CN1460018A - 埋植凝胶组合物及其制备方法 - Google Patents
埋植凝胶组合物及其制备方法 Download PDFInfo
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- CN1460018A CN1460018A CN00808477A CN00808477A CN1460018A CN 1460018 A CN1460018 A CN 1460018A CN 00808477 A CN00808477 A CN 00808477A CN 00808477 A CN00808477 A CN 00808477A CN 1460018 A CN1460018 A CN 1460018A
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Abstract
描述了可降低有益试剂从埋植系统中突释的方法和组合物。所述系统采用有益试剂的压制微粒,任选与溶出度调节剂或低水溶性试剂混合,例如硬脂酸和棕榈酸的混合物,分散到生物溶蚀和生物相容性载体中。
Description
发明背景
发明领域
本发明涉及可控释有益试剂的埋植组合物。具体地说,本发明涉及载体如凝胶和有益试剂的组合物,其中与有益试剂有关的水性微环境和凝胶本体特性,可调节有益试剂与凝胶组分或所用水环境间的作用或溶解性。本发明还涉及制备所述组合物的方法。
相关技术描述
已有许多系统从埋植聚合物骨架运送药物和其他有益试剂。例如,与此系统相关的代表性专利包括:US5,085,866描述了口内植入系统。US5,019,400描述了控释微球制剂;US4,938,763及其分案US5,278,201描述了可就地形成的生物降解性固体埋植剂;US5,599,552描述了热塑性和热固性的聚合物组合物,其中采用可与水溶混的溶剂例如N-甲基-2-吡咯烷酮,形成了可从周围组织快速吸水的聚合物溶液;US5,242,910描述了含有治疗牙周疾病药物的缓释组合物;US5,620,700描述了用于牙周腔局部给药的聚合物-药物骨架,其中任选包括高达30wt%的增塑剂;和US5,556,905描述了可降解的热塑性组合物,它可用含有多个柠檬酸偏酯的增塑剂加以调节。
已知埋植系统在活性剂给药方面存在困难,特别是当活性剂为高度水溶性时,植入后即以一种控制的形式释放,但是常产生释放过多活性剂的“突释”效应,而这是不需要的。已有技术中描述了许多旨在解决此问题的组合物和方法。
US5,759,563描述了可形成固体结构的液体给药系统,其中的活性剂掺入到控释组分中,该结构可溶解、分散或混于液体组分中。如其所述,控释组分包括微细结构、大结构、共轭物、络合物或低水溶性盐。据称该控释组分可延迟释放活性剂,并可固化制剂使大量活性剂不致于在初始损失。在其公开的许多控释组分中,该专利披露活性剂可与载体分子通过共价键结合成共轭物,所述载体典型地为聚合物,但可以是有机小分子如可通过酯或酰胺键结合的硬脂酸。在该专利的实施例2中,80℃下将醋酸ganirelix熔于聚(癸二酸)中形成醋酸ganirelix粉末,据称它可以减少醋酸ganirelix简单地溶于聚乳酸/N-甲基-2-吡咯烷酮溶液中形成制剂时出现的突释。
US5,162,057描述了用于制备容纳或含有聚甘油脂肪酸酯的固体制剂的包衣材料。该包衣材料可含有软化剂如类脂或蜡,其中包括脂肪酸如硬脂酸和棕榈酸,或它们的盐。其中包衣可采用锅包衣等方法,将其与试剂和其他添加剂熔化和混合成乳状,或通过加热,然后与水混合而乳化。将乳液喷雾到固体制剂的表面并干燥而获得包衣制剂。
US4,341,759描述了一种包衣颗粒,它可降低活性剂向颗粒表面透入的浓度。该专利描述了用于控制释放速率的非活性lipofile物质例如蜡,脂肪酸及其酯,和脂肪酸醇,包括硬脂酸,甘油单硬脂酸酯和十六基醇。其中包衣可采用包衣锅或流化床。
US4,351,825描述了控释片剂的制备,其中活性剂混于颗粒状组合物中,然后与控释剂例如大分子脂肪酸酯混合,并压成片。所述的控释剂为脂(溶)性的,且活性剂颗粒间的空间控制了水分向片基的透入。
