CN111386120A - 含磷酸胆碱衍生物的脂解组合物 - Google Patents
含磷酸胆碱衍生物的脂解组合物 Download PDFInfo
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- CN111386120A CN111386120A CN201880053822.2A CN201880053822A CN111386120A CN 111386120 A CN111386120 A CN 111386120A CN 201880053822 A CN201880053822 A CN 201880053822A CN 111386120 A CN111386120 A CN 111386120A
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- Prior art keywords
- phosphocholine
- glycero
- stearoyl
- acid
- composition
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- 150000001875 compounds Chemical class 0.000 claims description 64
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- 239000000243 solution Substances 0.000 claims description 41
- CITHEXJVPOWHKC-UUWRZZSWSA-N 1,2-di-O-myristoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCC CITHEXJVPOWHKC-UUWRZZSWSA-N 0.000 claims description 36
- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-N 0.000 claims description 29
- MZWGYEJOZNRLQE-KXQOOQHDSA-N 1-stearoyl-2-myristoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCC MZWGYEJOZNRLQE-KXQOOQHDSA-N 0.000 claims description 29
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Abstract
本发明提供了一种用于脂解或用于改善、抑制或治疗局部脂肪沉积(LFD)的组合物,其包含某些磷酸胆碱衍生物或其药学上可接受的盐。本发明的组合物显示出优异的脂解活性以及均匀的脂解活性。此外,本发明的组合物可以将施用部位处的副作用例如炎症、组织坏死等最小化。另外,本发明的组合物具有优异的储存稳定性。
Description
技术领域
本发明涉及用于脂解或用于改善、抑制或治疗局部脂肪沉积的组合物,其包含磷酸胆碱衍生物或其药学上可接受的盐。
背景技术
脂肪来自白色脂肪组织中过量能量的积累,而其在白色脂肪组织中的过量积累通常被称为肥胖症。例如通过激素敏感性脂肪酶(HSL)将甘油三酸酯分解为游离脂肪酸(FFA)和甘油的过程被称为脂解。
为了改善包括局部脂肪沉积(LFD)在内的肥胖,进行外科手术,抽脂术(liposuction)。抽脂术,也被称为脂肪整形术(lipoplasty)或脂肪塑形抽吸脂肪切除术(liposculpture suction lipectomy),是一种整容外科手术,用于从身体的各个部位(例如腹部、大腿、臀部、颈部、上臂等)去除脂肪。但是,人们担心抽脂术可能会引起严重的副作用,包括伤口、肿胀、麻痹和烧灼感、手术部位感染的风险;皮肤或神经的损伤;和重要器官的穿刺伤口。另外,它需要相当长的一段时间来进行治疗和恢复;而且还有麻醉相关的风险,因为在手术过程中需要局部麻醉或全身麻醉。
磷脂酰胆碱(PC)是一类包含胆碱为首基的磷脂。它们广泛存在于动物、植物、酵母和真菌中,也称为卵磷脂或不饱和卵磷脂。它们主要包含在哺乳动物的大脑、神经、血细胞、卵黄等中;以及包含在植物中的大豆、葵花籽、小麦胚芽等中。由于磷脂酰胆碱在其分子中具有四个双键,因此其在制备过程中或在储存过程中容易被氧化,从而使其结构变形。为了克服这种缺点,已经开发了饱和卵磷脂形式,其通过向不饱和卵磷脂中加氢来制备。美国公开专利公开号US2005/0287199已经公开了一种减少脂肪组织的方法,该方法包括注射卵磷脂。另外,美国公开专利公开号US2016/0339042已经公开了一种减少局部脂肪组织的方法,该方法包括将包含卵磷脂和胆汁酸或其盐的组合物局部施用至在脂肪组织处或脂肪组织附近的部位。然而,局部注射卵磷脂以诱导脂解导致了副作用问题,例如红斑、炎症、组织坏死、水肿、凹陷(dimpling)等。此外,当将含卵磷脂的制剂长时间储存时,会导致诸如稳定性和脂解活性降低的问题。
发明内容
技术问题
本发明人进行了各种研究,以便开发用于脂解或用于改善、抑制或治疗局部脂肪沉积的组合物,该组合物具有优异的脂解活性和稳定性而没有明显的副作用。本发明人评估了各种胆碱衍生物的活性、副作用和稳定性。作为其结果,本发明人发现与常规的含磷脂酰胆碱的制剂相比,含有某些磷酸胆碱衍生物的组合物具有更优异且均匀的脂解活性和稳定性,并且可以将施用或应用部位处的副作用(例如炎症、组织坏死等)最小化。
因此,本发明提供了一种包含所述磷酸胆碱衍生物作为活性成分的用于诱导脂解或用于改善、抑制或治疗局部脂肪沉积的组合物。
此外,本发明提供了一种在有需要的哺乳动物中诱导脂解或改善、抑制或治疗局部脂肪沉积的方法,该方法包括向哺乳动物施用有效量的所述磷酸胆碱衍生物。
此外,本发明还提供了所述磷酸胆碱衍生物在制备用于诱导脂解或用于改善、抑制或治疗局部脂肪沉积的药物中的用途。
技术方案
根据本发明的一方面,提供了一种用于诱导脂解或用于改善、抑制或治疗局部脂肪沉积的组合物,其包含有效量的式1的化合物或其药学上可接受的盐作为活性成分:
<式1>
其中,
X和Y彼此独立地为C9~C17烷基基团;或具有一个或两个双键的C15~C21烯基基团,条件是X和Y不同时为C17烷基基团;以及X和Y不同时为具有两个双键的C17烯基基团。
在本发明的组合物中,式1的化合物可以是选自以下的一种或多种:
1,2-二癸酰基-sn-甘油-3-磷酸胆碱;
1,2-二月桂酰基-sn-甘油-3-磷酸胆碱;
1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱;
1-肉豆蔻酰基-2-棕榈酰基-sn-甘油-3-磷酸胆碱;
1-肉豆蔻酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱;
