CN111491625A - 溶解尿酸单钠以治疗痛风 - Google Patents
溶解尿酸单钠以治疗痛风 Download PDFInfo
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- CN111491625A CN111491625A CN201880080770.8A CN201880080770A CN111491625A CN 111491625 A CN111491625 A CN 111491625A CN 201880080770 A CN201880080770 A CN 201880080770A CN 111491625 A CN111491625 A CN 111491625A
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Abstract
本发明提供了用于治疗痛风的尿酸单钠的溶解度增强剂。溶解度增强剂可以是药学上可接受的碱、溶剂、脂质、表面活性剂、药学上可接受的酸、环糊精、至少一种对羟基苯甲酸酯或其组合。
Description
本发明涉及医学用途,特别是痛风的治疗。
痛风是一种炎症性关节炎的形式。它是一个严重的全球性健康问题,在美国、欧盟和日本的总患病人数约为1800万。随着生活水平的提高和更长的预期寿命,痛风正变得越来越普遍,并且是男性和绝经后女性中最常见的炎症性关节炎形式。
痛风是嘌呤代谢的疾病。它由尿酸单钠(MSU)一水合物晶体形式的尿酸(如下所示)沉淀到患者关节内和周围引起。这些MSU晶体引起炎症反应,导致患者感到疼痛。
MSU晶体通常存在于患者受影响关节的滑液中或周围组织内,例如滑膜或软骨。这些MSU晶体的沉淀在患者的关节中形成沉积物,称为“痛风石”。
痛风的初始阶段是无症状的高尿酸血症(即血液中尿酸水平升高)。据信,血液中尿酸水平升高会导致痛风的风险增加,但确切的关系尚不清楚。许多无症状高尿酸血症的患者不会遭受痛风发作。
痛风的症状包括受影响的关节周围突然剧烈的疼痛,以及肿胀和红斑(发红)。这种疼痛通常发生1至3天,并且通常在夜间发生。大脚趾底部的关节是急性痛风发作的最常见部位。其他可能受影响的关节包括脚踝、膝盖、手腕、手指和肘部。
罕见的关节痛和痛风发作的初始阶段称为急性痛风。但是,如果不进行治疗,痛风会发展成慢性疾病。急性症状缓解后会发生间歇性痛风,并且低度炎症可能会保留在关节内,从而引起不明显的损害。在此阶段,血液中尿酸水平升高,促使MSU晶体沉淀到患者受影响的关节(或多个关节)中,从而导致痛风石形成和骨骼侵蚀性变化。慢性痛风表现为持续的关节痛,伴有反复的急性痛风发作,并因痛风石的形成而复杂化。
目前,痛风的治疗选择有限,没有一种疗法可以快速治疗痛风病因。通常,当前治疗的最初目的是通过预防炎症来解决急性痛风发作的症状。通常使用非甾体类抗炎药(NSAID)、秋水仙碱或糖皮质激素类药物来实现。但是,这些治疗方法并未解决痛风的根本原因,即MSU结晶进入关节。
对于患有痛风的患者,最常见的长期治疗是着重于降低血液中的尿酸水平。这可以通过改变患者的饮食来实现,从而减少尿酸的供应(通过减少嘌呤的摄入量)进入血液。另一种方法是通过使用抑制尿酸产生或增加尿酸排泄的药物。
尿酸是通过嘌呤的代谢在体内形成的,特别是黄嘌呤氧化酶在黄嘌呤的代谢中形成的,因此任何黄嘌呤氧化酶抑制剂最终都会降低血液中的尿酸水平。这些治疗方法背后的想法是减少血尿酸以解决关节中的晶体形成。但是,已经观察到,即使将血尿酸水平降低到可接受的水平或更低的水平(例如,每分升约6mg),MSU晶体的去除也可能需要两到三年的时间(E.Pascual等人,Annal of Rheumatic Disease,2007,66,2056-2058)。因此,患有痛风的患者在进行治疗的同时经常遭受明显的疼痛和不适以及进一步的急性痛风发作。
因此,在本领域中需要一种更有效的痛风治疗,特别是易于施用、有效减轻症状、毒性低并且比目前可用的治疗更便宜的痛风治疗。
因此,本发明提供了用于痛风治疗的尿酸单钠的溶解度增强剂。本发明还提供了用于尿酸单钠的溶解度增强剂,其用于通过溶解MSU晶体来治疗痛风。
令人惊讶地发现,在痛风的治疗中使用本发明的溶解度增强剂增加了MSU晶体的溶解度和MSU晶体在体内溶解的速率。进而,MSU晶体溶解速度的增加减轻了痛风患者的痛苦,并降低了患者遭受进一步的急性痛风发作的风险。
溶解度增强剂可以选自至少一种药学上可接受的碱、至少一种溶剂、至少一种脂质组分、至少一种表面活性剂、至少一种药学上可接受的酸、至少一种环糊精、至少一种对羟基苯甲酸酯或其组合。这些“通常被认为是安全的”赋形剂(被FDA认可)增加MSU晶体在患者体内的局部溶解度,从而有效治疗痛风。
在一个实施方案中,溶解度增强剂是药学上可接受的碱,并且选自金属碳酸盐、金属氢氧化物、伯胺、仲胺、叔胺、芳族胺或其组合。
在另一个实施方案中,溶解度增强剂是溶剂,并且选自醇、二醇、多元醇、芳基或杂芳基醇、芳基烷基或杂芳基烷基醇、醚、聚醚、内酰胺、酰胺、烷基亚砜、酮、醛、腈、酯、异氰化物或其组合。
在另一个实施方案中,溶解度增强剂是脂质,并且选自C4-C28羧酸、C11-C28醇、C1-C28烷基C1-C28链烷酸酯、C6-C12甘油一酯、C6-C12甘油二酯、C6-C12甘油三酯、C1-C28烷基N,N-二取代的C1-C6氨基C1-C28链烷酸酯,或其组合。
在另一个实施方案中,溶解度增强剂是选自以下的表面活性剂:山梨聚糖酯、乙氧基化山梨聚糖酯、山梨醇酯、乙氧基化山梨醇酯、聚氧乙烯化蓖麻油、聚乙氧基化C11-C28醇、聚乙氧基化C4-C28羧酸酯、聚氧乙烯-聚氧丙烯嵌段共聚物,或其组合。
在另一个实施方案中,溶解度增强剂是药学上可接受的酸,并且选自C1-C7羧酸、C2-C10二羧酸、C1-C5α羟基酸、C1-C5β羟基酸、C1-C5γ羟基酸、磺酸,或其组合。
在另一个实施方案中,溶解度增强剂是环糊精。优选地,环糊精是具有6-8个吡喃葡萄糖苷单元的环糊精。更优选地,环糊精选自α-环糊精、羟丙基-β-环糊精或磺基丁基醚-β-环糊精。
在另一个实施方案中,溶解度增强剂是对羟基苯甲酸酯,而对羟基苯甲酸酯是C1-C20对羟基苯甲酸烷基酯。
