CN115335040A - 口服萜烯环糊精包合物媒介物 - Google Patents
口服萜烯环糊精包合物媒介物 Download PDFInfo
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- CN115335040A CN115335040A CN202180023966.5A CN202180023966A CN115335040A CN 115335040 A CN115335040 A CN 115335040A CN 202180023966 A CN202180023966 A CN 202180023966A CN 115335040 A CN115335040 A CN 115335040A
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- cyclodextrin
- inclusion
- enzyme
- extract
- guest molecule
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Abstract
本发明提供了口服萜烯环糊精包合物递送媒介物,其包括其中与具有环糊精降解活性、能够水解环糊精的酶一起提供该环糊精包合物的制剂,从而一旦将该媒介物递送至靶标,则激活该酶并且从该环糊精空腔释放客体分子。在替代方面,例如,以延时释放制剂形式提供这些环糊精包合物递送媒介物,例如,用于治疗气道粘液功能障碍。还提供了具有勃起效力的制剂。
Description
技术领域
本发明属于用于作为可以包括具有环糊精降解活性的酶的口服制剂中的环糊精内的包含物,递送生物活性萜烯,包括莰烯的生物化学构建体领域。
背景技术
环糊精是非还原性环状葡萄糖寡糖,通常是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。环糊精可以具有多种结构(参见Saenger等人,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,所述空腔根据葡萄糖单元的数目而具有不同的直径。所选的环糊精(CD)结构的大小列于表1中。还可能是较大的环糊精,如环麦芽九糖(δ-CD)和环麦芽十糖(ε-CD),以及多种基于环糊精的超分子结构(参见Zhang and Ma,Adv Drug DelivRev.2013Aug;65(9):1215-33)。
表1:环糊精结构
环糊精通常是两亲性的,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,该疏水性内腔可以含有水分子,例如,约3个(α-CD)、7个(β-CD)或9个(γ-CD)不稳定容纳但低熵,并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,从而形成环糊精包含体或络合物。例如,可以结合非极性脂族和芳香族化合物,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期望的性质,如气味或味道最小化。为此,环糊精包含物被广泛用于药物、食品和化妆品领域(参见Hedges,Chem.Rev.98(1998)2035-2044)。例如,环糊精已被用于多种缓释药物制剂,如用于医用化合物与疏水性环糊精衍生物的包合物(美国专利No.4,869,904)。
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或卡布迪索(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。环糊精的替代形式包括: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。尽管如这些的CD已被开发为具有良好的药理学和毒理学谱,但是仍然存在这样的可能性,即在施用后,残留的CD可能干扰药物的药代动力学性质,包括共施用的药物,特别是在肠胃外施用后(参见Stella and He,Toxicol Pathol 2008年1月,第36卷,第1期30-42)。
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的治疗剂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的条件来正确引发胰淀粉酶的释放。提高抗酸剂、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可以产生类似的作用。
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(或者环糊精酶或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),其已被报道能够水解CD,并且在一些情况下,能够水解其他底物,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CD酶,并且此后已鉴定了多种来自细菌的CD酶,如来自芽孢杆菌属(Bacillus sp.)、产乙醇热厌氧杆菌(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。已鉴定了来自闪烁古生球菌(Archaeoglobus fulgidus)、嗜热球菌(Thermococcus sp.)B1001、嗜热球菌(Thermococcus sp.)CL1、下垂热丝菌(Thermofilum pendens)和激烈火球菌(Pyrococcusfuriosus)的古细菌CD酶。以详细鉴定了来自黄杆菌属(Flavobacterium sp.)的CD酶的结构(参见Sun等人,Archaea,2015卷(2015),文章编号397924,其报道了编码来自Thermococcus kodakarensis KOD1的环糊精酶(CDase-Tk)的基因鉴定)。
莰烯是具有双环骨架的单萜,它是在2位被偕甲基取代并且在3位被亚甲基取代的双环[2.2.1]庚烷。它是通常作为处于不同比例的D-莰烯和L-莰烯的外消旋混合物存在于多种精油中的广泛分布的天然产物(Ochocka等人,2002,Pharmaceutical Biology,40:5,395-399)。它已广泛用作调味剂和香料。莰烯还已被描述为具有多种生理作用,如降血脂作用(Vaillianou等人,PLoS One,2011;6(11)e20516)。
气道粘液功能障碍促进了多种气道疾病和病况或者是它们的症状(参见Fahy&Dickey,2010),其通常表现为咳嗽或气喘。以气道粘液功能障碍为特征的疾病包括囊性纤维化、哮喘、慢性阻塞性肺病、原发性纤毛运动障碍、非囊性纤维化支气管扩张、泛细支气管炎、多种免疫缺陷状况。与气道粘液功能障碍有关的病况可以包括多种正常肺力学的破坏,例如,在插管、瘫痪、昏迷或术后患者中,其中问题可能与保留的粘液有关。