1-棕榈酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1-棕榈酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-棕榈酰基-sn-甘油-3-磷酸胆碱;
1,2-二芥酰基-sn-甘油-3-磷酸胆碱;
1,2-二油酰基-sn-甘油-3-磷酸胆碱;
1-棕榈酰基-2-油酰基-sn-甘油-3-磷酸胆碱;和
1-硬脂酰基-2-油酰基-sn-甘油-3-磷酸胆碱。
优选地,在本发明的组合物中,式1的化合物可以是选自以下的一种或多种:
1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二癸酰基-sn-甘油-3-磷酸胆碱;
1-棕榈酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱;和
1,2-二月桂酰基-sn-甘油-3-磷酸胆碱。
更优选地,在本发明的组合物中,式1的化合物可以是选自以下的一种或多种:
1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二癸酰基-sn-甘油-3-磷酸胆碱;和
1-棕榈酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱。
最优选地,在本发明的组合物中,式1的化合物可以是1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱。
本发明的组合物可以进一步包含有效量的胆汁酸或其药学上可接受的盐。胆汁酸或其药学上可接受的盐可以为选自胆酸、甘氨胆酸、甘氨脱氧胆酸、脱氧胆酸、牛磺胆酸、熊去氧胆酸、牛磺熊去氧胆酸、牛磺去氧胆酸、鹅去氧胆酸、甘氨熊去氧胆酸、脱氧胆酸钠和牛磺胆酸钠中的一种或多种。优选地,胆汁酸或其药学上可接受的盐可以为选自甘氨胆酸、脱氧胆酸、牛磺胆酸、牛磺熊去氧胆酸、甘氨熊去氧胆酸、脱氧胆酸钠和牛磺胆酸钠中的一种或多种。在实施方案中,式1的化合物或其药学上可接受的盐与胆汁酸或其药学上可接受的盐的重量比可以在0.5:1至40:1的范围内。
本发明的组合物可以是用于局部施用的药物组合物的形式。用于局部施用的药物组合物可以是用于经皮施用的制剂的形式、用于皮下施用的制剂的形式、用于肌肉内施用的制剂的形式或用于腹膜内施用的制剂的形式。此外,用于局部施用的药物组合物可以是液体制剂的形式或干粉制剂的形式;优选为溶液、乳液或冻干粉末的形式。用于局部施用的药物组合物可以包含一种或多种选自以下的药学上可接受的辅料:pH控制剂、等渗剂、表面活性剂、稳定剂、防腐剂、螯合剂、缓冲剂和冷冻保护剂;以及一种或多种选自以下的药学上可接受的载体:油、有机溶剂和水性溶剂。
本发明的组合物可以是应用于皮肤、皮下组织、肌肉组织或腹部组织的化妆品组合物形式。化妆品组合物可以是液体形式或干粉形式;优选地,可以是干粉形式。优选为溶液、乳液或冻干粉末的形式。该化妆品组合物可以包含一种或多种选自以下的辅料:pH控制剂、等渗剂、表面活性剂、稳定剂、防腐剂、螯合剂、缓冲剂和冷冻保护剂;以及选自以下的一种或多种载体:油、有机溶剂和水性溶剂。
根据本发明的另一方面,提供了一种在有需要的哺乳动物中诱导脂解或改善、抑制或治疗局部脂肪沉积的方法,该方法包括向哺乳动物施用有效量的式1的化合物或其药学上可接受的盐。
在本发明的方法中,式1的化合物可以是选自以下的一种或多种:
1,2-二癸酰基-sn-甘油-3-磷酸胆碱;
1,2-二月桂酰基-sn-甘油-3-磷酸胆碱;
1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱;
1-肉豆蔻酰基-2-棕榈酰基-sn-甘油-3-磷酸胆碱;
1-肉豆蔻酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱;
1-棕榈酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1-棕榈酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-棕榈酰基-sn-甘油-3-磷酸胆碱;
1,2-二芥酰基-sn-甘油-3-磷酸胆碱;
1,2-二油酰基-sn-甘油-3-磷酸胆碱;
1-棕榈酰基-2-油酰基-sn-甘油-3-磷酸胆碱;和
1-硬脂酰基-2-油酰基-sn-甘油-3-磷酸胆碱。
优选地,在本发明的方法中,式1的化合物可以是选自以下的一种或多种:
1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二癸酰基-sn-甘油-3-磷酸胆碱;
1-棕榈酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱;和
1,2-二月桂酰基-sn-甘油-3-磷酸胆碱。
更优选地,在本发明的方法中,式1的化合物可以是选自以下的一种或多种:
1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二癸酰基-sn-甘油-3-磷酸胆碱;和
1-棕榈酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱。
最优选地,在本发明的方法中,式1的化合物可以是1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱。
根据本发明的另一方面,提供了式1的化合物或其药学上可接受的盐在制备用于诱导脂解或用于改善、抑制或治疗局部脂肪沉积的药物中的用途。
在本发明的用途中,式1的化合物可以是选自以下的一种或多种:
1,2-二癸酰基-sn-甘油-3-磷酸胆碱;
1,2-二月桂酰基-sn-甘油-3-磷酸胆碱;
1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱;
1-肉豆蔻酰基-2-棕榈酰基-sn-甘油-3-磷酸胆碱;
1-肉豆蔻酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱;
1-棕榈酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1-棕榈酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-棕榈酰基-sn-甘油-3-磷酸胆碱;
1,2-二芥酰基-sn-甘油-3-磷酸胆碱;
1,2-二油酰基-sn-甘油-3-磷酸胆碱;
1-棕榈酰基-2-油酰基-sn-甘油-3-磷酸胆碱;和
1-硬脂酰基-2-油酰基-sn-甘油-3-磷酸胆碱。
优选地,在本发明的用途中,式1的化合物可以是选自以下的一种或多种:
1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二癸酰基-sn-甘油-3-磷酸胆碱;
1-棕榈酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱;和
1,2-二月桂酰基-sn-甘油-3-磷酸胆碱。
更优选地,在本发明的用途中,式1的化合物可以是选自以下的一种或多种:
1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二癸酰基-sn-甘油-3-磷酸胆碱;和
1-棕榈酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱。
最优选地,在本发明的用途中,式1的化合物可以是1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱。
发明的有益效果
与常规的含磷脂酰胆碱的制剂相比,包含某些磷酸胆碱衍生物,即式1的化合物或其药学上可接受的盐的本发明的组合物不仅显示出优异的脂解活性,而且还显示出其脂解活性的均匀性。此外,本发明的组合物可以将施用或应用部位处的副作用(例如炎症、组织坏死等)最小化。另外,本发明的组合物具有优异的储存稳定性。因此,本发明的组合物可以抑制皮下脂肪的不均匀分布和由此引起的美学损害;因此本发明的组合物可有效地用于诱导脂解或用于改善、抑制或治疗局部脂肪沉积(LFD)。
附图说明
图1和图2示出了通过观察施用了本发明的制剂、比较例的制剂和溶媒(vehicle)的大鼠的非施用部位(虚线圆圈)和施用部位(深色圆圈)处的脂解活性而获得的结果。
图3示出了通过取自施用了本发明的制剂、比较例的制剂和溶媒的大鼠的皮下脂肪的苏木精和曙红染色测量副作用(例如炎症)而获得的结果。
图4示出了通过取自施用了本发明的制剂、比较例的制剂和溶媒的大鼠的皮下脂肪的油红O反应测量脂解活性的均匀性而获得的结果。在图4中,红油尺寸越小表示脂解作用越好。
图5示出了在室温下储存7天和30天后,通过评价本发明的制剂和比较例的制剂的稳定性而获得的结果。每个小图(panel)的第一个样品、第二个样品和第三个样品分别示出了在制备时、在室温下储存7天后和在室温下储存30天后的外观。
具体实施方式
根据本发明的磷酸胆碱衍生物具有优异且均匀的脂解活性,并且可以将施用或应用部位处的副作用(例如炎症、组织坏死等)最小化;因此可有效地用于诱导脂解或用于改善、抑制或治疗局部脂肪沉积(LFD)。因此,本发明提供了一种用于诱导脂解或用于改善、抑制或治疗局部脂肪沉积的组合物,其包含所述磷酸胆碱衍生物作为活性成分。具体地,本发明提供了一种用于诱导脂解或用于改善、抑制或治疗局部脂肪沉积的组合物,其包含有效量的式1的化合物或其药学上可接受的盐作为活性成分:
<式1>
其中,
X和Y彼此独立地为C9~C17烷基基团;或具有一个或两个双键的C15~C21烯基基团,条件是X和Y不同时为C17烷基基团;以及X和Y不同时为具有两个双键的C17烯基基团。
在本发明的组合物中,式1的化合物可以是选自以下的一种或多种:
1,2-二癸酰基-sn-甘油-3-磷酸胆碱(DDPC);
1,2-二月桂酰基-sn-甘油-3-磷酸胆碱(DLPC);
1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱(DMPC);
1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱(DPPC);
1-肉豆蔻酰基-2-棕榈酰基-sn-甘油-3-磷酸胆碱(MPPC);
1-肉豆蔻酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱(MSPC);
1-棕榈酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱(PMPC);
1-棕榈酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱(PSPC);
1-硬脂酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱(SMPC);
1-硬脂酰基-2-棕榈酰基-sn-甘油-3-磷酸胆碱(SPPC);
1,2-二芥酰基-sn-甘油-3-磷酸胆碱(DEPC);
1,2-二油酰基-sn-甘油-3-磷酸胆碱(DOPC);
1-棕榈酰基-2-油酰基-sn-甘油-3-磷酸胆碱(POPC);和
1-硬脂酰基-2-油酰基-sn-甘油-3-磷酸胆碱(SOPC)。
优选地,在本发明的组合物中,式1的化合物可以是选自以下的一种或多种:
1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱(DMPC);
1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱(DPPC);
1-硬脂酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱(SMPC);
1,2-二癸酰基-sn-甘油-3-磷酸胆碱(DDPC);
1-棕榈酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱(PSPC);和
1,2-二月桂酰基-sn-甘油-3-磷酸胆碱(DLPC)。
更优选地,在本发明的组合物中,式1的化合物可以是选自以下的一种或多种:
1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二癸酰基-sn-甘油-3-磷酸胆碱;和
1-棕榈酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱。
最优选地,在本发明的组合物中,式1的化合物可以是1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱(DMPC)。
作为已知化合物的式1的化合物或其盐可以根据已知方法制备。例如,式1的化合物或其盐可以通过水解和纯化大豆卵磷脂以获得甘油磷酸胆碱;然后将甘油磷酸胆碱与脂肪酸(例如肉豆蔻酸)反应来制备。此外,可以购买式1的化合物或其盐,因为其是可商购获得的(例如,Sigma-Aldrich)。
式1的化合物或其药学上可接受的盐可以具有含有不对称碳的取代基,并因此为外消旋混合物(RS)的形式或为光学异构体的形式,例如(R)或(S)异构体。因此,除非另外说明,否则式1的化合物或其药学上可接受的盐包含外消旋混合物(RS)和光学异构体(例如(R)或(S)异构体)两者。
本发明的式1的化合物可以是药学上可接受的盐形式。该盐可以是酸加成盐的形式,其包括例如衍生自无机酸的盐,该无机酸例如为盐酸、氢溴酸、硫酸、磷酸、硝酸或碳酸;以及衍生自有机酸的盐,该有机酸例如为柠檬酸、乙酸、乳酸、酒石酸、马来酸、富马酸、乳糖酸、水杨酸、丙二酸、甲酸、丙酸、草酸、三氟乙酸、苯甲酸、葡糖酸、甲磺酸、乙醇酸、琥珀酸、对甲苯磺酸、谷氨酸或天冬氨酸,但不限于此。此外,该盐包括碱金属盐,例如锂盐、钠盐或钾盐;碱土金属盐,例如钙盐或镁盐;或铬盐。