Mesiha等的“含有Brij35,52,58或92和硬脂酸的口服胰岛素制剂的低血糖作用”,J.Pharm.Pharmacol.,33,733-734页(1981年)描述了硬脂酸与吸收促进剂Brij和胰岛素在85℃制备的熔化物。该文章推测,硬脂酸的乳化胶束可携带胰岛素进入粘膜,并且硬脂酸与Brij的颗粒呈疏水性,这样可提高胰岛素的稳定性。
Foldvari,M.和Moreland,A.在“局部给予干扰素α脂质体治疗生殖器乳头病毒感染的临床观察”,Journal of Liposome Research,7(1):155-126页(1977年)描述了采用溶剂蒸发法将α-干扰素-2b包封于多室脂质体中,其中含2∶1∶1.4摩尔比的大豆卵磷脂∶胆固醇∶硬脂酸。
先有技术中描述了许多脂肪酸和脂肪酸酯的盐用于缓释给药。例如,US4,851,220描述了含有凝胶剂如单脂肪酸酯铝的油状凝胶。US4,650,665描述了一种优选为硬脂酸钙、右旋糖酐和蓖麻油的骨架。US5,474,980描述了用于多肽给药的组合物,它含有由多种脂肪酸酯如甘油三酯、或甘油三酯与脂肪酸混合物(优选游离脂肪酸占小部分,例如低于约10%)制备的生物相容性油。US5,628,993描述了非肠道给药的药物制剂,其中骨架中含有肽或蛋白质和饱和脂肪酸如棕榈酸和硬脂酸的聚甘油二酯。
1997年12月18日提交的相关申请08/993,208,描述了控制有益试剂从埋植剂突释的高效系统。该系统含有聚合物/溶剂组合物,它可形成凝胶并能控制水分向整个聚合物系统透入的速率,这样就减少了有益试剂暴露于施用环境中时出现的突释。虽然该系统通过控制聚合物骨架的整体性能而达到所述效果和优点,但是业已发现:将该系统与在此描述的处于可控凝胶微环境中的药物结合,可进一步改善活性剂的控释。
发明概述
本发明包括埋植组合物及其制备方法,所述组合物含有分散于载体中的有益试剂压制微粒。压缩可降低表面积与微粒质量的比率,并且当有益试剂暴露于施用环境的体液时,压制可降低其溶出、分散或扩散速率。本发明减少了有益试剂的突释,使可能的副作用最小化并提高了载体对有益试剂的负载能力,这样就可用单一植入剂实现有益试剂的延迟给药。采用少量的植入剂,即可达到对所需有益试剂的延迟给药数月或甚至数年。
一方面,本发明组合物包括载体如生物相容和生物溶蚀型粘性凝胶,和分散于载体中的含有益试剂压制微粒。微粒可为单独压制的有益试剂,或与药用惰性组分混合的形式。载体可含有生物相容性聚合物并可与上述的适宜溶剂结合而形成凝胶。
另一方面,本发明组合物包括载体如粘性凝胶,和分散于载体中的有益试剂压制微粒,所述压制微粒是与在施用环境中调节有益试剂溶出的试剂混合的形式,或者是压制的有益试剂单独与溶出度调节剂溶于或分散所述载体中,任选含有其它药用惰性组分。所述载体是生物相容性且可生物溶蚀的。
另一方面,本发明组合物包括载体如粘性凝胶,和分散于载体中的压制微粒,所述微粒是有益试剂与低水溶性试剂的混合压制物。所述低水溶性试剂可为疏水性的。载体为生物相容性且可生物溶蚀的。
一方面,疏水性试剂可选自药用油,脂肪,脂肪酸,脂肪酸酯,蜡或它们的疏水性衍生物。优选地,组合物中的疏水性试剂包括C16-C24脂肪酸,或酯或及其药用盐,或它们的混合物。组合物中的疏水性试剂可包括硬脂酸和棕榈酸的混合物。通常,市售硬脂酸为硬脂酸和棕榈酸的混合物,其中硬脂酸和棕榈酸至少占疏水性试剂中脂肪酸重量的90%,硬脂酸至少占疏水性试剂中脂肪酸重量的40%。在较纯的制品中,硬脂酸和棕榈酸至少占疏水性试剂中脂肪酸重量的96%,硬脂酸至少占疏水性试剂中脂肪酸重量的90%。另一市售等级的硬脂酸为包括约90%重量的硬脂酸,余量部分主要为棕榈酸。
另一方面,上述组合物中的压制微粒包括粉末。粉末经整粒后,有90%或更多的颗粒可通过50目筛,剩余部分可通过400目筛。通常采用通过70目筛并经400目筛截留而筛选颗粒。本文所用的筛目为美国标准。
有益试剂可以是水溶或水不溶性的,可以是小分子或大分子。然而,水溶性有益试剂最利于实现本发明的优点。通常,如果水不溶有益试剂可与载体组分,例如典型地为粘性凝胶载体中的聚合物或溶剂,或者与施用的水性环境相互作用,也可实现本发明优点。
本发明发现了组合物的特定应用,其中有益试剂选自DNA,cDNA,生物活性大分子,蛋白质,肽和多肽。此类有益试剂的实例为人生长激素,α-、β-或ν-干扰素,红细胞生成素,glugacon,降钙素,肝素,白介素例如白介素-1,白介素-2,白介素-11和白介素-12,因子VIII,因子IX,促黄体激素,松弛素,促卵泡成熟激素,心钠素或人粒细胞集落刺激因子。
