然后使溶液通过输送阀8,通过喷嘴9用短脉冲减压,收集到粉末收集容器2中,并通过最终产物出口10按粒径分选。
图8示出了用于本文提供的工艺的另外的实施例的简化设备。将一种或多种亲水性环糊精通过进料阀22进料到加热的加压容器12中,并在通过压力控制阀21控制的压力和受控的温度下溶解在亲水性液体中,以形成亲水性环糊精水溶液。将API通过进料阀17插入加热的加压容器11。然后将超临界、亚临界、高压气体或液体二氧化碳从CO2罐中通过进料阀15释放,在冷却室13中冷却,并用泵14通过入口阀16泵送到加热的加压容器11中以溶解API。然后使API溶液通过输送阀18,并通过喷嘴19用短脉冲减压到加热的加压容器12中,其中API溶液的液滴分散到环糊精水溶液中。由此形成的水溶性亲水API浓缩物通过最终产物出口20收集。
图9示出了环糊精包封的API样品与含有相等API量的原API相比的溶解曲线。
具体实施方式
提供以下术语解释以更好地描述本公开并指导本领域普通技术人员实践本公开。如本文所用,“包含”意指“包括”,并且不意指组合物和方法排除未列举的要素。当用于定义组合物和方法时,“基本上由…组成”应意指排除对组合具有任何实质意义的其它元素。例如,基本上由本文定义的元素组成的组合物不排除不会实质上影响要求保护的发明的基本和新颖特征的其它元素。“由…组成”应意指排除多于痕量的其它成分和所列举的实质方法步骤。单数形式“一个”(a、an、the)包括复数指代,除非上下文另有明确说明。术语“或”是指所述替代元素中的单个元素或两个或更多个元素的组合,除非上下文另有明确说明。所有数字标记,例如pH、温度、时间、浓度、量和分子量,包括范围,是近似值,其适当变化(+)或(-)10%、1%或0.1%。还应当理解,尽管不总是明确说明,但本文所述的试剂仅是示范性的,并且其等同物是本领域已知的。除非另外说明,否则本文使用的所有技术和科学术语具有与本公开所属领域的普通技术人员通常理解的相同含义。材料、方法和实例仅是说明性的而不是限制性的。
为了便于审查本公开的各种实施例,提供以下对特定术语的解释:
关于:一个术语用于表示值的+/-10%,或任选地值的+/-5%,或在一些实施例中值的+/-1%的值变化。
给药:通过有效途径提供或给予受试者组合物,例如补充剂组合物。应用是局部的。示范性的应用途径包括但不限于口服和局部途径。
搅拌或搅动:一种机械运动,其可以包括但不限于旋转、振动、涡流、涡旋、摇动、超声、搅拌或引起混合的任何运动。机械运动包括用手或旋转器进行的运动。
活性药物成分:一种成品中的生物活性成分,其对疾病的诊断、治愈、缓解、治疗或预防,或对受试者(例如人或动物受试者)的一种或多种生理功能的恢复、纠正或改性具有直接作用。
醇:一种有机化合物,其含有与碳结合的羟基官能团–OH。
类似物:一种化合物,其结构与另一种类似,但在例如一个或多个原子、官能团或亚结构上有所不同。API类似物包括结构上与天然存在的API相关,但其化学和生物特性可以不同于天然存在的API的化合物,以及通过对天然存在的API进行化学、生物或半合成转化而衍生自天然存在的API的化合物。
大麻素:一类不同的化合物,其激活大麻素受体。由植物产生的大麻素称为植物大麻素。从大麻属植物分离的典型大麻素包括但不限于四氢大麻酚(THC)、大麻二酚(CBD)、大麻萜酚(CBG)、大麻环萜酚(CBC)、大麻双环(CBL)、次大麻酚(CBV)、四氢次大麻酚(THCV)、次大麻二酚(CBDV)、次大麻环萜酚(CBCV)、次大麻萜酚(CBGV)和大麻萜酚单甲醚(cannabigerol monomethyl ether,CBGM)。
细胞:活的生物细胞,其后代或潜在后代,可能与亲本细胞相同或不同。
接触:进行直接的物理关联。
助溶剂:一种溶剂,其以小于总体积的50%的量添加到流体中。
环糊精:一种通过酶转化从淀粉产生的环状寡糖家族,其具有包含通过α-1,4糖苷键连接的α-D-吡喃葡萄糖苷单元的大环的结构。典型的环糊精在环中含有六至八个葡萄糖亚单位,形成圆锥形状。α-环糊精含有六个葡萄糖亚单位;β-环糊精含有七个葡萄糖亚单位;以及γ-环糊精含有八个葡萄糖亚单位。因为环糊精具有内部疏水核心和亲水外部,它们与疏水化合物形成复合物。
有效量:活性剂(单独或与一种或多种其它活性剂一起)的量足以诱导所需反应,例如预防、治疗、减轻和/或改善病症。
乳化剂:一种表面活性剂,其降低油和水之间的界面张力,通过形成小球使表面能最小化。乳化剂包括树胶、脂肪酸缀合物和阳离子、阴离子和两性表面活性剂,其能够悬浮油相并通过涂覆油滴和避免内部油相分离来稳定乳液。由乳化剂产生的薄膜包衣是不混溶相之间的屏障,并且它还防止液滴缔合、凝结和聚结。乳化剂的实例包括但不限于卵磷脂、单硬脂酸甘油酯、甲基纤维素、十二烷基硫酸钠、油酸钠、脱水山梨糖醇单棕榈酸酯、脱水山梨糖醇单硬脂酸酯、脱水山梨糖醇三硬脂酸酯、黄芪胶、三乙醇胺油酸酯、聚乙烯脱水山梨糖醇单月桂酸酯、泊洛沙姆、洗涤剂、吐温80(聚氧乙烯脱水山梨糖醇单油酸酯)、吐温20(聚氧乙烯脱水山梨糖醇单月桂酸酯)、鲸蜡硬脂基葡糖苷、聚葡糖苷、脱水山梨糖醇单油酸酯(Span 80)、脱水山梨糖醇单月桂酸酯(Span 20)、聚氧乙烯单硬脂酸酯(Myrj 45)、聚氧乙烯植物油(乳化剂)、氯化十六烷基吡啶、多糖胶、黄原胶、黄芪胶、阿拉伯胶、阿拉伯树胶、或能够在甘油乳液中形成和保护稳定油的蛋白质和缀合蛋白质。
亲水性:一种聚合物、物质或化合物,其能够在100%相对湿度(RH)下吸收大于10%的水。
