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1. 发明申请

WO2011089202A1 METHOD FOR EVALUATING THE SOLUBILITY OF A CRYSTALLINE SUBSTANCE IN A POLYMER 审中-公开
标题翻译：评估聚合物中晶体物质的溶解性的方法
公开(公告)号：WO2011089202A1
公开(公告)日：2011-07-28
申请号：PCT/EP2011/050792
申请日：2011-01-21
申请人： ABBOTT GMBH & CO. KG , ZHANG, Geoff G. Z. , YU, Lian , TAO, Jing , SUN, Ye , MAEGERLEIN, Markus
发明人： ZHANG, Geoff G. Z. , YU, Lian , TAO, Jing , SUN, Ye , MAEGERLEIN, Markus
IPC分类号： G01N25/48 , G01N33/15
CPC分类号： G01N33/15 , G01N25/4866 , G01N2013/006
摘要： A method for evaluating the solubility of a crystalline substance in a polymer comprises a) providing at least one sample of an intimate crystalline substance/polymer mixture at a predetermined crystalline substance concentration; b) annealing the sample at a constant temperature T a for a period of time; c) heating the annealed sample while recording the heat flux over time by DSC; d) identifying a DSC dissolution endotherm in the recorded heat flux, if any; e) considering the crystalline substance concentration as a concentration above the crystalline substance solubility in the polymer at temperature T a when there is a DSC dissolution endotherm identified, and considering the crystalline substance concentration as a concentration less than or equal to the crystalline substance solubility in the polymer at temperature T a when there is no DSC dissolution endotherm identified. Thus, the method yields the upper and lower bounds for the equilibrium solubility at a given temperature or the upper and lower bounds for the equilibrium solubility temperature at a given crystalline substance concentration. The method improves accuracy of measurement near the glass transition temperature.
摘要翻译：用于评价结晶物质在聚合物中的溶解度的方法包括a）以预定的结晶物质浓度提供至少一种紧密结晶物质/聚合物混合物的至少一个样品; b）在恒温Ta下将样品退火一段时间; c）加热退火样品，同时通过DSC随时间记录热通量; d）识别记录的热通量中的DSC溶解吸热（如果有的话）; e）当确定DSC溶解吸热时，考虑结晶物质浓度高于结晶物质在聚合物中的溶解度的浓度，考虑到结晶物质浓度小于或等于结晶物质溶解度的浓度聚合物在温度Ta时没有DSC溶解吸热确定。因此，该方法产生在给定温度下的平衡溶解度的上限和下限，或者给定在给定结晶物质浓度下的平衡溶解度温度的上限和下限。该方法提高玻璃化转变温度附近的测量精度。

2. 发明申请

WO2009135799A2 METHOD FOR EVALUATING THE SOLUBILITY OF A CRYSTALLINE SUBSTANCE IN A POLYMER 审中-公开
标题翻译：评估聚合物中晶体物质的溶解性的方法
公开(公告)号：WO2009135799A2
公开(公告)日：2009-11-12
申请号：PCT/EP2009/055233
申请日：2009-04-29
申请人： ABBOTT GMBH & CO. KG , ZHANG, Geoff, G., Z. , YU, Lian , TAO, Jing , SUN, Ye , MAEGERLEIN, Markus
发明人： ZHANG, Geoff, G., Z. , YU, Lian , TAO, Jing , SUN, Ye , MAEGERLEIN, Markus
IPC分类号： G01N33/15
CPC分类号： G01N33/15 , G01N25/4866
摘要： A viable strategy to enhance the bioavailability of poorly soluble drugs is to use amorphous solids in place of the more commonly used crystalline solids in pharmaceutical formulations. However, amorphous solids are physically meta-stable and tend to revert back to their crystalline counterpart. An effective approach to stabilizing an amorphous drug against crystallization is to disperse it in a polymer matrix. The drug's solubility in the chosen polymer defines the upper limit of drug loading without any risk of crystallization. Measuring the solubility of a drug in a polymer has been a scientific and technological challenge because the high viscosity of polymers makes achieving solubility equilibrium difficult and because pharmaceutically important drug/polymer dispersions are glasses, which undergo structural relaxation over time. The invention provides a method based on Differential Scanning Calorimetry (DSC) for measuring the solubility of crystalline drugs in polymeric matrices. The method relies on the detection of the dissolution endpoint of a drug/polymer mixture prepared by cryomilling.
摘要翻译：提高难溶性药物的生物利用度的可行策略是使用无定形固体代替药物制剂中更常用的结晶固体。然而，无定形固体物理上是元稳定的，并且倾向于回复到它们的结晶对应物。稳定无定形药物抗结晶的有效方法是将其分散在聚合物基质中。药物在所选聚合物中的溶解度限定了药物负载的上限，而没有结晶的风险。测量药物在聚合物中的溶解度已经是科学和技术挑战，因为聚合物的高粘度使得难以实现溶解度平衡，并且因为药物重要的药物/聚合物分散体是随时间经历结构松弛的玻璃。本发明提供了一种基于差示扫描量热法（DSC）测量结晶药物在聚合物基质中的溶解度的方法。该方法依赖于通过冷冻法制备的药物/聚合物混合物的溶解终点的检测。