除了式1的化合物或其药学上可接受的盐之外,本发明的组合物可以进一步包含有效量的胆汁酸或其药学上可接受的盐作为活性成分。胆汁酸可以为选自胆酸、甘氨胆酸、甘氨脱氧胆酸、脱氧胆酸、牛磺胆酸、熊去氧胆酸、牛磺熊去氧胆酸、牛磺去氧胆酸、鹅去氧胆酸、甘氨熊去氧胆酸、脱氧胆酸钠和牛磺胆酸钠中的一种或多种。优选地,胆汁酸或其药学上可接受的盐可以为选自甘氨胆酸、脱氧胆酸、牛磺胆酸、牛磺熊去氧胆酸、甘氨熊去氧胆酸、脱氧胆酸钠和牛磺胆酸钠中的一种或多种。更优选地,胆汁酸或其药学上可接受的盐可以为选自甘氨胆酸、脱氧胆酸、牛磺熊去氧胆酸、脱氧胆酸钠和牛磺胆酸钠中的一种或多种。最优选地,胆汁酸或其药学上可接受的盐可以是甘氨胆酸或其盐(例如钠盐)或者牛磺胆酸或其盐(例如钠盐)。当本发明的组合物除了式1的化合物或其药学上可接受的盐以外进一步包含有效量的胆汁酸或其药学上可接受的盐作为活性成分时,式1的化合物或其药学上可接受的盐与胆汁酸或其药学上可接受的盐的重量比可以在0.5:1至40:1的范围内,优选在1:1至35:1的范围内,更优选在1:1至20:1的范围内,还更优选在1:1至10:1的范围内,以将副作用(例如炎症、组织坏死等)最小化,并提供有效的脂解。
本发明的组合物可以肠胃外施用,更优选通过肠胃外途径局部施用。局部施用包括对诸如眼下(under-eye)、颔下(under-chin)、腋下(under-arm)、臀部、小腿、背部、大腿、脚踝、腹部等区域的局部应用。例如,本发明的组合物可以是用于局部施用的药物组合物的形式。用于局部施用的药物组合物可以是用于经皮施用的制剂的形式、皮下施用的形式、肌肉内施用的形式或腹膜内施用的形式。此外,用于局部施用的药物组合物可以是用于单次施用或多次施用的制剂。可将用于多次施用的制剂制备成适合于以约0.5ml的体积每天至少一次以3至14天的间隔施用。如果需要,可以将用于多次施用的制剂重复施用至以0.5至2.0cm的距离分隔开的部位。
用于局部施用的药物组合物可以是液体制剂的形式或干粉制剂的形式。液体制剂包括溶液、乳液、悬浮液等,优选为溶液或乳液的形式。可以将液体制剂用细菌过滤器等进行无菌过滤,然后填充到安瓿或小瓶中。干粉制剂包括粉末形式,粉末形式是通过常规干燥方法(例如旋转蒸发干燥、喷雾干燥、流化床干燥和冷冻干燥(冻干),优选通过冷冻干燥)干燥溶液、乳液、悬浮液等而获得的。在对个体施用之前,可以将干粉制剂用注射用水、无菌蒸馏水、注射用水、生理盐水、葡萄糖溶液、葡萄糖注射液、木糖醇注射液、D-甘露糖醇注射液、果糖注射液、右旋糖酐-40(Dexran-40)注射液、右旋糖酐-70(Dexran-70)注射液、氨基酸注射液、林格氏溶液、乳酸林格氏溶液等稀释。
液体制剂的形式或干粉制剂的形式的用于局部施用的药物组合物可以根据药学领域中采用的常规方法,利用药学上可接受的辅料和/或溶剂来制备。因此,用于局部施用的药物组合物可以包含一种或多种选自以下的药学上可接受的辅料:pH控制剂、等渗剂、表面活性剂、稳定剂、防腐剂(或抗菌剂)、螯合剂、缓冲剂和冷冻保护剂;以及一种或多种选自以下的药学上可接受的载体:油、有机溶剂和水性溶剂。
pH控制剂包括常规用于注射制剂的pH控制剂,例如氢氧化钠、柠檬酸、乙酸、磷酸、葡糖酸、抗坏血酸、琥珀酸等,但不限于此。本发明的药物组合物可以具有在pH 3至pH 9的范围内的pH,优选具有在pH 5至pH 8的范围内的pH。当将其局部施用时,具有所述pH范围的药物组合物可以使疼痛和/或炎症最小化。
等渗剂包括糖、糖醇、盐等,例如葡萄糖、甘油、氯化钠、氯化钙、硫酸钠、甘油、丙二醇、聚乙二醇(例如具有1000以下分子量的聚乙二醇)、右旋糖、羟丙基β-环糊精(hydroxypropyl betadex)、甘露糖醇、氯化钾、右旋糖酐、聚蔗糖、明胶、羟乙基淀粉等,但不限于此。在实施方案中,等渗剂可以是甘油和/或氯化钠。特别地,甘油也可以帮助改善制剂的稳定性。等渗剂可以以适合于提供生理上可接受的重量克分子渗透压浓度(osmolality)的量使用。
表面活性剂包括离子表面活性剂、非离子表面活性剂和/或两性表面活性剂。在实施方案中,表面活性剂可以是非离子表面活性剂。非离子表面活性剂包括例如聚氧乙烯脱水山梨糖醇脂肪酸酯(例如吐温系列表面活性剂)、聚氧乙烯聚氧丙烯嵌段共聚物(例如泊洛沙姆系列表面活性剂)等,但不限于此。
稳定剂包括例如胆固醇、β-胆固醇、谷甾醇、麦角固醇、豆甾醇、乙酸豆甾醇酯、羊毛甾醇及它们的组合,但不限于此。在实施方案中,稳定剂可以是胆固醇。
防腐剂包括常规用于药物领域的抗菌剂。防腐剂包括苯甲醇、甘油、间甲酚、苯酚、苯扎氯铵、苄索氯铵、阿拉伯胶、白蛋白、乙醇、藻酸、抗坏血酸棕榈酸酯、阿斯巴甜、硼酸、柠檬酸、甘油、喷替酸(pentetic acid)、乙酸钠、山梨酸、氯丁醇、邻甲酚、对甲酚、氯甲酚、硝酸苯汞、硫柳汞、苯甲酸、胆固醇等,但不限于此。在实施方案中,防腐剂可以是苯甲醇和/或甘油。
螯合剂包括乙二胺四乙酸(EDTA)、丁二胺四乙酸、环己烷-1,2-二胺四乙酸(CyDTA)、,二乙三胺五乙酸(DETPA)、乙二胺四丙酸、(羟乙基)乙二胺三乙酸(HEDTA)、乙二胺四(亚甲基膦酸)(EDTMP)、三乙四胺六乙酸(TTHA)、1,3-二氨基-2-羟基丙烷-N,N,N’,N’-四乙酸(DHPTA)、甲基亚氨基二乙酸、丙二胺四乙酸、1,5,9-三氮杂环癸烷-N,N’,N”-三(亚甲基膦酸)(DOTRP)、1,4,7,10-四氮杂环癸烷-N,N’,N”,N”’-四(亚甲基膦酸)(DOTP),次氮基三(亚甲基)三膦酸、二乙三胺五(亚甲基膦酸)(diethylenetriaminephenta(methylenephosphonic acid))(DETAP),氨基三(亚甲基膦酸)、1-羟基亚乙基-1,1-二膦酸、双(六亚甲基)三胺膦酸、1,4,7-三氮杂环壬烷-N,N’,N”-三(亚甲基膦酸)(NOTP)、2-膦酰基丁烷-1,2,4-三羧酸(2-phophoobuthan-1,2,4-tricarboxy acid)、次氮基三乙酸(NTA)、柠檬酸、富马酸、苹果酸、麦芽酚、酒石酸、葡糖酸、甘油酸、草酸、邻苯二甲酸、马来酸、扁桃酸、丙二酸、乳酸、水杨酸、水杨酸甲酯、5-磺基水杨酸、没食子酸、没食子酸丙酯、邻苯三酚、8-羟基喹啉、半胱氨酸等,但不限于此。
缓冲剂包括磷酸氢二钠(dibasic sodium phosphate)、柠檬酸、柠檬酸钠水合物、柠檬酸钾、乙酸、乙酸钠、碳酸钠、碳酸钙、磷酸三钙、乳酸钙、甘氨酸、马来酸、苹果酸、谷氨酸钠、谷氨酸一钠、乳酸钠、磷酸钠及它们的混合物,但不限于此。
冷冻保护剂可以是糖、糖醇或它们的混合物。糖可以为选自乳糖、麦芽糖、蔗糖、甘露糖、海藻糖、木糖、果糖和棉子糖中的一种或多种。糖醇可以为选自甘露糖醇、山梨糖醇、肌醇、麦芽糖醇、木糖醇和乳糖醇中的一种或多种。此外,冷冻保护剂可以还包括甘氨酸、组氨酸、聚乙烯吡咯烷酮(PVP)等,但不限于此。