另一方面,组合物中所含的聚合物选自聚交酯,聚乙醇酸交酯,聚己内酯,聚酐,聚胺,聚氨酯,聚酯酰胺,聚原酸酯,聚二噁酮,聚缩醛,聚缩酮,聚碳酸酯,聚原碳酸酯,含磷氮链聚合物,琥珀酸酯,聚(苹果酸),聚(氨基酸),聚乙烯吡咯烷酮,聚乙二醇,聚羟基纤维素,壳多糖,脱乙酰壳多糖,和共聚物,三聚物及其混合物。
另一方面,聚合物也可与能控制水分向埋植剂本体透入的溶剂或溶剂系统结合。在此定义了这类溶剂和溶剂系统,它们包括苯甲酸的烷基或芳烷基酯。本发明组合物中优选包括聚合物聚(乳酸-共聚-羟基乙酸)(poly(lactide-co-glycolic)acid)(″PLGA″)和溶剂苯甲酸苄酯或苯甲酸乙酯,硬脂酸与有益试剂混合物的压制微粒分散与其中。
另一方面,通过对聚合物的溶剂加以适当选择,可方便地调控有益试剂的持续释放时间。例如,对于PLGA和人生长激素,苯酸苄酯可提供一个月或更长的持续释放时间,而苯甲酸乙酯可提供一周的持续释放时间。
另一方面,本发明包括含有生物溶蚀型载体的组合物,所述载体中的聚合物选自聚交酯,聚乙醇酸交酯,聚己内酯,聚酐,聚胺,聚氨酯,聚酯酰胺,聚原酸酯,聚二噁酮,聚缩醛,聚缩酮,聚碳酸酯,聚原碳酸酯,含磷氮链聚合物,琥珀酸酯,聚(苹果酸),聚(氨基酸),聚乙烯吡咯烷酮,聚乙二醇,聚羟基纤维素,壳多糖,脱乙酰壳多糖,和共聚物,三聚物及其混合物,和选自苯甲酸的烷基或芳烷基酯的溶剂,和分散于凝胶中的含有有益试剂与低水溶性试剂混合物的压制微粒,其中低水溶性试剂选自药用油,脂肪,脂肪酸,脂肪酸酯,蜡,及其衍生物,或上述物质的混合物。
优选地,组合物中的疏水性试剂包括C16-C24脂肪酸,或酯或及其药用盐,或上述物质的混合物。组合物中疏水性试剂最优选包括硬脂酸和棕榈酸的混合物。通常,市售硬脂酸为硬脂酸和棕榈酸的混合物,其中硬脂酸和棕榈酸至少占疏水性试剂中脂肪酸重量的90%,硬脂酸至少占疏水性试剂中脂肪酸重量的40%。在较纯的制品中,硬脂酸和棕榈酸至少占疏水性试剂中脂肪酸重量的96%,硬脂酸至少占疏水性试剂中脂肪酸重量的90%。上述组合物中的压制微粒包括粉末。粉末可通过50目筛,优选有90%或更多的颗粒可通过70目筛,余量部分被400目筛截留。
另一方面,本发明包括制备含有压制有益试剂颗粒或粉末的本发明组合物方法,任选在与溶出度调节剂或低水溶性试剂混合、制粒后,制成含有有益试剂和任选组分的压制微粒。单独压制有益试剂或压制混合物,视情况采用压片、滚压、或用适宜型号的冲模挤压,以足够高的压力将其压制成压缩体。然后将压缩体碾磨或粉碎成微粒,例如压制物质的细粒或研碎颗粒的粉末。将压制微粒分散于生物相容性载体中,形成本发明的埋植组合物。
附图简述
结合以下附图,阅读下述详细描述将更容易地理解本发明的上述和其它目的、特征和优点:
图1为制备本发明组合物的总流程图;
图2为溶菌酶体外从含有PLGA聚合物凝胶的3种不同植入剂组合物中释放的随时间(小时)的变化曲线,采用美国药典(USP)溶出流室法,以磷酸盐缓冲液介质测得,转速为100rpm。其中溶菌酶单独存在于聚合物凝胶中(正方形),溶菌酶与硬脂酸的压制混合物存在于聚合物凝胶中(三角形),和溶菌酶与棕榈酸的压制混合物存在于聚合物凝胶中(环形);
图3为溶菌酶体外从含有PLGA聚合物凝胶的3种不同植入剂组合物中释放的随时间(分钟)的变化曲线,采用USP溶出流室法,以磷酸盐缓冲介质测得,转速为100rpm。其中溶菌酶单独存在于聚合物凝胶中(菱形),溶菌酶与硬脂酸的压制混合物存在于聚合物凝胶中(正方形),和溶菌酶与棕榈酸的压制混合物存在于聚合物凝胶中(环形);
图4为溶菌酶体外从含有PLGA聚合物凝胶的3种不同植入剂组合物中释放的随时间(分钟)的变化曲线,采用USP溶出流室法,以磷酸盐缓冲介质测得,转速为100rpm。其中溶菌酶单独存在于聚合物凝胶中(实心环形,最上部的曲线),溶菌酶与肉豆蔻酸以1∶1混合的压制物存在于聚合物凝胶中(半实心环形),溶菌酶与硬脂酸以1∶1混合的压制物(菱形),和溶菌酶与棕榈酸以1∶1混合的压制物存在于聚合物凝胶中(正方形);
图5为鼠血清测定的3种制剂体内从代表性的注射贮库中释放的比较曲线:人生长激素(″hGH″)/硬脂酸制剂(1∶1hGH∶硬脂酸,正方形;1∶2的hGH∶硬脂酸,三角形),hGH颗粒剂(环形);和
