CN102202647B - 具有基于聚氨酯的聚合物的长期药物输送装置及其制造 - Google Patents
具有基于聚氨酯的聚合物的长期药物输送装置及其制造 Download PDFInfo
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Abstract
本发明涉及将基于聚氨酯的聚合物用作药物输送装置以将生物活性化合物以恒定的速度输送延长的时间段及其制造方法。所述装置非常生物相容和生物稳定,并用作患者(人及动物)内的植入管以将适当的生物活性物质输送到组织或器官。
Description
相关申请交叉引用
本申请要求2008年9月30日申请的美国申请12/242,497的优先权,该申请的全部内容通过引用组合于此。
背景
由于其极好的生物相容性、生物稳定性和物理性质,聚氨酯或包含聚氨脂的聚合物已用于制造大量可植入装置,包括起搏器引线、人造心脏、心瓣、支架覆膜、人造腱、动脉和静脉。然而,使用聚氨酯可植入装置输送活性剂的模式需要液态介质或载体用于以零级率扩散药物。
发明内容
在此描述了基于意想不到的发现的方法和合成物,包括一种或多种活性剂的固体制剂可用在聚氨酯可植入装置的核心处使得活性剂按受控释放、零级方式从可植入装置释放。活性剂和聚氨酯涂层可基于多个物理参数进行选择,继而可植入装置的活性剂释放速度基于临床和/或体外试验优化为临床相应的释放速度。
一实施例致力于在受治疗者体内输送活性剂的方法,包括:将可植入装置植入受治疗者内,其中可植入装置包括由基于聚氨酯的聚合物包围的活性剂,其中基于聚氨酯的聚合物根据一个或多个物理性质进行选择以使能优化可植入装置在植入受治疗者体内之后的活性剂释放。在特定实施例中,可植入装置还包括一个或多个制药学上可接受的载体。在特定实施例中,基于聚氨酯的聚合物根据其平衡水量或弯曲模量进行选择。在特定实施例中,基于聚氨酯的聚合物根据活性剂的分子量进行选择。
一实施例致力于在延长的时间段内进行至少一活性剂的受控释放以产生局部或全身药理学效果的药物输送装置,包括:a)形成为具有中空空间的基于聚氨酯的聚合物,其中基于聚氨酯的聚合物包括选自下组的一个或多个官能基:亲水性侧基、疏水性侧基、及其混合物,及其中这些官能基确定聚合物的亲水或疏水度;及b)固体药物制剂,包括至少一活性剂及可选地包括一种或多种制药学上可接受的载体,其中固体药物制剂处于圆柱形储槽的中空空间中,及其中选择聚合物性质和至少一活性剂的水溶性特性以在装置植入后提供所希望的活性剂释放速度。在特定实施例中,药物输送装置在选择为与至少一活性剂的水溶性特性匹配的条件下进行调节和引发。在特定实施例中,当至少一活性剂为亲水性活性剂时,调节和引发条件包括使用水介质(如盐溶液)。在特定实施例中,当至少一活性剂为疏水性活性剂时,调节和引发条件包括使用疏水性介质(如基于油的介质)。在特定实施例中,至少一活性剂从下组选择:可作用于中央神经系统的药物、抗抑郁药、安定药、抗惊厥药、肌肉松弛药、抗帕金森剂、镇痛药、消炎药、麻醉剂、抗痉挛药、肌肉收缩药、抗菌剂、抗疟药、激素类药物、拟交感神经药、心脏血管剂、利尿剂和抗寄生虫药。在特定实施例中,亲水性侧基选自下组:离子基、羧基、醚基和羟基。在特定实施例中,疏水性侧基选自下组:烷基和硅氧烷基。在特定实施例中,固体药物制剂包括制药学上可接受的载体(如硬脂酸)。在特定实施例中,基于聚氨酯的聚合物为热塑性聚氨酯或热固性聚氨酯。在特定实施例中,热塑性聚氨酯包括:大二醇、二异氰酸酯、双官能增链剂、或其混合物。在特定实施例中,热固性聚氨酯包括多官能多元醇、异氰酸酯、增链剂或其混合物。在特定实施例中,热固性聚氨酯包括包含不饱和键的聚合物链,及其中适当的交联剂和/或引发剂用于使聚合物亚基交联。在特定实施例中,可选择适当的调节和引发参数以建立至少一活性剂的所希望的输送速度,其中引发参数为时间、温度、调节介质和引发介质。
附图说明
图1为具有两个开口端的植入管的侧视图。
图2为用于塞植入管的预制端塞的侧视图。
图3为具有一个开口端的植入管的侧视图。
图4为使用植入管的组氨瑞林(histrelin)洗脱速度曲线。
图5为植入管的纳曲酮(naltrexone)洗脱速度曲线。
图6为聚氨酯植入管的纳曲酮洗脱速度曲线。
图7为聚氨酯植入管的LHRH激动剂(纳曲酮)洗脱速度曲线。
图8为聚氨酯植入管的可乐定(clonidine)洗脱速度曲线。
