CN105101962A - 用于减脂的比马前列素、比马前列素类似物、前列腺酰胺和前列腺素的持续释放 - Google Patents
用于减脂的比马前列素、比马前列素类似物、前列腺酰胺和前列腺素的持续释放 Download PDFInfo
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Abstract
本发明涉及用于注射到脂肪沉积体中以持续释放导致局部减脂的化合物的组合物和方法。
Description
相关申请的交叉引用
本申请要求2013年4月12日提交的美国临时专利申请序列No.61/811,682的权益,该临时专利申请的全部公开内容以引用方式并入本文。
发明概述
本发明涉及出于减脂(包括局部减脂)的目的从可注射和可植入的储库持续释放比马前列素、比马前列素类似物、比马前列素前药、前列腺酰胺、前列腺素、前列腺素类似物和前列腺素衍生物的组合物和方法。
已显示局部用比马前列素在局部施用后可在动物模型中有效阻止脂肪细胞形成和成熟并使脂肪细胞萎缩。此外,局部施用比马前列素后的减脂的临床证据已有报道。本发明涉及用于局部减脂的比马前列素、比马前列素类似物、比马前列素前药、前列腺酰胺、前列腺素、前列腺素类似物和衍生物和前列腺素类似物(例如拉坦前列素和曲伏前列素)的持续释放方法和制剂。
附图简述
图1示出采用可注射PLGA植入物的比马前列素的体外释放曲线;
图2示出采用可注射SynBiosys植入物的比马前列素的体外释放曲线;
图3A和3B示出100天内ReGel100或ReGelB的释放数据;
图4A-4C示出ReGel100或ReGelB递送体系的拉坦前列素释放数据的比较;
图5示出注射后40分钟的2-DMR图像,该图像透过腓肠肌纵向取向以显示每条腿的MGL和MGM肌群。右腿注射HA/白蛋白-钆,左腿仅注射白蛋白-钆;
图6A示出在含有20%比马前列素、45%R203s、20%RG752s10%R202H、5%PEG-3350的制剂中的比马前列素的释放速率;
图6B示出在图6B底部示出的制剂中的比马前列素的释放速率;
图6C示出表I中制剂的化合物#1的释放速率;
图7A示出可用于持续释放比马前列素以进行局部减脂的比马前列素微球体;
图7B示出比马前列素从拉坦前列素微球体的释放速率;
图8A和8B示出含有10%比马前列素的二乙二醇二苯甲酸酯(凝胶);以及,
图8C示出比马前列素从含有10%比马前列素的二乙二醇二苯甲酸酯储库(凝胶)释放的实例。
本发明的一些实施方案包括于以下段落中:
1)一种减脂的方法,其包括将选自比马前列素、比马前列素类似物、比马前列素前药、前列腺酰胺、前列腺素、前列腺素类似物、拉坦前列素和曲伏前列素以及前列腺素衍生物及其混合物的化合物的持续释放制剂注射到脂肪沉积体中。
2)根据段落1所述的方法,其中所述化合物选自比马前列素、拉坦前列素、曲伏前列素和化合物#1及其混合物。
3)根据段落1所述的方法,其中所述持续释放制剂选自可注射储库、凝胶混悬液、ReGel递送体系、透明质酸释放平台、植入物、微球体、大球体和可注射溶剂。
4)根据段落2或3所述的方法,其中所述化合物为比马前列素。
5)根据段落1-4所述的方法,其中将所述持续释放制剂直接注射到所述脂肪沉积体中。
6)根据段落1所述的方法,其中所述减脂是在注射部位处及其周围的局部减脂。