图6为鼠血清测定的hGH颗粒剂体内释放的曲线:按说明书所述,与硬脂酸混合的压制物,分别制成含有2-N-甲基吡咯烷酮(菱形)、甘油三乙酸酯(正方形)、苯甲酸乙酯(环形)和苯甲酸苄酯(三角形)的PLGA凝胶。
发明详述
本发明涉及改良的组合物及其制备方法,含有本发明组合物的埋植系统植入受治疗者体内后,可将有益试剂经全身或局部给予受治疗者。定义
术语“AUC”指在受治疗者的体内分析中,从植入后到时间“t”的期间内有益试剂的血药浓度对时间作图的曲面下面积。时间t相当于将有益试剂给予受治疗者的时间。
术语“有益试剂”指当单独或与其它药用赋形剂或惰性组分联合给予人或动物时,可产生所需有益的,通常药理学上的,效果的试剂。
术语″突释指数″,对于全身运送有益试剂的特定组合物而言,是指以下系数(i)在给受治疗者植入组合物后预定期间内的AUC与预定期的小时数的比值,除以(ii)有益试剂释药期间内的AUC与整个释放期的小时数的比值所得的商值。所述突释指数中采用的预定期间可为24小时。然而,已认识到在其它应用中,预定期间取决于有益试剂的性质和治疗应用,预定的时间可以是植入后较短但可测量的时间段或较长的时间段。然而,在大多数应用中,最长时间段不期望超过96小时。
术语″压制″指一种经压制或压缩的物质或物质的混合物,与压制或压缩前相比其堆密度增大。采用常规方法对上述物质压片或造粒或采用滚压或挤压上述物质,可实现对其的压制或压缩。
术语″压制微粒″指经压制或压缩的微粒,其中含有有益试剂,或含有有益试剂与溶出调节剂的混合物,或含有有益试剂与低水溶性试剂的混合物。较大的压制或压缩物经制粒,例如压片、造粒、采用滚压或挤压操作,或者粉碎,可形成呈细粒或粉末状的上述压制微粒。为达到这个目的,微粒的最大尺寸或大小通常约为0.1微米-500微米,更常见为5微米-400微米。″颗粒″通常指平均粒径大于粉末的微粒。术语″微粒″为包括颗粒和粉末。
措词″分散″指将有益试剂、或有益试剂与溶出调节剂的混合物、或有益试剂与低水溶性试剂的混合物的压制微粒混入载体或分散体、混悬液等中的所有方法。
术语″全身″指将有益试剂运送或给予受治疗者后,在受治疗者血浆中可检测到生物有效量的有益试剂。
术语″局部″指将有益试剂经局部定位运送或给予受治疗者后,在受治疗者血浆中检测不到生物有效量的有益试剂。
术语″凝胶″或″凝胶载体″在此可交互使用,是指混合聚合物与溶剂所制得的不含有益试剂的组合物,包括例如,聚合物溶液、水凝胶、乳剂和凝胶等。
术语″延长期″指有益试剂从本发明埋植剂中释放的持续时间,通常约1周或更长,优选约30天或更长,但也可为3个月或更长。
术语″初始突释″与本发明特定组合物有关,是指用(i)在植入后预定的初始期内、典型地为植入后96小时内从组合物中释放的有益试剂的量,除以(ii)从植入组合物中释放的有益试剂总量所得的商值。可以理解,初始突释非常依赖于植入物的形状和表面积。因此,与在此描述的初始突释有关的百分比和突释指数,可用于由标准注射器调剂的待试组合物。
除非另有所指,在此所用的术语″硬脂酸″指以硬脂酸为名市售的硬脂酸(C18H36O2)和棕榈酸(C16H32O2)混合物。优选地,混合物中硬脂酸的含量不低于40%,且两种酸的总量不低于混合物的90%。典型地,高压和高温下,氢化棉籽和其它植物油或者水解脂肪可制备硬脂酸,得到上述混合物。
术语″受治疗者″指给予本发明组合物的动物或人。
鉴于在分子水平上,所有溶剂均可以非常有限量溶于水中(即可与水溶混溶),所以在此所用术语″不混溶″是指7%重量或更低的溶剂可溶于或混溶于水中。本发明中所采用溶剂的水溶解度在20℃下测得。众所周知,所报道的溶解度值并不一定总是在这种条件下测得的,所以在此以水中混溶或溶解百分重量表述的溶解度限度,其中的部分或上限并不是绝对的。例如,对于水溶解度报道为7.17g/100ml水的溶剂″甘油三乙酸酯″而言,如果其水溶解度上限在此表述为″7%重量″,并且不对其作进一步限定,则可认为是包括在7%的限度内。在此所用的水溶解度限度低于7%重量的溶剂,不包括甘油三乙酸酯或水溶解度等于或高于甘油三乙酸酯的溶剂。
