CN1137756A - 微囊密封的3-哌啶基取代的1，2-苯并异噁唑类和1，2-苯并异噻唑类 - Google Patents
微囊密封的3-哌啶基取代的1，2-苯并异噁唑类和1，2-苯并异噻唑类 Download PDFInfo
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- CN1137756A CN1137756A CN94194190A CN94194190A CN1137756A CN 1137756 A CN1137756 A CN 1137756A CN 94194190 A CN94194190 A CN 94194190A CN 94194190 A CN94194190 A CN 94194190A CN 1137756 A CN1137756 A CN 1137756A
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Abstract
一种药物组合物，包括在聚合物基质中含有通式(I)的1，2-吲哚或其药物学上允许的酸加成盐的可生物降解的和可生物配伍的微粒，式(I)中，R为氢或C1-6烷基；R1和R2相互独立地为氢、卤原子、羟基、C1-6烷氧基和C1-6烷基；X为O或S；Alk为C1-4链烷双基；以及R3为氢或C1-6烷基；Z为-S-、-CH2-或-CR4＝CR5-；其中R4和R5相互独立地为氢或C1-6烷基；A为二价基团-CH2-CH2-、-CH2-CH2-CH2-或-CR6＝CR7-；其中R6和R7为氢、卤原子、氨基或C1-6烷基；以及R8为氢或羟基。
Description
发明背景
本发明涉及微囊密封的3-哌啶基取代的1，2-苯并异噁唑类和1，2-苯并异噻唑类，它们的制备和它们在精神病治疗上的应用。
美国专利US 4,804,663公开了具有抗精神病性质的3-哌啶基-1，2-苯并异噻唑类和3-哌啶基-1，2-苯并异噁唑类。具体地公开了3-[2-[4-(6-氟代-1，2-苯并异噁唑-3-基)-1-哌啶基]乙基]-6，7，8，9-四氢-2-甲基-4H-吡啶并[1，2-a]嘧啶-4酮(“risperidone”)。
美国专利US 5,158,952描述了具有长效抗精神病性质的3-哌啶基-1，2-苯并异噁唑类。具体地公开了3-[2-[4-(6-氟代-1，2-苯并异噁唑-3-基)-1-哌啶基]乙基]-6，7，8，9-四氢-9-羟基-2-甲基-4H-吡啶并[1，2-a]嘧啶-4-酮(“9-羟基-risperidone”)。
已知许多可将化合物以微粒形式包胶的方法。在许多这些工艺中，将被包胶的材料分散于含有成壁材料的溶剂中。在单级工艺中，从微粒中除去溶剂，然后就获得微粒产品。
美国专利US 3,737,337公开了一种成壁或成壳聚合材料在部分溶于水的溶剂中的制备方法。将一种固体或芯体材料溶解或分散于含有聚合物的溶液中，然后，将含有芯体材料的溶液分散在不溶于有机溶剂的水溶液中，以便从微粒中除去溶剂。
从含有一种物质的微粒中除去溶剂的工艺的另一个实例公开于美国专利US 3,523,906中。该工艺中，使被包胶的材料在聚合材料在不溶于水的溶剂中的溶液中乳化，然后使乳液在含有亲水性胶体的水溶液中乳化。接着通过蒸发从微粒中除去溶剂，从而获得产品。
在美国专利US 3,691,090中，将有机溶剂从微粒在水溶液介质的分散液中蒸发除去，优选在减压下蒸发除去。
美国专利US 3,891,570中公开了一种方法，其中，通过加热或通过对微粒进行减压处理，使来自多元醇介质微量分散体中的溶剂从微粒中蒸发。除去溶剂工艺的另一个实例示于美国专利US3,960,757。
美国专利US 4,389,330和4,530,840描述了一种含有活性剂的微粒的制备方法，采用的方法包括：(a)使活性剂溶解或分散于溶剂中，并使一种成壁材料溶解于该溶剂中；(b)将含有活性剂和成壁材料的溶剂分散于一种连续相工艺介质中；(c)从步骤(b)的分散液中蒸发部分溶剂，由此在悬浮液中形成含有活性剂的微粒；以及(d)从微粒中抽提剩余溶剂。
发明详述
本发明涉及一种药物组合物，包括含有通式(I)的1，2-吲哚或其药物学上允许的酸加成盐的可生物降解的和可生物配伍的微粒，
其中，
R为氢或C1～6烷基；
R1和R2相互独立地为氢、卤原子、羟基、C1～6烷氧基和C1～6烷基；
X为O或S；
Alk为C1～4链烷双基(alkanediyl)，以及
R3为氢或C1～6烷基；
Z为-S-、-CH2-或-CR4＝CR5-；其中R4和R5相互独立地为氢或C1～6烷基；
A为二价基团-CH2-CH2-、-CH2-CH2-CH2-或-CR6＝CR7-；其中R6和R7为氢、卤原子、氨基或C1～6烷基；以及
R8为氢或羟基。