发明内容
提供了含莰烯环糊精包合物递送媒介物,例如,其用于治疗气道粘液功能障碍,或者用于在男性受试者中提供勃起作用。除莰烯之外,制剂可以包括其他包合物客体分子,包括其他萜烯,如植物萜烯。其他客体分子可以(例如)包括:桉树脑(即1,3,3-三甲基-2-氧杂二环[2.2.2]辛烷;CAS 470-82-06;桉叶素;1,8-环氧-p-薄荷烷);愈创醇(即2-[(3S,5R,8S)-3,8-二甲基-1,2,3,4,5,6,7,8-八氢-5-薁基]-2-丙醇;CAS 489-86-1;黄兰醇),和/或δ-3蒈烯(即3,7,7-三甲基二环[4.1.0]庚-3-烯;CAS 13466-78-9)。可以(例如)在植物提取物或组合物,如胡椒薄荷和/或葫芦巴组合物,如胡椒薄荷油或葫芦巴粉的CD包含物中提供其他客体分子。
可以为环糊精包合物提供生物学可接受的载体,从而通过环糊精将所述客体分子稳定保留在所述生物学可接受的载体内。还可以在媒介物中提供具有能够水解保留客体分子的环糊精的环糊精降解活性的酶。可以所述酶被配制,从而在将所述媒介物递送至靶标时激活所述环糊精降解活性,从而从环糊精空腔释放所述客体分子。
在递送媒介物的替代方面,可以将所述酶与环糊精包合物共配制,或者可以将所述酶与环糊精包合物在递送媒介物中共包装。当将所述酶共包装时,所述递送媒介物还可以包括所述酶的生物化学可接受的载体。
所述酶可以(例如)是淀粉酶、环糊精酶、麦芽糖淀粉酶或新普鲁兰酶。淀粉酶可以(例如)是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。环糊精酶可以(例如)是微生物环糊精酶。
所述环糊精可以(例如)是CD衍生物,如疏水性烷基化环糊精或混合的甲基化/乙基化环糊精。
环糊精与客体分子之比可以(例如)为5:1、4:1、3:1、2:1、1:1、1:2、1:3、1:4或1:5,尽管该参数宽泛的替代值也是可能的,包括非整数比例。
环糊精可以(例如)是α、β或γ环糊精,尽管仍可以使用非常宽范围的替代CD结构。
在所选实施方式中,可以(例如)提供其他客体分子,如药物或前体药物、PDE5抑制剂、黄酮类(槲皮素)、大麻素或抗炎剂(包括对乙酰氨基酚)。在该情况下,所述生物学可接受的载体可以有利地为药学上可接受的载体。可以将递送媒介物配制用于客体分子的缓释。
以这种方式,本发明提供了其中CD递送媒介物可以用作药剂的替代实施方式。
提供了用于治疗具有作为疾病,如囊性纤维化、哮喘、慢性阻塞性肺病、原发性纤毛运动障碍、非囊性纤维化支气管扩张、泛细支气管炎或免疫缺陷状况的症状的气道粘液功能障碍的患者的方法。作为另外一种选择,气道粘液功能障碍可以是与肺力学破坏有关的病况,例如,插管、瘫痪、昏迷或手术创伤的症状。
还提供了用于在男性受试者,例如,大于50、60或70岁的男性或患有勃起功能障碍的男性受试者中提供勃起作用的方法。
具体实施方式
递送媒介物的具体制剂可以(例如)包括通过将从一些来源,包括天然植物提取来源制备的环糊精包含物合并所制备的环糊精包合物制剂。例如,在(例如)单一制剂或以组合提供的不同制剂中合并从以下2、3、4、5或6种所制备的CD包合物的制剂:
在CD包含物,例如,在βCD或γCD包含物中,桉树(桃金娘科(Myrtaceae))提取物(例如,桉树脑标准化为6mg,或4-8mg);和/或
在CD包含物,例如,在βCD或γCD包含物中,松节树(Syncarpia glomulifera)提取物(例如,莰烯标准化为6mg,或4-8mg);和/或
在CD包含物,例如,在βCD或γCD包含物中,胡椒薄荷(椒样薄荷(Menthapiperita))油6mg,或4-8mg;和/或
在CD包含物,例如,在βCD或γCD包含物中,松属(Pinus)(例如,海岸松(Pinaster)和/或湿地松(Elliotii)和/或欧洲赤松(Sylvestris))提取物(例如,蒈烯δ3标准化为4mg,或2-6mg);和/或
在CD包含物,例如,在βCD或γCD包含物中,葫芦巴提取物,例如葫芦巴净油(葫芦巴(Trigonella foenum-graecum))4mg,或2-6mg;和/或
在CD包含物,例如,在βCD或γCD包含物中,玉檀木(Bulnesia sarmientoi)提取物(例如,愈创醇标准化为4mg,或2-6mg)。
可以(例如)以每剂量任一种包合物5-250mg提供不同比例的成分。所选制剂可以仅是植物源活性成分。具体剂量形式可以(例如)如下所示,作为单一0缓释胶囊剂:
在CD包含物,例如,在βCD或γCD包含物中,桉树(桃金娘科)提取物(例如,桉树脑标准化为6mg,或4-8mg);
在CD包含物,例如,在βCD或γCD包含物中,松节树提取物(例如,莰烯标准化为6mg,或4-8mg);
在CD包含物,例如,在βCD或γCD包含物中,胡椒薄荷(椒样薄荷)油6mg,或4-8mg;
在CD包含物,例如,在βCD或γCD包含物中,松属[例如,海岸松和/或湿地松和/或欧洲赤松]提取物(例如,蒈烯δ3标准化为4mg,或2-6mg);
在CD包含物,例如,在βCD或γCD包含物中,葫芦巴提取物,例如葫芦巴净油(葫芦巴)4mg,或2-6mg;
在CD包含物,例如,在βCD或γCD包含物中,玉檀木提取物(例如,愈创醇标准化为4mg,或2-6mg);
K250延时释放剂80mg;
淀粉酶7mg;
月桂酸Ca 5mg。
如在本文中的制剂中所使用的,薄荷油可以是胡椒薄荷植物椒样薄荷的提取物。胡椒薄荷油的组成不同,但是已鉴定包含薄荷脑(40.7%)和薄荷酮(23.4%)、(+/-)-乙酸薄荷酯、1,8-桉树脑、柠檬烯、β-蒎烯和β-石竹烯(Schmidt等人,2009,Nat Prod Commun 4(8):1107;CAS号8006-90-4,MDL号MFCD00147870)。
葫芦巴(Trigonella foenum-graecum)的组成是普遍已知的,并且理解为包含多种生物碱、氨基酸、皂苷、类固醇皂苷元和黄酮(Wani and Kumar,2018,J.of the Saudisociety of Agricultural Sciences 17(2):97)。例如,可以通过溶剂提取葫芦巴种子来产生葫芦巴提取物,有时鉴定为葫芦巴净油(CAS号84625-40-1、FEMA号2486、EC号283-415-1、MDL号MFCD01772302)。