本发明包括生物溶蚀和生物相容性载体,例如粘性凝胶,和分散于载体中的含有压制有益试剂的微粒。微粒可单独用压制有益试剂或者与药用惰性组分的混合物。而且,在压制前,可先将有益试剂与溶出度调节剂、或低水溶性如疏水性试剂混合。生物溶蚀载体可包括在此描述的聚合物,并且可与在此描述的适宜溶剂混合形成粘性凝胶,例如可限制本体水分吸收的凝胶。
与常规方法如喷雾干燥或液中沉淀等制备的有益试剂微粒相比,将有益试剂造粒压片后经磨碎而形成的有益试剂微粒,其表面积与质量之比降低。但是表面积与质量比的降低并不能使水分吸收和有益试剂的溶出或分散明显降低,在体外溶出研究中,将这种压制微粒与在此描述的粘性聚合物凝胶结合,与同样凝胶中未压制的颗粒相比,可明显降低这种微粒的水分吸收。
例如,经喷雾干燥制得的平均粒径为5微米的未压制hGH微粒,在USP溶出分析法中的溶出时间为数秒,而同样粒径的压制微粒的溶出时间为数分钟。在采用上述混溶溶剂制备的粘性聚合物凝胶中,压制hGH颗粒可保持其完整性,并可连续数天或数周地从埋植剂中的溶出或扩散。有益试剂微粒微环境水分吸收的降低,控制或消除了突释现象,并可延迟有益试剂从埋植剂中的释放。
出于说明之目的,本发明组合物的制备将示例性地采用有益试剂与一种或多种低水溶性如疏水性试剂的混合物。制备单独采用可含有药用赋形剂或任选与溶出度调节剂混合的有益试剂压制微粒,除了不含疏水性试剂以外,其它与疏水性试剂混合的方法相同。如果微粒含有有益试剂与溶出度调节剂的混合物,以溶出度调节剂替换疏水性试剂,采用在此描述的方法可获得便于进一步处理的所需材料。典型地,采用常规压片方法,制得单独含有有益试剂或混合物的压片后,将片基研磨或碾磨,所得的微粒经筛选可得到所述粒径的微粒。将整粒后的微粒与凝胶掺合,在一个优选优选实施方案中,将其填充到注射器中。另外,可用滚压机将上述单独或以混合物形式的有益试剂压缩,然后研磨或碾磨成适宜粒径的微粒。
因此,在本发明的一个实施方案中,含有有益试剂与低水溶性试剂压制混合物的压制微粒分散在埋植载体中。采用压片或造粒,通常可将有益试剂与低水溶性试剂混合物制成压制微粒。虽非绝对必要,但优选将两组分紧密混合使其基本上均匀,这样混合物中不同组分的浓度就大致相同。为达到预期的混合度,可在混合前将有益试剂与低水溶性试剂研磨成粉状。
混合后,微粒混合物经压制形成片剂或小丸、或者经滚压或挤出形成压制物,该压制物的密度比压制前的混合物颗粒聚集体密度要大。采用制药工业中常规的压片机,将有益试剂与低水溶性试剂的混合物压片。如果是小批量生产,可采用简单的手动Carver压片机。批量生产时可采用自动压片机。许多市售压片机可参见Remington’s PharmaceuticalSciences,第18版,1647-1653页(1990年),Mack出版公司,Easton,宾外法尼亚,和包括Stokes-Pennwalt,Manesty等生产的压片机。然后,压片混合物经粉碎或碾磨成压制微粒混合物,进一步筛选可得到所述粒径的微粒。也可适宜滚压机和挤压机形成压制品,再经筛选获得可分散于载体中的微粒。市售压缩机可购自Alexander Werk,Remsheid,德国和Gerteis,Jona,瑞士。
如果有益试剂是热敏的,例如在持续升温条件下可变性的蛋白质或肽,其压制时间要相对地短。因此,在组合物的压制过程中,任何可导致压制压制组合物温度升高的操作时间要尽量缩短。同时,压片机的冲模和冲压机应配有供消散热量的散热器,否则这些热量会对有益试剂产生不良影响。如果温度升高是短暂的,将不会对有益试剂如蛋白质、肽或其它热敏性物质产生不良影响。
然后将压制微粒分散到生物溶蚀型载体中,载体可以是生物相容性聚合物。载体可以是经手术植入受治疗者体内的固体或半固体形式,或者将载体制成可供注射植入的凝胶或原位固化的液体形式。为了保持微粒在载体中的分散度,在注射植入时优选采用粘性凝胶。
本发明所采用的低水溶性试剂包括阴离子、阳离子、两性非离子表面活性剂,和其他对有益试剂无不良影响并且在与有益试剂混合时可与压制物配伍的疏水性物质,表面活性剂的水溶解度比有益试剂低。适宜试剂可选自表面活性剂,例如在Remington’s PharmaceuticalSciences,supra,267-268页中所描述的。试剂优选包括C16-C24长链脂肪酸、其酯及药用盐和混合物。特别优选为硬脂酸、棕榈酸和肉豆蔻酸,及其酯和药用盐,和上述物质的混合物。使有益试剂压制微粒具有疏水性的其他试剂包括胶原、蜡、类脂、脂质体和聚合物材料。
