CN1160074C - 亚微细粒9-羟基雷士培力酮(Risperidone)脂肪酸酯类的含水悬浮液 - Google Patents

亚微细粒9-羟基雷士培力酮(Risperidone)脂肪酸酯类的含水悬浮液 Download PDF

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CN1160074C
CN1160074C CNB988111551A CN98811155A CN1160074C CN 1160074 C CN1160074 C CN 1160074C CN B988111551 A CNB988111551 A CN B988111551A CN 98811155 A CN98811155 A CN 98811155A CN 1160074 C CN1160074 C CN 1160074C
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M·K·J·弗兰科伊斯
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W·M·A·C·德里斯
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E·D·G·巴斯塔尼
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Abstract

本发明关于一种适合作为经肌内或皮下注射给药的储存调配物的药物组合物，其包含(1)一种作为活性成份的治疗有效量的亚微细粒形式的9-羟基雷士培力酮(Risperidone)脂肪酸酯类或其盐类，或者其立体异构物或立体异构混合物及(2)一种医药上可接受的载体；其中医药上可接受的载体是水而该活性成份则悬浮于其中；以及制备该组合物的方法。本发明另外关于此种药物组合物用于作为治疗精神病、精神分裂症、感情分裂症、非精神分裂症、与神经变性症有关的行为障碍如痴呆，智能迟钝和自闭性的行为障碍，图雷特(Tourette)综合症，两极狂(bipolar mania)，沮丧，焦虑等的药剂。

Description

亚微细粒9-羟基雷士培力酮 (Risperidone)脂肪酸酯类的含水悬浮液
本发明关于一种适合作为经肌内或皮下注射给药的储存调配物的医药组合物，其包含
(1)一种作为活性成分的治疗有效量的亚微细粒形式的9-羟基雷士培力酮(Risperidone)脂肪酸酯类或其盐类，或者其立体异构物或立体异构混合物及
(2)一种医药上可接受的载体；其中医药上可接受的载体是水，而该活性成分悬浮于其中；
以及制备该组合物的方法。
本发明另外包括此种药物组合物用作治疗精神病、精神分裂症、感情分裂症、非精神分裂症、神经变性症引起的行为障碍如痴呆，智能迟钝和自闭性的行为障碍，图雷特(Tourette)综合症，两极狂(bipolar mania)，沮丧，焦虑等的药剂。
雷士培力酮是3-〔2-〔4-(6-氟-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-酮的总称。其制法和药理活性则描述于EP-0,196,132(相当于US-4,804,663)中。其中列举各种惯用药物剂量形式，包括片剂、胶囊、点滴、栓剂、口服溶液和注射溶液等。事实上，雷士培力酮通常以片剂或缓冲、口服或肌内溶液中的基料形式给药。特别是口或肌内给药溶液是描述于WO-96/01652。
雷士培力酮是一种治疗指数相当窄的高效能药。过量时，其会产生不想要的副作用，最明显的是锥体外症候群(EPS)及较低程度的低血压(由于周边α-肾上腺素激导性的活性)。为了达到在病人身上产生抗精神病效果的目的，雷士培力酮每日总剂量范围是从约2至约8毫克；为了减轻神经变性症所引起的行为障碍，每日总剂量范围通常较低，一般范围是从约0.5至约2毫克。个人间的差异和共-药效可能需要对病人作剂量测定。