疏水性:一种聚合物、物质或化合物,其能够在100%相对湿度(RH)下吸收不大于1%的水。
亲脂性:一种物质或化合物,与极性或水性环境相比,其对非极性环境具有亲和力。
纳米颗粒:一种物质颗粒,其可在纳米尺度上测量。纳米颗粒可以是固体或半固体形式。
油:任何脂肪物质,其在室温(25℃)和大气压(760mmHg)下呈粘性液体形式。油是疏水性和亲脂性的,具有高的碳和氢含量,并且通常是可燃的和表面活性的。油可以是动物、植物或石油化学来源的,并且可以是挥发性或非挥发性的。油可以用于食品、燃料、医疗目的,以及用于制造油漆和塑料。
有机溶剂:一种烃基溶剂,其任选地包含一个或多个能够溶解在水中具有低溶解度的物质的极性基团。
渗透增强剂:一种天然或合成的分子,其促进共同给药的活性剂转运穿过生物膜。
pH调节剂或改性剂:一种分子或缓冲液,其用于在制剂中实现所需的pH控制。示范性pH改性剂包括酸(例如乙酸、己二酸、碳酸、柠檬酸、富马酸、磷酸、山梨酸、琥珀酸、酒石酸)、碱性pH改性剂(例如氧化镁、磷酸三钾)及其药学上可接受的盐。
迷幻剂药物:一种致幻剂,其通过血清素2A受体激动作用触发非正常意识状态和迷幻体验。
纯化或提纯:任何技术或方法,其提高来自包含目标物质的样品的目标物质(例如酶、蛋白质或化合物)的纯度。纯化方法的非限制性实例包括硅胶柱色谱、尺寸排阻色谱、疏水相互作用色谱、离子交换色谱,包括但不限于阳离子和阴离子交换色谱、自由流动电泳、高效液相色谱(HPLC)和示差沉淀。
纯度:通过所公开的方法获得未掺杂、未污染和安全产品的质量,并且符合药物标准。
回收:一种工艺,其涉及从反应混合物中分离和收集产物。回收方法可以包括但不限于色谱法例如硅胶色谱和HPLC、活性炭处理、过滤、蒸馏、沉淀、干燥、化学衍生及其任何组合。
超临界流体:温度和压力高于其临界点的任何物质,其中不存在明显的液相和气相。材料在流体中的溶解度随着流体密度的增加而增加。流体的密度随着压力增加,并且在恒定密度下,材料在流体中的溶解度随着温度增加而增加。示范性超临界流体包括但不限于二氧化碳、水、甲烷、丙烷、乙烷、乙烯、丙烯、甲醇、乙醇、丙酮和氮氧化物。
粘度:流体抵抗剪切应力或拉伸应力的逐渐变形的量度。
水不混溶性:任何非水性或疏水性流体、液体或溶剂,当与水混合时,其从溶液中分离成两个不同相。
水不溶性:一种化合物或组合物,在20℃的水中测量,其在水中的溶解度小于5%,小于3%或小于1%。
制备高生物利用度的可食用、可吸入、可溶或可饮用的药物级纯活性药物成分的方法
迄今为止,用于生产具有高生物利用度的纯亲脂性API化合物的有效工艺的开发受到API在水性和酸性条件下的低溶解度的阻碍。因此,经典的亲脂性API制备和精制是耗时的过程,其通常需要使用毒性有机溶剂。此外,通过目前可用的方法生产的API缺乏纯度并具有低生物利用度。
本文公开了克服这些挑战的快速有效的方法,通过利用超临界、亚临界、高压气体或液体二氧化碳和乙酰化和/或亲水性环糊精形成适于肺部和口服递送的高纯度、超细API-环糊精包合复合物。本文提供的方法显著降低API粒径,不包括使用毒性有机溶剂,并且产生符合最具限制性的健康要求的纯活性药物化合物。环糊精包封保护API在生产后免于降解,并且因此根据所公开的方法生产的纯活性药物化合物在室温下,在延长的时间段(例如16个月或更长)内是高度稳定的并且不随时间降解。此外,由于二氧化碳在大气压下是气体,所以CO2的去除比有机溶剂的去除更快更安全,并且在最终产物中不留下残余溶剂。
因此,在一些实施例中,提供了一种方法,其包含:(i)在反应室中将API和一种或多种乙酰化环糊精溶解在超临界、亚临界、高压气体或液体二氧化碳中;(ii)在设定压力和设定温度下将二氧化碳泵送预定时间段以获得乙酰化环糊精包封的API溶液;(iii)将乙酰化环糊精包封的API溶液减压;(iv)将乙酰化环糊精包封的API溶液喷雾到加热的沉淀器中并通过喷嘴以获得乙酰化环糊精包封的活性药物成分的可吸入超细纳米颗粒;以及(v)按粒径收集和分选乙酰化环糊精包封的活性药物成分的可吸入超细纳米颗粒。
所公开的方法产生可吸入的药物级高度生物利用度的环糊精包封的活性药物成分的超细纳米颗粒。可吸入超细纳米颗粒的平均粒径在100nm与40μm之间并且粒径分布在平均粒径的约1%和约50%内。超细纳米颗粒也可以添加到食品中,例如固体食品、饮料、调味品和营养品中,并且可以用于医疗和药物应用中的立即释放、持续释放和控制释放制剂,用于延长和可持续的效果。
在一些其它实施例中,提供了一种方法,其包含:将亲水性环糊精粉碎成平均粒径在100nm与5μm之间的颗粒;(ii)在反应室中将API和一种或多种乙酰化环糊精溶解在超临界、亚临界、高压气体或液体二氧化碳中;(iii)在设定压力和设定温度下将二氧化碳泵送预定时间段以获得乙酰化环糊精包封的API溶液;(iv)将乙酰化环糊精包封的API溶液减压;(v)将亲水性环糊精颗粒加入乙酰化环糊精包封的API溶液中以形成亲水性环糊精悬浮液-乙酰化环糊精包封的API溶液混合物;(vi)将混合物喷雾到加热的沉淀器中并通过喷嘴以获得环糊精包封的活性药物成分的可吸入超细干粉;以及(vii)按粒径收集和分选环糊精包封的活性药物成分的可吸入超细干粉。
所公开的方法产生环糊精包封的活性药物成分的药物级高生物利用度超细可吸入干粉。干粉的粒径可以通过测定亲水性环糊精的粒径来改变,而不是在二氧化碳中溶解形成悬浮液。通过调节乙酰化和亲水性环糊精之间的比例来控制可吸入干粉的疏水性。由此产生的干粉易溶于水、亲水性液体、酿造或发酵的酒精和非酒精饮料、果汁,可以添加到食品中,例如固体食品、饮料、调味品和营养品,并且可以用于医疗和药物应用中的立即释放、持续释放和控制释放制剂,以获得延长和可持续的效果。