7)根据段落1或3所述的方法,其中所述持续释放制剂为具有约20%比马前列素、约45%R203s、约20%RG752s、约10%R202H和约5%PEG-3350的制剂的植入物。
8)根据段落1或3所述的方法,其中所述方法导致褐色和白色脂肪细胞两者萎缩并且导致局部减脂。
9)根据段落7所述的方法,其中所述植入物在超过100天的时间内将比马前列素释放到所述脂肪沉积体中。
10)根据段落1所述的方法,其中所述持续释放制剂全身性地释放所述化合物,以靶向在体内未处于所述持续释放制剂所在位置或处于难以到达的区域的脂肪沉积体。
11)根据段落1或10所述的方法,其中所述持续释放制剂被注射或植入到,作为非限制性实例的,允许减少腹部脂肪沉积体、内脏脂肪沉积体、心外膜脂肪沉积体、皮下脂肪沉积体和异位脂肪沉积体的位置处。
12)一种用于局部减脂的组合物,其中所述组合物为选自可注射储库、凝胶混悬液、ReGel递送体系、基于透明质酸的平台、植入物、微球体、大球体和可注射溶剂的持续释放组合物。
13)根据段落12所述的组合物,其中所述组合物还包含选自比马前列素、比马前列素类似物、比马前列素前药、前列腺酰胺、前列腺素、前列腺素类似物、拉坦前列素和曲伏前列素以及前列腺素衍生物的化合物。
14)根据段落12和13所述的组合物,其中所述持续释放组合物为Regel递送体系,并且所述化合物为比马前列素。
15)根据段落14所述的组合物,其中所述组合物被注射到局部脂肪沉积体中。
16)根据段落15所述的组合物,其中所述组合物在多个注射部位被注射到单一局部脂肪沉积体中。
17)根据段落15所述的组合物,其中所述组合物在超过100天的时间内将比马前列素释放到所述局部脂肪沉积体中。
18)根据段落12或13所述的组合物,其中所述持续释放制剂为由约20%比马前列素、约45%R203s、约20%RG752s、约10%R202H和约5%PEG-3350组成的植入物。
19)根据段落18所述的组合物,其中所述组合物被注射到选自腹部脂肪沉积体、内脏脂肪沉积体、心外膜脂肪沉积体、皮下脂肪沉积体和异位脂肪沉积体中的至少一者中。
20)根据段落18所述的组合物,其中所述组合物的注射导致在所述局部脂肪沉积体中的脂肪细胞的萎缩以及局部脂肪的减少。
21)根据段落12或13所述的组合物,其中所述持续释放制剂为由选自聚(d,l-丙交酯-共-乙交酯)、聚(d,l-丙交酯)、聚(己内酯)、聚(对二氧环己酮)、聚(乙二醇)、聚(原酸酯)、聚酯、聚(膦嗪)、聚(磷酸酯)、聚己内酯、硅酮、天然聚合物如乳胶、明胶或胶原或聚合物掺混物中的至少一种聚合物组成的植入物,并且所述化合物选自比马前列素、拉坦前列素、曲伏前列素及其混合物。
22)根据段落12或13所述的组合物,其中所述持续释放制剂为由选自透明质酸钠、交联透明质酸、硫酸软骨素、纤维素材料、明胶、胶原、糖胺聚糖或其它合成的或天然存在的多糖中的至少一种化合物组成的凝胶混悬液,并且所述化合物选自比马前列素、拉坦前列素、曲伏前列素及其混合物。
23)根据段落22所述的组合物,其中所述凝胶混悬液为热胶凝递送体系。
24)根据段落22所述的组合物,其中所述热胶凝体系由A-B-A或B-A-B三嵌段共聚物或B-A嵌段共聚物的溶液组成。
25)根据段落12或13所述的组合物,其中所述持续释放制剂为可注射储库,其包含选自DMSO、NMP和DMAC或其混合物的生物相容性溶剂。
发明详述