在所选实施方式中,可以以植物提取物的形式提供客体分子,例如,来自桉树的桉树脑(例如,桉树油,CAS号8000-48-4、FEMA号2466、EC号283-406-2);来自聚果木属(Syncarpia)的莰烯;来自松树(例如,种:海岸松;湿地松;欧洲红松、雪松、罗勒、松树、迷迭香和灯笼椒)的δ-3-蒈烯(δ-3-蒈烯);来自玉檀木的愈创醇(倍半萜醇,也存在于柏松和愈创木属中);含有薄荷脑的薄荷油;来自葫芦巴种子的葫芦巴提取物。替代实施方式可以(例如)包括来自下列的提取物、萜烯或油剂:桉树(桃金娘科)、松节树、松属(海岸松和/或湿地松和/或欧洲赤松)和玉檀木、胡椒薄荷(椒样薄荷)和葫芦巴。可以将这些提取物在β和γ糊精纤维基质中与高和低粘度羟丙基甲基纤维素(缓释)、羟丙甲纤维素(来源于纤维素)胶囊剂、纤维素、月桂酸钙和淀粉酶(如植物或微生物淀粉酶)一起配制。
在所选实施方式中,制剂可以(例如)在植物纤维素胶囊剂中(例如)包含:
在βCD包含物中,桉树脑(10wt%(重量百分比))75mg;
在βCD包含物中,莰烯(10wt%)75mg;
在βCD包含物中,蒈烯δ3(10wt%)50mg;
在γCD包含物中,愈创醇(10wt%)50mg;
在βCD包含物中,薄荷油(15wt%)50mg;
在γCD包含物中,葫芦巴净油(oil)(10wt%)50mg;
K250延时释放剂80mg;
淀粉酶5mg;和
月桂酸Ca 5mg。
可以在本发明的递送媒介物中作为其他不同成分和/或作为其他客体分子,例如,以药物组合物的形式包含多种生物学活性化合物,如:多西他赛(US专利公开20140336149、20130296268);卡马西平(US专利公开20140080812);利福平(美国专利No.7001893);强心苷,具体为地高辛(美国专利No.4555504);黄体酮(参见Zoppetti等人,Journal ofInclusion Phenomena and Macrocyclic 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(MCC);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;舒林酸;甲苯咪唑;舒林酸;酚酞;达那唑(参见Challa等人,2005,AAPS PharmSciTech2005;6(2)论文号43);伊曲康唑;甲磺酸奈非那韦;替米沙坦;5-氟尿嘧啶及其他核苷类似物;喜树碱;律草烯(也称为α-律草烯或α-石竹烯);或者黄酮。
所选实施方式为药物食品组合物,其包含在βCD包含物中,桉树脑(例如,~10wt%)75mg;在βCD包含物中,莰烯(例如,~10wt%)75mg;在βCD包含物中,蒈烯δ3(例如,~10wt%)50mg;在γCD包含物中,愈创醇(例如,~10wt%)50mg;在βCD包含物中,薄荷油(例如,~15wt%)50mg;在γCD包含物中,葫芦巴净油(油)(例如,~10wt%);和律草烯。
在所选实施方式中,可以配制在媒介物中所提供的酶,从而在将所述媒介物递送至靶标时激活所述环糊精降解活性,从而从环糊精空腔释放所述客体分子。例如,酶激活可以在(例如)用于口服递送的药剂,在干燥剂型,如胶囊剂或片剂中完成,其中所述酶为混合的,从而所述酶直至在宿主胃肠道中被水分激活才会有活性。类似地,已知多种延时释放基质和制剂,其可以适合于在CD递送媒介物中使用,从而在递送至靶标时协调CD-降解酶的适当激活。
在多个方面,就以上所讨论的实例来说,CD递送媒介物可以具有与环糊精包合物共配制的酶,或者可以将所述酶与环糊精包合物在递送媒介物中共包装。就共包装来说,所述递送媒介物可以(例如)包括所述酶的生物化学可接受的载体——不同于所述CD包合物的载体。例如,递送媒介物可以设置包含CD包合物和CD-降解酶的分离隔室,从而所述递送媒介物将由与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-降解酶从递送媒介物中各自隔室组合释放的机构。例如,可以提供具有这类不同隔室的注射器,其通过共同排出机构排出,如通过在每个隔室中协同移动活塞以排出CD包合物和CD-降解酶等份的机构,从而然后可以将酶和络合物混合以激活客体分子从CD中的酶促释放。这类媒介物可以(例如)用于分配局部用乳膏剂或其他表面活性制剂。多种这类递送媒介物可以由已知用于分配两组分组合物,如环氧树脂、两组分药物或牙科制剂的装置改造,举例而言,如在美国专利No.4538920、8100295、8308340、8875947、8499976和国际专利公开WO2007041266和WO2000021842中所公开的。
存在多种可用于制备CD包合物的技术,举例而言,如在:Chaudhary&Patel,IJPSR,2013,4卷(1):68-76;Carneiro等人,2019,Int.J.Mol.Sci.2019,20,642;美国专利公开US20090029020;US20090214446;US专利No 5,070,081;5,552,378;5,674,854和8,658,692中所述。一种常见的方法被称为捏合法,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,并揉捏所指定的时间。然后,可以将揉捏的混合物干燥,并根据需要过筛。作为另外一种选择,浆料法包括以下步骤:将生物活性分子和环糊精混合,向所述混合物添加适量的水,通常剧烈混合,直至形成糊状物或浆料;继续混合适合的一段时间,如15分钟,如有必要,进一步添加水以维持糊状物或浆料粘稠度,以形成包合物;和将该最终步骤的产物干燥。其他成分,如乳化剂,可以帮助形成包合物,例如,包括以下步骤的方法:将环糊精和乳化剂(例如,果胶)干混;将所述环糊精和乳化剂的干混物与溶剂,如水在反应器中混合,并搅动;添加客体分子并搅拌(例如,约5至8小时);任选地,边搅拌边冷却所述反应混合物;并在干燥环糊精包合物之前乳化所述混合物以形成粉末。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递送媒介物可以在存在载体,如脂质体、佐剂或任何药物或生物学可接受的载体的情况下单独或与其他化合物(例如,核酸分子、小分子、肽或肽类似物)组合提供。所选实施方式包括处于适合于向动物宿主,如哺乳动物,例如人施用的形式的药剂。如本文所使用的“药学上可接受的载体”或“赋形剂”包括生理学相容的任何和所有溶剂、分散媒介物、涂层、抗菌和抗真菌剂、等渗和吸收延迟剂等。所述载体可以适合于任何适当的施用形式,包括局部、皮下、皮内、静脉内、肠胃外、腹膜内、肌内、舌下、吸入、肿瘤内或口服施用。药学上可接受的载体包括无菌水溶液或分散系和用于无菌可注射溶液或分散系的即时制备的无菌粉末。这类媒介物和药剂用于药学活性物质的使用在本领域中是熟知的。除了任何常规媒介物或试剂与所述生物学活性化合物不相容以外,考虑了其在本发明的药物组合物中的使用。还可以将补充性活性化合物引入所述组合物中。