在前述定义中，术语“卤原子”通常为氟、氯、溴和碘；“C1～6烷基”是指包括具有1～6个碳原子的直链和支链的饱和烃基，例如，甲基、乙基、丙基、丁基、戊基、己基及其异构体；“C1～4链烷双基”是指包括具有1～4个碳原子的二价直链或支链的亚烷基，例如，亚甲基、亚乙基、亚丙基、亚丁基及其异构体。
本发明的优选化合物中，R3为C1～6烷基且特别地为甲基，A为二价基团-CH2-CH2-、-CH2-CH2-CH2-或-CR6＝CR7-；其中R6和R7相互独立地为氢或C1～6烷基。
特别优选的化合物是这些优选化合物，其中X为氧，R为氢，R1为卤原子或特别为氢，R2为氢、卤原子、羟基或C1～6烷氧基。
更加特别优选的化合物是这些特别优选化合物，其中-Z-A-为-CH2-CH2-CH2-CH2-、-S-CH2-CH2-、-S-(CH2)3-、-S-CR6＝CR7-或-CH＝CH-CR6＝CR7-，其中R6和R7相互独立地为氢或甲基，R8为氢或9-羟基。
最优选的化合物是3-[2-[4-(6-氟代-1，2-苯并异噁唑类-3-基)-1-哌啶基]乙基]-6，7，8，9-四氢-2-甲基-4H-吡啶并[1，2-a]嘧啶-4-酮(“Risperidone”)及其药物学上允许的酸加成盐。
通式(I)的化合物通常按US 4,804,663或US 5,158,952中描述的方法来制备。
通式(I)的化合物具有碱性，并且因此可通过用适当的酸转化成它们的在治疗上具有活性的无毒酸加成盐形式，所说的酸包括例如无机酸，如氢卤酸(例如盐酸、氢溴酸等)；硫酸、硝酸、磷酸等；或有机酸，例如乙酸、丙酸、氢化乙酸(hydroaceticacid)、2-羟基丙酸、2-氧代丙酸、乙二酸、丙二酸、丁二酸、(Z)-2-丁烯二酸、(E)-2-丁烯二酸、2-羟基丁二酸、2，3-二羟基丁二酸、2-羟基-1，2，3-丙三羧酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸、环己烷氨基磺酸、2-羟基苯甲酸、4-氨基-2-羟基苯甲酸等。
通式(1)的化合物是一系列神经传递质(neurotransmitters)的有效拮抗物，其结果，具有有用的药理学性质。特别地，通式(I)的化合物被血清基和多巴胺拮抗物结合。因此，它们被用作抗精神病药，并且在各种释放血清基的疾病的治疗中占有重要地位，例如，支气管细胞的血清基诱发收缩阻塞和血管、动脉以及静脉阻塞。使用本化合物的治疗表现主要是在CNS领域，即，作为抗精神病药剂并且因此它们可被用于抗精神病，特别是精神分裂症、攻击行为、焦虑、抑郁症和周期性偏头痛。另外，通式(I)的化合物也被用作为镇静剂、抗焦虑剂、抗侵袭素、防应力剂和肌肉防护剂。
本发明进一步提供一种治疗温血动物精神混乱的方法，所说方法包括一种有效量的微囊密封的通式(I)化合物或其药物学上允许的酸加成盐以与药物载体混合物的形式系统地给药。或者换句话说，提供用于制备一种微囊密封的通式(I)化合物的药物，用于治疗精神混乱。或者再换句话说，提供微囊密封的通式(I)化合物或其药物学上允许的酸加成盐以与药物载体的混合物形式的应用，用于治疗精神混乱。通常，期望有效量的活性成分本身为0.01mg/kg～4mg/kg体重，更优选地，为0.04mg/kg～2mg/kg体重。
此处所用的术语“给药”，意指将含1，2-吲哚的本发明微粒输送至温血动物体内的任何方法，例如，肠胃外(静脉、肌肉、皮下)给药。“微粒”是指含有以溶液或结晶形式的活性剂(此处为1，2-吲哚)的固体颗粒。该活性剂被分散或溶解于作为颗粒基质的聚合物中。
另一方面，本发明涉及一种抑制温血动物的血清基或多巴胺的过度刺激的方法，所说的方法包括用一种在聚合物基质中含有通式(I)1，2-吲哚的可生物降解和可生物配伍的微粒组分进行给药。或者，另一方面，提供一种药物的制备方法，该药物是一种可生物降解和可生物配伍的微粒组分，在聚合物基质中含有通式(I)的1，2-吲哚，用于抑制温血动物的血清基或多巴胺的过度刺激。或者将一种在聚合物基质中含有通式(I)的1，2-吲哚的可生物降解和可生物配伍的微粒组合物用于抑制温血动物的血清基或多巴胺的过度刺激。
另一方面，本发明涉及由含有通式(I)化合物或其药物学上允许的酸加成盐的可生物降解和可生物配伍的基质制成的微粒。
本发明组分对于治疗温血动物，优选哺乳动物，更优选人类(以下共同称为“患者”)的精神病是有用的，包括向这类患者提供如上所述的载带1，2-吲哚的可生物降解的微粒。
本发明组合物包含一种微粒，该微粒设计成可使有效量的通式(I)的1，2-吲哚从一种可生物配伍和可生物降解的基质中在较长的时间内可控地释放。它们提供超过本技术领域中已知组合物的优点，这类优点包括，特别地，它是一种可生物降解体系，一种可防止在治疗过程中损失的注射体系，具有能混合含有不同药物微粒的能力，和根据需要进行程序释放(多阶段释放模式)以达到较快或较慢的药物释放的能力。
在优选的实施方案中，1，2-吲哚向患者的给药是通过将载带微粒的药物一次给药，以一个恒定或脉冲方式将药物释放到患者体内并消除所需的重复注射来完成的。