图9A和9B为PC-3575A的洗脱曲线。图9A示出了一部分管子的开始、中间和末端的管段。洗脱在水槽或轨道振荡器中进行。图9B为PC-3575A聚氨酯植入管(弯曲模量620psi)的利培酮释放速度图,该植入管由表示一卷管子的开始、中间和末端的管段制成,作为特定批内材料均匀性评估的一部分。样本在一年内每周进行使用水槽的洗脱评估。所有植入管具有一样的几何结构和药物装载量。
图10为PC-3575A聚氨酯植入管(弯曲模量620psi)的利培酮释放速度图,作为使用盐对水羟丙基β纤维素溶液(15%磷酸盐缓冲液)作为洗脱介质的效果评估的一部分。样本在11周内每周进行评估。所有植入管具有一样的几何结构和药物装载量。
图11A和11B为比较PC-3595A聚氨酯植入管(弯曲模量4500psi)和HP-60D-20聚氨酯植入管(EWC,14.9%)的利培酮释放速度的图,作为亲水和疏水聚氨酯材料的活性剂释放评估的一部分。对于植入管,样本在22周内每周进行评估。对于植入管,样本在15周内每周进行评估。所有植入管具有一样的几何结构和药物装载量。图11B为HP-60D-20聚氨酯植入管(EWC,14.9%)的利培酮释放速度图,每周取样15周。
图12为EG-80A聚氨酯植入管(弯曲模量1000psi)和两个等级的聚氨酯植入管HP-60D-35及HP-60D-60(EWC分别为23.6%和30.8%)的利培酮释放速度的比较图。所有均在10周内每周进行取样。所有植入管具有一样的几何结构和药物装载量。
图13为用作例8描述的猎兔犬研究中使用的植入管的体外控制的PC-3575A聚氨酯植入管(弯曲模量620psi)的利培酮释放速度图。这些植入管的体外洗脱研究在受治疗者植入管植入之日开始,作为体内-体外关联评估的一部分。
图14为例8描述的猎兔犬研究中体内血浆利培酮浓度的图。下面的曲线表示在植入一PC-3575A聚氨酯植入管(弯曲模量620psi)的狗中获得的平均血浆浓度。上面的曲线表示在植入两个PC-3575A聚氨酯植入管(弯曲模量620psi)的狗中获得的平均血浆浓度。
具体实施方式
为利用基于聚氨酯的聚合物的极好的性质,本发明致力于使用基于聚氨酯的聚合物作为药物输送装置,用于在延长的时间段以受控的速率释放药物从而产生局部或全身药理学效力。药物输送装置可包括由基于聚氨酯的聚合物包围的圆柱形储槽,前述聚合物控制储槽内的药物的输送速率。储槽包含制剂如固体制剂,包括一种或多种活性成分,及可选地还包括制药学上可接受的载体。载体配制成有助于活性成分通过聚合物扩散及确保储槽内药物的稳定性。
聚氨酯为由通过氨酯键结合的有机单元链组成的任何聚合物。聚氨酯聚合物通过使包含至少两种异氰酸酯官能基的单体在存在催化剂的情形下与包含至少两种醇基的另一单体反应而形成。聚氨酯制剂覆盖极宽范围的刚性、硬度和密度。
聚氨酯属于称为“反应聚合物”的化合物类,其包括环氧树脂类、不饱和聚酯及酚醛塑料。氨酯键合通过使异氰酸酯基-N=C=O与羟基(醇基)-OH反应而产生。聚氨酯通过多异氰酸酯与多元醇在存在催化剂和其它添加剂的情形下进行聚加成反应而产生。在该情形下,多异氰酸酯为具有两个以上异氰酸酯官能基的分子R-(N=C=O)n≥2,及多元醇为具有两个以上羟基官能基的分子R′-(OH)n≥2。反应产物为包含氨酯键合-RNHCOOR′-的聚合物。异氰酸酯与包含活性氢的任何分子反应。重要的是,异氰酸酯与水反应以形成脲键合和二氧化碳气体;它们也与聚醚胺反应以形成聚脲。
聚氨酯在商业上通过使液态异氰酸酯与多元醇、催化剂和其它添加剂的液态混合物反应而产生。这两个组成称为聚氨酯系,或简单地称为系。异氰酸酯在北美通常称为“A侧”或仅称为“iso”并代表该系的刚性主链(或“硬链段”)。多元醇及其它添加剂的混合物通常称为“B侧”或“poly”并代表该系的官能部分(或“软链段”)。该混合物也可称为“树脂”或“树脂混合物”。树脂混合物添加剂可包括增链剂、交联剂、表面活性剂、阻燃剂、发泡剂、颜料和填料。在药物输送应用中,“软链段”代表聚合物的透露确定活性药用成分(API)通过该聚合物的扩散性的特性的部分。
这些材料的弹性性质源自聚合物的硬和软共聚物链段的相分离,使得氨酯硬链段区用作无定形聚醚(或聚酯)软链段区之间的交联。该相分离之所以产生是因为主要非极性低熔点软链段与极性高熔点硬链段不相容。由高分子量多元醇形成的软链段可移动且通常按盘绕形式存在,而由异氰酸酯和增链剂形成的硬链段硬且不能移动。由于硬链段与软链段共价耦连,它们抑制了聚合物链的塑性流动,因而产生弹性材料弹性。在机械变形时,软链段的一部分因开卷而被压,及硬链段在应力方向对齐。硬链段的这种重定向及随之发生的强有力氢结合有助于高抗张强度、伸长及抗扯强度值。