在另一个实施方案中,溶解度增强剂选自山梨聚糖单油酸酯,富马酸,PEG-8辛酸辛酸甘油二酯(以出售),二甲基甲酰胺,四甘醇,N-甲基吡咯烷酮,肉豆蔻酸异丙酯,二甲基乙酰胺,乙酸香叶酯,PEG 200,PEG 300,聚氧乙烯(20)山梨聚糖单油酸酯,glucopon,苄醇,4-羟基苄醇,三醋精,PEG-35蓖麻油(以EL出售),油酸,PEG-40氢化蓖麻油(以RH40和RH40出售),卵磷脂(以PG50出售),苯甲酸,4-羟基苯甲酸,对羟基苯甲酸甲酯,对羟基苯甲酸丙酯,水杨酸或其组合。
在另一个实施方案中,溶解度增强剂是PEG-40氢化蓖麻油、2-(2-乙氧基乙氧基)乙醇或其组合。
在另一个实施方案中,用途包括通过注射至患病区域来施用溶解度增强剂。该方法具有将溶解度增强剂直接递送至患病区域的优点。这使得溶解度增强剂具有高生物利用度,并允许溶解度增强剂的快速作用。因此,本发明还提供了一种包含本发明溶解度增强剂的注射器。
在另一个实施方案中,用途包括经皮向患病区域施用所述溶解度增强剂。这种方法具有将溶解度增强剂直接施用于患病区域的优点,同时降低了全身性副作用的风险。当经皮施用时,溶解度增强剂可以与皮肤渗透促进剂组合施用。这提供了增加经皮施用的溶解度增强剂的生物利用度的优点。因此,本发明还提供了包含本发明的溶解度增强剂的透皮贴剂。透皮贴剂及其制造在本领域中是众所周知的,例如参见EP 1 047 409。透皮贴剂可包括:远离皮肤的层,称为“背衬层”;包含本发明的溶解度增强剂的层,称为“储层”;面对皮肤的包含硅聚合物和增粘剂的层,称为“粘合层”;和溶解度增强剂不可渗透层,例如硅化的PET、硅化的聚丙烯、硅化的聚乙烯、含氟聚合物涂覆的PET、含氟聚合物涂覆的聚丙烯、含氟聚合物涂覆的聚乙烯,其在施用前将其从贴剂上除去。
在另一个实施方案中,用途包括与至少一种非甾体抗炎药、至少一种黄嘌呤氧化酶抑制剂、秋水仙碱、至少一种糖皮质激素或其组合联合施用溶解度增强剂。该实施方案可以提供改善MSU晶体的溶解速率并减少患有痛风的患者所感到的疼痛的优点。因此,本发明还提供了一种包含本发明的溶解度增强剂和至少一种非甾体抗炎药的注射器。本发明还提供了包含本发明的溶解度增强剂和至少一种非甾体抗炎药的透皮贴剂。
在另一个实施方案中,所述用途包括与超声疗法、热疗法和/或饮食改变组合施用溶解度增强剂,以降低患者的尿酸水平。该实施方案可以提供改善MSU晶体的溶解速率的优点。
本发明还提供了一种治疗痛风的方法,该方法包括给予有效量的本发明的溶解度增强剂的步骤。它还提供了本发明的溶解度增强剂在制备用于治疗痛风的药物中的用途。还提供了本发明的溶解度增强剂在制备用于通过溶解MSU晶体治疗痛风的药物中的用途。
现在将参考附图描述本发明,在附图中图1示出了患有痛风的患者的典型的患痛风的关节。
本发明提供了用于治疗痛风的尿酸单钠的溶解度增强剂。溶解度增强剂可以是药学上可接受的碱、溶剂、脂质、表面活性剂、药学上可接受的酸或其组合。
治疗促进了引起痛风的尿酸单钠晶体溶解到滑液中,提供快速有效的痛风治疗。
患痛风的典型关节如图1所示。关节具有关节囊10、滑膜11、包含滑液12的腔和关节软骨13。如图所示,MSU晶体14在受影响关节的滑液内形成。这些可以被吸收到关节囊或滑膜15中。如果血液中的尿酸水平长期处于高水平,则可能在关节中形成MSU晶体16的沉积物。
已经发现,溶解度增强剂能够增加MSU晶体在体内(特别是在滑液中)的局部溶解度。这有助于快速溶解MSU晶体,从而有效治疗痛风。痛风的这种治疗有效地从患病的关节中及时清除了MSU晶体。
MSU通常是MSU一水合物。
溶解度增强效果可以通过简单的测试来测量:
将5mg MSU晶体的样品悬浮在4.75mL磷酸盐缓冲盐水(由水和0.14mol/L NaCl和0.01N磷酸盐缓冲液组成,pH值为7.4)中;
加入0.25mL溶解度增强剂;
将样品混合16小时;
取等分的上清液,过滤并确定溶液中MSU的浓度;
将浓度与不含溶解度增强剂的对照样品进行比较;
如果溶液中的MSU比对照要多,则发现阳性结果。
本发明的溶解度增强剂改善了尿酸单钠的溶解度。通常,本发明的溶解度增强剂将溶解度提高至少5%。优选地,本发明的溶解度增强剂将溶解度提高至少10%,更优选至少20%,最优选至少30%。所述提高是基于与对照(即,上文描述的不存在溶解度增强剂的磷酸盐缓冲盐水)的比较。
溶解度增强剂可以选自至少一种药学上可接受的碱、至少一种溶剂、至少一种脂质组分、至少一种表面活性剂、至少一种药学上可接受的酸、至少一种环糊精、至少一种对羟基苯甲酸酯或其组合。优选地,溶解度增强剂选自至少一种药学上可接受的碱、至少一种溶剂、至少一种脂质组分、至少一种表面活性剂、至少一种药学上可接受的酸、至少一种环糊精或其组合。
在一个实施方案中,溶解度增强剂是药学上可接受的碱,并且选自金属碳酸盐、金属氢氧化物、氨、伯胺、仲胺、叔胺、二胺、含氮杂芳基、三胺或它们的组合。
优选地,药学上可接受的碱是金属碳酸盐,例如第1、2、3或12族金属碳酸盐。更优选地,金属碳酸盐选自碳酸钠、碳酸钾、碳酸镁、碳酸钙、碳酸铝或碳酸锌。
优选地,药学上可接受的碱是金属氢氧化物或其组合。优选地,金属氢氧化物选自1、2、3或12族金属氢氧化物。甚至更优选地,金属氢氧化物选自氢氧化钠、氢氧化钾、氢氧化镁、氢氧化钙、氢氧化铝或氢氧化锌。
或者,药学上可接受的碱可以是伯胺。优选地,伯胺选自伯C1-C8烷基胺(例如乙胺、叔丁胺)、赖氨酸或三(羟甲基)氨基甲烷。
药学上可接受的碱也可以是仲胺。优选地,仲胺选自二-C1-C8烷基取代的胺(例如二甲胺和二乙胺)或葡甲胺。
药学上可接受的碱也可以是叔胺。优选地,叔胺选自三-C1-C8烷基取代的胺(例如三甲胺和三乙胺)或普鲁卡因。
药学上可接受的碱也可以是二胺。优选地,二胺选自二胺取代的C1-C8烷基(例如1,2-二氨基丙烷和乙二胺)或苄星青霉素。
药学上可接受的碱也可以是含氮杂芳基。优选地,含氮杂芳基是4-8元杂芳基。更优选地,含氮杂芳基是吡啶。
药学上可接受的碱也可以是三胺。优选地,三胺选自三胺取代的C1-C8烷基(例如二亚乙基三胺)。
如本文所用,术语Cn-烷基表示包含n个碳原子的烷基链。烷基链可以是支链或直链的,并且可以是单不饱和的、二不饱和的或多不饱和的。术语Cn-芳基表示含有n个碳原子的芳基环。例如C6-芳基可以表示苯基。术语Cn杂芳基表示含有n个碳原子和最多3例独立地选自N、O或S的杂原子的芳基环。例如,C5杂芳基可以表示吡啶。