已知雷士培力酮可代射成9-羟基雷士培力酮，后者具有可与原药雷士培力酮相提并论的药理和效力，且具有较长的消除半衰期。雷士培力酮比其新陈代谢产物9-羟基雷士培力酮更快速地分布和自脑组织消除。9-羟基雷士培力酮，其对应异构型及其C2-20烷酸酯皆描述于EP-0,368,388(相当于US-5,158,952和US-5,254,556)。该酯类可被视为用于储存调配物的雷士培力酮的活性新陈代谢产物的重要前药。
为了许多理由，要求持续或延迟释放(储存)调配物中的雷士培力酮，其有效性可持续一段相当长的时间，最好是约3周或更久，特别是约1个月。
WO-94/25460(相当于EP-0,697,019)关于第一个此种储存调配物并且关于雷士培力酮帕蒙酸盐(pamoate)，即一种水溶解度极差的雷士培力酮盐类形式，其可悬浮于医药上可接受的载体中，如水或油中并且可从皮下或肌内给药。但此盐具有次佳的药动力性质。活性成份自调配物中释放出来明显很快，这造成相当高的初血浆量和不适当的平均动作时限，应在确实有效的储存调配物中改善这两个特点。
WO-95/13814关于非经肠给药的持续释放调配物，其中雷士培力酮是微包被在生物可配合性、生物可降级的薄壁形成物质中(如一种聚合物如dl-(聚丙交酯-共-乙交酯))。经微包被的调配物具有适合的药动力性质，但在设置工厂的目的下，其需要复杂的制备方法。
PCT/EP97/02504揭示9-羟基雷士培力酮脂肪酸酯类于水中的含水悬浮液，其中活性成份的前药是以微细粒形式存在。出乎意料之外地，这些调配物证明其可长期停留在人体内使其可用于治疗。
因此，仍需要一种有效和容易获得的雷士培力酮储存调配物或似雷士培力酮的化合物。
在先前技术中，毫微细粒子是为人所熟知的，例如曾被描述于EP-A-0,499,299。这些粒子实际上包含具有吸附在粒子表面上的表面改良剂的结晶药剂物质，使有效平均粒径低于约400毫微米。也已知该粒子对于调配对水溶解度差的活性成份是特别有用的。
本发明从研究中获得一种有效、耐药性佳、持续或延迟释放(储存)的9-羟基雷士培力酮烷酸酯调配物的发展，其中9-羟基雷士培力酮烷酸酯在治疗上的有效期至少为三周或更长，特别是约一个月。“有效期至少为三周或更长”意指有效成份9-羟基雷士培力酮烷酸酯的血浆量(由烷酸酯水解释放出的游离醇)应高于约10毫微克/毫升。另一方面，该血浆量应随时保持在低于约100毫微克/毫升的极限值使可称为调配物的“效力”。极限值是指在一段相当长的时间内如超过15分钟，血浆量若高于此值，则病人可能会遭受不想要的副作用，或者相反地，血浆量值若低于此值，则调配物的系统耐药性是仍可接受的。由于，例如出乎意料之外地大量释放活性成份，使在短时间内如低于15分钟，短暂、高血浆量无法控制在极限值之下。
前面所提的两个特点-血浆量高于最低治疗浓度但低于会造成副作用的极限值-是被视为基本需求，而其是当代储存调配物应具备的条件以便欲使用的病人可以接受。限制药物服用的数目和每次服药后不想要的副作用的发生，毫无疑问地将可改善病人对治疗的接受度。但是除了这些基本的要求之外，可指出许多其他需求以进一步改善病人的接受度；两个最重要的需求是好的局部耐药性和服药的容易性。
好的局部耐药性是指在注射位置所引起的刺激感和发炎最低；服药的容易性关系到针头尺寸和服用一剂量特定药剂调配物所需的时间长短。而且，储存调配物应稳定且在正常状况下应具有至少两年的储存寿命。
对于发展一种符合上述条件的有效、耐药性佳、持续或延迟释放(储存)的9-羟基雷士培力酮烷酸酯调配物的研究，导致发现一种适合作为经肌内或皮下注射给药的储存调配物医药组合物，此调配物应包含：
一种粒子分散液，其基本上包含治疗有效量的具有下式的结晶9-羟基雷士培力酮脂肪酸酯
Figure C9881115500061