微粒混合物中的低水溶性试剂可用溶出度调节剂替代,这类调节剂的选择取决于有益试剂的理化性质。在某些情况下,有必要将溶出度调节剂分散到已分散有压制微粒的生物溶蚀载体中。
在相关申请和公开专利及文献中,均有对溶出度调节剂的描述,其中包括,例如US5,656,297描述的金属阳离子和US5,674,534描述的试剂,在此引入作为参考。另外,溶出度调节剂也包括可产生体积排阻效应和/或从微粒微环境中清除水分的物质。在某种程度上,这种材料的吸水能力是重要的,因为与不含清除剂相比,具有净清除作用的清除剂可有效地阻止水分向微粒微环境的透入。这可典型地通过测定在含有或不含清除剂的条件下,凝胶载体与有益试剂微粒混合物的总吸水量而选择。这种调节剂可选自单-,双-,三羧酸,其酯,盐和醇的水溶性聚合物,例如聚乙二醇和泊咯沙姆。聚乙二醇的分子量为3,000-10,000道尔顿,但通常优选具有更高分子量的材料。在压制以前,用常规方法例如喷雾干燥、冻干或锅包衣,将这种调节剂与有益试剂掺合。
有益试剂为任何生理学或药理学活性物质或任选可与药用载体和附加组分结合的物质,所述附加组分是例如抗氧剂、稳定剂、渗透促进剂等对本发明有益效果基本无副作用的物质。有益试剂可以是任何可给予人或动物的已知试剂,优选在水中而非在聚合物-溶剂中溶解。这些试剂包括药物、药剂、维生素、营养素等。其中包括低分子量化合物、生物活性大分子、蛋白质、肽、遗传物质、营养素、维生素、食品添加剂、性绝育剂、生育力抑制剂和生育力促进剂。
可通过本发明运送的药物包括作用于外周神经、肾上腺素受体、胆碱能受体、骨胳肌、心血管系统、平滑肌、血液循环系统、synoptic sites、神经效应器连接点、内分泌和激素系统、免疫系统、生殖系统、骨骼系统、自体有效系统、消化和排泄系统、组胺系统和中枢神经系统的药物。适宜的试剂选自,例如DNA,cDNA,蛋白质,酶,激素,多核苷酸,核蛋白,多糖,糖蛋白,脂蛋白,多肽,类固醇,镇痛药,局部麻醉剂,抗生素,抗炎性皮质类固醇,眼用药和它们的合成类似物。
可用本发明组合物运送的药物实例包括但不限于:prochlorperzineedisylate,硫酸亚铁,亮氨酸,盐酸美加明,盐酸普鲁卡因胺,硫酸苯丙胺,盐酸脱氧麻黄碱,盐酸benzamphetamine,硫酸异丙肾上腺素,盐酸芬美曲嗪,氯贝胆碱,氯醋甲胆碱,盐酸毛果芸香硷,硫盐阿托品,东莨菪碱溴化物,异丙酰胺碘化物,曲地氯铵,盐酸苯乙双胍,盐酸哌醋甲酯,胆茶碱,盐酸头孢氨苄,二苯哌啶丁醇,盐酸美其敏,马来酸普鲁氯嗪,酚苄明,马来酸thiethylperzine,茴茚二酮,二苯茚酮丁四硝酯e,地高辛,异氟磷,乙酰唑胺,醋甲唑胺,苄氟噻嗪,chloropromaide,妥拉磺脲,氯地孕酮,非那二醇,别嘌醇,乙酰水杨酸铝,甲氨蝶呤,乙酰磺胺异#唑,红霉素,氢化可的松,醋酸氢化可的松,醋酸可的松,地塞米松和其衍生物例如倍他米松,去炎松,甲睾酮,17-S-雌二醇,炔雌醇,炔雌醇3-甲基醚,氢化泼尼松,17a-羟孕酮乙酸酯,19-nor-孕甾酮,炔诺孕酮,炔诺酮(norethindrone),炔诺酮(norethisterone),norethiederone,孕甾酮,诺孕酮,异炔诺酮,阿斯匹林,消炎痛,萘普生,非诺洛芬,舒林酸,吲哚洛芬,硝酸甘油,消心痛,心得安,噻吗洛尔,阿替洛尔,阿普洛尔,西米地丁,可乐定,丙咪嗪,左旋多巴,氯丙嗪,甲基多巴,二羟苯基丙氨酸,茶碱,葡萄糖酸钙,酮洛芬,布洛芬,头孢氨苄,红霉素,氟哌啶醇,佐美酸,乳酸亚铁,长春蔓胺,地西泮,酚苄明,地尔硫,米力农,mandol,quanbenz,氢氯噻嗪,雷尼替丁,氟比洛芬,fenufen,氟联苯丙酸,托美丁,阿氯芬酸,甲灭酸,氟灭酸,difuinal,激素,多核苷酸,核蛋白,多糖,糖蛋白,脂蛋白,多肽,类固醇,镇痛药,局麻药,尼莫地平,尼群地平,尼索地平,尼卡地平,非洛地平,利多氟嗪,噻烷丙胺,加罗帕米,胺氯地平,mioflazine,赖诺普利,伊那普利,依那普利拉,卡托普利,雷米普利,法莫替丁,尼扎替丁,硫糖铝,etintidine,tetratolol,米诺地尔,利眠宁,地西泮,阿米替林和丙咪嗪。