在另一个实施方案中,溶解度增强剂是溶剂,并且选自醇、二醇、多元醇、芳基醇、杂芳基醇、芳基烷基醇、杂芳基烷基醇、醚、聚醚、内酰胺、酰胺、烷基亚砜、酮、醛、腈、酯、异氰化物、环糊精或其组合。
溶剂可以是醇。优选地,醇选自C1-C10醇。更优选地,醇选自甲醇、乙醇、丙醇、丁醇、薄荷醇或戊醇。
溶剂可以是二醇。优选地,所述二醇选自C1-C10二醇。更优选地,二醇选自单乙二醇、丙二醇、1,3-丙二醇、1,2-丁二醇、1,3-丁二醇、1,4-丁二醇或1,5-戊二醇。
溶剂可以是多元醇。优选地,多元醇选自C1-C10多元醇。更优选地,多元醇选自甘油。
溶剂可以是芳基醇。优选地,芳基醇选自C4-C8芳基醇或羟基取代的苄基醇。更优选地,芳基醇是2-羟基苄基醇、3-羟基苄基醇、4-羟基苄基醇、苄基醇或d-α-生育酚。
溶剂可以是杂芳基醇。优选地,杂芳基醇是C4-C8杂芳基醇。
溶剂可以是芳基烷基醇。优选地,芳基烷基醇选自C5-C10芳基C4-C8烷基醇。
溶剂可以是杂芳基烷基醇。优选地,杂芳基烷基醇选自C4-C10杂芳基C4-C8烷基醇。
溶剂可以是醚。优选地,醚是C2-C20醚。更优选地,醚选自二甲氧基乙烷、1,4-二噁烷或四氢呋喃(THF)。
溶剂可以是聚醚。优选地,聚醚是聚氧乙烯、聚氧丙烯-聚氧乙烯共聚物或其组合。更优选地,聚醚选自PEG 200、PEG 300、PEG 400四甘醇,泊洛沙姆188(被称为F-68)或泊洛沙姆407(被称为Pluronic F127)或泊洛沙姆182(被称为Pluronic L62)。
溶剂可以是内酰胺。优选地,内酰胺是C3-C7内酰胺。更优选地,内酰胺是N-甲基-2-吡咯烷(NMP)。
溶剂可以是酰胺。优选地,酰胺是C1-C10酰胺。更优选地,C1-C10酰胺选自二甲基乙酰胺(DMA)和二甲基甲酰胺(DMF)。
溶剂可以是烷基亚砜。优选地,烷基亚砜选自C2-C10烷基亚砜。更优选地,C2-C10烷基亚砜是二甲基亚砜(DMSO)。
溶剂可以是酮。优选地,所述酮选自C3-C10酮。更优选地,酮是丙酮或薄荷酮。
溶剂可以是醛。优选地,醛是C1-C10醛。醛更优选为乙醛。
溶剂可以是腈。优选地,腈是C2-C10腈。更优选地,腈是乙腈。
溶剂可以是酯。优选地,该酯是C2-C8酯。更优选地,该酯是乙酸乙酯、油酸乙酯或三醋精。
溶剂可以是异氰化物。优选地,异氰酸酯选自C2-C10异氰化物。更优选地,异氰化物选自甲基异氰化物。
在另一个实施方案中,溶解度增强剂是脂质,并且选自C4-C28羧酸,C11-C28醇,C1-C28烷基C1-C28链烷酸酯,C6-C12甘油一酯,C6-C12甘油二酯,C6-C12甘油三酯,C1-C28烷基N,N-二-C1-C6取代的氨基C1-C28链烷酸酯,C10-C30烷烃,磷脂或其组合。
脂质可以是C4-C28羧酸。更优选地,脂质是C10-C25羧酸。优选地,C4-C28羧酸是ω-3、ω-6或ω-9脂肪酸。优选地,C4-C28羧酸选自癸酸,油酸,亚油酸,亚麻酸,癸酸,十一烷酸,月桂酸,十三烷酸,肉豆蔻酸,十五烷酸,棕榈酸,硬脂酸,乙基十八烷酸,反式亚油酸(linelaidic acid),新癸酸,天竺葵酸,十八碳烯酸,癸酸(capric acid)(癸酸(decanoicacid)),己酸(caproic acid)(己酸(hexanoic acid)),辛酸(caprylic acid)(辛酸(octanoic acid)),蓖麻油酸,十一碳烯酸,苯甲酸或羟基取代的苯甲酸(例如4-羟基苯甲酸、3-羟基苯甲酸、2-羟基苯甲酸)。优选地,脂质是C4-C28羧酸的组合,例如在蓖麻油、棉籽油、橄榄油、花生油、薄荷油、红花油、芝麻油、大豆脂肪酸、大豆油和氢化大豆中发现的那些羧酸。
脂质可以是C11-C28醇。优选地,C11-C28醇选自癸醇、月桂醇、亚油基醇、橙花叔醇、1-壬醇、正辛醇或油醇。
脂质可以是C4-C28烷基C4-C28链烷酸酯。优选地,C4-C28烷基C4-C28链烷酸酯是C6-C25烷基C6-C25链烷酸酯,更优选地是C8-C20烷基C8-C20链烷酸酯。优选地,C4-C28烷基C4-C28链烷酸酯选自异硬脂酸异丙酯,亚油酸异丙酯,肉豆蔻酸异丙酯,棕榈酸异丙酯,乙酸甲酯,癸酸甲酯,月桂酸甲酯,丙酸甲酯,戊酸甲酯,乙酸辛酯,油酸油酯,乙酸乙酯,丙酸乙酯,乙酸香叶酯,乙酸丁酯,月桂酸十六烷基酯或1-单己酰基甘油。
脂质可以是C6-C12烷基甘油一酯。优选地,脂质组分是二-C6-C12烷基甘油酯。优选地,脂质组分是三-C6-C12烷基甘油酯。
脂质可以是C1-C28烷基N,N-二-C1-C6烷基取代的氨基C1-C28链烷酸酯。更优选地,脂质组分是C5-C15烷基N,N-二-C1-C6烷基取代的氨基C1-C10链烷酸酯。优选地,C1-C28烷基N,N-二-C1-C6烷基取代的氨基C1-C28链烷酸酯选自癸基N,N-二甲基氨基乙酸酯,癸基N,N-二甲基氨基异丙酸酯,十二烷基N,N-二甲基氨基乙酸酯,十二烷基N,N-二甲基氨基异丙酸酯,十二烷基N,N-二甲基氨基丁酸酯,十二烷基2-(二甲基氨基)丙酸酯,十四烷基N,N-二甲基氨基乙酸酯或N,N-二甲基氨基乙酸辛酯。
脂质可以是磷脂。优选地,磷脂选自二硬脂酰基磷脂酰甘油(也称为DSPG)、L-α-二肉豆蔻酰基磷脂酰胆碱(DMPC)、L-α-二肉豆蔻酰基磷脂酰甘油或1-油酰基-2-棕榈酰基-磷脂酰胆碱。
脂质可以是选自以下的各种各样脂质:癸二酸二乙酯,琥珀酸二乙酯,癸二酸二异丙酯,乙酰乙酸乙脂,甘油单醚,甘油单月桂酸酯,甘油单油酸酯,甘油单亚油酸酯,苄基烟酸酯,正戊基N-乙酰基脯氨酸酯,蔗糖单油酸酯或蔗糖单月桂酸酯。
在另一个实施方案中,溶解度增强剂是选自以下的表面活性剂:山梨聚糖酯,山梨糖醇酯,乙氧基化山梨聚糖酯,乙氧基化山梨糖醇酯,聚氧蓖麻油,乙氧基化二醇烷基醚,C4-C28羧酸的聚氧化烯酯,C4-C28链烷酸钠或其组合。
表面活性剂可以是山梨聚糖酯。优选地,山梨聚糖酯是山梨聚糖单C4-C28烷基酯。更优选地,山梨聚糖单C4-C28烷基酯选自山梨聚糖单月桂酸酯(Span20)、山梨聚糖单油酸酯(Span 80)和山梨聚糖单棕榈酸酯(Span 40)。优选地,山梨聚糖酯是山梨聚糖二-C4-C28烷基酯。更优选地,山梨聚糖二-C4-C28烷基酯选自山梨聚糖二月桂酸酯、山梨聚糖二油酸酯。优选地,山梨聚糖酯是山梨聚糖三-C4-C28烷基酯。优选地,山梨聚糖三-C4-C28烷基酯选自山梨聚糖三月桂酸酯、山梨聚糖三油酸酯或山梨聚糖三硬脂酸酯(Span 65)。