或其盐类，或者其立体异构物或立体异构混合物于包括水的医药上可接受的载体中，其中R代表直链C9-19烷基；具有有效量的表面活性剂吸附在其表面上以保持比表面积＞4平方米/克(相当于低于约2,000毫微米的有效平均粒径)。
令人惊讶的是其显示出微粒化9-羟基雷士培力酮C10-20烷酸酯类的含水悬浮液(其中R代表直链C9-19烷基)在人体中具有出乎预料之外的长期持续作用，但在试验动物，特别是在狗中则无。这是非常出乎预料之外的。因为药物在人体和在狗体中的药动力学经常是可比较的。9-羟基雷士培力酮烷酸酯类的含水悬浮液在人体中的药动力学性质则是视粒径而定至比先前可能控制更大的程度。
C10-20烷酸是选自癸酸、十一烷酸、十二烷酸(月桂酸)、十三烷酸、十四烷酸(肉豆蔻酸)、十五烷酸、十六烷酸(棕榄酸)、十七烷酸、十八烷酸(硬脂酸)、十九烷酸和二十烷酸。从药动力学性质和从耐药性的观点来看，发现C15(十五烷基)链和相当于其的有效成分为9-羟基雷士培力酮棕榄酸酯的酯类是最佳酯类。
本发明的毫微粒子具有吸附于其表面上的其量足以维持比表面积＞4平方米/克(即相当于低于约2,000毫微米的平均粒径)，优选比表面积＞6平方米/克，特别是10至16平方米/克的表面活性剂或表面改良剂。相信可用的表面改良剂包括那些可物理性粘在活性成分表面上但不会化学键合其上的表面改良剂。
适合的表面改良剂最好选自已知有机和无机医药赋形剂。此种赋形剂包括各种聚合物、低分子量低聚物、天然产物和表面活性剂。较佳的表面改良剂包括非离子和阴离子表面活性剂。赋形剂代表性实例包括明胶、酪朊、卵磷脂(磷脂)、阿拉伯树胶、胆固醇、黄蓍胶、硬脂酸、氯化苄基烷铵、硬脂酸钙、单硬脂酸甘油、十六烷基硬脂酰基醇、十六烷基巨醇乳化蜡、山梨糖醇酯、聚氧乙烯烷基醚，如聚乙二醇醚如十六烷基聚乙二醇1000、聚氧亚乙基蓖麻油衍生物、聚氧亚乙基山梨糖醇脂肪酸酯如商业上可获得的TweensTM、聚乙二醇、聚氧亚乙基硬脂酸酯、胶态二氧化硅、磷酸酯、十二烷基硫酸钠、羧甲基纤维素钙、羧甲基纤维素钠、甲基纤维素、羟基乙基纤维素、羟基丙基纤维素、羟基丙基甲基纤维素酞酸酯、非晶纤维素、硅酸铝镁、三乙醇胺、聚乙烯基醇(PVA)、波洛克渣模(poloxamer)、太洛渣波(tyloxapol)和聚乙烯吡咯烷酮(PVP)。这些赋形剂大部分被详细地描述在1986年，医药出版社所出版美国医药协会和英国医药联合发表的医药赋形剂手册中。表面改良剂为商业上可获得和/或可藉已知技术制成。两种或多种表面改良剂可合并使用。
特佳的表面改良剂包括聚乙烯吡咯烷酮；太洛渣波(tyloxapol)；波洛克渣模(poloxamer)，如PluronicTM  F68、F108和F127，其是从BASF取得的环氧乙烷和环氧丙烷的嵌段共聚物；波洛克渣模(poloxamer)，如TetronicTM 908(T908)，其是从BASF取得衍生自连续加成环氧乙烷和环氧丙烷至乙二胺的四官能基嵌段共聚物；葡聚糖；卵磷脂；Aerosol OTTM(AOT)，其是从Cytec工业技术公司取得磺基琥珀酸钠的二辛基酯；DuponolTM P，其是从杜邦(DuPont)取得的月桂基硫酸钠；TritonTM X-200，其是从Rohm和Haas取得的烷基芳基聚醚磺酸酯；TweensTM 20、40、60和80，其是从ICI特殊化学公司取得的聚氧亚乙基山梨糖醇脂肪酸酯；SpanTM 20、40、60和80，其是脂肪酸的山梨糖醇酯；ArlacelTM 20、40、60和80，其是从Hercules公司取得的脂肪酸的山梨糖醇酯；CarbowaxTM 3550和934，其是从Union Carbide公司取得的聚乙二醇；CrodestaTM F110，其是从Croda公司取得的蔗糖硬脂酸酯和蔗糖二硬脂酸酯的混合物；从Croda公司所获得的CrodestaTM SL-40；氯化十六烷基三甲基铵(CTAC)；牛血清蛋白和SA90HCO，其为C18H17CH2(CON(CH3)CH2(CHOH)4CH2OH)2。已发现特别有用的表面改良剂包括太洛渣波(tyloxapol)和波洛克渣模(poloxamer)。较佳为PluronicTM F108和PluronicTM F68。