有机溶剂包括醇,例如乙醇(包括无水乙醇、发酵酒精等)、甲醇、丙酮、双丙酮、辛醇、异丙醇、月桂醇、聚乙烯醇;二醇,例如聚乙二醇、乙二醇、丙二醇、二丙二醇、丁二醇、戊二醇、巯基乙酸,但不限于此。
油包括植物油、中链甘油三酸酯(MCT)、胆固醇、硬脂酸甘油酯、油酸等,但不限于此。在实施方案中,油可以是植物油和/或油酸。植物油可以选自棉籽油、玉米油、芝麻油、大豆油、橄榄油、椰子油、花生油、葵花籽油、红花籽油、杏仁油、鳄梨油、棕榈油、棕榈仁油、巴巴苏油、山毛榉坚果油、亚麻籽油、菜籽油(canola oil)及它们的组合。在实施方案中,植物油可以是大豆油。
水性溶剂包括注射用水、无菌蒸馏水、生理盐水、右旋糖水溶液和蔗糖水溶液等等,没有限制。
根据本发明的用于局部施用的药物组合物通常包含在密封和灭菌的塑料容器或有机容器中。容器可以以经限定的体积的形式提供,例如安瓿、小瓶、注射器或药筒(cartridge),或者可以以大体积的形式提供,例如注射用袋子或注射用瓶子。
在根据本发明的用于局部施用的药物组合物中,式1的化合物或其药学上可接受的盐可以以每天在约1mg/kg至约1500mg/kg范围内的有效量施用,该量可以根据患者的年龄、体重、易感性、症状、剂型等而变化。在实施方案中,式1的化合物或其药学上可接受的盐可以以在1至1000mg范围内、优选在1至500mg范围内的量包含在每单位制剂(unitformulation)中。此外,如上所述,所述胆汁酸或其药学上可接受的盐的有效量可以通过考虑与式1的化合物或其药学上可接受的盐的重量比来适当地确定。
本发明的组合物也可以是应用于皮肤、皮下组织、肌肉组织或腹部组织的化妆品组合物的形式。可以将本发明的化妆品组合物制备成适合于以约0.5ml的体积每天至少一次以3至14天的间隔应用。如果需要,可以将本发明的化妆品组合物重复施用于以0.5至2.0cm的距离分隔开的部位。
本发明的化妆品组合物可以具有各种形式,并且形式不受限制。即,本发明的化妆品组合物可以为常规的化妆品组合物形式,例如霜剂、涂敷剂(pack)、洗剂、精华、清洁水、粉底、化妆底料、局部注射剂等。化妆品组合物可以是液体的形式或干粉的形式。液体形式包括溶液、乳液、悬浮液等,优选以溶液或乳液的形式。如果需要,可以将液体形式用细菌过滤器等进行无菌过滤,然后将其装入安瓿或小瓶中。干粉形式包括通过常规干燥方法(例如旋转蒸发干燥、喷雾干燥、流化床干燥和冷冻干燥(冻干),优选通过冷冻干燥)来干燥溶液、乳液、悬浮液等而获得的粉末形式。在应用于个体之前,可以将干粉剂用注射用水、无菌蒸馏水、注射用水、生理盐水等稀释。
液体形式或干粉形式的化妆品组合物可以根据化妆品领域中采用的常规方法,使用辅料和/或载体来制备。因此,化妆品组合物可以包含一种或多种选自以下的辅料:pH控制剂、等渗剂、表面活性剂、稳定剂、防腐剂、螯合剂、缓冲剂和冷冻保护剂;以及一种或多种选自以下的载体:油、有机溶剂和水性溶剂。所述辅料和载体与上文所描述的相同。此外,化妆品组合物通常包含在密封和灭菌的塑料容器或有机容器中。容器可以以经限定的体积的形式提供,例如安瓿、小瓶、注射器或药筒,或者可以以大体积的形式提供,例如注射用袋子或注射用瓶子。
在根据本发明的化妆品组合物中,式1的化合物或其药学上可接受的盐可以以每天在约1mg/kg至约1500mg/kg范围内的量应用,该量可以根据个体的年龄、体重、易感性、症状、剂型等而变化。在实施方案中,式1的化合物或其药学上可接受的盐可以以在1至1000mg范围内、优选在1至500mg范围内的量包含在每单位化妆品组合物中。此外,如上所述,所述胆汁酸或其药学上可接受的盐的量可以通过考虑与式1的化合物或其药学上可接受的盐的重量比来适当地确定。
在本发明的范围内,本发明还包括在有需要的哺乳动物中诱导脂解或改善、抑制或治疗局部脂肪沉积的方法,该方法包括向哺乳动物施用有效量的式1的化合物或其药学上可接受的盐。
在本发明的方法中,式1的化合物可以是选自以下的一种或多种:
1,2-二癸酰基-sn-甘油-3-磷酸胆碱;
1,2-二月桂酰基-sn-甘油-3-磷酸胆碱;
1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱;
1-肉豆蔻酰基-2-棕榈酰基-sn-甘油-3-磷酸胆碱;
1-肉豆蔻酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱;
1-棕榈酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1-棕榈酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-棕榈酰基-sn-甘油-3-磷酸胆碱;
1,2-二芥酰基-sn-甘油-3-磷酸胆碱;
1,2-二油酰基-sn-甘油-3-磷酸胆碱;
1-棕榈酰基-2-油酰基-sn-甘油-3-磷酸胆碱;和
1-硬脂酰基-2-油酰基-sn-甘油-3-磷酸胆碱。
优选地,在本发明的方法中,式1的化合物可以是选自以下的一种或多种:
1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二癸酰基-sn-甘油-3-磷酸胆碱;
1-棕榈酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱;和
1,2-二月桂酰基-sn-甘油-3-磷酸胆碱。
更优选地,在本发明的方法中,式1的化合物可以是选自以下的一种或多种:
1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二癸酰基-sn-甘油-3-磷酸胆碱;和
1-棕榈酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱。
最优选地,在本发明的方法中,式1的化合物可以是1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱。
在本发明的范围内,本发明还包括式1的化合物或其药学上可接受的盐在制备用于诱导脂解或预防或用于改善、抑制或治疗局部脂肪沉积的药物中的用途。
在本发明的用途中,式1的化合物可以是选自以下的一种或多种:
1,2-二癸酰基-sn-甘油-3-磷酸胆碱;
1,2-二月桂酰基-sn-甘油-3-磷酸胆碱;
1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱;
1-肉豆蔻酰基-2-棕榈酰基-sn-甘油-3-磷酸胆碱;
1-肉豆蔻酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱;
1-棕榈酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1-棕榈酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-棕榈酰基-sn-甘油-3-磷酸胆碱;