表面活性剂可以是山梨糖醇酯。优选地,山梨糖醇酯是C4-C28烷基山梨糖醇酯。
表面活性剂可以是乙氧基化的山梨聚糖酯。优选地,乙氧基化的山梨聚糖酯选自聚氧乙烯(20)山梨聚糖单月桂酸酯(吐温20)、聚氧乙烯(20)山梨聚糖单油酸酯(吐温80)、聚氧乙烯(20)山梨聚糖单棕榈酸酯(Tween 40)、聚氧乙烯(20)山梨聚糖单硬脂酸酯(60)、和聚氧乙烯(20)山梨聚糖三油酸酯(吐温85)。
表面活性剂可以是C4-C28羧酸聚氧化烯酯。优选地,C4-C28羧酸聚氧化烯酯选自PEG300油酸甘油酯(也称为M-1944CS),PEG 300亚油酸甘油酯(也称为M-2125CS),PEG 400辛酸/癸酸甘油酯(也称为),PEG 400单硬脂酸酯,PEG 1750单硬脂酸酯,月桂酰聚氧基32甘油酯(也称为Gellucire 44/14),硬脂酰聚氧基-32甘油酯(也称为Gellucire 50/13),PEG 300辛酸/癸酸甘油酯(也称为Softigen 767),聚乙二醇(15)-羟基硬脂酸酯(称为HS 15)或丙二醇单辛酸酯(也称为Capmul PG-8NF)。
表面活性剂可以是C4-C28醇的聚氧乙烯醚。优选地,C4-C28醇被2至100个氧化乙烯单元取代。更优选地,C4-C28醇的聚氧乙烯醚选自聚氧乙烯(4)月桂基醚(Brij 30),乙氧基化十二烷醇(Brij 36T),聚氧乙烯月桂基醚(Brij 35),聚氧乙烯(2)鲸蜡基醚(Brij 52),聚氧乙烯(10)鲸蜡基醚(Brij 56),聚氧乙烯(2)十六烷基醚(Brij 58),聚氧乙烯(2)硬脂基醚(Brij 72),聚氧乙烯10硬脂基醚(Brij 76),聚氧乙烯(20)硬脂基醚(Brij 78),聚氧乙烯(2)油基醚(Brij 92),聚氧乙烯(10)油基醚(Brij 96),或聚氧乙烯(2)油基醚(Brij-98)。
表面活性剂可以是C4-C28链烷酸钠。优选地,C4-C28链烷酸钠选自月桂酸钠或油酸钠。
表面活性剂可以是选自以下的各种各样表面活性剂:d-α-生育酚聚乙二醇1000琥珀酸酯(TPGS),十六烷基三甲基溴化铵,羟基聚乙氧基十二烷,月桂酰肌氨酸,壬氧基酚,辛氧基酚,苯磺酸酯,聚氧乙烯(8)壬基酚(称为NP),或4-辛基苯酚聚乙氧基化物(称为Triton X-100)。
在另一个实施方案中,溶解度增强剂是药学上可接受的酸,并且选自C1-C7羧酸、C2-C10二羧酸、C1-C5羟基酸、磺酸或其组合。
优选地,药学上可接受的酸是C1-C7羧酸。优选地,药学上可接受的酸是C1-C3羧酸。甚至更优选地,C1-C3羧酸是甲酸、乙酸或丙酸。
药学上可接受的酸可以是C2-C10二羧酸。优选地,C2-C10二羧酸选自草酸、丙二酸、癸二酸、琥珀酸、己二酸、富马酸或马来酸。
药学上可接受的酸可以是C1-C5羟基酸。
药学上可接受的酸可以是磺酸。优选地,磺酸选自2-羟基乙磺酸、苯磺酸、樟脑-10-磺酸(+)、乙烷-1,2-二磺酸、乙烷磺酸、甲磺酸、萘-1,5-二磺酸、萘-2-磺酸或对甲苯磺酸。
药学上可接受的酸可以是选自以下的各种各样酸:4-羟基苯甲酸,1-羟基-2-萘甲酸,2,2-二氯乙酸,2-氧戊二酸,4-乙酰氨基苯甲酸,4-氨基水杨酸,抗坏血酸(L),天冬氨酸(L),苯甲酸,樟脑酸(+),碳酸,肉桂酸,柠檬酸,环酰胺酸,十二烷基硫酸,乳酸,半乳糖酸,龙胆酸,葡庚糖酸(D),葡糖酸(D),葡萄糖醛酸(D),谷氨酸,戊二酸,甘油磷酸,乙醇酸,马尿酸,氢溴酸,盐酸,异丁酸,乳酸(DL),乳糖酸,苹果酸(-L),扁桃酸(DL),烟酸,硝酸,双羟萘酸,磷酸,焦谷氨酸(-L),水杨酸,硫酸,酒石酸(+L)或硫氰酸。
在另一个实施方案中,溶解度增强剂是环糊精。优选地,环糊精是具有6-8个吡喃葡萄糖苷单元的环糊精。更优选地,环糊精选自α-环糊精、羟丙基-β-环糊精或磺丁基醚-β-环糊精。
在另一个实施方案中,溶解度增强剂是C1-C34烷基对羟基苯甲酸酯(即4-羟基苯甲酸的C1-C34烷基酯)或其组合。优选地,对羟基苯甲酸酯选自对羟基苯甲酸甲酯,对羟基苯甲酸乙酯,对羟基苯甲酸正丙酯,对羟基苯甲酸异丙酯,对羟基苯甲酸丁酯,对羟基苯甲酸异丁酯,对羟基苯甲酸戊酯,对羟基苯甲酸己酯,对羟基苯甲酸庚酯,对羟基苯甲酸辛酯,对羟基苯甲酸壬酯,对羟基苯甲酸癸酯,对羟基苯甲酸苄酯,4-羟基苯甲酸苄酯,其盐(例如钾盐),和/或其组合。甚至更优选地,对羟基苯甲酸酯是对羟基苯甲酸甲酯,对羟基苯甲酸乙酯,对羟基苯甲酸丙酯,对羟基苯甲酸异丙酯,对羟基苯甲酸丁酯。
在优选的实施方案中,溶解度增强剂选自脱水山梨醇单油酸酯,富马酸,PEG-8辛酸辛酸甘油二酯(以出售),二甲基甲酰胺,四甘醇,N-甲基吡咯烷酮,肉豆蔻酸异丙酯,二甲基乙酰胺,乙酸香叶酯,PEG 200,PEG 300,聚氧乙烯(20)脱水山梨醇单油酸酯,glucopon,苄醇,三醋精,PEG-35蓖麻油(以EL出售),油酸,PEG-40氢化蓖麻油(以40和RH40出售),卵磷脂(以PG50出售),苯甲酸,4-羟基苯甲酸,对羟基苯甲酸甲酯,对羟基苯甲酸丙酯,水杨酸或其组合。更优选地,溶解度增强剂选自脱水山梨醇单油酸酯,富马酸,PEG-8辛酸辛酸甘油二酯(以出售),二甲基甲酰胺,四甘醇,N-甲基吡咯烷酮,肉豆蔻酸异丙酯,二甲基乙酰胺,乙酸香叶酯,PEG 200,PEG 300,聚氧乙烯(20)脱水山梨醇单油酸酯,葡糖苷,苄醇,三醋精,PEG-35蓖麻油(以EL出售),油酸,PEG-40氢化蓖麻油(以40和RH40出售),卵磷脂(以PG50出售),或其组合。
甚至更优选地,溶解度增强剂是PEG-40氢化蓖麻油,2-(2-乙氧基乙氧基)乙醇,油酸,苯甲醇,4-羟基苯甲醇,苯甲酸,4-羟基苯甲酸,对羟基苯甲酸甲酯,对羟基苯甲酸丙酯或其组合。甚至更优选地,溶解度增强剂是PEG-40氢化蓖麻油、2-(2-乙氧基乙氧基)乙醇或其组合。