本发明的产品提供具有7至多于200天持续作用时间的优点，这取决于所选择的微粒类型。一种优选的实施方案中，微粒被设计成提供治疗患者达14～100天的时间，特别地14至50或至60，或30至60天。持续作用时间可通过控制聚合物组分、聚合物∶药物比和微粒尺寸来控制。
本发明的另一个重要优点是实际上所有的活性剂被输送到患者体内，因为所用的聚合物是可生物降解的，因此允许所有的包覆(entrapped)剂被释放入患者体内。
本发明微粒的聚合物基质材料是一种可生物配伍和可生物降解的聚合材料。术语“可生物配伍”定义为一种对人体无毒，是非致癌物，并且不会显著地诱发体内组织炎症的聚合材料。该基质材料从某种意义上说应是可生物降解的，即，聚合材料经体内处理应降解成易被人体排出且不会在体内积累的产物。生物降解产物从同种意义上说也应是可与人体配伍的，即聚合物基质可与人体生物配伍。
聚合物基质材料的合适例子包括聚乙醇酸、聚-D，L-乳酸、聚-L-乳酸、上述化合物的共聚物、聚(脂肪族羧酸)、草酸酯的共聚物、聚己内酯、聚二氧杂环戊二烯酮、聚原碳酸酯、聚乙缩醛、聚(乳酸-己内酯)、聚原酸酯、聚(乙醇酸己内酯)、聚酐类以及天然聚合物，包括白蛋白、酪蛋白和石蜡，诸如硬脂酸单或二甘油酯，等等。对于本发明实际应用，优选的聚合物是外消旋(聚丙交酯-共-乙交酯)，即聚乙醇酸和聚-D，L-乳酸的共聚物。在这类共聚物中优选的丙交酯与乙交酯的摩尔比在约85∶15～35∶65的范围内，更特别地，在约75∶25～50∶50的范围内，例如，85∶15、75∶25、65∶35或50∶50。
微粒中掺混的活性剂的量通常在约1重量％～90重量％的范围内，优选30～50重量％，更优选35～40重量％。重量％是指微粒总重量中活性剂所占的份数。例如，10重量％活性剂意指10重量份活性剂和90重量份聚合物。
聚合物基质材料的分子量是比较重要的。分子量应高到足以允许形成令人满意的聚合物层，即，聚合物应是一个良好的成膜剂。通常，令人满意的分子量在5,000～500,000道尔顿范围内，优选50,000～400,000，更优选100,000～300,000，特别地100,000～200,000，尤其是约150,000道尔顿。然而既然膜的性质部分取决于被使用的特定聚合材料，因此，很难确定一个对所有聚合物都合适的分子量范围。从对聚合物生物降解速率的影响观点来看，聚合物的分子量也很重要。考虑到药物释放的扩散机理，聚合物应保持完整，直到所有药物从微粒中释放出来，然后聚合物再降解。当聚合物赋形剂发生生物浸蚀时，药物也可从微粒中释放出来。通过适宜选择聚合材料，可以制成一种能使生成的微粒显示出扩散释放和生物降解释放两种性质的微粒制剂。这对于提供多阶段释放模式很有用。
本发明的微粒产物可通过能生产在注射组合物可接受的粒径范围内的微粒的任何方法来制备，诸如US.4,389,330和US.530,840中描述的方法。一个优选的制备方法被描述于上述专利中，它包括使活性剂溶解或分散于适当的溶剂中，向含有介质的活性剂中，以相对于活性成分的量加入聚合物基质材料，提供出一种具有希望的活性剂装载量的产品。任选地，微粒产物的所有组分可一起被混入溶剂介质中。
用于活性剂和聚合物基质材料的溶剂均可用于本发明的实践，包括有机溶剂，诸如丙酮、卤代烃(诸如氯仿、二氯甲烷等)、芳烃化合物、卤代芳烃化合物、环醚、醇类(诸如苄醇)、乙酸乙酯等。一种优选的溶剂是苄醇和乙酸乙酯的混合物。
溶剂中各成分的混合物在一种连续相工艺介质中被乳化；在连续相介质中形成这样一种含有所述成分的微粒分散体的该连续相工艺介质。自然，连续相工艺介质和有机相必须基本上不互溶。最常用的连续相工艺介质是水，但也可以使用非水介质，诸如二甲苯、甲苯以及合成油和天然油。
通常，将表面活性剂加入连续相工艺介质中，用于防止微粒的附聚作用并且控制乳液中的溶剂微粒大小。一种优选的表面活性剂分散介质组合物是0.1～10重量％，更优选0.5～2重量％的聚乙烯醇的水溶液。通过机械搅拌混合材料而形成该分散体。也可通过将活性剂-成壁材料溶液的小液滴加入连续相工艺介质来形成乳液。
在乳液形成过程中的温度没有特别的限制，但可影响微粒的粒径和质量以及连续相中活性剂的溶解度。当然，希望连续相中具有尽可能少的活性剂。此外，取决于所使用的溶剂和连续相工艺介质，温度不应太低，否则溶剂和工艺介质将固化或变得非常粘而不能用于颗粒目的。另一方面，温度不应太高，以免工艺介质蒸发或液体工艺介质不能维持。再有，介质温度不能太高，以免待掺混到微粒中的颗粒活性剂的稳定性受到不利影响。因此，分散工序可在维持稳定操作条件的任何温度下进行，优选约为20℃～60℃，这取决于所选择的活性剂和赋形剂。