可以使用常规药物实践以提供适合的制剂或组合物以将所述递送媒介物施用于受试者。可以使用任何适当的施用途径,例如,肠胃外、静脉内、皮内、皮下、肌内、颅内、眶内、眼、心室内、囊内、脊柱内、鞘内、脑池内、腹膜内、鼻内、吸入、气溶胶、局部、肿瘤内、舌下或口服施用。治疗性制剂可以处于液体溶液或混悬液的形式;对于口服施用,制剂可以处于片剂或胶囊剂的形式;对于鼻内制剂,处于粉末剂、滴鼻剂或气溶胶的形式;并且对于舌下制剂,处于滴剂、气溶胶或片剂形式。
环糊精降解或消化酶可以(例如)配制用于口服递送。例如,可以提供肠酶制剂,如通过乳液溶剂蒸发制备的亚微米颗粒制剂(Sharma等人,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US专利公开20140094433),或药用树胶(参见US专利公开20130022652)。
本领域熟知用于制备制剂的方法可见于(例如)“Remington'sPharmaceuticalSciences”(第20版),A.Gennaro主编,2000,Mack Publishing Company,Easton,PA。用于肠胃外施用的制剂例如可以含有赋形剂、无菌水或盐水、聚亚烷基二醇,如聚乙二醇、植物来源的油剂或氢化萘。生物相容的、生物可降解的丙交酯聚合物、丙交酯/乙交酯共聚物或聚环氧乙烷-聚氧化丙烯共聚物可以用于控制化合物的释放。其他潜在有用的肠胃外递送系统包括乙烯-醋酸乙烯共聚物颗粒、渗透泵、可植入输注系统和脂质体。用于吸入的制剂可以含有赋形剂,如乳糖,或者可以是含有(例如)聚环氧乙烷-9-月桂基醚、甘胆酸盐和脱氧胆酸盐的水溶液,或者可以是用于以滴鼻剂形式施用的油溶液,或者作为凝胶。
本发明的药物组合物可以处于允许将组合物施用于患者的任何形式。例如,所述组合物可以处于固体、液体或气体(气溶胶)的形式。典型的施用途径无限制地包括口服、局部、肠胃外、舌下、经直肠、经阴道和鼻内。如本文所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。配制本发明的药物组合物,从而一旦将所述组合物施用于患者,则允许其中所含的活性成分是生物可用的。将施用于患者的组合物采取一种或多种剂量单位的形式,其中,例如,片剂、胶囊剂或扁囊剂可以是单一剂量单位,并且处于气溶胶形式的化合物的容器可以容纳多个剂量单位。
在制备所述药物组合物中使用的材料应是药物纯的并且在所使用的量是无毒的。本发明的组合物可以包括对于特别期望的作用已知的一种或多种化合物(活性成分)。对于本领域那些技术人员将显而易见地,所述活性成分在药物组合物中的最优剂量将取决于多种因素。相关因素无限制地包括受试者(例如,人)的类型、所述活性成分的具体形式、施用方式和所使用的组合物。
通常,所述药物组合物包括与一种或多种载体混合的如本文所描述的本发明的递送媒介物。所述载体可以是颗粒,从而所述组合物处于(例如)片剂或粉末形式。所述载体可以是液体,其中所述组合物是(例如)口服糖浆或可注射液体。另外,所述载体可以是气体,以提供在(例如)吸入施用中有用的气溶胶组合物。
当预期用于口服施用时,所述组合物优选地处于固体或液体形式,其中半固体、半液体、混悬液和凝胶形式包含在本文中认为是固体或液体的形式内。
作为用于口服施用的固体组合物,可以将所述组合物配制成粉末剂、颗粒剂、片剂、丸剂、胶囊剂、扁囊剂、口香糖、薄片剂、糖锭等形式。这种固体组合物通常将含有一种或多种惰性稀释剂或可食用载体。另外,可以存在以下佐剂中的一种或多种:粘结剂,如糖浆、阿拉伯胶、山梨糖醇、聚乙烯吡咯烷酮、羧甲基纤维素、乙基纤维素、微晶纤维素、黄芪胶或明胶及其混合物;赋形剂,如淀粉、乳糖或糊精、崩解剂,如海藻酸、海藻酸钠、羧甲基淀粉钠、玉米淀粉等;润滑剂,如硬脂酸镁或Sterotex;填充剂,如乳糖、甘露糖醇、淀粉、磷酸钙、山梨糖醇、甲基纤维素及其混合物;润滑剂,如硬脂酸镁、高分子聚合物,如聚乙二醇、高分子量脂肪酸,如硬脂酸、二氧化硅、润湿剂,如月桂基硫酸钠、助流剂,如胶体二氧化硅;甜味剂,如蔗糖或糖精、调味剂,如胡椒薄荷、水杨酸甲酯或橙味调味剂和着色剂。
当所述组合物处于胶囊剂的形式时,例如胶囊,除上述类型的材料外,它可以含有液体载体,如聚乙二醇或脂油。
所述组合物可以处于液体形式,例如酏剂、糖浆、溶液、水或油乳液或混悬液,或甚至可以在使用前用水和/或其他液体媒介物复原的干粉。作为两种实例,所述液体可以用于口服施用或用于通过注射递送。当预期用于口服施用时,除本发明的化合物之外,优选的组合物含有甜味剂、增稠剂、防腐剂(例如,p-羟基苯甲酸烷基酯)、染料/着色剂和风味增强剂(香味素)中的一种或多种。在预期通过注射施用的组合物中,可以包括表面活性剂、防腐剂(例如,p-羟基苯甲酸烷基酯)、润湿剂、分散剂、助悬剂(例如,山梨糖醇、葡萄糖或其他糖浆)、缓冲液、稳定剂和等张剂中的一种或多种。乳化剂可以选自卵磷脂或山梨糖醇单油酸酯。
无论它们是溶液、混悬液或其他类似形式,本发明的液体药物组合物可以包括以下佐剂中的一种或多种:无菌稀释剂,如注射用水、盐溶液,优选地生理盐水、林格氏溶液、等渗氯化钠、可以用作溶剂或混悬媒介物的固定油剂,如合成单甘油酯或甘油二酯、聚乙二醇、甘油、丙二醇或其他溶剂;抗菌剂,如苯甲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、柠檬酸盐或磷酸盐和用于调整张度的试剂,如氯化钠或葡萄糖。可以将胃肠外制剂封闭在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。可注射用药物组合物优选地是无菌的。
所述药物组合物可以预期用于局部施用,在此情况下,所述载体可以适当地包括溶液、乳液、软膏剂、乳膏剂或凝胶基底。例如,所述基底可以包括以下中的一种或多种:石蜡油、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。增稠剂可以存在于用于局部施用的药物组合物中。如果预期用于透皮施用,则所述组合物可以包括透皮贴片或离子电渗装置。局部制剂可以含有约0.1至约25%w/v(每单位体积的重量)的生物学活性化合物的浓度。
所述组合物可以预期用于直肠施用,其处于(例如)将在直肠中融化并释放药物的栓剂形式。用于直肠施用的组合物可以含有作为适合的无刺激性赋形剂的油质基底。这些基底无限制地包括羊毛脂、可可脂和聚乙二醇。低熔点蜡对于栓剂的制备是优选的,其中脂肪酸甘油酯和/或可可脂的混合物是适合的蜡。可以将所述蜡熔化,并且通过搅拌将氨基环己基醚化合物均匀分散其中。然后,将熔化的均匀混合物倾倒至适当尺寸的模具中,使其冷却并由此固化。
所述组合物可以包括改变固体或液体剂量单位的物理形式的多种材料。例如,所述组合物可以包括围绕所述活性成分形成涂层外壳的材料。形成涂层外壳的材料通常是惰性的,并且可以选自(例如)糖、虫胶和其他肠溶衣试剂。作为另外一种选择,所述活性成分可以包封在明胶胶囊剂或扁囊剂中。