在另外的实施例中,提供了一种方法,其包含:(i)在受控的压力和温度下将亲水性环糊精溶解在亲水性液体中以形成亲水性环糊精水溶液;(ii)在反应室中将API溶解在超临界、亚临界、高压气体或液体二氧化碳中;(iii)在设定压力和设定温度下将二氧化碳泵送预定时间段以获得API溶液;(iv)将API溶液减压;以及(v)将API溶液喷雾到亲水性环糊精水溶液中并通过喷嘴以获得亲水性环糊精包封的活性药物成分的可饮用溶液或悬浮液。亲水性液体包括但不限于水、果汁、糖浆、牛奶或任选地含有赋形剂的酒精饮料。在一些实施例中,受控压力在50巴与100巴之间,并且受控温度在30℃与70℃之间。将API溶液喷雾到环糊精水溶液中导致形成分散在环糊精水溶液中的API液滴,并产生水溶性环糊精包封的API浓缩物。环糊精水溶液可以包含稳定剂、增稠剂和表面活性剂以增强API化合物在溶液中的稳定性。
所公开的方法产生药物级高度生物利用度可溶性或可饮用溶液或悬浮液,其包含超细环糊精包封的活性药物成分。环糊精包封的API溶液和悬浮液无需任何进一步制备即可消耗,并且可以稀释于水、亲水性液体、酿造或发酵的酒精和非酒精饮料、果汁或任何其它可饮用液体。
可以根据所公开的方法加工的合适的活性药物成分包括但不限于任何形式的大麻素、迷幻剂、镇痛剂、麻醉剂、抗炎剂、抗菌剂、抗病毒剂、抗凝剂、抗惊厥剂、抗抑郁剂和肌肉松弛剂。
API可以是粗植物提取物、馏出物、精制馏出物、二次精制馏出物、三次精制馏出物或分离物的形式。植物提取物可以含有植物材料(例如脂质和蜡、叶绿素)和萜烯(例如月桂烯、香叶醇、柠檬烯、萜品醇、蒎烯、薄荷醇、百里酚、香芹酚、樟脑和倍半萜烯)。可以通过将提取物与醇混合并过滤混合物以除去植物材料,随后加热以除去醇来制备馏出物。为了进一步精制,可以将馏出物加热以进行短程蒸馏,并且可以将该工艺重复若干次以获得二次精制馏出物、三次精制馏出物或具有较高纯度的分离物。在替代实施例中,API可以是结晶形式。
合适的大麻素和大麻素前体包括但不限于大麻萜酚酸(CBGA)、次大麻萜酚酸(CBGVA)、四氢大麻酚酸(THCA)、大麻环萜酚酸(CBCA)、大麻二酚酸(CBDA)、四氢次大麻酚酸(THCVA)、次大麻环萜酚酸(CBCVA)、次大麻二酚酸(CBDVA)、(-)-反式-Δ9-四氢大麻酚(Δ9-THC)、(-)-反式-Δ9-庚基延伸四氢大麻酚(Δ9-THCP)、大麻萜酚(CBG)、大麻环萜酚(CBC)、大麻环酚(CBL)、大麻二酚(CBD)、脱氢大麻二酚(CBND)、大麻酚(CBN)、其类似物或其任何混合物。
合适的迷幻剂包括但不限于脱磷酸裸盖菇素和裸盖菇素。
在一些实施例中,本文公开的方法提供环糊精乙酰化以增加路易斯酸:环糊精与二氧化碳的路易斯碱相互作用并显著增加它们的溶解度。在其它实施例中,本文公开的方法提供使用乙酰化环糊精以增加API在二氧化碳中的溶解度,和使用亲水性环糊精以形成超细环糊精包封的API可吸入粉末。在其它实施例中,本文公开的方法提供使用亲水性环糊精以分散API液滴并产生水溶性API浓缩物。
合适的环糊精包括但不限于α-环糊精、β-环糊精和γ-环糊精。环糊精的乙酰化形式包括但不限于分别为α-环糊精十六乙酸酯(AACD)、β-环糊精二十一乙酸酯(ABCD)和γ-环糊精十八乙酸酯(AGCD)。合适的亲水性环糊精包括但不限于亲水性α-环糊精、亲水性β-环糊精、亲水性γ-环糊精及其任何混合物。
对于加工,API提取物、馏出物、精制馏出物、二次精制馏出物、三次精制馏出物或高质量分离物可以与乙酰化和/或亲水性环糊精组合,API:环糊精的摩尔比范围在1:0.5至1:10。在一些实例中,API:环糊精摩尔比为1:0.5、1:0.75、1:1、1:1.5、1:2、1:2.5、1:3、1:3.5、1:4、1:4.5、1:5、1:5.5、1:6、1:6.5、1:7、1:7.5、1:8、1:8.5、1:9、1:9.5或1:10。
API和环糊精可以混合一段时间,该时间由所用API的类型和形式、所用环糊精的类型、温度和压力条件以及用于混合的力限定。在一些实施例中,预设压力在2,500psi与6,500psi之间的范围内,并且预设温度在37℃与55℃之间的范围内。在加压之后,API溶液以超音速减压,通过喷嘴短脉冲释放API溶液以诱导颗粒形成。喷嘴的直径在1μm至10μm的范围内。在一些实施例中,喷嘴的直径为1μm、2μm、3μm、4μm、5μm、6μm或7μm。最好通过喷嘴短脉冲(例如0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9或1秒脉冲)释放超临界溶液来实现减压。
超临界、亚临界、高压气体或液体二氧化碳可以包含赋形剂或分散剂。在一些实施例中,所公开的方法可以进一步包含(vi)将二氧化碳转化为气体;(vii)过滤并加压二氧化碳气体以实现超临界、亚临界、高压气体或液体状态;以及(viii)在反应室中再循环二氧化碳用于下一批加工。
通过本文提供的方法生产的大麻素精细纳米颗粒的平均粒径在约100nm与约40μm之间并且粒径分布在平均粒径的约1%和约50%内。
本文提供的方法存在许多优点。具体地讲,所公开的方法显著降低了API粒径,不需要使用有毒有机溶剂,并且快速有效地生产纳米颗粒、干粉、溶液和悬浮液形式的高纯度超细API-环糊精包合复合物,其适用于肺部和/或口服递送。通过所公开的方法生产的环糊精包封的API具有99.9%纯度,与非环糊精包封的活性药物成分制剂相比增加200%的生物利用度,并且在室温下在延长的时间段(例如16个月、24个月、3年、4年和5年)内具有优异的稳定性。