聚合反应通过叔胺如二甲基环己胺及有机金属化合物如二月桂酸二丁基锡或辛酸铋进行催化。此外,催化剂可基于它们是否促成氨酯(凝胶)反应进行选择,例如1,4-二氮杂二环[2.2.2]辛烷(也称为DABCO或TEDA),或脲(吹)反应如双二甲胺基乙基醚,或者具体地驱动异氰酸酯三聚反应如辛酸钾。
对于形成聚氨酯聚合物,需要具有两个以上官能基的异氰酸酯。体积方面芳族异氰酸酯占总体二异氰酸酯产物的大部分。脂族和脂环族异氰酸酯也是聚氨酯材料的重要组成部分,但体积小得多。这源自多个原因。首先,芳链异氰酸酯基远比脂族的反应大。其次,芳族异氰酸酯使用更经济。脂族异氰酸酯仅在最终产品需要特殊性质时使用。例如,光稳定涂层和弹性体仅可用脂族异氰酸酯获得。脂族异氰酸酯还由于其固有稳定性和弹性性质而利于生产聚氨酯生物材料。
脂族和脂环族异氰酸酯的例子例如包括:1,6-己二异氰酸酯(HDI)、1-异氰酸-3-异氰酸甲基-3,5,5-三甲基环已烷(异佛尔酮二异氰酸酯、IPDI)、及4,4′-二异氰酸酯二环己基甲烷(H12MDI)。它们用于产生光稳定、非发黄聚氨酯涂层及弹性体。H12MDI预聚物用于产生具有光学透明度和抗水解作用的高性能涂层和弹性体。和聚氨酯均由H12MDI预聚物制成。
多元醇为由引发剂和单体组成制造的更高分子量的材料,组合到聚氨酯系内时表示聚合物的“软链段”。它们大部分容易分类为聚醚多元醇,其通过环氧化物(环氧乙烷)与包含活性氢的起动化合物反应而制成;或分类为聚酯多元醇,其通过多官能羧酸和羟基化合物缩聚而制成。
聚氨酯和聚氨酯均为脂环族聚合物并属于由基于聚醚的多元醇产生的类型。对于聚氨酯,多元醇链段的一般结构表示为:
O-(CH2-CH2-CH2-CH2)x-O-
其中“x”的增加代表柔性的增加(“弯曲模量”FM减少),导致从约1000到92,000psi范围的FM。从这些材料的药物释放的立场,随着FM增加,相对疏水的API的释放减少。
对于(亲水)聚氨酯,多元醇链段的一般结构表示为:
-[O-(CH2)n]x-O-
其中“n”和“x”的增加代表亲水性的变化,并导致从约5%到43%的平衡水量(%EWC)。从这些材料的药物释放的立场,随着%EWC增加,相对亲水的API的释放增加。
具体地,多元醇例如包括聚碳酸酯多元醇、聚己酸内酯多元醇、聚丁二烯多元醇和聚硫化物多元醇。
聚氨酯均为脂环族聚合物并属于由基于聚碳酸酯的多元醇产生的类型。多元醇链段的一般结构表示为:
O-[(CH2)6-CO3]n-(CH2)-O-
其中“n”的增加代表柔性的增加(FM减少),导致从约620到92,000psi范围的FM。从这些材料的药物释放的立场,随着FM增加,相对疏水的API的释放减少。
增链剂和交联剂均为低分子量羟基和胺端化合物,其在聚氨酯纤维、弹性体、粘合剂和某些完整皮肤和微细胞泡沫体的聚合物形态方面扮演重要角色。增链剂的例子包括乙二醇、1,4-丁二醇(1,4-BDO或BDO)、1,6-己二醇、环己烷二甲醇、和对苯二酚二羟乙基醚(HQEE)。所有这些二醇形成相分离的聚氨酯,形成明确的硬链段区,及可熔化处理。它们均适合热塑性聚氨酯,但乙二醇例外,因为其派生的二苯基尿烷在高硬链段水平经受不利的降级。和均包括将1,4-丁二醇用作增链剂。
本发明提供可实现下述目标的药物输送装置:受控释放速度(如零级释放速度)以使治疗效果最大化及使有害副作用最小化,如果必须结束治疗则很容易收回装置,生物利用率增加而吸收变化较小及没有首过代谢。
当药物施加到圆柱形储槽装置(药筒)时,药物的释放速度受Fick扩散定律控制。下面的等式描述了不同参数之间的关系:
其中:
dM/dt:药物释放速度;
h:装置填充部分的长度;
ΔC:跨储槽壁的浓度梯度;
ro/ri:装置的外半径和内半径的比;及
p:所使用聚合物的渗透率系数。
渗透率系数主要由聚合物的亲水性或疏水性、聚合物的结构、及药物和聚合物的相互作用控制。一旦选定聚合物和活性成分,p恒定不变,一旦圆柱形装置产生,h、ro和ri均固定和保持不变。ΔC保持不变。
为尽可能精确地保持装置的几何结构,该装置如圆柱形装置可通过热塑性聚氨酯聚合物的精确挤压成形或精确模塑及热固聚氨酯聚合物的反应注塑或旋转成型进行制造。
药筒可制造成一端封闭或两端开口。开口端可用预制端塞塞上以确保端部平滑及固体密封,或在热塑性聚氨酯的情形下,通过使用本领域技术人员众所周知的热密封技术进行。固体活性剂和载体可压为粒丸形式以使活性剂的装载量最大化。
为识别植入管的位置,射线透不过的材料可通过将其插入储槽或通过将其放入用于密封药筒的端塞中而组合在输送装置内。