形成的分散体是稳定的，并且在溶剂除去工序的第一步骤中有机相流体可从该分散液中被部分除去。溶剂可容易地采用普通技术(诸如加热、应用减压或二者结合使用)被除去。用来从微粒中蒸发溶剂的温度没有严格限制，但不应太高，以免使在特定微粒的制备过程中所用的活性剂降解，或是避免以足够快的速度蒸发溶剂而引起成壁材料中的缺陷。通常，在溶剂除去第一步骤中，除去10～90％，优选40～60％的溶剂。第一步骤之后，采用分离的任何常规方法，将在不溶于溶剂的流体介质中分散的微粒与流体介质分离。因此，例如可从微粒中滗去流体，或可将微粒悬浮液过滤。如果希望的话，可使用分离技术的各种其他组合。
在从连续相工艺介质中的微粒分离操作之后，用抽提法将微粒中残存的溶剂除去。该步骤中，可将微粒悬浮于与步骤1所用相同的连续相工艺介质中，这时，可以使用或不使用表面活性剂，或者也可悬浮在其他液体中。抽提介质将溶剂从微粒中除去，但不溶解微粒。在抽提过程中，含有溶解了的溶剂的抽提介质必须除去并用新鲜的抽提介质取代。该操作最好是在不停的或连续的基础上进行，在此情况下必须严格控制抽提介质的再补给速率。如果速率太低，则活性剂晶体可能会从微粒中突出或在抽提介质中生长。显然，对于一个特定的工序，抽提介质再补给速率是可变的，在工艺进行过程中可容易地选定，因此，对于可预定的速率不必精确限制。在将残余溶剂除去之后，采用暴露于空气或通过其它常规的干燥技术(诸如真空干燥、用干燥剂干燥等)，将微粒干燥。由于可获得最高为80重量％，优选最高为50重量％的芯体装载量，因此，该工序在包胶活性剂方面非常有效。
将活性剂包胶形成本发明的可控释放微粒的更优选的方法包括使用静态混合器的方法。静态或非动态混合器由导管或管子组成，其中容纳若干静态混合部件。静态混合器可在相对短的导管长度和相对短的时间内提供均匀的混合。静态混合器中，流体穿过混合器，而不是混合器的某些部位，例如一种通过流体运动的浆叶。一种静态混合器在美国专利US 4,511,258中有较全面的描述。
当使用静态混合器来形成乳液时，许多因素都决定乳液的颗粒大小。这些因素包括将要被混合的各种溶液或相的密度和粘度、相的体积比、各相间的界面张力、静态混合器参数(导管直径、混合部件的长度、混合部件的数目)和流过静态混合器的线速度。温度是可变的，因为它影响密度、粘度和界面张力。可控制的可变因素是线速度、剪切速率和静态混合器的每单位长度的压力降。特别地，线速度增加，液滴尺寸减小；压力降减小，液滴尺寸增加。对于一种给定的流速、在经过固定数目的部件之后，液滴将达到平衡的尺寸。流速越高，所需部件越少。由于这些关系，从实验室的批量生产到工业规模的批量生产都是可靠和精确的，因此相同的设备可用于实验室和工业批量生产。
为了制造含有活性剂的微粒，可将有机相和水相结合使用。有机相和水相大体上或基本上是互不溶混的，以水相构成乳液的连续相。有机相包括一种活性剂以及成壁聚合物或聚合物基质材料。可通过将活性剂溶解于有机溶剂或其他合适的溶剂，或通过形成一种含有活性剂的分散液或乳液的方法来制备有机相。优选是用泵来输送有机相和水相，以便于两相同时流经静态混合器，由此形成乳液，该乳液包含含有被聚合物基质材料包胶的活性剂的微粒。有机相和水相经过静态混合器，被抽送到大体积的急冷液体中。该急冷液体可以是普通的水、水溶液或其他合适的液体。当微粒在急冷液体中被洗涤或被搅拌时，有机溶剂可以从微粒中除去。将微粒在急冷液体中洗涤以抽提或除去有机溶剂，然后将它们分离(如过筛)并加以干燥。
用于进行静态混合器工序的实验室装置如图1所示。有机相或油相30是通过溶解和任选地在一块加热板上加热在搅拌釜32中的活性剂和聚合物基质材料或聚合物来制备的。然而，本发明的方法不限于通过溶解活性剂来制备有机相30。作为替换方法，可通过将活性剂分散到含有聚合物基质材料的溶液中来制备有机相30。在这类分散液中，活性剂只是微溶于有机相30。另一种方法可通过制备含有活性剂和聚合物基质材料的乳液来制备有机相30(双乳化工序)。在双乳化工序中，制备的第一乳液含有一种活性剂和一种聚合物基质材料(有机相30)，第一乳液可以是油包水型乳液、水包油型乳液或任何合适的乳液。接着，第一乳液(有机相30)和一种水相被泵入静态混合器来形成第二乳液，第二乳液包含含有被聚合物基质材料包胶的活性剂的微粒。
用一台磁力驱动齿轮泵34将有机相30从搅拌槽32中抽出。泵34的出料口向Y形连接器36供料。Y形连接器36的一条支线361返回搅拌槽32，用于再循环流动。另一条支线362向线上静态混合器10供料。采用搅拌槽42、磁力驱动齿轮泵44和Y形连接器46，以类似的方式制备水溶液或水相40。Y形连接器46的一条支线461返回搅拌槽42，用于再循环流动。另一条支线462向在线静态混合器10供料。有机相30和水相40基本上不混溶。
来自各溶液并向在线静态混合器10供料的支线362和462由另一个Y形连接器50连接到一起，并经过混合器入口管线51进入静态混合器10。静态混合器10经过混合器出口管线52排料入洗涤槽60。硅树脂管和聚丙烯接头被用于图1所示系统。除了混合器出口管线52之外，所有管线的硅树脂管均具有9.53mm ID。较小直径的管子(4.76mm ID)被用于混合器出口管线52，以防止混合器出口管线52和洗涤槽60上游的乳液衰竭。