用于生产药物级纯超细环糊精包封的API的设备
用于执行所公开的方法的示范性设备的示意图在图6、7和8中示出。然而,可以使用本领域已知的任何设备、系统或装置来执行本文提供的方法。
在图6示出的示意图中,罐1包含99%的纯流体,例如CO2。入口阀2打开并控制溶剂流体向进入HPLC泵3的入口的流动。出口阀4打开并控制高压溶剂向提取容器8的流动。集成作为HPLC泵一部分的压力计5指示入口管线和提取容器8中溶剂的压力。温度计6指示提取容器8的内部温度。加热带7调节提取容器8中的内部热量水平。提取容器8含有溶解在CO2中的具有或不具有乙酰化环糊精的API。一旦形成API溶液,喷雾阀9通过将溶液经由喷雾嘴11释放到沉淀室10中而使提取容器中的API溶液减压,在该沉淀室中收集最终产物。压力反应阀或排气口12降低沉淀室10中的压力,并导致自发形成超细API纳米颗粒或干粉,然后可以根据其尺寸进行收集和分选。
在图7示出的示意图中,将API和一种或多种乙酰化环糊精通过进料阀插入加热的加压容器1。然后将超临界、亚临界、高压气体或液体二氧化碳从CO2罐中通过进料阀5释放,在冷却室3中冷却,并用泵4通过入口阀6泵送到加热的加压容器1中以将API和乙酰化环糊精溶解到环糊精包封的API溶液中。然后使溶液通过输送阀8,通过喷嘴9用短脉冲减压,收集到粉末收集容器2中,并通过最终产物出口10按粒径分选。
在图8示出的示意图中,将一种或多种亲水性环糊精通过进料阀22进料到加热的加压容器12中,并在通过压力控制阀21控制的压力和受控的温度下溶解在亲水性液体中,以形成亲水性环糊精水溶液。将API通过进料阀17插入加热的加压容器11。然后将超临界、亚临界、高压气体或液体二氧化碳从CO2罐中通过进料阀15释放,在冷却室13中冷却,并用泵14通过入口阀16泵送到加热的加压容器11中以溶解API。然后使API溶液通过输送阀18,并通过喷嘴19用短脉冲减压到加热的加压容器12中,其中API溶液的液滴分散到环糊精水溶液中。由此形成的水溶性亲水API浓缩物通过最终产物出口20收集。
药物级超细环糊精包封的API
本文另外提供了通过所公开的方法生产的稳定的可食用、可吸入、可溶或可饮用的药物级环糊精包封的活性药物成分。稳定的可食用、可吸入、可溶或可饮用的药物级环糊精包封的活性药物成分具有99.9%纯度和与非环糊精包封的活性药物成分制剂相比增加200%的生物利用度。活性药物成分可以是大麻素、迷幻剂、镇痛剂、麻醉剂、抗炎剂、抗菌剂、抗病毒剂、抗凝剂、抗惊厥剂、抗抑郁剂或肌肉松弛剂。
在一些实施例中,药物级环糊精包封的活性药物成分为可吸入纳米颗粒形式,其平均粒径在100nm与40μm之间并且粒径分布在平均粒径的1%与50%内。
在一些实施例中,药物级环糊精包封的活性药物成分为可吸入超细干粉形式,其平均粒径在100nm与5μm之间。
在一些实施例中,药物级环糊精包封的活性药物成分为可饮用或可溶的溶液或悬浮液的形式。
由于其稳定性,所公开的可食用、可吸入、可溶或可饮用的药物级环糊精包封的活性药物成分可以容易地制造,与其它可食用成分或制剂混合、消耗或分配而没有任何再悬浮或分离的风险。具体地,所公开的可食用、可吸入、可溶或可饮用的药物级环糊精包封的活性药物成分完全可溶于水,与非环糊精包封的活性药物成分相比,其平均生物利用度增加200%(+/-10%),并且它们可以在生产后无限期地保存。
包含药物级超细环糊精包封的API的组合物
所公开的可食用、可吸入、可溶或可饮用的药物级环糊精包封的活性药物成分可以被配制成用于口服、肺部、肠内、肠胃外、静脉内、局部、粘膜和粘膜下给药的组合物,作为医疗和药物产品的处方、非处方和零售提供,用于治疗、预防和减轻疾病、病症、症状和不适,包括但不限于阿尔茨海默病、癫痫、轻度和慢性疼痛、化疗诱导周围神经病变、失眠、阿片类物质和药物成瘾、戒瘾、炎性肺病、焦虑症、PTSD、恐慌发作、恐怖症、过敏症、呼吸困难损害和疾病,包含冠状病毒、哮喘和COPD、美尼尔症。
所公开的组合物可以配制成立即释放形式、持续释放形式或控制释放形式,并使用促进或降低API释放的化合物进行包衣。因此,所公开的组合物可以包含肠溶包衣、延长释放包衣、持续释放包衣、延迟释放包衣和立即释放包衣。用于包衣组合物的方法以及用于制造此类包衣的材料在药物制剂领域中是熟知的。包衣材料可以包括但不限于单硬脂酸甘油酯、二硬脂酸甘油酯、聚合物质和蜡。
适于口服给药的固体剂型可以包括但不限于胶囊、片剂、丸剂、粉剂、珠粒、锭剂、糖锭剂、颗粒剂、气凝胶、屑粒、按扣等。此类固体剂型可以包括至少一种药学上可接受的赋形剂或载体,例如柠檬酸钠或磷酸二钙;填充剂或增量剂,例如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;粘合剂,例如羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶;湿润剂,例如甘油;崩解剂,例如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、硅酸盐和碳酸钠;溶液阻滞剂,例如石蜡;吸收促进剂,例如季铵化合物;润湿剂,例如乙酰基醇和单硬脂酸甘油酯;吸收剂,例如高岭土和膨润土;润滑剂,例如滑石,硬脂酸钙,硬脂酸镁,固体聚乙二醇,月桂基硫酸钠及其混合物;以及缓冲剂。