一旦药筒两端密封且储槽填满,它们在适当的时间段可进行任意调节和引发以确保恒定的输送速度。
药物输送装置的调节包括将活性剂(药物)装入包围储槽的基于聚氨酯的聚合物。进行引发以停止将药物装入基于聚氨酯的聚合物因而防止在实际使用植入管之前损失活性剂。用于调节和引发步骤的条件取决于执行这些步骤时的活性剂、温度和介质。在一些情形下,用于调节和引发的条件可以一样。
在药物输送装置制备过程中进行调节和引发步骤以获得特定药物的、确定的释放速度。包含亲水药物的植入管的调节和引发步骤可在水介质如盐溶液中进行。包括疏水药物的药物输送装置的调节和引发步骤通常在疏水介质如基于油的介质中进行。调节和引发步骤可通过控制三个具体的因素进行,即温度、介质和时间段。
本领域技术人员应当理解,药物输送装置的调节和引发步骤受该装置置于其中的介质的影响。亲水药物例如可在水溶液如盐溶液中进行调节和引发。例如,组氨瑞林和纳曲酮植入物已在盐溶液中进行调节和引发,更具体地,在0.9%钠含量的盐溶液中调节及在1.8%氯化钠含量的盐溶液中引发。
用于调节和引发药物输送装置的温度可跨宽温度范围变化,如约37℃。
根据具体植入管或药物所希望的释放速度,用于调节和引发药物输送装置的时间段可在约一天到几周之间变化。所希望的释放速度由本领域技术人员根据粒丸制剂中使用的特定活性剂进行确定。
本领域技术人员将理解,调节和引发植入管的步骤是优化包含在植入管内的药物的释放速度。这样,相较于经历较长调节和引发步骤的类似药物输送装置,花在药物输送装置调节和引发上的时间段更短导致药物的释放速度更低。
调节和引发步骤中的温度也将影响释放速度,因为,当与经历更高温度下的处理的类似药物输送装置比较时,较低的温度导致包含在药物输送装置中的药物的释放速度较低。
类似地,在水溶液如盐溶液情形下,溶液的氯化钠含量确定药物输送装置将获得什么类型的释放速度。更具体地,相较于已经历其中氯化钠含量较高的调节和引发步骤的药物输送装置,较低的氯化钠含量导致更高的药物释放速度。
相同的条件应用于疏水药物,其中调节和引发步骤的主要差别在于调节和引发介质为疏水介质,更具体地,为基于油的介质。
可输送的药物(活性剂)包括:可作用于中央神经系统的药物、抗抑郁药、安定药、抗惊厥药、肌肉松弛药、抗帕金森剂、镇痛药、消炎药、麻醉剂、抗痉挛药、肌肉收缩药、抗菌剂、抗疟药、激素类药物、拟交感神经药、心脏血管剂、利尿剂和抗寄生虫药等。药物还包括泌尿外科学中使用的药物以治疗或防止泌尿紊乱或用于避孕的药物,例如但不限于戊柔比星(valrubicin)、阿霉素(doxorubicin)、膀胱癌细胞毒素剂、5-氨基水杨酸(5-ASA)、氢化可的松、地塞米松、消炎药、曲司氯铵、坦洛新(tamsulosin)、奥昔布宁(oxybutinin)、及任何激素(例如乙炔基雌二醇、左炔诺孕酮、雌二醇、睾酮等)。泌尿用途包括但不限于膀胱癌、间质性膀胱炎、膀胱炎症、膀胱过度活动症、良性前列腺增生(BPH)、避孕、绝经后症状及性腺功能减退症。在膀胱中使用的可植入装置的直径大小可在约2mm到约10mm之间,如约3mm到约6mm,或约2.7mm,及高达约50mm长。
本发明致力于将热塑性或热固性基于聚氨酯的聚合物应用于产生可植入药物装置以在延长的时间段按受控速度输送生物活性化合物。例如,根据所使用的聚氨酯的类型,聚氨酯聚合物可通过挤压成型、(反应)注射成型、压模或旋转成型(例如参见美国专利5,266,325和5,292,515)制成具有一个或两个开口端的圆柱形中空管。
热塑性聚氨酯可通过挤压成型、注射成型或压模进行处理。热固性聚氨酯可通过反应注射成型、压模或旋转成型进行处理。圆柱形中空管的尺寸应尽可能精确。
基于聚氨酯的聚合物由多官能多元醇、异氰酸酯和增链剂合成。每一聚氨酯的特性可归属于其结构。
热塑性聚氨酯由大二醇、二异氰酸酯和双官能增链剂制成(例如美国专利4,523,005和5,254,662)。大二醇构成软区。二异氰酸酯和增链剂构成硬区。硬区用作聚合物的物理交联场所。改变这两个区的比可改变聚氨酯的物理特性如弯曲模量。
热固性聚氨酯可由多官能(多于双官能)多元醇和/或异氰酸酯和/或增链剂制成(例如美国专利4,386,039和4,131,604)。热固性聚氨酯也可通过在聚合物链中引入不饱和键及适当的交联剂和/或引发剂以进行化学交联而制成(例如美国专利4,751,133)。通过控制交联场所的量及它们怎样分布,可控制活性剂的释放速度。