PluronicTM F108相当于poloxamer 338并且其是聚氧乙烯和聚氧丙烯嵌段共聚物，其一般适用于式HO[CH2CH2O]x[CH(CH3)CH2O]y[CH2CH2O]zH，其中x、y和z的平均值各为128、54和128。其他poloxamer 338的商品名称为取自Hodag的Hodag NonionicTM 1108-F和取自ICI美国公司的SynperonicTMPE/F108。
抗精神病剂表面改良剂的最佳相对量是视各种变数而定。表面改良剂的最佳量例如可视特定的抗精神病剂和所选的表面改良剂、表面改良剂形成微胞时的临界微胞浓度、抗精神病剂的表面积等而定。对于每平方米表面积抗精神病剂，特定表面改良剂最好是以0.1至1毫克的量存在。如果使用9-羟基雷士培力酮棕榄酸酯作为抗精神病剂和PluronicTM F108作为表面改良剂，两成份的相对量(重量/重量)是以约6∶1为佳。
如在此所使用的，低于2,000毫微米的有效平均粒径意指至少90％粒子的直径是低于2,000毫微米，其直径是以如沉积场流体分离、质子校正光谱法或圆盘离心等技术上已知的惯用技术所测得。关于有效平均粒径，最好至少95％和较佳至少99％粒子的粒径是低于有效平均粒径，如2,000毫微米。基本上最好所有粒子的粒径皆低于2,000亳微米。
本发明粒子可以一种包括分散抗精神病剂于液体分散介质中，以及在研磨介质的存在下应用机械装置将抗精神病剂的粒径降低至有效平均粒径低于2,000毫微米等步骤的方法制成。在表面改良剂的存在下，可降低粒子的尺寸。或者，粒子磨碎后与表面改良剂接触。
制造本发明粒子的一般程序包括
(a)获得微细粒形式的抗精神病剂；
(b)将微细粒化抗精神病剂加入液体介质中以形成一种预混物；和
(c)在研磨介质的存在下，将预混物送入机械装置中以降低有效平均粒径。
所选的微细粒形式的抗精神病剂可自商业界获得或利用技术上已知的技术制得。微细粒化抗精神病剂的粒径最好是低于约100微米，其中粒径是经筛析所测得。若微细粒化抗精神病剂的粒径大于约100微米，最好将抗精神病剂粒子的尺寸降低至低于100微米。
然后将微细粒化抗精神病剂加入液体介质中，其中微细粒化抗精神病剂基本上是不溶于其中，而形成一种预混物。抗精神病剂在液体介质中的浓度(重量/重量％)可广泛地变化并且视所选的抗精神病剂、所选的表面改良剂和其他因素而定。组合物中适合的抗精神病剂浓度从0.1变化至60％，较佳是从0.5变化至30％及最佳为约7％(重量/体积)。
一种较佳程度包括在预混物送入机械装置中以降低有效平均粒径之前，将表面改良剂加入预混物中。表面改良剂的浓度(重量/重量％)可从0.1变化至90％，较佳是从0.5％变化至80％及最佳为约7％(重量/体积)。
通过将预混物送入机械装置中以降低其在分散液中的有效平均粒径至低于2,000毫微米以直接使用预混物。当使用球磨机进行研磨时最好直接使用预混物。或者，抗精神病剂和视情况选用的表面改良剂可利用适合的搅拌器例如轧制机或Cowles型混合器将其分散于液体介质中，直到获得一均匀分散液。
以降低抗精神病剂的有效平均粒径的常用机械装置可采用分散碾磨机形式。适合的分散碾磨机包括球磨机、磨碎机、振动碾磨机、行星式碾磨机、介质碾磨机如砂碾磨机和颗粒碾磨机。较佳为介质碾磨机，因为提供想要的粒径降低所需的研磨时间相对较短。对于介质碾磨机，预混物的表观粘度最好是介于0.1和1帕秒之间。对于球磨机预混物的表观粘度最好是介于1和100毫帕秒之间。