本文公开的许多溶解度增强剂可以盐的形式存在,例如碱金属盐。所有这些盐在本发明的范围内,并且本发明的溶解度增强剂的提及包括盐形式,例如钠盐、钾盐、镁盐。本发明的盐可以通过常规的化学方法,例如在《药用盐:性质、选择和用途》,P.HeinrichStahl(编辑),Camille G.Wermuth(编辑),ISBN:3-90639-026-8,精装,388页,2002年8月中描述的方法,由含有碱性或酸性部分的母体溶解度增强剂合成。通常,这些盐可以通过使溶解度增强剂的游离酸或碱形式与适当的碱或酸在水中或在有机溶剂中或在两者的混合物中反应来制备;通常,使用非水介质,例如醚、乙酸乙酯、乙醇、异丙醇或乙腈。药学上可接受的盐的一些实例在Berge等人,1977,"Pharmaceutically Acceptable Salts,"J.Pharm.Sci.,Vol.66,pp.1-19.中讨论。本发明优选的盐包括苄氧基锂,苯甲酸锂,4-羟基苯甲酸锂,苄基氧化钠,苯甲酸钠,4-羟基苯甲酸钠,苄基氧化钾,苯甲酸钾,4-羟基苯甲酸钾,苄基氧化钙,苯甲酸钙,4-羟基苯甲酸钙,苄氧基镁,苯甲酸镁和4-羟基苯甲酸镁。
施用的溶解度增强剂的量将取决于施用途径、受影响的关节和患者的大小。每次施用的典型量为0.1-10g。溶解度增强剂可以b.i.d.或q.d或更少频次施用,例如每周一次。
本发明的溶解度增强剂可以肠胃外施用。在一实施方案中,溶解度增强剂通过注射至患病区域进行施用。
可以使用标准制剂和制造技术来生产合适的稳定的无菌注射用媒介物,其包含本发明的溶解度增强剂。这可以直接施用于存在MSU晶体的身体区域,例如关节周围的滑液。该方法的优点是将增溶制剂直接递送至作用部位。缺点是将需要医疗专业人员进行注射。
在另一个实施方案中,将溶解度增强剂经皮施用至患病区域。同样,可以使用标准制剂和制造技术生产合适的制剂。这种方法具有将溶解度增强剂直接施用于患病区域的优点,同时降低了全身性副作用的风险。
当经皮施用时,溶解度增强剂可以与皮肤渗透增强剂(也称为皮肤渗透增强剂)组合施用。这些是已知有助于通过皮肤输送药物和赋形剂的成分。合适的皮肤渗透增强剂的例子可参见:“Skin Penetration Enhancers Cited in the Technical Literature”.D.W.Osbourne和J.J.Henke,Pharmaceutical Technology,November 1997;page 58;“Permeation Enhancers for Transdermal Drug Delivery”,V.R.Sinha和M.Pal Kaur;Drug Development and Industrial Pharmacy,2000,26(11),1131-1140;以及“ChemicalPenetration Enhancers for Transdermal Drug Delivery Systems”,I.B.Pathan和C.M.Setty,Tropical Journal of Pharmaceutical Research,2009年4月,8(2),173-179。非限制性实例包括(也称为2-(2-乙氧基乙氧基)乙醇)和2-N,N-二甲基氨基丙酸十二烷基酯。
本发明的溶解度增强剂也可以局部用乳膏、凝胶的形式施用。这可能需要包含增稠剂,例如卡波姆、羟丙基纤维素(HPC,以出售),二山嵛酸甘油酯(以888出售),单硬脂酸甘油酯(以出售),硬脂酸,羟乙基纤维素,海藻酸丙二醇酯。
本发明的另一方面涉及以微乳液形式施用溶解度增强剂。微乳液是油、水和表面活性剂(和可选的助表面活性剂)的热力学稳定体系,其液滴尺寸为1至100nm,通常为10至50nm。这些体系具有诸如热力学稳定性、增加的透皮性和透皮药物递送、增强的药物溶解度、高生物相容性和易于制备的优点。由于液滴尺寸很小,微乳液的表面张力很低,界面面积大。在该专利描述的优选系统中使用微乳液的具体优点包括简单稳定的均质系统以局部施用或注射到患病区域。这允许溶解度增强剂对痛风影响区域的最大生物利用度。
在一个实施方案中,本发明的溶解度增强剂以包含油、水和表面活性剂的微乳液组合物的形式施用。在一个实施方案中,本发明的溶解度增强剂被选择为脂质并且选自先前描述的脂质。在该实施方案中,溶解度增强剂可以形成微乳液的油组分的一部分。可以使用本领域中可获得的标准配制技术来选择微乳液的其他组分。
在另一个实施方案中,本发明的溶解度增强剂被选择为表面活性剂并且选自先前描述的那些。在该实施方案中,溶解度增强剂可以形成微乳液的表面活性剂或助表面活性剂组分的一部分。
因此,显然本发明提供了包含本发明的溶解度增强剂和一种或多种赋形剂(其不同于溶解度增强剂)的药物组合物。
本发明的溶解度增强剂也可以与至少一种非甾体抗炎药(也称为NSAID)、至少一种黄嘌呤氧化酶抑制剂、秋水仙碱、至少一种糖皮质激素或其组合联合施用。
NSAID的实例包括氨基芳基羧酸衍生物,例如烯非那酸,依托芬那酸酯,氟苯那酸,异硫辛,甲氯芬那酸,甲芬那酸,尼氟酸,他尼氟甲酸酯,特罗氨酯和托芬那酸;芳基乙酸衍生物,例如醋氯芬酸,醋氨丁净,阿科芬酸,安非那克,呱氨托美丁,溴芬酸,布非昔马酸,桂美辛,氯吡酸,双氯芬酸钠,双氯芬酸,其他双氯芬酸盐,双氯芬酸二乙铵,双氯芬酸钾,依多酸,联苯乙酸,芬克洛酸,芬替酸,葡美辛,异丁芬酸,吲哚美辛,三苯唑酸,伊索克酸,lonazonlac,甲硫唑酸,莫非唑酸,奥沙美他星,吡拉唑酸,普罗格他汀,舒林酸,提拉米特,托美汀,tropesin,佐美酸;芳基丁酸衍生物,例如布马地宗,布替布芬,芬布芬,Xenbucin;芳基羧酸,例如环氯茚酸,酮咯酸,替诺立定;芳基丙酸衍生物,如阿明洛芬,苯诺沙普罗芬,bermaprofen,布氯酸,卡洛芬,非诺洛芬,氟洛沙普罗芬,氟比洛芬,布洛芬,布洛芬的盐,异丁普生,吲哚洛芬,酮洛芬,洛索洛芬,萘普生,噁普罗芬,吡酮洛芬,吡洛芬,普拉洛芬,甲嗪丙酸,舒洛芬,噻洛芬酸,西莫洛芬,扎托洛芬;吡唑类,如地非那唑,epiraozole;吡唑酮类,如阿帕宗,苯并哌隆,非普拉宗,莫非布宗,莫拉宗,氧苯丁酮,苯基丁酮,哌布宗,丙苯酮,前列腺素,雷非那酮,舒西布宗,噻唑啉并布宗;水杨酸衍生物,例如醋氨沙罗,阿司匹林,扑炎痛,溴水杨皂苷,乙酰水杨酸钙,二氟尼柳,依特柳酯,芬多沙尔,龙胆酸,乙二醇水杨酸酯,咪唑水杨酸酯,赖氨酸乙酰水杨酸酯,美沙拉嗪,吗啉水杨酸酯,1-萘基水杨酸酯,奥沙拉嗪,丙炔柳胺,苯基乙酰基水杨酸酯,水杨酸苯酯,乙酰水杨酰胺,水杨酰胺邻乙酸,水杨基硫酸,双水杨酯,柳氮磺吡啶;噻嗪羧酰胺类,如安吡昔康,曲恶昔康,伊索昔康,氯诺昔康,吡罗昔康,替诺昔康;环氧合酶II抑制剂(COX-II抑制剂),例如Celebrex(塞来昔布),Vioxx,Relafen,Lodine,Voltaren;和其他诸如ε-乙酰胺基己酸,s-腺苷甲硫氨酸,3-氨基-4-羟丁酸,阿米替林,苯达唑酸,苄达明,α-红没药醇,bucololome,双芬比拉胺,地他唑,艾莫法酮,fepredinol,愈创蓝油烃,萘普罗酮,尼美舒利,奥沙西罗,胍苯叉芴,哌立索唑,普罗夸酮,替尼达普,齐仑通。