根据所希望的性质,不同的官能基可通过修改多元醇的主链而引入聚氨酯聚合物链。在装置用于输送水溶性药物的情形下,亲水性侧基如离子基、羧基、醚基和羟基组合到多元醇内以增加聚合物的亲水性(例如美国专利4,743,673和5,354,835)。在装置用于输送疏水性药物的情形下,疏水性侧基如烷基、硅氧烷基组合到多元醇内以增加聚合物的疏水性(例如美国专利6,313,254)。活性剂的释放速度也可通过聚氨酯聚合物的亲水性/疏水性进行控制。
对于热塑性聚氨酯,为产生具有一致物理尺寸的双开口端中空管(图1),首选精确挤压成型和注射成型。储槽可用包含活性剂和载体的适当制剂自由装载或用预制粒丸填充以使活性剂的加载最大化。在将制剂装入中空管之前需要首先密封一个开口端。为密封两个开口端,可使用两个预制端塞(图2)。密封步骤可通过加热、溶剂或任何其它手段密封端部而实现,优选永久密封。
对于热固性聚氨酯,根据固化机制,首选精确反应注射成型或旋转成型。如果固化机制通过加热进行,则使用反应注射成型;如果固化机制通过光和/或热进行,则使用旋转成型。例如,具有一个开口端的中空管(图3)可通过旋转成型制得。例如,具有两个开口端的中空管可通过反应注射成型制得。储槽可以与热塑性聚氨酯一样的方式进行装载。
为密封开口端,适当的光引发和/或热引发热固性聚氨酯制剂可用于填充开口端,及其用光和/或热固化。例如,预制端塞也可用于密封开口端,其通过在预制端塞和开口端之间的界面上施加适当的光引发和/或热引发热固性聚氨酯制剂并用光和/或热或任何其它手段使其固化以密封端部而实现,首选永久密封。
最后的过程涉及调节和引发植入管以实现所需要的活性剂输送速度。根据活性成分的类型,即亲水还是疏水,选择适当的调节和引发介质。对于亲水性活性剂,首选基于水的介质;及对于疏水性活性剂,首选基于油的介质。
本领域技术人员容易知道,在不背离本发明范围的情形下可对其优选实施方式进行许多变化。在此包含的所有内容均应视为是对本发明的说明而非限制。
示例
例1
聚氨酯聚合物管由ThermedicsPolymerProducts提供并通过精确挤压成型工艺制造。聚氨酯为脂肪族基于聚醚的热塑性聚氨酯,其可配制成具有高达干树脂重量的150%的不同平衡水量(EWC)。挤压成型级模式设计成提供热成形管或其它构件的最大物理性质。示例性的管和端盖结构如图1-3中所示。
聚合物的物理数据提供如下,并可通过ThermedicsPolymerProduct获得(进行的测试由AmericanSocietyforTestingandMaterials(ASTM)概述,表1)。
表1:典型物理测试数据
ASTM | HP-60D-20 | HP-60D-35 | HP-60D-60 | HP-93A-100 | |
硬度计(肖氏硬度) | D2240 | 43D | 42D | 41D | 83A |
比重 | D792 | 1.12 | 1.12 | 1.15 | 1.13 |
弯曲模量(psi) | D790 | 4,300 | 4,000 | 4,000 | 2,900 |
干态极限拉伸(psi) | D412 | 8,900 | 7,800 | 8,300 | 2,200 |
湿态极限拉伸(psi) | D412 | 5,100 | 4,900 | 3,100 | 1,400 |
干态伸长(%) | D412 | 430 | 450 | 500 | 1,040 |
湿态伸长(%) | D412 | 390 | 390 | 300 | 620 |
HP-60D-20挤压成型为厚度0.30mm、内径1.75mm的管。之后,该管切割为25mm的长度。管的一侧使用热密封器加热密封。密封时间低于一分钟。四个醋酸组氨瑞林粒丸装入管内。每一粒丸重约13.5mg,总重量54mg。每一粒丸由98%的组氨瑞林和2%的硬脂酸的混合物组成。管的第二开口端以与第一端一样的方式加热密封。之后,调节和引发装入的植入物。调节在室温下在0.9%盐溶液中进行一天。在调节结束后,植入物经历引发。引发在室温下在1.8%盐溶液中进行一天。每一植入物在选择为模拟人体中发现的pH的介质中进行体外测试。所选介质的温度在测试期间保持在约37℃。释放速度如图4和表2中所示。
表2:组氨瑞林洗脱速度
周 | HP-60D-20(μg/日) |
1 | 451.733 |
2 | 582.666 |
3 | 395.9 |
4 | 310.29 |
5 | 264.92 |
6 | 247.17 |
7 | 215.93 |
8 | 201.78 |
9 | 183.22 |
10 | 174.99 |
11 | 167.72 |
12 | 158.37 |
13 | 153.95 |