本发明所述的药物组合物可以由气体剂量单位组成,例如,它可以处于气溶胶的形式。术语气溶胶用于表示从具有胶体性质的那些到由加压包装组成的系统的多种系统。可以通过液化或压缩气体或者通过分配活性成分的适合的泵系统递送。可以在单相、双相或三相系统中递送本发明的化合物的气溶胶以递送所述活性成分。气溶胶的递送包括必需的容器、触发器(activator)、阀门、子容器等,它们可以共同形成试剂盒。
生物学活性化合物可以处于游离碱的形式或者处于药学上可接受的盐的形式,如盐酸盐、硫酸盐、磷酸盐、柠檬酸盐、延胡索酸盐、甲烷磺酸盐、乙酸盐、酒石酸盐、马来酸盐、乳酸盐、扁桃酸盐、水杨酸盐、琥珀酸盐和本领域中已知的其他的盐。对于适合的使用模式(例如,口服或肠胃外施用途径),将选择合适的盐来提高化合物的生物利用度或稳定性。
可以通过将本发明的递送媒介物与水和优选地缓冲剂合并以形成溶液来制备预期通过注射施用的组合物。所述水优选地为无菌无热原水。可以添加表面活性剂来帮助形成均相溶液或悬浮液。表面活性剂是与氨基环己基醚化合物非共价相互作用的化合物,从而帮助氨基环己基醚化合物在含水递送系统中溶解或均匀混悬。在本发明的含水组合物中期望存在表面活性剂,因为根据本发明的氨基环己基醚化合物可以是疏水性的。其他注射用载体无限制地包括无菌无过氧化物的油酸乙酯、无水酒精、丙二醇及其混合物。
适合于注射溶液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环氧乙烷粘度调节剂。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,商业包装将包含所述药物组合物的一个或多个单位剂量。例如,这种单位剂量可以是足以制备静脉内注射的量。对于本领域普通技术人员将显而易见的是光敏和/或气敏化合物可能需要特殊的包装和/或制剂。例如,可以使用对光不透明,和/或密封以避免接触环境空气,和/或用适合的涂层或赋形剂配制的包装。
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”是指以所必需的剂量和持续时间,对于实现所期望的治疗结果有效的量。递送媒介物的治疗有效量可以根据以下因素改变,如疾病状态、个体的年龄、性别和体重以及化合物在个体中引起所期望的反应的能力。可以调节剂量方案以提供最优的治疗反应。治疗有效量还可以是其中治疗有益效果大于所述递送媒介物或活性化合物的任何毒性或不利作用的量。“预防有效量”是指以所必需的剂量和持续时间,对于实现所期望的预防结果有效的量。通常,在疾病之前或在疾病早期,在受试者中使用预防剂量,从而预防有效量可以小于治疗有效量。对于任何特定受试者,可以根据个体需要和施用或监督所述组合物的施用的人的专业判断,随时间(例如,时间可以是每天、每隔一天、每周、每月)调整治疗时机和剂量。
在所选实施方式中,本发明提供了包含与药学上可接受的载体、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、药学上可接受的盐、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、晶体或无定形形式、代谢产物、代谢前体或其前体药物,包括其分离的对映体、非对映体和几何异构体,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。
尽管本文公开了本发明的多种实施方式,但是根据本领域技术人员的一般常识,可以在本发明的范围内做出多种改进和修改。这些修改包括已知等价物对本发明的任何方面的替换,从而以基本相同的方式实现相同的结果。数值范围包括限定范围的数值。单词“包含”在本文中作为开放术语使用,其基本等价于术语“包括(但不限于)”并且单词“包含”具有相应含义。除非上下文明确规定,否则如本文所使用的,单数形式的“一个”和“所述”包括复数对象。因此,例如,对“一个事物”的提及包括不止一个该事物。
本文中对参考文献的引用不是对这些参考文献是本发明的现有技术的承认。在本说明书中引用的任何在先文档和所有专利公开,包括(但不限于)专利和专利申请作为参考并入本文。在本文引用的文档中引用或参考的所有文档以及在本文中或在作为参考并入本文的任何文档中提及的用于任何产品的任何生产商的说明书、描述、产品说明书和产品页由此作为参考并入本文并且可以用于本发明的实践。更具体地,所有参考的文档以每个单个的出版物具体且单独表明作为参考并入本文且在本文中完全说明的相同程度作为参考并入。本发明包括基本如上文所描述并且参考实施例和附图的所有实施方式和变化。
在一些实施方式中,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:粘液配方I
使用浆料法,以来自Vigon Corporation的食品级莰烯,以莰烯与α环糊精1:2的摩尔比制备了莰烯的环糊精包合物。以下列每个胶囊剂的配方制备了这种莰烯包合物(6.5%)的缓释胶囊剂:
莰烯包含物.............400mg(净含量26mg)
K-100M纤维素(Colorcon)...80mg
E4M纤维素(Colorcon).......20mg
淀粉酶...................4mg
月桂酸钙(流动增强剂)..4mg
实施例2:粘液配方II
制备了其他环糊精包合物制剂以用于向粘液配方I添加,如下所示:使用浆料法,以油比γ环糊精1:4的摩尔比的薄荷油(NOW Foods)。使用浆料法,以桉树脑比α环糊精1:1的摩尔比的桉树脑(Vigon)。
将上述薄荷油和桉树脑包合物制剂加入至粘液配方I的组分中,以提供粘液配方II的胶囊剂:
莰烯包含物(6.5%).................150mg(10mg净含量)
桉树脑包含物(10%)...................135mg(13.5mg净含量)
薄荷油包含物(15%)..............46mg(7mg净含量)
K-100M纤维素(Colorcon)...............70mg
E4M纤维素(Colorcon)...................17mg
淀粉酶...............................4mg
实施例3:与非酒精性脂肪性肝炎(NASH)有关的粘膜炎
受试者BC具有肝癌,和所产生的与非酒精性脂肪性肝炎(NASH,非酒精性脂肪肝病的进行性形式的亚型)有关的粘膜炎,结合肝硬化的病史。BC经历了肝内肝胆管型肝癌的肝脏手术,以及随后包括化疗和放疗的癌症治疗。放疗的副作用是粘膜炎(粘液过量产生)的出现,它是对常规疗法的抵抗。
BC在第1天开始以每天3次,3粒胶囊剂的剂量用实施例2的粘液配方II治疗。到第5天,呼吸粘液显著改善,肺充血明显改变,尽管仍伴有持续咳嗽。到用胶囊剂治疗的第10天,过量呼吸粘液实际上已症状性消失,并且咳嗽基本解决。用该胶囊剂继续治疗提供了粘膜炎症状的持续改善,从而提供了在治疗气道粘液功能障碍中的意外效力的迹象,包括止咳效力。
实施例4:支气管扩张