黄嘌呤氧化酶抑制剂的实例包括嘌呤类似物,例如别嘌呤醇、羟嘌呤醇和异紫嘌呤;以及其他,例如非布索坦、托泊司他和肌醇。
糖皮质激素的实例包括11-脱氢皮质酮,11-脱氧皮质酮,11-脱氧皮质醇,11-酮孕酮,11β-羟基孕烯醇酮,11β-羟基孕酮,11β,17α,21-三羟基孕烯醇酮,17α,21-二羟基孕烯醇酮,17α-羟基孕烯醇酮,17α-羟基孕酮,18-羟基-11-脱氧皮质酮,18-羟基皮质酮,18-羟基孕酮,21-脱氧皮质醇,21-脱氧可的松,21-羟基孕烯醇酮,醛固酮,皮质酮,皮质醇,可的松,孕烯醇酮,孕酮,氟孕酮,氟米龙,甲羟孕酮,乙酰氧基孕烯醇酮,氯泼尼松,氯泼尼醇,二氟泼尼松,氟氢可的松,氟轻松,氟哌隆,氟丁尼松龙,洛替泼诺,甲基泼尼松龙,泼尼甲酸盐,泼尼松龙,泼尼松,替考克松醇,曲安西龙,地塞米松,阿氯米松,氯地米松,倍他米松,氯倍他索,氯倍他松,氯可托龙,去羟米松,二氟拉松,地氟考酮,氟氯龙,氟米松,氟可汀,氟可酮,氟泼尼定,氟替卡松,氟替卡松糠酸酯,卤米松,甲泼尼松,莫米松,糠酸莫米松,对甲米松,甲烯强的松龙,利美索龙,乌倍他索,酰胺化物,安西奈德,布地奈德,环索奈德,地夫可特,地索奈德,福莫可他,氟氯奈德,氟氢缩松,氟尼缩松醋酸氟轻松,氟轻松醋酸酯,哈西奈德,曲安奈德和可的伐唑(cortivazol)。
在另一个实施方案中,所述用途包括与超声疗法、热疗法、改变饮食以降低患者的尿酸水平联合施用所述溶解度增强剂。
在US 2009/0177123中提到了通过液体喷雾从非接触距离使用超声疗法来减少炎性疾病(包括痛风)中的炎症。该方法通常仅用于伤口治疗,并且可以从AlliquaBiomedical Inc.以“MIST Therapy”商购。但是,超声专门用于减少炎症反应。没有提及使用超声来辅助MSU晶体的原位溶解。
本发明可以使用治疗水平的超声波,该治疗水平在外部施加至与痛风影响的区域周围的皮肤接触。该超声以多种方式帮助MSU晶体的溶解,例如提供晶体的一些局部扰动,这可以帮助水性介质在晶体周围流动,从而帮助溶解。超声波的另一个作用是帮助原位破碎晶体,从而增加溶解速度。还有一些局部温和的温热,这也有助于溶解。
可以从与商业上可获得的设备类似的单来源设备提供超声。优选地,超声可以从作为共聚焦超声设备的两个或更多个源传递,以将更多的超声能量聚焦在特定的目标区域,即,沉积有MSU晶体的位置(例如,关节内和关节周围的滑液和组织)。
当与经皮递送的溶解度增强剂一起使用时,可能具有通过超声透入疗法(PH)增强增溶系统制剂经皮递送的附加优势。治疗性超声可以帮助药物和化学物质渗透皮肤(如在“Physical enhancement of dermatologic drug delivery:Intophoresis andphonophoresis”,D.G.Kassan、A.M.Lynch和M.J.Stiller;J Am Acad Dermatol,1996,34,657-66中报告的)。
通常,将1-3MHz的超声用于治疗。总体上,超声治疗有两种不同的施用模式,连续模式或调制模式。连续波超声使用强度通常限制为0.5-2.5W/cm2的未调制光束。该模式通常负责伴随的加热作用。调制超声使用调制光束在无功率的情况下短暂停顿。这通常与很少或没有加热作用有关。两种方法均可用于帮助提高MSU晶体的溶解速率和治疗痛风。
热疗法也可以与本发明的溶解度增强剂组合使用。热疗法通常用于获得镇痛作用,减少肌肉痉挛,增加胶原蛋白的可扩展性并加速代谢过程。通常有两种形式的热疗。诸如热敷袋之类的表面剂会温暖皮肤和皮下组织,或诸如治疗性超声波之类的深层加热剂会在8厘米深度处产生4-5℃的温度升高。两种方法都为温和地加热MSU晶体可在体内溶解的环境提供了可行的选择,因此可以帮助提高MSU晶体的溶解速度和治疗痛风。
存在可以通过改变饮食(减少代谢成尿酸的嘌呤的供应)或增加尿酸从体内的清除率来长期降低体液中尿酸盐水平的全方位治疗(如丙磺舒)或有助于分解尿酸的药物/酶(如拉布立酶)。
为了提高去除溶解的MSU的速率,需要鼓励从滑膜液向血液中和体内排出尿酸盐。小分子(例如尿酸盐)易于从滑液中快速进入血液,因此采取措施降低血液中的尿酸盐水平并鼓励从血液中清除尿酸盐将有助于从滑液中清除尿酸盐,进而从MSU晶体周围清除尿酸盐(如在“Synovial perfusion and synovial fluid solutes”,P.A Simkin,Annal ofthe Rheumatic Disease,1995,54,424-428中解释的)。
短期内降低血液中MSU水平的措施包括喝水和减少食用富含嘌呤的食物。事实证明,增加患者的饮水量可以减少患者痛风发作的机会(“Study on dehydration andgout”,Annual Meeting of the American College of Rheumatology,Tuhina Neogi,2009,Philadelphia)。另一种选择是减少富含嘌呤的食物例如器官肉(例如肝脏、肾脏、牛羊胰脏和脑)和普通肉(例如培根、牛肉、猪肉和羊肉)、油性鱼(例如凤尾鱼、沙丁鱼、鲱鱼和鲭鱼)和啤酒的摄入量。
优选将这种稀释方法与本发明的溶解度增强剂的施用结合使用。
现在将参考以下非限制性实施例描述本发明。
实施例
实施例1
尿酸单钠晶体在NaCl水溶液中的溶解度增强
通过将8.2g NaCl溶于1L去离子水中来制备NaCl溶液。然后将约8mg的尿酸单钠晶体悬浮在2.5mL的NaCl溶液中。然后将2.5mL量的溶解度增强剂添加至尿酸单钠晶体的悬浮液中。在溶解度增强剂为组分的混合物的情况下,加入等体积份的每种组分。然后将其在辊式混合器上混合约16小时。
然后取出上清液样品,使用标准技术(例如注射器过滤器)过滤,并通过高效液相色谱(HPLC)分析以确定溶液中存在的尿酸/MSU的浓度。结果如下表1所示。