14 | 146.46 |
15 | 139.83 |
16 | 129.6 |
17 | 124.46 |
18 | 118.12 |
19 | 120.35 |
例2
HP-60D-35挤压成型为厚度0.30mm、内径1.75mm的管。之后,该管切割为32mm的长度。管的一侧使用热密封器加热密封。密封时间低于一分钟。六个纳曲酮粒丸装入管内,及管的两开口侧加热密封。每一粒丸重约15.0mg,总重量91mg。管的第二开口端以与第一端一样的方式加热密封。之后,调节和引发装入的植入物。调节在室温下在0.9%盐溶液中进行一周。在调节结束后,植入物经历引发。引发在室温下在1.8%盐溶液中进行一周。每一植入物在选择为模拟人体中发现的pH的介质中进行体外测试。所选介质的温度在测试期间保持在约37℃。释放速度如图5和表3中所示。
表3:纳曲酮洗脱速度
周 | HP-60D-35-1 | HP-60D-35-2 | HP-60D-35-3 |
0 | (μg/日) | (μg/日) | (μg/日) |
1 | 1529.26 | 767.38 | 1400.95 |
2 | 1511.77 | 1280.03 | 1498.86 |
3 | 1456.01 | 1635.97 | 1449.49 |
4 | 1378.27 | 1607.13 | 1500.42 |
5 | 1393.05 | 1614.52 | 1558.37 |
6 | 1321.71 | 1550.39 | 1436.03 |
7 | 1273.07 | 1424.24 | 1300.73 |
8 | 1172.82 | 1246.48 | 1221.57 |
例3
图6为使用两个不同水含量的两个等级的聚合物时纳曲酮的释放速度比较图。对植入管的聚合物具有24%水含量的情形执行和分析3批,及对植入管的聚合物具有30%水含量的情形执行和分析3批。释放速度相对于时间进行绘制。用于24%水含量批次的聚合物为来自Thermedics的HP-60-D35。用于30%水含量批次的聚合物为来自Thermedics的HP-60-D60。在该例子中,所获得的数据证明根据本发明制备的植入管具有良好的再现性。
例4
图7为组氨瑞林(LHRH激动剂)释放速度对时间的曲线图。在该例子中,聚合物具有15%的水含量。所使用的聚合物为来自Thermedics的HP-60-D20。每周取数据点。
例5
图8为可乐定释放速度对时间的曲线图。在该例子中,聚合物具有15%的水含量。所使用的聚合物为来自Thermedics的HP-60-D20。每周取数据点。
例6
表4A-C示出了三个不同类的聚氨酯化合物(和)的活性剂释放速度。释放速度已归一化到植入管的表面积,从而针对微小差异调节各个可植入装置的大小。选择活性剂以覆盖一可溶性范围(如LogP值所指示的;对于所提供数据的目的,大于约2.0的LogP值视为不容易溶解在水溶液中)和分子量范围。选择聚氨酯以具有变化的水溶活性剂亲和性及变化的柔性(由弯曲模量变化指示)。
对于聚氨酯用于在此所述的装置和方法的应用,聚氨酯展现适合将要输送的特定活性剂的物理性质。例如,聚氨酯可得到或可被制成具有一定的EWC或弯曲模量范围(表4)。表4A-C示出了多种活性成分自聚氨酯化合物的归一化释放速度。表4D-F示出了同样的活性成分的非归一化释放速度,连同植入管合成物。
表4A
表4B
表4C
表4D
表4E
表4F
水环境中的活性剂的溶解度可基于其分配系数(定义为水相化合物的浓度与不相混溶剂的浓度的比)进行测量和预测。分配系数(P)是脂质(油)和水之间的物质配方如何好的度量。基于P的溶解度的度量通常设为LogP。通常,溶解度通过LogP和熔点(其受化合物的大小和结构影响)确定。通常,LogP值越低,化合物越可溶于水中。然而,例如由于其低熔点,可能具有高LogP值的化合物仍然可溶。也可能具有高熔点的低LogP化合物非常不可溶。
特定聚氨酯的弯曲模量是应力和应变的比。其是化合物“刚性”的度量。该刚性通常按帕(Pa)或磅每平方英寸(psi)表示。
活性剂自聚氨酯化合物的洗脱速度可因多个因素而变化,例如包括聚氨酯的相对疏水性/亲水性(例如由logP指示)、聚氨酯的相对“刚性”(例如由弯曲模量指示)、和/或将要释放的活性剂的分子量。
例7:利培酮自聚氨酯可植入装置洗脱
图9-14为在变化的时间段,利培酮从各种可植入装置洗脱的曲线表示。
获得PC-3575A聚氨酯植入管(F.M.620psi)的利培酮释放速度,其由表示一卷管的开始、中间和结束的管段组成,作为特定批内材料均匀性评估的一部分(图9)。样本在一年内每周进行评估。所有植入管具有一样的几何结构和药物装载量。