1,2-二芥酰基-sn-甘油-3-磷酸胆碱;
1,2-二油酰基-sn-甘油-3-磷酸胆碱;
1-棕榈酰基-2-油酰基-sn-甘油-3-磷酸胆碱;和
1-硬脂酰基-2-油酰基-sn-甘油-3-磷酸胆碱。
优选地,在本发明的用途中,式1的化合物可以是选自以下的一种或多种:
1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二癸酰基-sn-甘油-3-磷酸胆碱;
1-棕榈酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱;和
1,2-二月桂酰基-sn-甘油-3-磷酸胆碱。
更优选地,在本发明的用途中,式1的化合物可以是选自以下的一种或多种:
1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二癸酰基-sn-甘油-3-磷酸胆碱;和
1-棕榈酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱。
最优选地,在本发明的用途中,式1的化合物可以是1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱。
将参考以下实施例和实验例更详细地描述本发明。这些实施例和实验例仅用于说明目的,并不意图限制本发明的范围。
实施例1:冻干制剂的制备
根据表1中所示的组分和量制备冻干干粉形式的冻干制剂。表1的量表示每种组分的重量(mg)。在300rpm的搅拌下,将油酸、甘油、胆固醇和苯甲醇溶解在乙醇(50ml)中。在70±10℃加热下,将DMPC溶解在所得溶液中,以获得第一溶液。
将第一溶液添加到甘露糖醇(62.5mg)的注射用水(800mL)溶液中,然后用高压均质器(Homogenizer Unidrive x1000D display,CAT GmbH,德国)以15000rpm均质化约60分钟,以获得乳液。将所得乳液用膜过滤器(PVDF 0.22μm过滤器,Millipore,美国)进行无菌过滤,然后在以下条件下冻干,以获得冻干干粉形式的制剂。将冻干的制剂储存在10ml小瓶中。
实施例2至实施例18:冻干制剂的制备
根据表1和2中所示的组分和量制备冻干干粉形式的冻干制剂。表1和表2的量表示每种组分的重量(mg)。按照与实施例1相同的方法,利用DMPC或其它磷酸胆碱衍生物制备第一溶液。
在不同的容器中,在300rpm的搅拌下将磷酸氢二钠、氯化钠和氢氧化钠溶解在注射用水(150ml)中。在所得溶液中,将胆汁酸或其盐溶解以获得各自的第二溶液。
将第一溶液(50mL)和第二溶液(150mL)在70±10℃的加热下相互混合,然后用高压均质器(Homogenizer Unidrive x1000D display,CAT GmbH,德国)以10000rpm均质化约30分钟以获得相应的乳液。将所得乳液加入到甘露糖醇(62.9mg)的注射用水(800mL)溶液中,然后用高压均质器(Homogenizer Unidrive x1000D display,CAT GmbH,德国)以15000rpm均质化约60分钟,以获得相应的乳液。将所得乳液用膜过滤器(PVDF 0.22μm过滤器,Millipore,美国)进行无菌过滤,然后在与实施例1相同的条件下冻干,以获得冻干干粉形式的制剂。将冻干的制剂储存在10ml小瓶中。
表1
表2
实施例19:溶液的制备
根据表3中所示的组分和量制备溶液形式的制剂。表3的量表示每种组分的重量(mg)。将苯甲醇和吐温80溶解在加热至约30℃的注射用水(7-8ml)中。在300rpm持续1小时的搅拌下,将DMPC溶解于所得溶液中。通过在约30℃的加热下将磷酸氢二钠、氯化钠和氢氧化钠溶解在所得溶液中来调节pH后,用注射用水将溶液的最终体积调节至10ml。将所得溶液用膜过滤器(PVDF 0.22μm过滤器,美国)进行无菌过滤,然后装入小瓶中。
实施例20至实施例36:溶液的制备
根据表3和表4中所示的组分和量制备溶液形式的制剂。表3和表4的量表示每种组分的重量(mg)。将苯甲醇和吐温80溶解在加热至约30℃的注射用水(7-8ml)中。在300rpm持续1小时的搅拌下,将各胆汁酸或其盐溶解于溶液中(第二溶液)。在300rpm持续1小时的搅拌下,同时将第二溶液在约30℃下加热,将DMPC或其它磷酸胆碱衍生物溶解在各第二溶液中。通过溶解磷酸氢二钠、氯化钠和氢氧化钠调节pH后,用注射用水将各溶液的最终体积调节至10ml。将所得的各溶液用膜过滤器(PVDF 0.22μm过滤器,Millipore,美国)进行无菌过滤,然后装入小瓶中。
表3
表4
比较例1
按照与实施例19相同的方法制备含有磷脂酰胆碱的溶液,不同之处在于采用磷脂酰胆碱(150mg)代替DMPC。
比较例2
按照与实施例20相同的方法制备含有磷脂酰胆碱和脱氧胆酸钠的溶液,不同之处在于分别使用磷脂酰胆碱(150mg)和脱氧胆酸钠(20mg)代替DMPC和牛磺胆酸钠。
实验例1:脂解活性的测量
1、动物模型的制作和给药
持续9周给Sprague-Dawley大鼠(4周龄,Orient Bio Inc.(城南市,大韩民国))饲喂高脂饮食(D12492,5%卡路里来自脂肪,20%卡路里来自蛋白质,35%卡路里来自碳水化合物,RESEARCH DIET Inc.,新不伦瑞克,新泽西州,美国)。将大鼠维持在20.0~24.0℃下,在40~60%的相对湿度的条件下,进行12小时光/暗循环,并自由饮水。监测大鼠的体重以获得高脂大鼠(饲喂9周,总共13周龄)。表5示出了各组中大鼠的平均体重(总共13周龄,n=10)。
将不含活性成分的0.2mL溶媒、实施例1至实施例36的制剂以及比较例1和比较例2的制剂各自皮下注射到各组的高脂大鼠的左腹股沟中(n=10),每周一次,持续4周。在将各种冻干的粉末溶解在注射用水(10mL)中之后,将实施例1至实施例18的制剂进行皮下注射。
表5
2、副作用和脂解作用的评估
从持续4周的给药恢复2周后,处死每组的大鼠,观察炎症和坏死。测量施用部位处的脂肪减少率;通过苏木精和曙红染色评估副作用,例如炎症;以及通过油红O反应测量脂解作用。
(1)炎症和坏死的观察
从持续4周的给药恢复2周后,处死每组的大鼠,然后用肉眼观察皮下注射位点并进行触觉测试。结果,在施用了本发明制剂的组中,注射位点处没有观察到坏死和炎症。并且在触觉测试中也没有触及任何坚硬(firm)的部分。然而,在施用了比较例1和比较例2的制剂的组中,注射位点处用肉眼观察到了坏死和炎症,并且在触觉测试中还触及到了特别坚硬的变化(firm change)。
(2)施用部位处的脂肪减少率的测量
从持续4周的给药恢复2周后,处死每组的大鼠并进行组织尸检。用肉眼观察右腹股沟和左腹股沟(施用部位)来源的皮下组织,以确认是否有任何异常发现,并拍摄其照片。然后,从中取出组织并称重。根据下式计算相对重量和减少率。其结果示于下表6中,其照片示于图1中。