比马前列素和其它化合物可溶解或分散在凝胶、可生物降解的固体植入物或含有溶剂化聚合物的生物相容性溶剂(其一经注射可形成固体储库)中。另外,还可利用比马前列素的热胶凝递送体系。用于持续释放的固体植入物可由聚(d,l-丙交酯-共-乙交酯)、聚(d,l-丙交酯)、聚(己内酯)、聚(对二氧环己酮)、聚(乙二醇)、聚(原酸酯)、聚酯、聚(膦嗪)、聚(磷酸酯)、聚己内酯、硅酮、天然聚合物如乳胶、明胶或胶原或聚合物掺混物组成。凝胶混悬液可含有透明质酸钠、交联透明质酸、硫酸软骨素、纤维素材料、明胶、胶原、糖胺聚糖或其它合成的或天然存在的多糖。用于注射原位成形储库的生物相容性溶剂包括DMSO(二甲基亚砜)、NMP(N-甲基吡咯烷酮)、DMAC(二甲基乙酰胺)或其它注射用非水性溶剂。
比马前列素递送体系和用于其它化合物的递送体系可通过植入物或可注射储库的注射或植入进行施用以减少脂肪组织。此类递送体系可用于减少局部脂肪组织(例如皮下脂肪)和/或作为用于持续全身性递送的方法来实现内脏脂肪和其它通过局部施用植入物或注射不容易到达的脂肪垫沉积物(例如心包脂肪沉积物)的减少。比马前列素为低熔点化合物,其持续从多种递送平台中释放的能力令人惊讶。具体的递送平台包括但不限于可注射比马前列素递送储库、原位成形比马前列素储库、透明质酸储库、固体形式的比马前列素植入物、比马前列素微球体和可注射溶剂储库。
可将本发明的递送体系注射或植入到一个位置来实现皮下脂肪沉积体和脂肪组织例如腹部脂肪、内脏脂肪、心外膜脂肪、颏下脂肪、眶周脂肪和异位脂肪垫的减少。
实施例I
可注射储库
已显示PLGA和多嵌段聚合物在储库形成时释放比马前列素。将聚合物和药物溶解在诸如N-甲基吡咯烷酮、二甲基乙酰胺或DMSO的生物相容性溶剂中。将制剂无菌过滤、高压处理或辐照以进行灭菌。
将溶液填充到无菌小瓶或单位剂量注射器中。注射后,生物相容性溶剂从储库扩散,留下稳固的载有前列腺酰胺或前列腺素的植入物。随着聚合物发生生物侵蚀,储库持续数天、数周或数月释放比马前列素、前列腺酰胺或前列腺素。溶液中的药物负载可在0.1%至50%的范围内。溶液中的聚合物负载可在15%至50%的范围内。赋形剂可包括聚(乙二醇)、短链脂肪酸、蜡、胆固醇、脂肪族醇、助溶剂或其它可调节储库疏水性的化合物。
采用包含PLGA和SynBiosys比马前列素两者的可注射储库,将药物连续释放至少一个月,如图1和图2所示。可通过改变药物负载、聚合物浓度、聚合物性质、制剂赋形剂或用于植入物制备的DMSO体积来进一步优化释放动力学。
实施例II
ReGel递送体系
还可使用响应于各种刺激而发生相转变的聚合物体系。此相转变导致体系中的显著的体积和/或粘度变化。所述体系可响应于pH、离子环境、温度、生物触发以及其它化学和物理触发。所述体系包含一种或多种聚合物,所述聚合物能够相互作用以引起导致体积或粘度增加的相转变。聚合物的实例包括聚丙烯酸和聚环氧乙烷共聚物。所述体系的其它组分包括本领域技术人员已知的赋形剂。
所述体系具有向局部组织提供受控和持续释放的治疗活性剂的另外优点。药物可以物理方式截留或经由共价键、氢结合、离子相互作用、范德华力(vanderWaalsforce)或疏水性相互作用而以化学方式结合。可通过将活性化合物物理截留在转变的凝胶中来控制药物的释放。也可以以物理或化学方式将化合物结合至包含相转变凝胶的聚合物。凝胶的相转变用于形成供药物递送的储库。