表1.MSU晶体在NaCl水溶液中的溶解度增强
使用配有可变波长紫外线检测器和反相柱(5μm ODS2,4.6mm x 150mm,WatersSpherisorb)的HPLC系统分析所有样品。流动相是在水中的35mM乙酸钠,使用乙酸将pH调节至5.0。流速设置为1mL/min,紫外线检测波长为292nm。样品进样量为50.0μL,所有操作均在25℃下进行。MSU的标准溶液的浓度范围为15-250μg/mL,并按上述方法进行分析。在15-250μg/mL的测试范围内,峰面积与MSU浓度线性相关,平均相关系数为0.993。
尽管为方便起见,本实施例是在室温(25℃)下进行的,但观察到的MSU溶解度增加与在37℃下观察到的溶解度增加具有相似的相关性(如Kippen等人,“Factors affectingurate solubility in vitro”,Annals of Rheumatic Diseases,1974,33,313-317解释的)。
实施例2A
尿酸单钠晶体在磷酸盐缓冲液中的溶解度增强
通过将8.2g NaCl和0.68g KH2PO4溶解在1L烧瓶中的500mL去离子水中来制备磷酸盐缓冲盐水稀释剂。通过将0.399g NaOH溶解在100mL去离子水中制备NaOH溶液。然后将39.1mL的0.1M NaOH溶液添加到1L烧瓶中,并用去离子水补足至1L。将pH调节至7.4。
然后将约5mg的尿酸单钠晶体悬浮在4.75mL的磷酸盐缓冲盐水稀释剂中。然后将0.25mL量的溶解度增强剂添加至尿酸单钠晶体的悬浮液中。除非在下表2中另外指出,否则这提供了按体积计5%的溶解度增强剂实验。在表2中指出不同百分比的情况下,改变磷酸盐缓冲盐水稀释剂和溶解度增强剂的量以提供5mL的总体积和指定体积%的溶解度增强剂。在溶解度增强剂是组分的混合物的情况下,除非另有说明,否则加入等体积份的每种组分。然后将其搅拌约16小时。
然后取出上清液样品,使用标准技术(例如注射器过滤器)过滤,并通过高效液相色谱(HPLC)分析以确定溶液中存在的尿酸/尿酸盐的浓度。结果示于下表2。
表2.MSU晶体在磷酸盐缓冲盐溶液中的溶解度增强
*制剂A包含10%油酸/26.7%Labrasol/8.3%Transcutol/5%Compritol/50%水。
如同上所述Kippen等解释,上述磷酸盐缓冲盐水稀释系统代表尿酸钠/尿酸在患者滑液和血浆中的溶解度。
实施例2B
尿酸单钠晶体在磷酸盐缓冲液中的溶解度增强的其他实例
根据实施例2A中概述的方法,测试了以下组分增强尿酸单钠晶体在磷酸盐缓冲盐水增强剂中的溶解度的能力。结果示于下表3。
表3.MSU晶体在磷酸盐缓冲盐溶液中的溶解度增强
*制剂B包含10%油酸/26.7%Labrasol/8.3%Transcutol/55%水。
制剂A如实施例2A中所述。
如同上所述Kippen等解释,上述PBS稀释系统代表尿酸钠/尿酸在患者滑液和血浆中的溶解度。因此,该实施例证明了所要求保护的溶解度增强剂治疗痛风的能力。
实施例3
溶解度增强组合
使用以下方法测试当经皮施用时本发明的溶解度增强剂的组合增加尿酸单钠晶体的局部溶解度的能力。
所述组合物包含组分1(三醋精或苄醇或PEG-200或甘油或丙二醇或Labrasol或Capryol或Lauroglycol或乙酸香叶酯)、RH40和Transcutol(2-(2-乙氧基乙氧基)乙醇),如下表4所示。
将所需量的组分1、RH40和Transcutol添加到小瓶中。组分1:RH40:Transcutol的比例(按体积计)在下表4中给出。将这些组分在约500rpm的搅拌下混合30分钟以形成本发明的溶解度增强组合物。
类似于实施例2,制备了磷酸盐缓冲盐水稀释剂系统以提供对血液和滑液中存在的离子混合物的代表性模仿。制备了0.14mol/L NaCl的水溶液和0.01N磷酸盐缓冲液。该溶液的pH为7.4,以下称为“PBS”。
将约5mg的MSU晶体悬浮在4.75mL的稀释剂中,然后加入0.25mL的制剂。将其在室温搅拌16小时。取上清液样品,通过注射器过滤器过滤,并通过HPLC分析以确定溶液中尿酸/尿酸盐的浓度。结果示于下表4。
表4.使用各种制剂提高MSU晶体的溶解度
如同上所述Kippen等解释,上述PBS稀释系统代表尿酸钠/尿酸在患者滑液和血浆中的溶解度。
实施例4
溶解度增强微乳液
将油酸、Labrasol和Transcutol(2-(2-乙氧基乙氧基)乙醇)添加到小瓶中。在约250rpm搅拌下将这些组分混合,并逐滴加入去离子水。然后将小瓶摇动约30秒,然后再搅拌30分钟以形成本发明的溶解度增强组合物。下表5给出了油酸∶Labrasol∶Transcutol∶水的比例(重量比)。
然后使用以下方法测试这些微乳液增加尿酸单钠晶体的局部溶解度的能力。
制备了稀释剂系统以提供对血液和滑液中存在的离子混合物的代表性模仿。制备了0.14mol/L NaCl的水溶液和0.01N磷酸盐缓冲液。该溶液的pH为7.4,以下称为“稀释剂”。
将约10mg的MSU晶体悬浮在10mL的稀释剂中,然后添加1mL的微乳液。将其在室温下在辊式混合器上混合16小时。取上清液样品,通过注射器过滤器过滤,并通过HPLC分析以确定溶液中尿酸/尿酸盐的浓度。结果示于下表4。
表5.使用微乳液制剂提高MSU晶体的溶解度
如同上所述Kippen等解释,上述磷酸盐缓冲盐水稀释系统代表尿酸钠/尿酸在患者滑液和血浆中的溶解度。
实施例5
Franz池实验中的溶解度增强
然后使用以下方法测试当经皮施用时本发明的微乳液增加尿酸单钠晶体的局部溶解度的能力。
Franz池被用来模仿通过皮肤的扩散。Franz池装置具有两个被膜隔开的腔室。在Franz池的一个腔室中,将约10mg的MSU晶体悬浮在约10mL的稀释剂溶液中(如实施例4中所制备)。将其以约200rpm搅拌约24小时以达到平衡的饱和悬浮液。然后将预先浸泡在稀释剂溶液中的膜夹在腔室的顶部,与含有MSU晶体悬浮液的稀释剂溶液接触。然后将约1.5mL的本发明的微乳液制剂(在实施例4中制备)置于膜的顶部,并且将池用实验室膜覆盖。然后从包含MSU晶体悬浮液的腔室中取出上清液样品。使用标准技术(即注射器过滤器)将其过滤,并通过HPLC分析以确定溶液中存在的尿酸/尿酸盐的浓度。该实验的结果显示在下表6中。