获得PC-3575A聚氨酯植入管(F.M.620psi)的利培酮释放速度,作为使用盐对水羟丙基β纤维素溶液(15%磷酸盐缓冲液)作为洗脱介质的效果评估的一部分(图10)。样本在11周内每周进行评估。所有植入管具有一样的几何结构和药物装载量。
比较PC-3595A聚氨酯植入管(F.M.4500psi)和HP-60D-20聚氨酯植入管(EWC,14.9%)的利培酮释放速度,作为亲水和疏水聚氨酯材料的活性剂释放评估的一部分(图11A和11B)。对于植入管,样本在22周内每周进行评估。对于植入管,样本在15周内每周进行评估。所有植入管具有一样的几何结构和药物装载量。
比较EG-80A聚氨酯植入管(F.M.1000psi)和两个等级的聚氨酯植入管HP-60D-35及HP-60D-60(EWC分别为23.6%和30.8%)的利培酮释放速度(图12)。所有均在10周内每周进行取样。所有植入管具有一样的几何结构和药物装载量。
获得用作例8描述的猎兔犬研究中使用的植入管的体外控制的PC-3575A聚氨酯植入管(F.M.620psi)的利培酮释放速度。这些植入管的体外洗脱研究在受治疗者植入管植入之日开始,作为体内-体外关联评估的一部分。
例8:包含利培酮的聚氨酯皮下植入装置在猎兔犬中的评估
该研究的目的是确定一个或两个植入管的血液利培酮水平及植入管释放药物的持续时间。包括含利培酮的粒丸的基于聚氨酯的可植入装置植入到猎兔犬内以确定利培酮体内释放速度。样本分析的结果如表5和图14中所示。在第三个月结束时,在狗血浆中仍存在高水平的利培酮。该研究根据WCFP的标准操作程序(SOP)、协议及任何修正协议进行。所有程序根据实验室动物照料和使用指南(NationalResearchCenter,NationalAcademyPress,Washington,DC,1996)进行,并得到WCFP的theInstitutionalAnimalCareandUseCommittee的批准。
植入管初始包含约80mg的利培酮,并设计成按约130mcg/日输送3个月。测试物品在使用之前在2-8℃之间保存。
前述动物如下:
物种:犬科
种类:猎兔犬
来源:GuangzhouPharm.IndustrilResearchInstitute
证书号:SCXK(YUE)2003-0007
治疗开始时的年龄:6~9月
体重:8~10kg
数量和性别:6只公狗
在研究开始之前,这些动物均被分配预处理标识号。所有动物均在给药之前一周一次称重,并在驯化期间接受有资格兽医师的每日笼边观察。在选择进行研究之前所有动物均进行临床检查。具有疾病或身体异常的动物不被选择用于研究。血液取样在植入之前第三天和第二天取为基准。之后,这些动物随机分为2组,具有如下提供的剂量计划:
每一动物均按30mg/kg的剂量经戊巴比妥钠通过一般麻醉进行麻醉以植入装置。药物稳态释放几个月。一半动物接收一根植入管(组1),及另一半接收两根植入管(组2)。在肩部剃出5cm2的区域,及皮下注射2mL的丁哌卡因以使该区域麻木。在肩部上切一小的切口并将装置滑到皮下。小切口缝合及使动物恢复活动。在接下来的5-7天,监视植入点是否有感染或反应病征。当皮肤充分愈合时去除缝皮钉。在三个月结束时,像临床一样去除这些装置。
在血液取样之前这些动物被禁食至少4个小时。由于血液取样在早上进行,整夜未给食物。血液样本使用20G针抽取并直接收集到包含肝素钠的5mL管中及保持冷冻直到离心分离为止。之后,样本在4℃以5000RPM离心分离5分钟。之后,分开的血浆传入两个3mL低温管中。这些样本用取样的实际日期、相应的研究日、狗标识及副样标识符(A或B)进行标记。样本保持在-20℃,直到准备分析为止。
在植入输送装置之前的两个连续日取基准血液样本。此外,在第一周期间每日取血液样本,及在植入后的三个月内每周取血液样本。每次从每只狗抽取两个5mL血液样本。血液样本主要从头静脉抽取;隐静脉或颈静脉用作备用。对于单和双植入管组,血液样本均在下表3中所示的适当时间抽取。分析需要至少2mL血浆,这需要每一样本抽取不少于10mL的血液。血浆利培酮浓度分析使用针对该化合物开发的LC/MS化验进行。对每一样本进行单一化验。样本收集、以适当的条件保存并按批分析。
表5
狗血浆中的利培酮浓度
*:再分析
**:再分析,异常数据
图14为猎兔犬研究中体内血浆利培酮浓度的图。下面的曲线表示在植入一PC-3575A聚氨酯植入管(F.M.620psi)的狗中获得的平均血浆浓度。上面的曲线表示在植入两个PC-3575A聚氨酯植入管(F.M.620psi)的狗中获得的平均血浆浓度。