50岁的受试者D具有长期严重且难治的支气管扩张的诊断,并且具有肺痰液假单胞菌阳性~20年。该患者经历了用沃格孟汀(阿莫西林和克拉维酸)对于窦感染的治疗以及雾化hypersol、沙丁胺醇和多粘菌素E抗生素治疗(用药28天,然后停药28天)。
该患者在6月11日开始以每天两次4粒胶囊剂用粘液配方II进行治疗。在6月14日,剂量增至每天两次6粒胶囊剂,并且这伴随有向整夜睡眠的转变,这归因于与俯卧或卧姿有关的长期咳嗽症状的解决。到6月17日,D睡眠良好,气道粘液继续改善,这是归因于粘液配方II治疗所介导的对患者肺充血的解决的结局。到6月19日,D报告继续改善,连续整夜睡眠。到6月20日,D报告了化痰作用,气道粘液更稀,全天易于咳出,粘液从浅绿色变为透明,即使在雾化抗生素治疗循环的“28天停药”部分的最坏部分(该循环的最后两周,在此期间D通常经历气道粘液转变为深绿色)。D报告胸闷降低、排痰性咳,能够整夜平躺睡眠。D从服用粘液配方II的第一天,6月12日起整夜睡眠。不考虑睡眠位置或倾斜,相对于由咳嗽导致醒来前,每次睡眠不超过2-3小时的持续、慢性史,这是意外的结果。在躺椅上间断睡眠数年后,这是显著且持续的变化。
在6月30日,D继续治疗,并转换为添加了愈创醇和葫芦巴油的粘液配方II,其表示为粘液配方II+。到7月3日,D报告气道粘液功能障碍持续显著改善,其中咳嗽较少,排痰性咳更多且粘液较少。改善包括咳嗽的频率、持续时间和强度降低,且咳嗽更排痰,但整体要控制的粘液较少。此时,患者D处于距28天用药的“用药”部分两周,即抗生素的28天停药循环。粘液为白色,且偶尔为黄色。通常,此时在抗生素循环中,粘液为黄色至浅黄色(从未为透明/白色)。D继续整夜睡眠。到7月10日,在抗生素循环“用药”部分的第四周开始,继续改善并且D报告多年来首次能够仰卧睡眠,粘液为白色(无黄色)且粘液较少。可注意到化痰作用,粘液即使与上一周相比也更易于移动。
本实施例显示了口服莰烯环糊精制剂,包括还包含愈创醇和葫芦巴油的制剂对气道粘液功能障碍的有效治疗。
实施例5:病毒性肺炎,粘液活性作用
以胶囊剂形式提供了用于口服施用的包含以下CD包含物的组合的组合物:
桉树(桃金娘科)提取物,桉树脑标准化为6mg(在βCD包合物中);
松节树提取物,对莰烯标准化为6mg(在βCD包合物中);
胡椒薄荷(椒样薄荷)油6mg(在βCD包合物中);
松属(海岸松和/或湿地松和/或欧洲赤松)提取物,对蒈烯δ3标准化为4mg(βCD或γCD包含物);
葫芦巴提取物(葫芦巴净油)4mg(在γCD包合物中);
玉檀木提取物,对愈创醇标准化为4mg(在γCD包合物中);
K250延时释放剂80mg;
淀粉酶7mg;和
月桂酸Ca 5mg。
成年男性患者诊断患有病毒感染,表现出口干、干咳至呕吐程度。患者开始每天两次,4粒上述制剂的胶囊剂的治疗2天。患者咳嗽变得排痰,制剂具有明显粘液活性作用,从而导致患者健康感改善。
实施例6:勃起作用
男性受试者A开始粘液配方I的剂量施用,每天两次3粒胶囊剂。48小时内,锻炼呼吸显著改善,呼吸粘液显著减少。在初始剂量施用粘液配方I的48小时内,受试者注意到夜间阴茎肿大的发生,这是67岁受试者一段时间内未经历的。受试者将粘液配方I的剂量升高至每天两次4粒胶囊剂,立即出现夜间阴茎肿大的作用,并且对日间和夜间勃起刺激的敏感性显著增强。受试者测量该勃起作用相当于25-50mg剂量的昔多芬(sildenafil)的作用的70-85%。受试者还发现当使用每天两次,4粒胶囊剂的粘液配方I剂量时,5毫克剂量的昔多芬实际上实现了与先前剂量施用25-50毫克昔多芬相同的勃起增强,且不存在先前使用25-50毫克昔多芬所经历的副作用(其可以(例如)包括头痛、脸红、肚子痛、视力异常、鼻子不通气或流鼻涕、背痛、肌肉疼痛和恶心)。
Claims (91)
1.一种环糊精(CD)包合物制剂,其包含:桉树脑βCD包含物;莰烯βCD包含物;蒈烯δ3βCD包含物;愈创醇γCD包含物;薄荷油βCD包含物;葫芦巴提取物γCD包含物;和环糊精降解酶,任选地还包含律草烯。
2.根据权利要求1所述的CD包合物制剂,其包含:在桉树脑βCD包含物中的桉树脑(5-15wt%)(任选地以50-100mg的量);在莰烯βCD包含物中的莰烯(5-15wt%)(任选地以50-100mg的量);在蒈烯δ3βCD包含物中的蒈烯δ3(5-15wt%)(任选地以25-75mg的量);在愈创醇γCD包含物中的愈创醇(5-15wt%)(任选地以25-75mg的量);在薄荷油βCD包含物中的薄荷油(10-20wt%)(任选地以25-75mg的量);在葫芦巴γCD包含物中的葫芦巴提取物(任选地,油)(5-15wt%)(任选地以25-75mg的量)。
3.根据权利要求1或2所述的CD包合物制剂,其包含:在桉树脑βCD包含物中的桉树脑(10wt%);在莰烯βCD包含物中的莰烯(10wt%);在蒈烯δ3βCD包含物中的蒈烯δ3(10wt%);在愈创醇γCD包含物中的愈创醇(10wt%);在薄荷油βCD包含物中的薄荷油(15wt%);和在葫芦巴γCD包含物中的葫芦巴提取物(任选地,油)(10wt%)。
4.根据权利要求1至3中任一项所述的CD包合物制剂,其包含一定比例的活性成分,所述比例基本相当于包含如下活性成分的制剂中的活性成分的比例:在桉树脑βCD包含物中处于50-100mg的量的桉树脑(10wt%);在莰烯βCD包含物中处于50-100mg的量的莰烯(5-15wt%);在蒈烯δ3βCD包含物中处于25-75mg的量的蒈烯δ3(5-15wt%);在愈创醇γCD包含物中处于25-75mg的量的愈创醇(5-15wt%);在薄荷油βCD包含物中处于25-75mg的量的薄荷油(10-20wt%);和在葫芦巴γCD包含物中处于25-75mg的量的葫芦巴提取物(任选地,油)(5-15wt%)。
5.根据权利要求1至4中任一项所述的CD包合物制剂,还包含延时释放剂。
6.根据权利要求5所述的CD包合物,其中所述延时释放剂是K250。
7.根据权利要求1至6中任一项所述的CD包合物,其中所述环糊精降解酶是淀粉酶。
8.根据权利要求1至7中任一项所述的CD包合物,还包含药学上可接受的载体。
9.根据权利要求8所述的CD包合物,其中所述药学上可接受的载体是月桂酸钙。
10.根据权利要求1至9中任一项所述的CD包合物制剂,其包含:在桉树脑βCD包含物中的桉树脑(10wt%)75mg;在莰烯βCD包含物中的莰烯(10wt%)75mg;在蒈烯δ3βCD包含物中的蒈烯δ3(10wt%)50mg;在愈创醇γCD包含物中的愈创醇(10wt%)50mg;在薄荷油βCD包含物中的薄荷油(15wt%)50mg;在葫芦巴γCD包含物中的葫芦巴净(油)(10wt%)50mg。
11.根据权利要求10所述的CD包合物制剂,还包含K250延时释放剂80mg。
12.根据权利要求10或11所述的CD包合物制剂,还包含:淀粉酶5mg。