本工艺的一个实施方案中，泵34和44起始于再循环模式并将有机相30和水相40的流速设定为期望值。水相40的流速优选高于有机相30的流速。但二个流速可以基本相同。水相40的流速与有机相30的流速之比优选在1∶1～10∶1的范围。然后，转换Y形连接器46，以使水相40经过支线462流向静态混合器10。一旦水相40充满混合器入口管线51、静态混合器10和混合器出口管线52，就转换Y形连接器36，以使有机相30经过支线362流向静态混合器10。现在，有机相30和水相40同时流过静态混合器10。当所希望体积的有机相被泵入静态混合器10时，转换Y形连接器36，使有机相30经支线361进行再循环。水相40继续流动一段短时间，以清洗出残留在混合器入口管子51、静态混合器10和混合器出口管线52中的任何有机相。然后转换Y形连接器46，使水相经支线461进行再循环。
使有机相30和水相40在静态混合器10中混合，形成一种乳液。形成的乳液包含含有被聚合物基质材料包胶的活性剂的微粒。
采用本发明方法生产的微粒通常为球形，但是它们可能是不规则的形状。采用本发明方法生产的微粒的大小可以在亚微米级至毫米级的直径范围内变化。在本发明的优选实施方案中，选择静态混合器10的静态混合部件14，以使生成的微粒范围在1～500微米(μm)，优选25～180微米，特别优选60～120微米，例如90微米，由此，用标准计量针就可进行微粒的给药。可在装有急冷液体的洗涤槽60中搅拌微粒。可通过筛子柱从急冷液体中分离出微粒。可使用常规干燥方法干燥微粒，并且进一步按大小分离。
载带活性剂的微粒可作为干料制得和储存。在向患者给药之前，可将干燥微粒悬浮于一种可接受的药物液态载体中，优选为2.5重量％羧甲基纤维素的溶液，以此形成将悬浮液注射到躯体所希望的部位。微粒可按大小或按类型混合，以便以多阶段方式和/或在不同时间向患者提供不同活性剂或在同一时间提供各种活性剂的混合物的方式向患者输送活性剂。
测定从本发明微粒释放出的risperidone的活体外溶解研究，显示出在一段时间内risperidone的释放几乎为一常数。同样，用本发明微粒配方特别是用下述实施例中描述的配方对狗进行肌内给药的活体内研究，显示出几乎恒定的和长时间持续的活性剂血浆内浓度。
以下的实施例进一步描述了用于实施本发明的材料和方法。这些实施例不应以任何方式限制本发明。
实施例1：35％理论载带的Risperidone微粒(prodex 2组)的制备
首先，称量并混合906.1g 1％的聚乙烯醇(Vinyl 205TM，AirProducts and Chemical Inc.)、29.7g苄醇和65.3g乙酸乙酯，制备水相(溶液A)。然后，将29.3g高粘度的75∶25的外消旋(聚交酯-共-乙交酯)溶解于108.7g乙酸乙酯和108.4g苄醇中，制备有机相(溶液B)。一旦聚合物完全溶解，向聚合物溶液中加入15.7g risperidone碱并使其溶解。被聚合物溶解了的risperidone的暴露时间保持一个最低值(＜10分钟)。然后用一台齿轮泵和泵头(Cole Parmer L07149-04、L07002-16)将溶液A和溶液B分别以198和24ml/min的流速泵压过一个6.35mm直径的静态混合器(Cole Parmer L04667-14)，而进入一个11℃的55升注射用水急冷液中，该注射用水含有1276.0g乙酸乙酯、92.3g(0.02mol)无水碳酸氢钠和116.2g(0.02mol)无水碳酸钠。将微粒在第一洗涤槽中搅拌1.75小时，然后用25微米筛孔的筛子将其分离。把筛子保留的产物转移到13℃的20升洗涤槽中。在筛后洗涤中搅拌2.25小时之后，用一套由25-和180-微米筛孔的不锈钢筛将微粒过筛分离并将其进行粒度分级。将微粒干燥过夜，然后将其收集并称重。
实施例2：40％理论载带的risperidone微粒(prodex 3组)的制备
首先，称量并混合904.4g 1％的聚乙烯醇(Vinyl 205TM，AirProducts and Chemical Inc.)、30.1g苄醇和65.8g乙酸乙酯，制备水相(溶液A)。然后，将27.1g高粘度的75∶25的外消旋(聚交酯-共-乙交酯)溶解于99.3g乙酸乙酯和99.1g苄醇中，制备有机相(溶液B)。一旦聚合物完全溶解，向聚合物溶液中加入18.1g risperidone碱并使其溶解。被聚合物溶解了的risperidone的暴露时间保持一个最低值(＜10分钟)。然后用一台齿轮泵和泵头(Cole Parmer L07149-04，L07002-16)将溶液A和溶液B分别以198和24ml/min的流速泵压过一个6.35mm直径的静态混合器(Cole Parmer L04667-14)，而进入一个12℃的55升注射用水急冷液中，该注射用水含有1375.6g乙酸乙酯、92.4g(0.02mol)无水碳酸氢钠和116.6g(0.02mol)无水碳酸钠。将微粒在第一洗涤槽中搅拌2小时，然后用25微米筛孔的筛子将其分离。把筛子保留的产物转移到12℃的20升洗涤槽中。在筛后洗涤中搅拌3小时之后，用一套25-和180-微米筛孔的不锈钢筛将微粒过筛分离并将其进行粒度分级。将微粒干燥过夜。然后将其收集并称重。