粒径降低步骤中的研磨介质可选自刚硬介质，较佳为平均粒径低子3毫米和较佳系低于1毫米的球状或颗粒形式。此种介质可理想地提供本发明粒子较短操作时间及给研磨装置带来较少的磨损。相信研磨介质物的选择并不严格。但是，95％以氧化镁稳定的ZrO、硅酸锆和玻璃研磨介质提供对制造医药组合物而言是可接受的污染物量的粒子。另外，可使用其他介质如聚合颗粒、不锈钢、二氧化钛、氧化铝和95％以钇稳定的ZrO。较佳研磨介质的密度是大于2.5克/立方厘米及包括95％以氧化镁稳定的ZrO和聚合颗粒。
研磨时间可广泛地变化并且主要是视特定机械装置和所选的加工条件而定。对于轧制机，可能需要长达2天或更长的加工时间。
粒子必须在不会明显降解抗精神病剂的温度下缩小尺寸。操作温度一般偏好低于30至40℃。若想要，操作装置可用冷却装置冷却。此方法通常是在室温条件下和对碾磨程序是安全和有效的操作压力下进行。
若表面改良剂不存在于预混物中，则表面改良剂必须在研磨后以上面预混物所描述的量加至分散液中。之后，分散液可通过例如激烈摇晃予以混合。视情况，将分散液送入利用例如超声波电力供应器的声波步骤。
根据本发明的含水组合物习惯地另外包含一种悬浮剂和一种缓冲剂及视情况选用一种或多种防腐剂和等渗透剂。特定成份可同时担任一种或多种这些试剂的功能，如作为防腐剂和缓冲剂或作为缓冲剂和等渗透剂。
适合用于本发明的含水悬浮液的悬浮剂是纤维素衍生物如甲基纤维素、羧甲基纤维素钠和羟基丙基甲基纤维素、聚乙烯基吡啶烷酮、藻酸盐、聚氨基葡糖、葡聚糖、明胶、聚乙二醇、聚氧基乙烯-和聚氧基丙烯醚。优选使用浓度为0.5至2％，最优选1％(重量/体积)的羧甲基纤维素钠。适合用于根据本发明的含水悬浮液的润湿剂是山梨糖醇酯的聚氧基乙烯衍生物如多乙氧基醚20和多乙氧基醚80、卵磷脂、聚氧基乙烯-和聚氧基丙烯醚、脱氧胆酸钠。优选使用浓度为0.5至3％，更优选0.5至2％，最优选1.1％(重量/体积)的多乙氧基醚20。
适合的缓冲剂是弱酸盐类且使用量应足以使分散液呈中性至非常弱的碱性(高至pH8.5)，较佳为7至7.5的pH范围内。特别优选使用磷酸氢二钠(无水)(一般约0.9％(重量/体积))。和磷酸二氢钠单水合物(一般约0.6％(重量/体积))。此缓冲剂也赋予分散液等渗透压，而且降低悬浮于其中的酯的絮凝作用的倾向。
防腐剂是杀菌剂和抗氧化剂，其可选自包含苯甲酸、苯甲基醇、丁基化羟基苯甲醚、丁基化羟基甲苯、三氯甲基叔丁醇、棓酸盐、羟基苯甲酸盐、EDTA、酚、氯甲酚、间-甲酚、苯索氯铵、肉豆蔻基-γ-皮考啉鎓氯化物、苯基醋酸汞和乙基汞硫代水杨酸钠。特别是可使用浓度高至2％(重量/体积)，较佳高至1.5％(重量/体积)的苯甲醇。
等渗剂是例如氯化钠、葡萄糖、甘露糖醇、山梨糖醇、乳糖、硫酸钠。悬浮液一般包含从0至10％(重量/体积)的等渗剂。可使用浓度从0至7％的甘露糖醇。但是，较佳使用从约1至约3％，(重量/体积)，特别是从约1.5至约2％(重量/体积)的一种或多种电解质以赋予悬浮液等渗压，清楚地因为离子可帮助防止悬浮酯的絮凝作用。特别是缓冲剂的电解质作为等渗剂。
特别想要的可注射储存调配物的特点是关于其服药的容易性。特别是此种利用尽可能细的针头在尽可能短的时间内注射应是可行的。这可以本发明含水悬浮液的粘度保持在低于75毫帕秒，较佳低于60毫帕秒而完成。此种粘度或粘度值更低的含水悬浮液两者皆可容易地以注射针筒吸取(如从小玻璃瓶中)并经由极细的针头(如21G 11/2、22G 2或22G 11/4针头)注射。
理想地，为了保持注射体积至最低量，根据本发明的含水悬浮液将包含可忍受量的前剂和尽可能少量的其他成份。特别地，此种组合物将包含以组合物总体积为基准的重量所表示的
(a)从3至20％(重量/体积)的前剂；
(b)从0.5至2％(重量/体积)的润湿剂；
(c)一种或多种缓冲剂足以赋予组合物中性至非常低的碱性(pH8.5)；
(d)从0.5至2％(重量/体积)的悬浮剂；