-相对重量(g)=腹股沟中脂肪的重量(g)/体重(g)
-减少率(%)=[1-(左(g)/右(g))]×100%
表6
如表6所示,可以确认的是,施用本发明的制剂的组在器官重量和施用部位的相对重量方面均表现出显著的降低,从而表现出优异的脂解活性。此外,如图1和图2所示,可以确认的是,当用肉眼观察时,与非施用部位(虚线圆圈)处的脂解活性相比,施用部位(深色圆圈)处的脂解活性明显更优异。
(3)通过苏木精和曙红染色测量副作用
在解剖已处死大鼠的腹部和腹股沟后,迅速取出各皮下脂肪,然后将其浸入10%中性缓冲甲醛溶液中固定。用水洗涤并脱水后,将细胞用石蜡溶液处理以制成石蜡块。将每个石蜡块切成4-5μm的厚度,用苏木精和曙红染色,然后用光学显微镜观察。其结果如图3所示,在施用本发明制剂的组中观察到基本完整的脂肪细胞,而在施用比较例1和比较例2的制剂的组中观察到炎症反应。
(4)通过油红O反应测量脂解作用
在解剖已处死大鼠的腹部和腹股沟后,迅速取出各皮下脂肪,然后将腹股沟中的脂肪组织用4%甲醛溶液固定24小时。用30%的蔗糖溶液脱水24小时后,利用冷冻切片机(FSE Cryostats,Thermo Scientific)制备OCT包埋的冷冻切片(OCT-embeddingcryostat)。在制备厚度为10μm的切片后,将脂肪组织用油红O(脂质染色)染色试剂盒(产品编号:ab150678,Abcam,美国)进行染色,并用光学显微镜观察脂解的水平。其结果如图4所示,可以确认的是,施用本发明制剂的组显示出均匀的脂肪分布,而施用比较例1和比较例2的制剂的组显示出聚集的脂肪,即不均匀的脂肪分布。因此,可以确认的是,本发明的制剂在施用部位具有均匀的脂解活性,而比较例1和比较例2的制剂不能实现均匀的脂解。
实验例2:稳定性测试
将实施例1至实施例4、实施例6、实施例12、实施例19至实施例22、实施例24、实施例26、实施例28和实施例30以及比较例1和比较例2的制剂在室温下储存7天和30天。将实施例1至实施例4、实施例6和实施例12的制剂溶解在注射用水(10ml)中之后,进行储存。图5中示出了各制剂的初始制备物、在室温下储存7天以及在室温下储存30天的结果。从图5的结果可以看出本发明的制剂具有优异的稳定性。
Claims (28)
2.根据权利要求1所述的组合物,其中所述式1的化合物是选自以下的一种或多种:
1,2-二癸酰基-sn-甘油-3-磷酸胆碱;
1,2-二月桂酰基-sn-甘油-3-磷酸胆碱;
1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱;
1-肉豆蔻酰基-2-棕榈酰基-sn-甘油-3-磷酸胆碱;
1-肉豆蔻酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱;
1-棕榈酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1-棕榈酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-棕榈酰基-sn-甘油-3-磷酸胆碱;
1,2-二芥酰基-sn-甘油-3-磷酸胆碱;
1,2-二油酰基-sn-甘油-3-磷酸胆碱;
1-棕榈酰基-2-油酰基-sn-甘油-3-磷酸胆碱;和
1-硬脂酰基-2-油酰基-sn-甘油-3-磷酸胆碱。
3.根据权利要求1所述的组合物,其中所述式1的化合物是选自以下的一种或多种:
1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二癸酰基-sn-甘油-3-磷酸胆碱;
1-棕榈酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱;和
1,2-二月桂酰基-sn-甘油-3-磷酸胆碱。
4.根据权利要求1所述的组合物,其中所述式1的化合物是选自以下的一种或多种:
1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二癸酰基-sn-甘油-3-磷酸胆碱;和
1-棕榈酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱。
5.根据权利要求1所述的组合物,其中所述式1的化合物是1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱。
6.根据权利要求1所述的组合物,其进一步包含有效量的胆汁酸或其药学上可接受的盐。
7.根据权利要求6所述的组合物,其中所述胆汁酸或其药学上可接受的盐为选自胆酸、甘氨胆酸、甘氨脱氧胆酸、脱氧胆酸、牛磺胆酸、熊去氧胆酸、牛磺熊去氧胆酸、牛磺去氧胆酸、鹅去氧胆酸、甘氨熊去氧胆酸、脱氧胆酸钠和牛磺胆酸钠中的一种或多种。
8.根据权利要求6所述的组合物,其中所述胆汁酸或其药学上可接受的盐为选自甘氨胆酸、脱氧胆酸、牛磺胆酸、牛磺熊去氧胆酸、甘氨熊去氧胆酸、脱氧胆酸钠和牛磺胆酸钠中的一种或多种。
9.根据权利要求6所述的组合物,其中所述式1的化合物或其药学上可接受的盐与所述胆汁酸或其药学上可接受的盐的重量比在0.5:1至40:1的范围内。
10.根据权利要求1至9中任一项所述的组合物,其中所述组合物为用于局部施用的药物组合物的形式。
11.根据权利要求10所述的组合物,其中所述用于局部施用的药物组合物为用于经皮施用的制剂的形式、用于皮下施用的制剂的形式、用于肌肉内施用的制剂的形式或用于腹膜内施用的制剂的形式。
12.根据权利要求10所述的组合物,其中所述用于局部施用的药物组合物为液体制剂的形式或干粉制剂的形式。
13.根据权利要求10所述的组合物,其中所述用于局部施用的药物组合物为溶液、乳液或冻干粉末的形式。
14.根据权利要求10所述的组合物,其中所述用于局部施用的药物组合物包含一种或多种选自以下的药学上可接受的辅料:pH控制剂、等渗剂、表面活性剂、稳定剂、防腐剂、螯合剂、缓冲剂和冷冻保护剂;以及一种或多种选自以下的药学上可接受的载体:油、有机溶剂和水性溶剂。
15.根据权利要求1至9中任一项所述的组合物,其中所述组合物为应用于皮肤、皮下组织、肌肉组织或腹部组织的化妆品组合物的形式。
16.根据权利要求15所述的组合物,其中所述化妆品组合物为液体的形式或干粉的形式。
17.根据权利要求15所述的组合物,其中所述化妆品组合物为溶液、乳液或冻干粉末的形式。
18.根据权利要求15所述的组合物,其中所述化妆品组合物包含一种或多种选自以下的辅料:pH控制剂、等渗剂、表面活性剂、稳定剂、防腐剂、螯合剂、缓冲剂和冷冻保护剂;以及一种或多种选自以下的载体:油、有机溶剂和水性溶剂。
20.根据权利要求19所述的方法,其中所述式1的化合物是选自以下的一种或多种:
1,2-二癸酰基-sn-甘油-3-磷酸胆碱;
1,2-二月桂酰基-sn-甘油-3-磷酸胆碱;