实施例3：来自Prodex 2和Prodex 3的两组微粒的冷冻干燥和γ辐射(样品Prodex 4A、Prodex 4B和Prodex 4C)
把来自Prodex 2和Prodex 3的两组微粒冷冻干燥。将微粒称重后加入5cc血清小瓶中。然后将一种由0.75％ CMC、5％甘露糖醇和0.1％吐温-80TM构成的水溶液载体加入该小瓶中。通过搅拌使微粒悬浮于载体中，然后将微粒在干冰/丙酮浴中迅速冷冻。接着，将小瓶置于一台中间规模的冻干器中，利用逐渐上升至30℃的最大温度循环将其冷冻干燥50小时。样品Prodex 4A和Prodex4C分别是来自Prodex 2和Prodex 3的冻干样品。样品Prodex 4B是Prodex 2的冻干样品，随后用钴-60放射源的2.2 MRadγ射线将其灭菌。
实施例4：活体内研究
研究了基于risperidone配方的微粒在狗体内的阿朴吗啡诱发呕吐试验中的持续作用时间。已知精神抑制药是在第四心室末端区域通过阻断多巴胺D2受体来对抗阿朴吗啡诱发呕吐的。试验通常用来预测精神抑制药在人体中的抗精神病作用的起始时间和持续过程(Janssen et al.，Arzneim.-Forsch./Drug Res.15：1196～1206(1965)；Niemegeers et al.，Life Sci.24：2201-2216(1979))。
9-羟基-risperidone具有实际上与risperidone相同的药理学特征。二者一起构成决定risperidone的生物学活性的“活性部分”。
在实验的全过程中，阿朴吗啡以0.31mg/kg的剂量对狗每星期皮下给药二次。阿朴吗啡给药之后观察这些狗在1小时之内的呕吐。在阿朴吗啡作用后1小时内完全没有呕吐。这一事实可认为产生了显著的抗呕吐活性。抗呕吐活性的持续时间被定义为可防止3条狗中的2条发生呕吐的时间间隔。
将0.5ml体积的制剂注射到一条后肢上相当于大腿部位的股二头肌中。在肌内注射后的若干时间间隔后抽取血样，随后立即用一剂量阿朴吗啡向狗投药。在阿朴吗啡作用后1小时内完全没有呕吐(此现象在对比动物中从未观察到；n＞1000)，这被认为产生了显著抗呕吐活性。
表1示出了在载体配方的肌内注射之后的各个不同的时间间隔内狗是否抗(+)或不抗(-)阿朴吗啡诱导呕吐。所有配方显示出立即产生抗呕吐作用。
| 表1：在给狗进行肌肉注射一种含有约2.5mg/kg剂量抗精神病的risperdone的微粒后，在一段连续的时间间隔内对阿朴吗啡引发的呕吐有无拮抗作用：有(+)；无(-) | |||||
| 项目 | Prodex 2 | Prodex 3 | Prodex 4A | Prodex 4B | Prodex 4C |
| 狗重(kg) | 14.2 11.5 9.8 | 12.9 12.4 13.4 | 10.0 12.3 9.2 | 9.7 8.6 10.6 | 13.2 16.4 16.2 |
| 体积(ml/狗) | 0.5’ 0.5’ 0.5’ | 0.5’ 0.5’ 0.5’ | 0 5’ 0.5’ 0.5’ | 0.5’ 0.5’ 0.5’ | 0.5’ 0.5’ 0.5’ |
| 剂量(mg/kg) | 2.5 2.5 2.8 | 2.5 2.5 2.5 | 2.5 2.3 2.6 | 2.5 2.5 2.6 | 2.4 2.4 2.5 |
| 时间经过 | im im im | im im im | im im im | im im im | im im im |
| 1h | + + - | + + + | + + + | - + + | + + + |
| 5h | + + + | + + + | + + + | + - + | + + + |
| 1d | + + + | + + + | + + + | + + + | + + + |
| 4d | - - + | + - + | + + - | - - + | + + + |
| 7d | - - - | - + + | - - - | - - + | + + + |
| 11d | - - - | + + + | + + - | - - + | + + + |
| 14d | + + + | + + + | - + + | + + + | |
| 18d | + + + | + + + | + + + | + + + | |
| 21d | + + + | + + + | + + + | + + + | |