13.根据权利要求10至12中任一项所述的CD包合物制剂,还包含月桂酸钙5mg。
14.根据权利要求1至13中任一项所述的CD包合物制剂用于人类患者中气道粘液功能障碍的口服治疗的用途。
15.环糊精包合物递送媒介物用以配制用于口服治疗气道粘液功能障碍的药剂的用途,所述递送媒介物包含:
环糊精,具有空腔;
莰烯,其作为客体分子在所述环糊精的所述空腔内至少部分保留,形成环糊精包合物;
用于所述环糊精包合物的生物学可接受的载体,其中通过所述环糊精将所述客体分子稳定保留在所述生物学可接受的载体内。
16.环糊精包合物递送媒介物用以配制用于口服治疗人类男性受试者以提供勃起作用的药剂的用途,所述递送媒介物包含:
环糊精,具有空腔;
莰烯,其作为客体分子在所述环糊精的所述空腔内至少部分保留,形成环糊精包合物;
用于所述环糊精包合物的生物学可接受的载体,其中通过所述环糊精将所述客体分子稳定保留在所述生物学可接受的载体内。
17.根据权利要求15或16所述的用途,其中所述递送媒介物还包含具有环糊精降解活性、能够水解保留所述客体分子的所述环糊精的酶,其中所述酶被配制,从而在将所述媒介物递送至靶标时激活所述环糊精降解活性,从而从所述环糊精的所述空腔释放所述客体分子。
18.根据权利要求17所述的用途,其中将所述酶与所述环糊精包合物共配制。
19.根据权利要求17或18所述的用途,其中将所述酶在所述递送媒介物中与所述环糊精包合物共包装,所述递送媒介物还包含用于所述酶的生物化学可接受的载体。
20.根据权利要求17至19中任一项所述的用途,其中所述酶是淀粉酶、环糊精酶、麦芽糖淀粉酶或新普鲁兰酶。
21.根据权利要求20所述的用途,其中所述淀粉酶是哺乳动物唾液淀粉酶、哺乳动物胰淀粉酶或微生物淀粉酶。
22.根据权利要求20所述的用途,其中所述环糊精酶是微生物环糊精酶。
23.根据权利要求16至22中任一项所述的用途,其中所述环糊精是α环糊精、β环糊精或γ环糊精。
24.根据权利要求16至23中任一项所述的用途,其中所述环糊精是混合的甲基化/乙基化环糊精或疏水性烷基化环糊精。
25.根据权利要求16至24中任一项所述的用途,其中所述递送媒介物还包含一种或多种附加客体分子。
26.根据权利要求25所述的用途,其中所述附加客体分子包含一种或多种植物萜烯。
27.根据权利要求25所述的用途,其中所述附加客体分子包含桉树脑、愈创醇、律草烯和/或δ-3蒈烯。
28.根据权利要求25至27中任一项所述的用途,其中通过植物提取物或组合物提供所述附加客体分子。
29.根据权利要求28所述的用途,其中所述植物提取物是薄荷提取物或葫芦巴组合物。
30.根据权利要求29所述的用途,其中所述薄荷提取物是薄荷油。
31.根据权利要求29或30所述的用途,其中所述葫芦巴组合物是葫芦巴粉。
32.根据权利要求16至31中任一项所述的用途,其中所述环糊精与一种或多种所述客体分子之比是5:1至1:5。
33.根据权利要求16至32中任一项所述的用途,其中所述环糊精是α环糊精。
34.根据权利要求16至33中任一项所述的用途,其中所述递送媒介物还包含药物或前体药物客体分子。
35.根据权利要求34所述的用途,其中所述药物或前体药物客体分子是磷酸二酯酶5型(PDE5)抑制剂。
36.根据权利要求35所述的用途,其中所述PDE5抑制剂是昔多芬、阿伐那非、罗地那非、米罗那非、他达拉非、伐地那非、乌地那非、扎普司特、kra-chai-dom、淫羊藿苷、本扎那非或达生他非。
37.根据权利要求16至36中任一项所述的用途,其中所述生物学可接受的载体是药学上可接受的载体。
38.根据权利要求16至37中任一项所述的用途,其中将所述递送媒介物配制用于一种或多种所述客体分子的缓释。
39.根据权利要求16或17-38中任一项所述的用途,其中所述气道粘液功能障碍是疾病症状,所述疾病是囊性纤维化、哮喘、慢性阻塞性肺病、原发性纤毛运动障碍、非囊性纤维化支气管扩张、泛细支气管炎或免疫缺陷状况。
40.根据权利要求16或18-38中任一项所述的用途,其中所述气道粘液功能障碍是与肺力学破坏有关的病况的症状。
41.根据权利要求40所述的用途,其中所述病况是插管、瘫痪、昏迷或手术创伤。
42.根据权利要求17-38中任一项所述的用途,其中所述人类男性受试者患有勃起功能障碍。
43.一种用于口服治疗人受试者中的气道粘液功能障碍的方法,其包括施用有效量的环糊精包合物递送媒介物,所述环糊精包合物递送媒介物包含:
环糊精,具有空腔;
莰烯,其作为客体分子在所述环糊精的所述空腔内至少部分保留,形成环糊精包合物;和
用于所述环糊精包合物的生物学可接受的载体,其中通过所述环糊精将所述客体分子稳定保留在所述生物学可接受的载体内。
44.一种用于口服治疗人类男性受试者以提供勃起作用的方法,其包括施用有效量的环糊精包合物递送媒介物,所述环糊精包合物递送媒介物包含:
环糊精,具有空腔;
莰烯,其作为客体分子在所述环糊精的所述空腔内至少部分保留,形成环糊精包合物;
用于所述环糊精包合物的生物学可接受的载体,其中通过所述环糊精将所述客体分子稳定保留在所述生物学可接受的载体内。
45.根据权利要求43或44所述的方法,其中所述递送媒介物还包含具有环糊精降解活性、能够水解保留所述客体分子的所述环糊精的酶,其中所述酶被配制,从而在将所述媒介物递送至靶标时激活所述环糊精降解活性,从而从所述环糊精的所述空腔释放所述客体分子。
46.根据权利要求45所述的方法,其中将所述酶与所述环糊精包合物共配制。
47.根据权利要求45或46所述的方法,其中将所述酶在所述递送媒介物中与所述环糊精包合物共包装,所述递送媒介物还包含用于所述酶的生物化学可接受的载体。
48.根据权利要求45至47中任一项所述的方法,其中所述酶是淀粉酶、环糊精酶、麦芽糖淀粉酶或新普鲁兰酶。
49.根据权利要求48所述的方法,其中所述淀粉酶是哺乳动物唾液淀粉酶、哺乳动物胰淀粉酶或微生物淀粉酶。
50.根据权利要求48所述的方法,其中所述环糊精酶是微生物环糊精酶。
51.根据权利要求43至50中任一项所述的方法,其中所述环糊精是α环糊精、β环糊精或γ环糊精。
52.根据权利要求43至51中任一项所述的方法,其中所述环糊精是混合的甲基化/乙基化环糊精或疏水性烷基化环糊精。
53.根据权利要求43至52中任一项所述的方法,其中所述递送媒介物还包含一种或多种附加客体分子。
54.根据权利要求53所述的方法,其中所述附加客体分子包含一种或多种植物萜烯。
55.根据权利要求53所述的方法,其中所述附加客体分子包含桉树脑、愈创醇、律草烯和/或δ-3蒈烯。
56.根据权利要求53至55中任一项所述的方法,其中通过植物提取物或组合物提供所述附加客体分子。
57.根据权利要求56所述的方法,其中所述植物提取物是薄荷提取物和/或葫芦巴组合物。
58.根据权利要求57所述的方法,其中所述薄荷提取物是薄荷油。
59.根据权利要求57或58所述的方法,其中所述葫芦巴组合物是葫芦巴粉。