(e)高至2％(重量/体积)的防腐剂；和
(f)加入适量的水至100％。
从9-羟基雷士培力酮在治疗许多病症上的可用性来看，本发明也关于一种如先前所描述的医药组合物，用于作为治疗精神病、精神分裂症、感情分裂症、非精神分裂症、神经变性症引起的行为障碍如痴呆，智能迟钝和自闭性的行为障碍，图雷特(Tourette)综合症，两极狂(bipolar mania)，沮丧，焦虑等的药剂。
而且，本发明关于使用先前所描述的组合物以制备治疗精神病、精神分裂症、感情分裂症、非精神分裂症、神经变性症引起的行为障碍如痴呆，智能迟钝和自闭性的行为障碍，图雷特(Tourette)综合症，两极狂(bipolar mania)，沮丧，焦虑等的药剂。
本发明另外关于一种治疗承受精神病、精神分裂症、感情分裂症、非精神分裂症、神经变性症引起的行为障碍如痴呆，智能迟钝和自闭性的行为障碍，图雷特(Tourette)综合症，两极狂(bipolar mania)，沮丧，焦虑等痛苦的温血动物，特别是人类的方法，该方法包括服用治疗上有效量的如先前所描述的含水悬浮液。一般而言，大约每三周或甚至更长的时间服用一次该调配物。剂量范围应从约2至4毫克/公斤体重。
以下实例用以说明本发明。
实验部分
A.9-羟基雷士培力酮棕榄酸酯的制备
将N，N′-二环己基碳化二亚胺(1.39克；6.8毫摩尔)加入于含十六烷酸(1.54克；6毫摩尔)的二氯甲烷(140毫升)溶液中，并在室温下搅拌10分钟。将9-羟基雷士培力酮(2.13克；5毫摩尔)加入于反应混合物中，接着加入4-吡咯烷并吡啶(93毫克；0.63毫摩尔)。混合物在室温下搅拌三天。将水(200毫升)加入于反应混合物中，其并以氯仿(100毫升)萃取三次。干燥(MgSO4)合并的有机相、过滤和蒸发。在二异丙基醚(100毫升)中碾制混合物、过滤并在异丙醇(60毫升)中重结晶。过滤结晶并干燥之，产生9-羟基雷士培力酮棕榄酸酯(2.67毫克；80.4％)。
B.组合物实例
根据下列一般方法制备以下调配物：在室温下将表面活性剂、悬浮剂和缓冲剂搅拌溶解于水中，并且此溶液在121℃下加热30分钟予以杀菌。活性成份(微细粒化)以25kGY的γ射线杀菌并且在无菌状况下悬浮在先前所制备的溶液中。以悬浮液和研磨介质将适当的小玻璃瓶填充至其总体积约30％，然后以约50rpm的速度摇晃数小时。然后亚微粒调配物过筛以除去研磨介质并在无菌状态下贮存。调配物A(微细粒化)是摇晃0小时，B是摇晃4小时，C是摇晃7小时，D是摇晃38小时。
调配物(重量/体积)
9-羟基雷士培力酮棕榄酸酯    7.02％(4.5％  9-羟基雷士培
                            力酮)
多乙氧基醚20                1.1％
羧甲基纤维素钠30亳帕秒      1％
苯甲基醇，非经肠的          1.5％
无水磷酸氩二钠              0.9％
磷酸二氢钠单水合物          0.6％
加适量的水                  100％
所得亚微粒分散液A-D的粘度和pH值如下：
    调配物     pH     粘度
    ABCD     8.197.98.027.98     ±7毫帕秒±8毫帕秒±9亳帕秒±10毫帕秒
粒径分布是利用Mastersizer X所测得和比表面积是利用Mastersizer S所测得。下列数值是由调配物A-D所获得：
    调配物     粒径(微米)10％          50％        90％     比表面积(平方米/克)
    ABCD     2.510.620.520.43     6.031.380.740.52     7.646.831.150.65     1.36.513.5＞15
取调配物C和D进行三个月的稳定性试验和下列数值是获自经储存的调配物C和D：