| 25d | + + + | + + + | + + + | + + + | + + + |
| 29d | + + + | + + + | + + + | + + + | + + + |
| 32d | + + + | + + + | + + + | + + + | + + + |
| 35d | + + + | + + + | + + + | + + + | + + + |
| 表1： 在给狗进行肌肉注射一种含有约2.5mg/kg剂量抗精神病的risperdone的微粒后，在一段连续的时间间隔内对阿朴吗啡引发的呕吐有无拮抗作用：有(+)；无(-) | |||||
| 39d | - + + | + - + | + + - | - - - | + + + |
| 42d | - - - | + - + | + - - | - - - | + + - |
| 46d | - - - | + - - | - - - | - - - | + + - |
| 49d | 停止 | - - - | - - - | 停止 | + + - |
| 53d | 停止 | 停止 | - + - | ||
| 56d | - - - | ||||
| 停止 | |||||
| 3注射体积：0.5ml/狗；微粒的浓度根据狗的体重选择 | |||||
Claims (14)
1.一种药物组合物，该组合物包含一种合适的药物载体，另外还包含一种含有通式(I)的1，2-吲哚或其药物学上允许的酸加成盐的可生物降解的和可生物配伍的微粒，其中，
R为氢或C1～6烷基；
R1和R2相互独立地为氢、卤原子、羟基、C1～6烷氧基和C1～6烷基；
X为O或S；
Alk为C1～4链烷双基，以及
R3为氢或C1～6烷基；
Z为-S-、-CH2-或-CR4＝CR5-；其中R4和R5相互独立地为氢或C1～6烷基；
A为二价基团-CH2-CH2-、-CH2-CH2-CH2-或-CR6＝CR7-；其中R6和R7为氢、卤原子、氨基或C1～6烷基；以及
R8为氢或羟基。
2.权利要求1的组合物，其中所说微粒的聚合物基质材料选自聚乙醇酸、聚-D，L-乳酸、聚-L-乳酸、前述化合物的共聚物、聚(脂肪族羧酸)、草酸酯的共聚物、聚己内酯、聚二氧杂环戊二烯酮、聚原碳酸酯、聚乙缩醛、聚(乳酸-己内酯)、聚原酸酯、聚(乙醇酸己内酯)、聚酐类、白蛋白、酪蛋白和石蜡。
3.权利要求2的组合物，其中所说微粒的聚合物基质材料是聚(乙醇酸)和聚-D，L-乳酸。
4.权利要求3的组合物，其中丙交酯与乙交酯的摩尔比在85∶15～50∶50的范围。
5.权利要求1的组合物，其中所说微粒含有1～90重量％的所说1，2-吲哚。
6.权利要求1的组合物，其中所说微粒含有约35～40重量％的所说1，2-吲哚。
7.权利要求1的组合物，其中所说微粒的粒度范围为1～500微米。
8.权利要求1的组合物，其中所说微粒的粒度范围为25～180微米。
9.权利要求1的组合物，其中所说微粒被配制到液体注射载体中。
10.权利要求1的组合物，其中所说液体载体为生理盐水溶液或羧甲基纤维素与表面活性剂的一种水溶液。
11.权利要求1～10任一项中限定的含有1，2-吲哚的可生物降解和可生物配伍的微粒。
12.权利要求1～10任一项中限定的含有通式(I)的1，2-吲哚的可生物降解和可生物配伍的微粒组合物，在制备一种用于治疗精神混乱的药物上的应用。
13.一种制备权利要求11所要求的微粒的工艺，其特征在于，将权利要求1中所限定的通式(I)的活性成分溶解或分散于合适的溶剂中，以一个相对于活性成分的量向其中加入聚合物基质材料，从而提供具有所希望的活性剂载量的产品。
14.权利要求1～10中任一项所要求的一种制备药物组合物的方法，其特征在于，将微粒与药物载体相混合。
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1994
- 1994-11-11 PL PL94314481A patent/PL314481A1/xx unknown
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- 1994-11-11 WO PCT/EP1994/003754 patent/WO1995013814A1/en active IP Right Grant
- 1994-11-11 AT AT95900721T patent/ATE288270T1/de active
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- 1996-05-20 NO NO962040A patent/NO309226B1/no not_active IP Right Cessation
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1999