1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱;
1-肉豆蔻酰基-2-棕榈酰基-sn-甘油-3-磷酸胆碱;
1-肉豆蔻酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱;
1-棕榈酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1-棕榈酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-棕榈酰基-sn-甘油-3-磷酸胆碱;
1,2-二芥酰基-sn-甘油-3-磷酸胆碱;
1,2-二油酰基-sn-甘油-3-磷酸胆碱;
1-棕榈酰基-2-油酰基-sn-甘油-3-磷酸胆碱;和
1-硬脂酰基-2-油酰基-sn-甘油-3-磷酸胆碱。
21.根据权利要求19所述的方法,其中所述式1的化合物是选自以下的一种或多种:
1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二癸酰基-sn-甘油-3-磷酸胆碱;
1-棕榈酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱;和
1,2-二月桂酰基-sn-甘油-3-磷酸胆碱。
22.根据权利要求19所述的方法,其中,所述式1的化合物是选自以下的一种或多种:
1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二癸酰基-sn-甘油-3-磷酸胆碱;和
1-棕榈酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱。
23.根据权利要求19所述的方法,其中所述式1的化合物是1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱。
25.根据权利要求24所述的用途,其中所述式1的化合物是选自以下的一种或多种:
1,2-二癸酰基-sn-甘油-3-磷酸胆碱;
1,2-二月桂酰基-sn-甘油-3-磷酸胆碱;
1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱;
1-肉豆蔻酰基-2-棕榈酰基-sn-甘油-3-磷酸胆碱;
1-肉豆蔻酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱;
1-棕榈酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1-棕榈酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-棕榈酰基-sn-甘油-3-磷酸胆碱;
1,2-二芥酰基-sn-甘油-3-磷酸胆碱;
1,2-二油酰基-sn-甘油-3-磷酸胆碱;
1-棕榈酰基-2-油酰基-sn-甘油-3-磷酸胆碱;和
1-硬脂酰基-2-油酰基-sn-甘油-3-磷酸胆碱。
26.根据权利要求24所述的用途,其中所述式1的化合物是选自以下的一种或多种:
1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二癸酰基-sn-甘油-3-磷酸胆碱;
1-棕榈酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱;和
1,2-二月桂酰基-sn-甘油-3-磷酸胆碱。
27.根据权利要求24所述的用途,其中所述式1的化合物是选自以下的一种或多种:
1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱;
1-硬脂酰基-2-肉豆蔻酰基-sn-甘油-3-磷酸胆碱;
1,2-二癸酰基-sn-甘油-3-磷酸胆碱;和
1-棕榈酰基-2-硬脂酰基-sn-甘油-3-磷酸胆碱。
28.根据权利要求24所述的用途,其中所述式1的化合物是1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆碱。
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PCT/KR2018/004296 WO2019088378A1 (en) | 2017-11-03 | 2018-04-12 | Lipolytic composition containing phosphocholine derivatives |
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CA2872279C (en) | 2014-11-21 | 2018-06-12 | Pankaj Modi | Topical lipolysis compositions and methods |
JP6426991B2 (ja) * | 2014-12-02 | 2018-11-21 | 白鳥製薬株式会社 | 体脂肪減少促進剤 |
WO2017187426A1 (en) * | 2016-04-29 | 2017-11-02 | Aptamir Therapeutics, Inc. | Inhibition of mir-22 mirna by apt-110 |
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WO2005063205A2 (en) * | 2003-12-22 | 2005-07-14 | Aventis Pharmaceuticals Inc. | Injectable phosphatidylcholine preparations |
US20100331281A1 (en) * | 2007-11-16 | 2010-12-30 | Baylor College Of Medicine | Phospholipid compositions and uses thereof |
CN101480402A (zh) * | 2008-12-17 | 2009-07-15 | 北京世纪博康医药科技有限公司 | 一种环木菠萝烯醇阿魏酸酯组合物及其制备方法 |
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CA3022733A1 (en) | 2019-05-03 |
MX2020002336A (es) | 2020-07-20 |
US20190134068A1 (en) | 2019-05-09 |
JP7082189B2 (ja) | 2022-06-07 |
EP3641781A4 (en) | 2021-03-10 |
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