本发明的一个具体实施例教导了热胶凝比马前列素递送用递送体系的用途,所述热胶凝比马前列素递送用递送体系由A-B-A或B-A-B三嵌段共聚物或B-A嵌段共聚物的溶液组成,其中A=聚丙交酯-共-乙交酯(PLGA/PLA),且B=聚环氧乙烷(PEO)和拉坦前列素。这些聚合物构成Regel原位胶凝递送体系。已显示其水溶液随着温度升高而发生溶胶至凝胶的转变行为。对于药物递送应用,生理相关温度(如37℃)下的胶凝对于用于医疗和药物递送目的的体系的效用而言特别重要并为其形成基础。
在该具体实施例中,拉坦前列素以3%的负载载入ReGel100或ReGelB中,即,100ul凝胶中3mg药物。所述体系在热胶凝后表现出拉坦前列素的无突释的持续释放。鉴于拉坦前列素的低熔点和溶解度,这是非常令人惊讶的,即缓慢释放,无突释。凝胶保持时间长于100天,如图3A和3B中所示。可通过向体系中加入其它聚合物(如CMC、琼脂糖和淀粉)来进行另外的修改。
实施例III
透明质酸
已显示交联透明质酸一经注射可局部化,从而提供潜在的持续释放平台。可将药物掺入交联透明质酸中或缀合到媒介物以供持续释放。在前者的情况下,平台的释放和侵蚀可通过凝胶孔隙度、交联剂长度和交联密度来控制。或者,在后者的情况下,可通过本领域已知的若干连接基之一将比马前列素或前列腺酰胺类似物共价或离子结合到透明质酸主链。最后,可将药物掺入另一种持续释放模式(例如微球体)中,然后掺入透明质酸(交联或非交联)中,并作为递送平台注射。
图5示出注射后40分钟的2-DMR图像,该图像透过腓肠肌纵向取向以显示每条腿的MGL(三回羽状外侧腓肠肌)和MGM(单羽状内侧腓肠肌)肌群。右腿注射HA/白蛋白-钆,左腿仅注射白蛋白-钆。左腿示出白蛋白-钆(蓝色)在整个MGL肌上以及跨越至相邻MGM肌的弥漫性扩散。此数据表明交联的HA储库可被局部化并为用于减脂的前列腺素或前列腺酰胺的局部持续释放提供平台。
实施例IV
植入物
已将比马前列素配制成植入物,该植入物可皮下注射或植入到内脏脂肪中或与器官直接对合。实例为如下制剂:20%比马前列素、45%R203s、20%RG752s10%R202H、5%PEG-3350,并且图6A示出比马前列素从此制剂的释放速率(R203S为酯封端的PLA,R202H为酸端基PLA,RG752S为具有酸端基的75:25PLGA,PEG_3350是分子量为3350的聚乙二醇)。其它植入物制剂及其释放速率在图6B中示出。
可用于减脂的另一种化合物(化合物#1)在下面公开:
包含化合物#1的植入物制剂及其性质见下表I:
实施例V
微球体
还可通过使用如图7A-7B所示的用于拉坦前列素的PLGA微球体和大球体来使比马前列素和拉坦前列素持续。拉坦前列素微球体由PLA和PLGA聚合物制备,如下表所示。可通过将20mg拉坦前列素和100mg聚合物溶解于0.8ml乙酸乙酯中来制备所述微球体。可添加最低量的二氯甲烷来完成聚合物的溶解。将此溶液经由微量移液管添加到40ml1%聚乙烯醇水溶液中,同时用均化器在高剪切力(sheer)、3000rpm下混合5分钟。
剪切后,形成乳状的白色乳液,将其在通风橱中温和搅拌3-5小时以使得溶剂蒸发。然后将此分散体在2000rpm下离心15min以除去上清液,然后添加10mL水来使微球体重构。将最终重构的微球体冻干。拉坦前列素从所述微球体到等渗磷酸盐缓冲盐水的释放在图7B中示出
实施例VI
可注射溶剂