60.根据权利要求43至59中任一项所述的方法,其中所述环糊精与一种或多种所述客体分子之比是5:1至1:5。
61.根据权利要求43至60中任一项所述的方法,其中所述环糊精是α环糊精。
62.根据权利要求43至61中任一项所述的方法,其中所述递送媒介物还包含药物或前体药物客体分子。
63.根据权利要求62所述的方法,其中所述药物或前体药物客体分子是磷酸二酯酶5型(PDE5)抑制剂。
64.根据权利要求63所述的方法,其中所述PDE5抑制剂是昔多芬、阿伐那非、罗地那非、米罗那非、他达拉非、伐地那非、乌地那非、扎普司特、kra-chai-dom、淫羊藿苷、本扎那非或达生他非。
65.根据权利要求43至64中任一项所述的方法,其中所述生物学可接受的载体是药学上可接受的载体。
66.根据权利要求43至65中任一项所述的方法,其中将所述递送媒介物配制用于一种或多种所述客体分子的缓释。
67.根据权利要求43或45-66中任一项所述的方法,其中所述气道粘液功能障碍是疾病症状,所述疾病是囊性纤维化、哮喘、慢性阻塞性肺病、原发性纤毛运动障碍、非囊性纤维化支气管扩张、泛细支气管炎或免疫缺陷状况。
68.根据权利要求43或45-66中任一项所述的方法,其中所述气道粘液功能障碍是与肺力学破坏有关的病况的症状。
69.根据权利要求68所述的方法,其中所述病况是插管、瘫痪、昏迷或手术创伤。
70.根据权利要求44-66中任一项所述的方法,其中所述人类男性受试者患有勃起功能障碍。
71.一种环糊精包合物递送媒介物,包含:
环糊精,具有空腔;
莰烯,其作为客体分子在所述环糊精的所述空腔内至少部分保留,形成环糊精包合物;
PDE5抑制剂;和
用于所述环糊精包合物和所述PDE5抑制剂的生物学可接受的载体,其中通过所述环糊精将所述客体分子稳定保留在所述生物学可接受的载体内。
72.根据权利要求71所述的递送媒介物,还包含具有环糊精降解活性、能够水解保留所述客体分子的所述环糊精的酶,其中所述酶被配制,从而在将所述媒介物递送至靶标时激活所述环糊精降解活性,从而从所述环糊精的所述空腔释放所述客体分子。
73.根据权利要求71或72所述的递送媒介物,其中所述PDE5抑制剂是附加客体分子,由此提供作为包合物的所述PDE5抑制剂。
74.根据权利要求71-73中任一项所述的递送媒介物,其中所述PDE5抑制剂是昔多芬、阿伐那非、罗地那非、米罗那非、他达拉非、伐地那非、乌地那非、扎普司特、kra-chai-dom、淫羊藿苷、本扎那非或达生他非。
75.一种环糊精(CD)包合物制剂,包含:
在CD包含物中包含桉树脑的桉树(桃金娘科(Myrtaceae))提取物;
在CD包含物中包含莰烯的松节树(Syncarpia glomulifera)提取物;
在CD包含物中的薄荷(椒样薄荷(Mentha piperita))油;
在CD包含物中包含蒈烯δ3的松属(Pinus)提取物;
在CD包含物中的葫芦巴提取物;和
在CD包含物中包含愈创醇的玉檀木(Bulnesia sarmientoi)提取物。
76.根据权利要求75所述的制剂,还包含:
延时释放剂;任选地K250延时释放剂。
77.根据权利要求75或76所述的制剂,还包含环糊精降解酶;任选地淀粉酶、环糊精酶、麦芽糖淀粉酶或新普鲁兰酶;任选地哺乳动物唾液淀粉酶、哺乳动物胰淀粉酶或微生物淀粉酶。
78.根据权利要求75至77中任一项所述的制剂,其中每个包含物中的环糊精(CD)是α环糊精、β环糊精或γ环糊精。
79.根据权利要求75至78中任一项所述的制剂,还包含月桂酸钙。
80.根据权利要求75至79中任一项所述的制剂,其中:
所述桉树(桃金娘科)提取物包含约4-8mg,任选地6mg的桉树脑;和/或
所述松节树提取物包含约4-8mg,任选地6mg莰烯;和/或
以约4-8mg,任选地6mg在所述CD包含物中提供所述薄荷(椒样薄荷)油;和/或
所述松属提取物包含约2-6mg,任选地4mg蒈烯δ3;和/或
以约2-6mg,任选地4mg在所述CD包含物中提供所述葫芦巴提取物;和/或
所述玉檀木提取物包含约2-6mg,任选地4mg愈创醇。
81.根据权利要求75至79中任一项所述的制剂,其中:
所述桉树(桃金娘科)提取物的CD包含物包含桉树脑βCD包含物;和/或
所述松节树提取物的CD包含物包含莰烯βCD包含物;和/或
在βCD包含物中至少部分提供所述薄荷(椒样薄荷)油;和/或
所述松属提取物的CD包含物包含蒈烯δ3βCD包含物;和/或
在γCD包含物中至少部分提供所述葫芦巴提取物;和/或
所述玉檀木提取物的CD包含物包含愈创醇γCD包含物。
82.根据权利要求75至79中任一项所述的制剂,还包含律草烯。
83.根据权利要求75至82中任一项所述的组合物作为粘液活性剂治疗对其有需要的受试者的用途。
84.根据权利要求75至82中任一项所述的组合物配制粘液活性药剂的用途。
85.根据权利要求75至82中任一项所述的组合物,用作治疗对其有需要的受试者的粘液活性剂。
86.根据权利要求75至82中任一项所述的组合物,用于配制粘液活性药剂。
87.一种治疗患者的气道病症的方法,其包含向所述患者施用治疗有效量的根据权利要求75至82中任一项所述的组合物。
88.根据权利要求87所述的方法,其中所述有效量对于帮助从所述患者的上和/或下气道清除粘液有效。
89.根据权利要求87或88所述的方法,其中所述有效量作为粘液活性剂有效;任选地作为化痰和/或溶粘液和/或粘液促动和/或粘液调节剂有效。
90.根据权利要求87至89中任一项所述的方法,其中所述气道病症是以粘液分泌过多或浓稠为特征的呼吸道疾病或病况。
91.根据权利要求87至90中任一项所述的方法,其中所述气道病症是哮喘、慢性阻塞性肺病(COPD)、囊性纤维化(CF)、CF相关支气管扩张、非CF支气管扩张、病毒性细支气管炎、细菌性细支气管炎或者微生物(任选地细菌或病毒)感染。
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US20230142208A1 (en) | 2023-05-11 |
KR20220156931A (ko) | 2022-11-28 |
EP4125830A1 (en) | 2023-02-08 |
CA3170465A1 (en) | 2021-09-30 |
WO2021191803A1 (en) | 2021-09-30 |
BR112022019223A2 (pt) | 2022-11-29 |
IL296661A (en) | 2022-11-01 |
AU2021240473A1 (en) | 2022-09-29 |
JP2023519232A (ja) | 2023-05-10 |
EP4125830A4 (en) | 2023-12-20 |
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