表6.Franz池实验中的溶解度增强
实施例6
Franz池实验中的溶解度增强
使用以下方法测试当经皮施用时本发明的溶解度增强剂的组合增加尿酸单钠晶体的局部溶解度的能力。
像实施例5一样,Franz池被用来模拟通过皮肤的扩散。Franz池装置具有两个被膜隔开的腔室。在Franz池的一个腔室中,将约10mg的MSU晶体悬浮在约10mL的PBS稀释剂溶液中(如实施例2中所制备)。然后将预先浸泡在稀释剂溶液中的膜夹在腔室的顶部,与含有MSU晶体悬浮液的稀释剂溶液接触。然后将约0.5mL的本发明的制剂(在实施例2中制备)置于膜的顶部,并用实验室膜覆盖池。将其以约500rpm搅拌约16小时以达到平衡的饱和悬浮液。然后从包含MSU晶体悬浮液的腔室中取出样品,并使用标准技术(即注射器过滤器)过滤,并通过HPLC分析以确定溶液中尿酸/尿酸盐的浓度。该实验的结果示于下表7。
表7.Franz池实验中的溶解度增强
Claims (15)
1.一种在治疗痛风中使用的尿酸单钠的溶解度增强剂。
2.根据权利要求1所述的溶解度增强剂,其中所述溶解度增强剂选自至少一种药学上可接受的碱、至少一种溶剂、至少一种脂质、至少一种表面活性剂、至少一种药学上可接受的酸、至少一种环糊精、至少一种对羟基苯甲酸酯或其组合。
3.根据权利要求2所述的溶解度增强剂,其中所述溶解度增强剂是药学上可接受的碱,并且选自金属碳酸盐、金属氢氧化物、伯胺、仲胺、叔胺、芳族胺或其组合。
4.根据权利要求2所述的溶解度增强剂,其中所述溶解度增强剂是溶剂,并且选自醇、二醇、多元醇、芳基或杂芳基醇、芳基烷基或杂芳基烷基醇、醚、聚醚、内酰胺、酰胺、烷基亚砜、酮、醛、腈、酯、或其组合。
5.根据权利要求2所述的溶解度增强剂,其中所述溶解度增强剂是脂质,并且选自C4-C28羧酸,C11-C28醇,C1-C28烷基C1-C28链烷酸酯,C6-C12甘油一酯,C6-C12甘油二酯,C6-C12甘油三酯,C1-C28烷基N,N-二取代C1-C6氨基C1-C28链烷酸酯,或其组合。
6.根据权利要求2所述的溶解度增强剂,其中所述溶解度增强剂是选自以下的表面活性剂:脱水山梨醇酯、乙氧基化脱水山梨醇酯、山梨醇酯、乙氧基化山梨醇酯、聚氧乙烯化蓖麻油、聚乙氧基化C11-C28醇、聚乙氧基化C4-C28羧酸酯、聚氧乙烯-聚氧丙烯嵌段共聚物,或其组合。
7.根据权利要求2所述的溶解度增强剂,其中所述溶解度增强剂是药学上可接受的酸,并且选自C1-C7羧酸、C2-C10二羧酸、C1-C5α羟基酸、C1-C5β羟基酸、C1-C5γ羟基酸、磺酸,或其组合。
8.根据权利要求2所述的溶解度增强剂,其中所述溶解度增强剂是环糊精,并且所述环糊精是具有6-8个吡喃葡萄糖苷单元的环糊精。
9.根据权利要求2所述的溶解度增强剂,其中所述溶解度增强剂是对羟基苯甲酸酯,并且所述对羟基苯甲酸酯是C1-C20对羟基苯甲酸烷基酯。
10.根据权利要求2所述的溶解度增强剂,其中所述溶解度增强剂选自山梨聚糖单油酸酯,富马酸,PEG-8辛酸辛酸甘油二酯,二甲基甲酰胺,四甘醇,N-甲基吡咯烷酮,肉豆蔻酸异丙酯,二甲基乙酰胺,乙酸香叶酯,PEG 200,PEG 300,聚氧乙烯(20)山梨聚糖单油酸酯,苄醇,4-羟基苄醇,PEG-35蓖麻油,油酸,PEG-40氢化蓖麻油,卵磷脂,苯甲酸,4-羟基苯甲酸,对羟基苯甲酸甲酯,对羟基苯甲酸丙酯,水杨酸或其组合。
11.根据权利要求9所述的溶解度增强剂,其中所述溶解度增强剂是PEG-40氢化蓖麻油,2-(2-乙氧基乙氧基)乙醇,油酸,苯甲醇,4-羟基苯甲醇,苯甲酸,4-羟基苯甲酸,对羟基苯甲酸甲酯,对羟基苯甲酸丙酯或其组合。
12.根据任一前述权利要求所述的溶解度增强剂,其中所述使用包括将所述溶解度增强剂胃肠外施用至患病区域。
13.根据权利要求1-10中任一项所述的溶解度增强剂,其中所述使用包括将所述溶解度增强剂经皮施用至所述患病区域;优选地其中所述溶解度增强剂与皮肤渗透增强剂组合施用。
14.根据任一前述权利要求所述的溶解度增强剂,其中所述使用包括与至少一种非甾体抗炎药、至少一种黄嘌呤氧化酶抑制剂、秋水仙碱、至少一种糖皮质激素或其组合联合施用所述溶解度增强剂。
15.根据任一前述权利要求所述的溶解度增强剂,其中所述使用包括与超声疗法、热疗法、改变饮食以降低患者的尿酸水平或其组合联合施用所述溶解度增强剂。
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CN113350328A (zh) * | 2020-09-27 | 2021-09-07 | 广州永华特医营养科技有限公司 | 甘油二酯及其组合物的新应用 |
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EP3681479B1 (en) | 2017-09-15 | 2024-01-31 | Dyve Biosciences, Inc. | Sodium bicarbonate for use in the treatment of gout and related disorders |
WO2021070066A1 (en) * | 2019-10-11 | 2021-04-15 | Zenvision Pharma Llp | Improved topical composition of colchicine |
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GB201720992D0 (en) | 2018-01-31 |
WO2019116045A1 (en) | 2019-06-20 |
US20210077420A1 (en) | 2021-03-18 |
CA3085403A1 (en) | 2019-06-20 |
AU2018383083A1 (en) | 2020-07-02 |
JP2021506967A (ja) | 2021-02-22 |
EP3723741A1 (en) | 2020-10-21 |
CN118001260A (zh) | 2024-05-10 |
CN111491625B (zh) | 2023-12-01 |
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