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2006
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2007
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1317064C (zh) * | 1999-08-27 | 2007-05-23 | 梅奈莱伯公司 | 通过在非氯化有机溶剂中聚合物的凝聚包囊活性物质的方法 |
| US7767230B2 (en) | 2001-10-30 | 2010-08-03 | Novartis Ag | Organic compounds |
| US8815293B2 (en) | 2001-10-30 | 2014-08-26 | Novartis Ag | Organic compounds |
| US8293765B2 (en) | 2002-07-15 | 2012-10-23 | Novartis Ag | Injectable depot formulation comprising crystals of iloperidone |
| US8614232B2 (en) | 2002-07-15 | 2013-12-24 | Novartis Ag | Injectable depot formulation comprising crystals of iloperidone |
| US8227488B2 (en) | 2002-07-15 | 2012-07-24 | Novartis Ag | Injectable depot formulation comprising crystals of iloperidone |
| CN103637977A (zh) * | 2005-07-18 | 2014-03-19 | 宾夕法尼亚大学理事会 | 含药植入物及其使用方法 |
| US9446135B2 (en) | 2011-04-25 | 2016-09-20 | Shandong Luye Pharmaceutical Co., Ltd. | Risperidone sustained release microsphere composition |
| US9532991B2 (en) | 2011-04-25 | 2017-01-03 | Shandong Luye Pharmaceutical Co., Ltd. | Risperidone sustained release microsphere composition |
| EP3199146A1 (en) | 2011-04-25 | 2017-08-02 | Shan Dong Luye Pharmaceutical Co., Ltd. | Risperidone sustained release microsphere composition |
| US10098882B2 (en) | 2011-04-25 | 2018-10-16 | Shandong Luye Pharmaceutical Co., Ltd. | Risperidone sustained release microsphere composition |
| US10406161B2 (en) | 2011-04-25 | 2019-09-10 | Shandong Luye Pharmaceutical Co., Ltd. | Risperidone sustained release microsphere composition |
| EP3566696A1 (en) | 2011-04-25 | 2019-11-13 | Shan Dong Luye Pharmaceutical Co., Ltd. | Risperidone sustained release microsphere composition |
| EP3772354A1 (en) | 2011-04-25 | 2021-02-10 | Shandong Luye Pharmaceutical Co., Ltd. | Risperidone sustained release microsphere composition |
| US11110094B2 (en) | 2011-04-25 | 2021-09-07 | Shandong Luye Pharmaceutical Co., Ltd. | Risperidone sustained release microsphere composition |
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