等效方案
本发明不限于在本申请中描述的具体实施方式,这些实施方式仅用于说明各个方面。对本领域技术人员显而易见的是,在不背离本发明的精神和范围的情形下,可进行许多修改和变化。除那些在此列举的之外,本领域技术人员可从前面的描述显而易见地得出在本发明范围内的功能上等效的方法、系统和装置。这些修改和变化均落在所附权利要求的范围之内。本发明仅由所附权利要求及其等效方案的全部范围限制。应当理解,本发明不限于特定方法、试剂、化合物组成或生物系统,这些当然可变化。还应当理解,在此使用的术语仅用于描述具体实施方式的目的,不意于限制。如本领域技术人员将理解的,对于任何及所有目的,如提供书面描述的目的,在此公开的所有范围还包括任何及所有可能的子范围及其组合。
在多个方面和实施方式已在此公开的同时,其它方面和实施方式对本领域技术人员显而易见。在此引用的所有文献均通过引用全部组合于此。
Claims (3)
1.可植入装置在制备药物中的应用,用于输送一种或多种活性成分,所述可植入装置包括聚氨酯聚合物,所述可植入装置包括由所述聚氨酯聚合物包围的圆柱形储槽,其中所述储槽包含具有一种或多种活性成分的固体制剂,其中所述一种或多种活性成分选自下组:纳曲酮、美托拉宗、可乐定和利培酮。
2.根据权利要求1的应用,其中所述固体制剂包括一个或多个制药学上可接受的载体。
3.根据权利要求2的应用,其中所述一个或多个制药学上可接受的载体包括硬脂酸。
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- 2009-09-28 CN CN200980142350.9A patent/CN102202647B/zh not_active Expired - Fee Related
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BRPI0920824A2 (pt) | 2018-05-29 |
JP5897077B2 (ja) | 2016-03-30 |
AU2009298720A1 (en) | 2010-04-08 |
CA2739178A1 (en) | 2010-04-08 |
HK1157646A1 (zh) | 2012-07-06 |
JP2012504138A (ja) | 2012-02-16 |
JP2014224137A (ja) | 2014-12-04 |
RU2508089C2 (ru) | 2014-02-27 |
US20150105746A1 (en) | 2015-04-16 |
UA106593C2 (uk) | 2014-09-25 |
US20140012222A1 (en) | 2014-01-09 |
US20090098182A1 (en) | 2009-04-16 |
US8784865B2 (en) | 2014-07-22 |
RU2011117328A (ru) | 2012-11-10 |
KR20110063536A (ko) | 2011-06-10 |
JP5677962B2 (ja) | 2015-02-25 |
AU2009298720B2 (en) | 2015-07-16 |
US7858110B2 (en) | 2010-12-28 |
AU2009298720C1 (en) | 2015-12-17 |
US20110184376A1 (en) | 2011-07-28 |
EP2344123A2 (en) | 2011-07-20 |
US8303977B2 (en) | 2012-11-06 |
US20120231061A1 (en) | 2012-09-13 |
WO2010039641A2 (en) | 2010-04-08 |
US8460274B2 (en) | 2013-06-11 |
CN102202647A (zh) | 2011-09-28 |
CA2739178C (en) | 2016-09-06 |
WO2010039641A3 (en) | 2010-07-29 |
IL211954A0 (en) | 2011-06-30 |
MX2011003299A (es) | 2011-06-09 |
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