    调配物     粒径(微米)10％      50％      90％     比表面积(平方米/克)
    CD   0.270.52   0.400.75   0.621.18     13.5未测定
C. 药理实例
C.1. F1和类似油调配物的药理试验
利用21G 1 1/2 BD Microlance针头个别在四条小猎犬的右后腿的m.股二头肌处经肌内注射2.5毫克/公斤体重的四种调配物A-D；注射针筒施打无困难。在两个月间吸取血液样品以测定9-羟基雷士培力酮血浆含量。下列药动力学参数是由实验数据(平均值±标准偏差)算得：
调配物    Cmax(毫微克/毫升)     Tmax(天)     AUC0-t(毫微克时/毫升)
    ABCD     41.1(±22.1)86.4(±30.5)139(±33)132(±60)     12(±5)7(±3)1.8(±1.5)6.3(±1.5)     19487(±7697)25769(±9782)28603(±4305)34852(±14055)

Claims (10)

1.一种适合作为经肌内或皮下注射给药的储存调配物的医药组合物，该药物组合物包含一种粒子分散液，该粒子分散液包含治疗有效量的具有下式的结晶9-羟基雷士培力酮脂肪酸酯
Figure C9881115500021
或其盐类，或者其立体异构物或立体异构混合物，其中R代表直链C9-19烷基；具有有效量的吸附在其表面的表面活性剂，以便在含水的医药上可接受的载体中保持比表面积＞4平方米/克，相当于低于2,000毫微米的有效平均粒径。
2.根据权利要求1的组合物，其中R代表直链C15链且9-羟基雷士培力酮脂肪酸酯是9-羟基雷士培力酮棕榄酸酯。
3.根据权利要求1的组合物，该组合物另外包含一种悬浮剂和缓冲剂。
4.根据权利要求3的组合物，该组合物还包含一种或多种防腐剂和等渗剂。
5.根据权利要求3的组合物，其中悬浮剂是羧甲基纤维素钠和表面活性剂是多乙氧基醚20。
6.根据权利要求4的组合物，其中防腐剂是苯甲醇和等渗剂是甘露糖醇或磷酸盐缓冲剂。
7.根据权利要求1的组合物，其粘度是低于75毫帕秒。
8.根据权利要求1的组合物，其包含以组合物总体积为基准的重量表示的
(a)从3至20％重量/体积的9-羟基雷士培力酮脂肪酸酯；
(b)从0.5至2％重量/体积的润湿剂；
(c)一种或多种缓冲剂足以赋予组合物中性至非常轻微的高至pH8.5的碱性；
(d)从0.5至2％重量/体积的悬浮剂；
(e)至多2％重量/体积的防腐剂；和
(f)加入适量的水至100％。
9.根据权利要求1至8任一项的医药组合物，其作为治疗精神病、精神分裂症、感情分裂症、非精神分裂症、神经变性症引起的行为障碍，痴呆，智能迟钝和自闭性的行为障碍，图雷特综合症，两极狂，沮丧或焦虑的药剂。
10.根据权利要求1至8任一项的医药组合物在制备治疗精神病、精神分裂症、感情分裂症、非精神分裂症、神经变性症引起的行为障碍，痴呆，智能迟钝和自闭性的行为障碍，图雷特综合症，两极狂，沮丧或焦虑药剂方面的用途。
CNB988111551A 1997-11-17 1998-11-10 亚微细粒9-羟基雷士培力酮(Risperidone)脂肪酸酯类的含水悬浮液 Expired - Lifetime CN1160074C (zh)

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CN102993200A (zh) * 2011-09-10 2013-03-27 鲁翠涛 帕潘立酮氨基酸酯及其制备方法
CN102993200B (zh) * 2011-09-10 2016-02-03 鲁翠涛 帕潘立酮氨基酸酯及其制备方法

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