3. 发明公开

EP2274609A2 METHOD FOR EVALUATING THE SOLUBILITY OF A CRYSTALLINE SUBSTANCE IN A POLYMER 有权转让
标题翻译：评估方法结晶物质的溶解度的聚合物
公开(公告)号：EP2274609A2
公开(公告)日：2011-01-19
申请号：EP09742017.8
申请日：2009-04-29
申请人： Abbott GmbH & Co. KG
发明人： ZHANG, Geoff, G., Z. , YU, Lian , TAO, Jing , SUN, Ye , MAEGERLEIN, Markus
IPC分类号： G01N33/15 , G01N25/48
CPC分类号： G01N33/15 , G01N25/4866
摘要： A viable strategy to enhance the bioavailability of poorly soluble drugs is to use amorphous solids in place of the more commonly used crystalline solids in pharmaceutical formulations. However, amorphous solids are physically meta-stable and tend to revert back to their crystalline counterpart. An effective approach to stabilizing an amorphous drug against crystallization is to disperse it in a polymer matrix. The drug's solubility in the chosen polymer defines the upper limit of drug loading without any risk of crystallization. Measuring the solubility of a drug in a polymer has been a scientific and technological challenge because the high viscosity of polymers makes achieving solubility equilibrium difficult and because pharmaceutically important drug/polymer dispersions are glasses, which undergo structural relaxation over time. The invention provides a method based on Differential Scanning Calorimetry (DSC) for measuring the solubility of crystalline drugs in polymeric matrices. The method relies on the detection of the dissolution endpoint of a drug/polymer mixture prepared by cryomilling.

4. 发明公开

EP2526413A1 METHOD FOR EVALUATING THE SOLUBILITY OF A CRYSTALLINE SUBSTANCE IN A POLYMER 审中-公开
标题翻译：评价聚合物中结晶物质溶解度的方法
公开(公告)号：EP2526413A1
公开(公告)日：2012-11-28
申请号：EP11700563.7
申请日：2011-01-21
申请人： Abbott GmbH & Co. KG
发明人： ZHANG, Geoff G. Z. , YU, Lian , TAO, Jing , SUN, Ye , MAEGERLEIN, Markus
IPC分类号： G01N25/48 , G01N33/15
CPC分类号： G01N33/15 , G01N25/4866 , G01N2013/006
摘要： A method for evaluating the solubility of a crystalline substance in a polymer comprises a) providing at least one sample of an intimate crystalline substance/polymer mixture at a predetermined crystalline substance concentration; b) annealing the sample at a constant temperature T
a for a period of time; c) heating the annealed sample while recording the heat flux over time by DSC; d) identifying a DSC dissolution endotherm in the recorded heat flux, if any; e) considering the crystalline substance concentration as a concentration above the crystalline substance solubility in the polymer at temperature T
a when there is a DSC dissolution endotherm identified, and considering the crystalline substance concentration as a concentration less than or equal to the crystalline substance solubility in the polymer at temperature T
a when there is no DSC dissolution endotherm identified. Thus, the method yields the upper and lower bounds for the equilibrium solubility at a given temperature or the upper and lower bounds for the equilibrium solubility temperature at a given crystalline substance concentration. The method improves accuracy of measurement near the glass transition temperature.
摘要翻译：用于评估结晶物质在聚合物中的溶解度的方法包括：a）提供至少一种处于预定结晶物质浓度的紧密结晶物质/聚合物混合物的样品; b）在恒定温度T a下将样品退火一段时间; c）加热退火的样品，同时通过DSC随时间记录热通量; d）确定记录的热通量中的DSC溶解吸热（如果有的话）; e）当鉴定到DSC溶解吸热时，将结晶物质浓度视为高于聚合物中结晶物质溶解度的温度T a时的浓度，并且将结晶物质浓度视为低于或等于结晶物质在在没有DSC溶解吸热峰确定时在温度T a下的聚合物。因此，该方法得到给定温度下平衡溶解度的上限和下限或给定结晶物质浓度下平衡溶解度温度的上限和下限。该方法提高了玻璃化转变温度附近的测量精度。

5. 发明授权

EP2274609B1 METHOD FOR EVALUATING THE SOLUBILITY OF A CRYSTALLINE SUBSTANCE IN A POLYMER 有权转让
标题翻译：评估方法结晶物质的溶解度的聚合物
公开(公告)号：EP2274609B1
公开(公告)日：2012-03-28
申请号：EP09742017.8
申请日：2009-04-29
申请人： Abbott GmbH & Co. KG
发明人： ZHANG, Geoff, G., Z. , YU, Lian , TAO, Jing , SUN, Ye , MAEGERLEIN, Markus
IPC分类号： G01N33/15 , G01N25/48
CPC分类号： G01N33/15 , G01N25/4866
摘要： A viable strategy to enhance the bioavailability of poorly soluble drugs is to use amorphous solids in place of the more commonly used crystalline solids in pharmaceutical formulations. However, amorphous solids are physically meta-stable and tend to revert back to their crystalline counterpart. An effective approach to stabilizing an amorphous drug against crystallization is to disperse it in a polymer matrix. The drug's solubility in the chosen polymer defines the upper limit of drug loading without any risk of crystallization. Measuring the solubility of a drug in a polymer has been a scientific and technological challenge because the high viscosity of polymers makes achieving solubility equilibrium difficult and because pharmaceutically important drug/polymer dispersions are glasses, which undergo structural relaxation over time. The invention provides a method based on Differential Scanning Calorimetry (DSC) for measuring the solubility of crystalline drugs in polymeric matrices. The method relies on the detection of the dissolution endpoint of a drug/polymer mixture prepared by cryomilling.

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