可使用其它赋形剂,诸如蔗糖醋酸异丁酸酯、苯甲酸乙酯、苯甲酸苄酯、三丙酸甘油酯(tripropionin)、二乙二醇二苯甲酸酯,来进行直接皮下注射或注射到脂肪中。图8A-8B示出含有10%比马前列素的二乙二醇二苯甲酸酯(凝胶),图8C示出比马前列素从含有10%比马前列素的二乙二醇二苯甲酸酯(凝胶)释放的实施例。
Claims (20)
1.一种减脂的方法,其包括将选自比马前列素、比马前列素类似物、比马前列素前药、前列腺酰胺、前列腺素、前列腺素类似物、拉坦前列素和曲伏前列素以及前列腺素衍生物及其混合物的化合物的持续释放制剂注射到脂肪沉积体中。
2.根据权利要求1所述的方法,其中所述化合物选自比马前列素、拉坦前列素、曲伏前列素和化合物#1及其混合物。
3.根据权利要求1所述的方法,其中所述持续释放制剂选自可注射储库、凝胶混悬液、ReGel递送体系、透明质酸释放平台、植入物、微球体、大球体和可注射溶剂。
4.根据权利要求3所述的方法,其中所述化合物为比马前列素。
5.根据权利要求1所述的方法,其中将所述持续释放制剂直接注射到所述脂肪沉积体中。
6.根据权利要求1所述的方法,其中所述减脂是在注射部位处及其周围的局部减脂。
7.根据权利要求3所述的方法,其中所述持续释放制剂为具有约20%比马前列素、约45%R203s、约20%RG752s、约10%R202H和约5%PEG-3350的制剂的植入物。
8.根据权利要求1所述的方法,其中所述方法导致褐色和白色脂肪细胞两者萎缩并且导致局部减脂。
9.根据权利要求7所述的方法,其中所述植入物在超过100天的时间内将比马前列素释放到所述脂肪沉积体中。
10.根据权利要求1所述的方法,其中所述持续释放制剂全身性地释放所述化合物,以靶向在体内未处于所述持续释放制剂所在位置的脂肪沉积体。
11.根据权利要求1或10所述的方法,其中所述持续释放制剂被注射或植入到允许减少腹部脂肪沉积体、内脏脂肪沉积体、心外膜脂肪沉积体、皮下脂肪沉积体和异位脂肪沉积体的位置处。
12.一种用于局部减脂的组合物,其中所述组合物为选自可注射储库、凝胶混悬液、ReGel递送体系、基于透明质酸的平台、植入物、微球体、大球体和可注射溶剂的持续释放组合物。
13.根据权利要求12所述的组合物,其中所述组合物还包含选自比马前列素、比马前列素类似物、比马前列素前药、前列腺酰胺、前列腺素、前列腺素类似物、拉坦前列素和曲伏前列素以及前列腺素衍生物的化合物。
14.根据权利要求12所述的组合物,其中所述持续释放组合物为Regel递送体系,并且所述化合物为比马前列素。
15.根据权利要求14所述的组合物,其中所述组合物被注射到局部脂肪沉积体中。
16.根据权利要求15所述的组合物,其中所述组合物在多个注射部位被注射到单一局部脂肪沉积体中。
17.根据权利要求15所述的组合物,其中所述组合物在超过100天的时间内将比马前列素释放到所述局部脂肪沉积体中。
18.根据权利要求12或13所述的组合物,其中所述持续释放制剂为由约20%比马前列素、约45%R203s、约20%RG752s、约10%R202H和约5%PEG-3350组成的植入物。
19.根据权利要求18所述的组合物,其中所述组合物被注射到选自腹部脂肪沉积体、内脏脂肪沉积体、心外膜脂肪沉积体、皮下脂肪沉积体和异位脂肪沉积体的至少一者中。
20.根据权利要求18所述的组合物,其中所述组合物的注射导致在所述局部脂肪沉积体中的脂肪细胞的萎缩以及局部脂肪的减少。
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