另外,蛋白质和肽的实例包括但不限于:骨形态发生蛋白质,胰岛素,秋水仙素,胰高血糖素,甲状腺刺激激素,甲状旁腺和脑垂激素,降钙素,肾素,促乳素,促皮质素,促甲状腺激素,滤泡刺激激素,绒毛膜促性腺激素,促性腺素释放激素,牛生长激素,猪生长激素,催产素,后叶加压素,GRF,生长抑素,赖氨加压素,促胰酶素,促黄体激素,LHRH,LHRH激动剂和拮抗剂,亮丙瑞林,干扰素例如干扰素α-2a,干扰素α-2b和共有干扰素,白介素,生长激素例如人生长激素和其衍生物如methione-人生长激素和脱-苯丙氨酸人生长激素,牛生长激素和猪生长激素,生育力抑制剂例如前列腺素,生育力促进剂,生长因子例如胰岛素样的生长因子,凝结因子,人胰腺激素释放因子,这些化合物的类似物和衍生物,和这些化合物的药用盐,或它们的类似物和衍生物。
本发明特别适于运送的有益试剂选自DNA,cDNA,生物活性大分子,蛋白质,肽和多肽。这些有益试剂的实例如人生长激素,α-、β-或ν-干扰素,红细胞生成素,glugacon,降钙素,肝素,白介素如白介素-1,白介素-2,白介素-11和白介素-12,因子VIII,因子IX,促黄体激素,松弛素,促卵泡成熟激素,心钠素或人粒细胞集落刺激因子。
本发明还发现,为了尽量避免或减小全身性副作用,这种试剂可用作局部给药的化学治疗剂。本发明含有化学治疗剂的凝胶可直接注射到肿瘤部位以达到试剂的缓释效果。在某些情况下,特别是肿瘤切除术后,可将凝胶直接植入所形成的腔内或者以包被的形式施用到存留组织上。在手术植入的情况下,可采用高粘度的凝胶,因为它们不能通过小口径的针头。可按本发明方法运送的代表性化学治疗剂包括,例如卡铂,顺铂,紫杉醇,BCNU,长春新碱,喜树碱,etopside,细胞因子,核酶,干扰素,低聚核苷酸和可抑制肿瘤基因翻译或转录的低聚核苷酸序列,上述物质的功能性衍生物,和如US5,651,986描述的已知化学治疗剂。本发明特别适于水溶性化学治疗剂如顺铂和卡铂和紫杉醇的水溶性衍生物的缓释给药。本发明可使突释效应最小化,特别适于运送各种水溶性有益试剂,也特别适于临床有效但有副作用的混合物。
除了上述提及的,也可采用前述US5,242,910描述的有益试剂。本发明的一个特有的优点在于,可将那些难于插掺入微囊或微球中的物质,例如蛋白质如溶菌酶,和结合到病毒和非病毒载体的cDNA和DNA,掺入本发明组合物中,但不存在其它制备技术中因暴露于高温和变性溶剂所造成的降解水平。
所用有益试剂可为粉末,若为液体则可掺入多孔固体颗粒中,例如Fuji化学工业(USA.)公司(Engelwood,新泽西)以商标名Fujicalin出售的无水磷酸钙,或者Fuji化学工业(USA.)公司(Toyam,日本)以商标名Neusilin出售的粉末化硅铝酸镁。
适于压制的有益试剂颗粒的粒径典型地约为0.1-200微米,优选约1-100微米和通常为1-50微米,和最优选为2-10微米。可采用常规冻干方法,用适宜的冷冻和干燥循环可制得不同粒径的有益试剂颗粒。
用于有益试剂的埋植载体可制成凝胶形式。所述凝胶可是由聚合物形成的粘性物。这些组分所形成的凝胶可限制埋植剂的本体水分吸收。载体系统优选包括1997年12月18日提交的共同未决申请08/993,208及其相应PCT申请WO 98/26359(1998年7约2日公开)中详述的那些系统。在此引入该公开申请,用以描述特别适于本发明的本体聚合物系统。但是也可采用其它聚合物。
本发明的聚合物、溶剂其它试剂应是生物相容性;即在施用环境中不应产生过度的刺激或坏死。施用环境为液体环境,并包括人或动物的皮下或肌内或体腔。
本发明所用聚合物是生物降解性,包括但不限于聚交酯,聚乙醇酸交酯,聚己内酯,聚酐,聚胺,聚氨酯,聚酯胺,聚原酸酯,聚二噁酮,聚缩醛,聚缩酮,聚碳酸酯,聚原碳酸酯,含磷氮链聚合物,琥珀酸酯,聚(苹果酸),聚(氨基酸),聚乙烯吡咯烷酮,聚乙二醇,聚羟基纤维素,壳多糖,脱乙酰壳多糖,和共聚物,三聚物及其混合物。
聚合物优选为聚交酯,即含有乳酸的聚合物,它可单独含有乳酸或者是含乳酸和羟基乙酸的共聚物,其中还可含有基本上不影响本发明有益效果的少量其它共聚单体。在此所用的术语″乳酸″包括异构体L-乳酸,D-乳酸,DL-乳酸和丙交酯,术语″羟基乙酸″包括乙交酯。最优选为聚(丙交酯-共聚-乙醇酸交酯)共聚物,即PLGA。聚合物中乳酸/羟基乙酸的单体比例约为100∶0-15∶85,优选地约60∶40-75∶25,特别有用的共聚物中乳酸/羟基乙酸的比例约为50∶50。