固体口服剂型也可以配制成膳食组合物,并且可以包含含有与食品混合的所公开的大麻素纳米颗粒的任何可摄入制剂。食品可以是干燥的、烹饪的、煮熟的、冻干的或烘焙的,并且可以是面包、饼干、茶、果汁、汤、谷物、沙拉、三明治、豆芽、蔬菜、糖果、丸剂、片剂等形式。
用于口服给药的液体剂型包括但不限于药学上可接受的乳液、溶液、悬浮液、糖浆和酏剂,并且可含有本领域常用的惰性稀释剂。例如,液体制剂可以含有水、聚乙二醇醚或任何其它药学上可接受的溶剂;增溶剂和乳化剂,例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺;油,例如棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油;甘油、四氢糠醇、聚乙二醇和脱水山梨醇脂肪酸酯;佐剂,例如润湿剂;乳化剂和悬浮剂,例如乙氧基化异硬脂醇、聚氧乙烯山梨糖醇、脱水山梨糖醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂、黄蓍胶及其混合物;甜味剂、调味剂、芳香剂及其任何混合物。
液体口服剂型也可以配制为膳食组合物,并且可以包含含有与饮料产品混合的所公开的大麻素纳米颗粒的任何可摄入制剂。饮料产品可以包括但不限于茶、果汁、糖浆、汤、苏打水、酿造饮料、发酵饮料、蒸馏饮料等。
肠胃外给药可以包括皮下注射、静脉内、肌肉内、胸骨内注射或输注技术。用于肠胃外给药的悬浮液可以用多种聚合物、糖和螯合剂包封,以产生稳定的制剂或颗粒。用于包封的聚合物可以包括交联聚合物、非交联聚合物,或分散在糖类淀粉或蛋白质分子的晶体结构内的聚合物。颗粒可以进一步加工以产生舌下膜、栓剂、可分散粉末、片剂、凝胶胶囊等。
用于肠胃外注射的组合物可以包含药学上可接受的无菌水性或非水性溶液、分散体、悬浮液或乳液以及用于在使用前重构为无菌可注射溶液或分散体的无菌粉末。合适的水性和非水性载体、稀释剂、溶剂或媒介物的实例包括但不限于水、乙醇、多元醇(例如甘油、丙二醇、聚乙二醇等)、羧甲基纤维素及其合适的混合物、植物油(例如橄榄油)、和可注射的有机酯(例如油酸乙酯)。例如,可以通过使用包衣材料例如卵磷脂,在分散体的情况下通过保持所需的粒径以及通过使用表面活性剂来保持适当的流动性。所公开的用于肠胃外给药的组合物还可以含有佐剂(例如,但不限于防腐剂、润湿剂、乳化剂和分散剂),等渗剂(例如糖、氯化钠等),以及延迟吸收的试剂(例如单硬脂酸铝和明胶)。
可注射的储存形式可以通过在生物降解的聚合物,例如但不限于聚交酯-聚乙醇酸交酯、聚(原酸酯)和聚(酐)中形成API的基质而制成的。还可以通过将公开的API包埋在与身体组织相容的脂质体中来制备储存的可注射制剂。可注射制剂可以被灭菌,例如,通过细菌截留过滤器过滤,或通过并入无菌固体组合物形式的灭菌剂,其可在使用前溶解或分散在无菌水或其它无菌可注射介质中。
所公开的组合物可以制成用于肺部递送的吸入制剂的形式。合适的制剂包括但不限于气雾剂、吸入器、呼吸激活吸入器、干粉吸入器、胶囊和泡罩吸入器、多剂量吸入器、计量吸入器、汽化器、喷雾剂、鼻喷雾剂等,并且可以包含制剂领域中已知的多种载体或赋形剂。
局部组合物可以为粉末、液体溶液、乳液、液体悬浮液、乳膏、油膏、凝胶、口香糖凝胶、漱口水、防晒霜、牙膏、洗发水、护发素、液体肥皂的形式,并且可以施用于受试者的面部、眼睛、嘴唇、牙齿、头发、前额、指甲、手、脚、肩膀、手臂、背部或腿。合适的受试者包括哺乳动物,例如动物或人类受试者。
所公开的组合物还可以是用于经皮应用的贴片、伤口敷料、绷带、硬膏剂、支架、植入物、气凝胶、屑粒、按扣或水凝胶的形式,并且被配制成用于立即释放、延长释放或持续释放。本领域技术人员已知的各种添加剂可以包含在经皮制剂中。添加剂的实例包括但不限于增溶剂、皮肤渗透增强剂、防腐剂例如抗氧化剂、保湿剂、胶凝剂、缓冲剂、表面活性剂、乳化剂、润肤剂、增稠剂、稳定剂、保湿剂、分散剂和药物载体。保湿剂的实例包括但不限于霍霍巴油和月见草油。合适的皮肤渗透增强剂包括但不限于低级烷醇,例如甲醇、乙醇和2-丙醇;烷基甲基亚砜,例如二甲亚砜(DMSO)、癸基甲基亚砜(C10 MSO)和十四烷基甲基亚砜;吡咯烷酮、脲;N,N-二乙基-间-甲苯甲酰胺;C2-C6链烷二醇;二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)和四氢糠醇。增溶剂的实例包括但不限于亲水性醚,例如二甘醇单乙醚和二甘醇单乙醚油酸酯;聚氧35蓖麻油、聚氧40氢化蓖麻油、聚乙二醇(PEG)和聚乙二醇衍生物,例如PEG-8辛酸/癸酸甘油酯;烷基甲基亚砜,例如DMSO;吡咯烷酮、DMA及其混合物。
可以通过在所公开的组合物中包含抗生素以及各种抗细菌剂和抗真菌剂,例如对羟基苯甲酸酯、氯丁醇、苯酚山梨酸等,来实现感染的预防和/或治疗。
所公开的组合物还可以通过各种其它途径给药,包括粘膜、皮下和肌肉内给药,并且可以包含制剂领域中已知的各种载体或赋形剂,例如无毒固体、半固体或液体填充剂、稀释剂、包封材料和药学上可接受的制剂助剂。
所公开的组合物可以包含制剂领域中已知的各种载体或赋形剂,例如无毒固体、半固体或液体填充剂、稀释剂、包封材料和药学上可接受的赋形剂、稀释剂、佐剂、稳定剂、乳化剂、防腐剂、着色剂、缓冲剂、风味赋予剂、抑菌剂、抑真菌剂、润肤剂、增塑剂、渗透增强剂、抗氧化剂、颜料、润滑剂、防腐剂、湿润剂、盐及其任何混合物。
实例
实例1:大麻素提取物、馏出物和分离物
大麻素前体大麻萜酚酸(CBGA)和次大麻萜酚酸(CBGVA)通过从大麻属植物提取或商业购买获得。大麻素四氢大麻酚酸(THCA)、大麻二酚酸(CBDA)、大麻环萜酚酸(CBCA)、(-)-反式-Δ9-四氢大麻酚酸(Δ9-THCA)、四氢次大麻酚酸(THCVA)、次大麻环萜酚酸(CBCVA)和次大麻二酚酸(CBDVA)通过有机溶剂提取、蒸汽或超临界流体提取从大麻植物中提取。大麻素的中性形式,四氢大麻酚(THC),大麻二酚(CBD)、(-)-反式-Δ9-四氢大麻酚(Δ9-THC)、大麻萜酚(CBG)、大麻环萜酚(CBC)、大麻环酚(CBL)、大麻二酚(CBD)、脱氢大麻二酚(CBND)和大麻酚(CBN),通过加热、干燥或燃烧使其对应的酸性形式脱羧而获得。对于通过加热脱羧,将大麻素提取物在95℃加热约20分钟直至熔化,然后在冰箱中冷却约15分钟。
将大麻素提取物进行分子蒸馏,并通过薄层色谱(THLC)、高效液相色谱(HPLC)、液相色谱-质谱和/或气相色谱-火焰离子化检测器(GC-FID)分析除去萜烯、有机物质和叶绿素来精制馏出物。
如上所述获得的大麻素液体油馏出物就这样使用。替代地,将精制大麻素液体油馏出物再精制一次以获得二次蒸馏大麻素。通过第三次精制二次蒸馏的大麻素获得高纯度的三次蒸馏大麻素分离物。
实例2:初步测试
如本文所公开的生产精细纳米颗粒。通过在添加大麻素前用CO2洗涤,系统优化以最小化湿度的影响,并将压力释放工艺优化至0.5秒,再加压循环25秒以防止喷嘴冻结并确保均匀性和再现性。
将提取物、馏出物或分离物形式的大麻素添加到10ml高压反应室中,并将液体CO2以1000psi的压力泵入反应室中。将反应器加热至40℃并将压力升至约1500psi至约1700psi的范围。温度保持在40℃或升高到50℃。然后使用注射泵以1000psi的增量将压力从约2500psi增加至约6500psi。选择40℃的温度和3500psi的压力用于初步测试。将所得溶液通过5μm喷嘴释放0.5秒脉冲。图1A示出了加工前的CBD分离物。CBD分离物具有结晶形态和大颗粒之间的大量附聚。图1B示出了在3500psi的压力和的40℃的温度下加工后的CBD馏出物。所得馏出物颗粒示出更似球形的无定形形态并且具有100nm与40μm之间的粒径。
实例3:与环糊精络合
为了增加大麻素在水中的溶解度,将如实例1中所述产生的大麻素提取物、馏出物和分离物与α-环糊精或β-环糊精组合,大麻素:环糊精的摩尔比范围在1:0.5至1:10,并添加到10ml反应室中。将超临界CO2以1,000psi的压力泵入反应室中,将反应室加热至40℃并将压力升高至3,500psi。将所得溶液通过5μm喷嘴释放0.5秒脉冲。发现环糊精在工艺条件下是不溶的。
为了增加在超临界流体中的溶解度,α-环糊精和β-环糊精通过用一个或多个乙酰基取代一个或多个羟基而乙酰化以增加路易斯酸:超临界流体中的路易斯碱相互作用。在100ml圆底烧瓶中,将2.0g的α-环糊精、β-环糊精或γ-环糊精在10ml乙酸酐中乙酰化。向混合物中加入0.05g碘并将烧瓶在黑暗中搅拌2小时。用50ml水淬灭反应,滴加1%(w/w)硫代硫酸钠水溶液直至溶液变澄清。将反应搅拌1小时,并将所得溶液用4份40ml二氯甲烷(DCM)提取。合并有机级分,用50ml水洗涤两次,在除去溶剂前用硫酸钠干燥。将最终产物在真空中干燥以分别产生α-环糊精十六乙酸酯(AACD)、β-环糊精二十一乙酸酯(ABCD)或γ-环糊精十八乙酸酯(AGCD)。
然后将乙酰化环糊精与大麻素提取物、馏出物和分离物复合,大麻素:环糊精摩尔比范围在1:0.5至1:10并加入到10ml反应室中。将超临界CO2以1,000psi的压力泵入反应室中,将反应室加热至40℃并将压力升高至3,500psi。将所得溶液通过5μm喷嘴释放0.5秒脉冲。
结果表明,在实验条件下,AACD、ABCD和AGCD在超临界CO2中的溶解度分别增加到1.1和1.3重量%。此外,在加工期间,大麻素与乙酰化环糊精的络合防止了大麻素及其杂质(例如萜烯和蜡)的再悬浮。
实例4:大麻素超细纳米颗粒的制备
根据实例3中所述制备大麻素复合物与乙酰化环糊精的大麻素:环糊精摩尔比范围在1:0.5至1:10并各自添加到10ml反应室中。在3500psi的压力和40℃的温度下将大麻素-环糊精复合物溶解在超临界流体中。将溶液通过5微米喷嘴减压到带有管状排气装置的19升膨胀室中以确保颗粒的最大回收。图2A和2B分别示出了以1:2.5w/w的大麻素:环糊精摩尔比与α-环糊精复合的CBD馏出物颗粒的32X放大图和200X放大图(250mg CBD与100mgα-环糊精复合)。所产生的CBD纳米颗粒示出球形形态,粒径在100nm与40μm之间,并且添加乙酰化环糊精会产生加工后不再悬浮的精细粉末,这表明CBD化合物整合到AACD环中,如图2A和2B中示出的。
实例5:大麻素超细纳米颗粒的生物利用度
根据实例4中所述获得的大麻素超细纳米颗粒的生物利用度通过视觉评估精细纳米颗粒在模拟胃条件中的溶解度来评估。将0.5g NaCl添加到0.155M HCl水溶液中以复制胃酸性条件。将10mg精细纳米颗粒、10mg结晶形式的分离物和10mg馏出物各自放入含有10ml酸性溶液的小瓶中,并在37℃下培养10小时。在10小时结束时,仅观察到制剂的最小溶解度。添加另外的10ml酸性溶液,并将混合物在37℃下再培养10小时。在20小时结束时,大麻素纳米颗粒溶解在酸性溶液中。相反,结晶形式的分离物和馏出物示出完全不溶性(图3至5)。
实例6:大麻素超细纳米颗粒的相对生物利用度测试
与水中的大麻素分离物(对照样品)相比,使用配备有UV检测器的高效液相色谱(HPLC)分离器进行如实例4中所述获得的大麻素超细纳米颗粒(测试样品)的相对生物利用度测试,以确定每种样品中CBD的浓度。通过0.45μm过滤器将1ml每种样品过滤到2ml HPLC小瓶中并将1ml甲醇(MeOH)添加到每种样品小瓶中来制备对照样品。HPLC流动相包含65%乙腈和35%水。1ml/分钟的流速导致CBD在大约4.5分钟后洗脱。
在经过32小时之后测量百分比面积,其代表每种样品中的CBD相对于每种样品中MeOH形成的背景信号的量。发现测试样品的面积百分比为总样品的4.1163%,相比之下,对照样品的面积百分比为总样品的0.7706%。
这些结果表明,当与对照大麻素分离物在水中相比时,所公开的纯化大麻素精细纳米颗粒增强CBD的溶解度。溶解度的显著增加(在这种情况下高达6倍)表明所公开的制剂的生物利用度有显著改善的潜力。生物利用度的显著增加可以明显改善治疗效果。
实例7:水溶性环糊精包封的API纳米颗粒的制备
为了增加API在水中的溶解度,将根据实例1中所述的大麻素馏出物与各种环糊精组合,并将所得混合物置于高压反应器中。将液化的CO2泵入反应器直到反应器压力达到5,000psi。将混合物在反应器中搅动30分钟以形成环糊精包封的大麻素。然后将混合物喷雾到旋风分离器中以使CO2蒸发并获得环糊精包封的大麻素干粉。回收的CO2储存在缓冲罐中以备将来使用。下表1示出了每种样品中大麻素含量的百分比。表1还示出了,环糊精包封的大麻素纳米颗粒中的平均大麻素百分比含量比标准的非环糊精包封的大麻素纳米颗粒中的平均大麻素含量高10倍。
表1
组分 | % | 平均% | STD |
Δ9-THC | 8.540 | 10.94 | 1.42 |
Δ9-THC | 11.860 | ||
Δ9-THC | 12.474 | ||
Δ9-THC | 11.813 | ||
Δ9-THC | 10.481 | ||
Δ9-THC | 10.497 |
实例8:环糊精包封的API粉末的溶解曲线
通过溶解从实例7获得的样品测定溶解曲线。商业THC油(Reign Drops,THC30mg/ml)用作标准对照。将含有等量大麻素(40mg)的每种样品溶解在200ml蒸馏水中。温度保持恒定在50℃。
在0.5、1、2、3、5、10、20和30分钟的时间间隔,从培养基中取出2ml的每种样品溶液并立即通过0.45μm注射器式滤器过滤。然后使用0.085%磷酸的甲醇溶液和0.085%的磷酸水溶液作为流动相,在220nm波长下通过HPLC分析过滤溶液。在下表2中总结并在图9中描述的结果示出了超过90%的环糊精包封的API干粉溶解于水中。相反,仅26%的标准对照非环糊精包封的大麻素干粉溶解在水中。这些结果证实,当与非环糊精包封的API相比时,环糊精包封的API具有优异的生物利用度和有效性。
表2
实例9:环糊精包封的大麻素的体内吸收测试
使用面包酵母(酿酒酵母,Saccharomyces cerevisiae)测量跨膜转运速度,并在两小时内评估活生物体对环糊精包封的大麻素的吸收,与未包封的THC吸收进行比较。
将酵母接种到糖溶液中并使其在35℃下适应15分钟。然后用含有未包封的THC的溶液处理一半酵母培养物作为对照,用含有等量环糊精包封的THC形式的等量THC的溶液处理一半酵母培养物。在35℃和温和搅动下处理2小时以促进气体交换。在处理结束时,通过离心除去溶液,用盐水溶液洗涤酵母细胞,裂解并进行有机提取。通过HPLC分析有机大麻素溶液。下表3中所示的结果表明,相对于未包封的THC的转运,环糊精微胶囊化增强了THC穿过酵母膜的转运和200%的THC吸收。总体上,这些结果证明环糊精微胶囊化改善了真核系统(例如人)中大麻素的吸收,并且可为用户提供增强的娱乐或医疗体验。
表3
应当认识到,绘视的实施例仅是所公开的方法的实例,而不应被认为是对本发明范围的限制。相反,本发明的范围由以下权利要求限定。
Claims (23)
1.一种稳定、不可降解、可食用、可吸入、可溶或可饮用的组合物,其包含药物级环糊精包封的活性药物成分(API)和药学上可接受的载体、赋形剂和/或粘合剂,所述环糊精包封的活性药物成分具有99.9%纯度和与非环糊精包封的活性药物成分制剂相比增加200%的生物利用度,其中所述活性药物成分是大麻素、迷幻剂、镇痛剂、麻醉剂、抗炎剂、抗菌剂、抗病毒剂、抗凝剂、抗惊厥剂、抗抑郁剂或肌肉松弛剂。
2.根据权利要求1所述的稳定、不可降解、可食用、可吸入、可溶或可饮用的组合物,其中所述药物级环糊精包封的活性药物成分为纳米颗粒形式,其平均粒径在100nm与40μm之间并且粒径分布在平均粒径的1%和50%内。
3.根据权利要求1所述的稳定、不可降解、可食用、可吸入、可溶或可饮用的组合物,其中所述药物级环糊精包封的活性药物成分为超细干粉形式,其平均粒径在100nm与5μm之间。
4.根据权利要求1所述的稳定、不可降解、可食用、可吸入、可溶或可饮用的组合物,其中所述药物级环糊精包封的活性药物成分为可饮用溶液或悬浮液的形式。
5.根据权利要求1所述的稳定、不可降解、可食用、可吸入、可溶或可饮用的组合物,其中所述迷幻剂是脱磷酸裸盖菇素(psilocin)或裸盖菇素(psilocybin),并且其中所述大麻素是大麻萜酚酸(cannabigerolic acid,CBGA)、次大麻萜酚酸(cannabigerovaric acid,CBGVA)、四氢大麻酚酸(tetrahydrocannabinolic acid,THCA)、大麻环萜酚酸(cannabichromene acid,CBCA)、大麻二酚酸(cannabidiolic acid,CBDA)、四氢次大麻酚酸(tetrahydrocannabivarinic acid,THCVA)、次大麻环萜酚酸(cannabichromevarinicacid,CBCVA)、次大麻二酚酸(cannabidivarinic acid,CBDVA)、(-)-反式-Δ9-四氢大麻酚((-)-trans-Δ9-tetrahydrocannabinol,Δ9-THC)、反式-Δ9-庚基延伸四氢大麻酚(trans-Δ9-tetrahydrocannabiphorol,Δ9-THCP)、大麻萜酚(cannabigerol,CBG)、大麻环萜酚(cannabichromene,CBC)、大麻环酚(cannabicyclol,CBL)、大麻二酚(cannabidiol,CBD)、脱氢大麻二酚(cannabinodiol,CBND)或大麻酚(cannabinol,CBN)中的一种或多种。
6.根据权利要求2所述的稳定、不可降解、可食用、可吸入、可溶或可饮用的组合物,其中所述API被包封在一种或多种乙酰化环糊精中,并且其中所述一种或多种乙酰化环糊精包含乙酰化α-环糊精、乙酰化β-环糊精、乙酰化γ-环糊精或其任何混合物。
7.根据权利要求3所述的稳定、不可降解、可食用、可吸入、可溶或可饮用的组合物,其中所述API被包封在一种或多种乙酰化环糊精和一种或多种亲水性环糊精中。
8.根据权利要求7所述的稳定、不可降解、可食用、可吸入、可溶或可饮用的组合物,其中所述一种或多种乙酰化环糊精包含乙酰化α-环糊精、乙酰化β-环糊精、乙酰化γ-环糊精或其任何混合物,并且其中所述一种或多种亲水性环糊精包含亲水性α-环糊精、亲水性β-环糊精、亲水性γ-环糊精或其任何混合物。
9.根据权利要求6或权利要求7所述的稳定、不可降解、可食用、可吸入、可溶或可饮用的组合物,其中所述API和所述一种或多种乙酰化环糊精的API:乙酰化环糊精摩尔比范围为1:0.5至1:10,或者其中所述API:乙酰化环糊精摩尔比为1:0.5、1:0.75、1:1、1:1.5、1:2、1:2.5、1:3、1:3.5、1:4、1:4.5、1:5、1:5.5、1:6、1:6.5、1:7、1:7.5、1:8、1:8.5、1:9、1:9.5或1:10。
10.根据权利要求4所述的稳定、不可降解、可食用、可吸入、可溶或可饮用的组合物,其中所述API被包封在一种或多种亲水性环糊精中,并且其中所述一种或多种亲水性环糊精包含亲水性α-环糊精、亲水性β-环糊精、亲水性γ-环糊精或其任何混合物。
11.根据权利要求6、权利要求7或权利要求10所述的稳定、不可降解、可食用、可吸入、可溶或可饮用的组合物,其中所述API是一种或多种大麻素或一种或多种迷幻剂。
12.根据权利要求11所述的稳定、不可降解、可食用、可吸入、可溶或可饮用的组合物,其中所述一种或多种大麻素是大麻二酚(CBD)。
13.根据权利要求11所述的稳定、不可降解、可食用、可吸入、可溶或可饮用的组合物,其中所述一种或多种大麻素是四氢大麻酚(THC)。
14.根据权利要求11所述的稳定、不可降解、可食用、可吸入、可溶或可饮用的组合物,其中所述一种或多种大麻素是大麻二酚(CBD)和四氢大麻酚(THC)。
15.根据权利要求11所述的稳定、不可降解、可食用、可吸入、可溶或可饮用的组合物,其中所述一种或多种大麻素是大麻酚(CBN)。
16.根据权利要求11所述的稳定、不可降解、可食用、可吸入、可溶或可饮用的组合物,其中所述一种或多种迷幻剂包含脱磷酸裸盖菇素或裸盖菇素。
17.根据权利要求1所述的稳定、不可降解、可食用、可吸入、可溶或可饮用的组合物,其中所述药学上可接受的载体、赋形剂或粘合剂包含柠檬酸钠、磷酸二钙、淀粉、乳糖、蔗糖、葡萄糖、甘露醇、硅酸、羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖、阿拉伯胶、湿润剂、增溶剂、乳化剂、崩解剂、溶液阻滞剂、吸收促进剂、润湿剂、吸收剂、润滑剂、油、佐剂、甜味剂、调味剂、香料或缓冲剂中的一种或多种。
18.根据权利要求17所述的稳定、不可降解、可食用、可吸入、可溶或可饮用的组合物,其中所述组合物为吸入器、胶囊、片剂、丸剂、粉末、珠粒、锭剂、糖锭剂、颗粒剂、膳食组合物、食品、饮料、乳液、溶液、悬浮液、乳膏、凝胶、防晒霜、洗发剂、牙膏、经皮贴片、膏药、植入物、糖浆、酏剂、注射剂或输注剂的形式。
19.根据权利要求18所述的稳定、不可降解、可食用、可吸入、可溶或可饮用的组合物,其中所述组合物被配制成立即释放形式、持续释放形式或控制释放形式。
20.根据权利要求19所述的稳定、不可降解、可食用、可吸入、可溶或可饮用的组合物,其中所述组合物进一步包含包衣,并且其中所述包衣是肠溶包衣、延长释放包衣、持续释放包衣、延迟释放包衣或立即释放包衣。
21.根据权利要求19所述的稳定、不可降解、可食用、可吸入、可溶或可饮用的组合物,其中所述组合物被配制成用于口服、粘膜、肺部、局部、肠胃外、经皮或粘膜下给药。
22.根据权利要求18所述的稳定、不可降解、可食用、可吸入、可溶或可饮用的组合物,其中所述食品是面包、饼干、汤、谷物、沙拉、三明治、豆芽、蔬菜或糖果。
23.根据权利要求18所述的稳定、不可降解、可食用、可吸入、可溶或可饮用的组合物,其中所述饮料是茶、果汁、糖浆、苏打水、发酵饮料、酒精饮料、非酒精饮料、蒸馏饮料或酿造饮料。
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