气相色谱测得含乳酸的聚合物的平均分子量约为1,000-120,000,优选约5,000-30,000。如前述US5,242,910指出的,聚合物可按US4,443,340的教导制备。另外,采用US5,310,865的工艺方法,用乳酸或乳酸与羟基乙酸(含或不含其它共聚单体)直接制备含有乳酸的聚合物。这些专利的内容在此引入作为参考。
适宜的含乳酸聚合物可经市售购得。例如,50∶50的乳酸∶羟基乙酸共聚物,其分子量为5000,10000,30000和100,000,优选约8,000-13,000,最优选约为10,000,并含有多种可改变聚合物链水解及解体敏感性的端基,可从Boehringer Ingelheim(Petersburg,VA)购得。附加的聚合物包括,例如,聚(D,L-交酯-共聚-乙醇酸交酯)50∶50 RESOMERL104,PLGA-L104,代号33007,聚(D,L-交酯-共聚-乙醇酸交酯)50∶50RESOMERRG206,PLGA-206,代号8815,聚(D,L-交酯-共聚-乙醇酸交酯)50∶50 RESOMERRG502,PLGA-502,代号0000366,聚(D,L-交酯-共聚-乙醇酸交酯)50∶50 RESOMERRG502H,PLGA-502H,代号260187,聚(D,L-交酯-共聚-乙醇酸交酯)50∶50 RESOMERRG503,PLGA-503,代号0080765,聚(D,L-交酯-共聚-乙醇酸交酯)50∶50 RESOMERRG506,PLGA-506,代号95051,聚(D,L-交酯-共聚-乙醇酸交酯)50∶50 RESOMERRG755,PLGA-755,代号95037,(Boehringer Ingellheim化学公司,Petersburg,VA)。
凝胶组合物中生物相容聚合物的含量可占粘性凝胶重量的5-80%,优选约30-70%和通常为40-60%,粘性凝胶含有混合量的生物相容聚合物和溶剂。向聚合物中加入在此描述量的溶剂,可形成植入用或注射用粘性凝胶。
溶剂应是生物相容性的,优选可与聚合物形成粘性凝胶,且可限制埋植剂的水分吸收。溶剂可以是具有前述特性的单一溶剂或溶剂混合物。除非另有所指,术语″溶剂″指单一溶剂或溶剂混合物。许多溶剂可用于本发明。可采用水溶性溶剂,包括具有较高、中等溶解度或几乎不溶的溶剂,及那些不溶或不混溶于水的溶剂。由于本发明欲建立用于阻滞吸收有益试剂中及附近水分的有益试剂微环境,因此水溶性溶剂虽然不是优选的,但也可用作聚合物的溶剂。这种溶剂包括但不限于:甘油三乙酸酯,甘油二乙酸酯,甘油三丁酸酯,柠檬酸酯例如柠檬酸三乙基酯,柠檬酸三丁基酯,柠檬酸乙酰基三乙基酯,和柠檬酸乙酰基三丁基酯,甘油三乙基酯,磷酸三乙基酯,邻苯二甲酸二乙基酯,酒石酸二乙基酯,矿物油,聚丁烯,硅流体,甘油,乙二醇,聚乙二醇,辛醇,乳酸乙酯,丙二醇,碳酸丙烯酯,碳酸乙烯酯,丁内酯,环氧乙烷,环氧丙烷,N-甲基-2-吡咯烷酮,2-吡咯烷酮,环亚甲基甘油醚,乙酸甲酯,乙酸乙酯,甲基乙基甲酮,二甲基甲酰胺,二甲亚砜,四氢呋喃,己内酰胺,癸基甲基亚砜,油酸,和1-月桂基氮杂环-庚-2-酮,及其混合物。
优选采用溶剂控制埋植剂的本体水分吸收,这基本上限制了埋植剂的水分吸收。这种溶剂可与水混溶,即水溶解度低于7%重量。优选溶剂的水溶解度为5%重量或更低;更优选为3%重量或更低;和甚至更优选为1%重量或更低。最优选溶剂的水溶解度等于或低于0.5%重量。
具有上述溶解度参数的溶剂选自芳基酸例如苯甲酸、邻苯二甲酸及水杨酸的低级烷基和芳烷基酯,柠檬酸的低级烷基酯如柠檬酸三乙基酯和柠檬酸三丁基酯等,和芳基,芳烷基和低级烷基酮。溶剂优选选自(i)具有上述溶解度的式结构化合物:和(i)其中R1为芳基或芳烷基,R2为低级烷基或芳烷基,R1和R2任选系相同或不同,当每个R1和R2为低级烷基时,R1和R2的总碳原子数为4或更多,和(ii)邻苯二甲酸、间苯二甲酸和对苯二甲酸的低级烷基或芳烷酯,和(iii)柠檬酸的低级烷基或芳烷基。所述低级烷基指具有1-6个碳原子的直链或支链烃,任选用非干扰性取代基取代; 芳烷基指(低级烷基)苯基,例如苄基,苯乙基,1-苯基丙基,2-苯基丙基等,其中烷基部分具有1-6个碳原子的的烷基组成;和芳基指苯基,任选任选用非干扰性取代基取代。本发明所用的许多溶剂是市售的(Aldrich Chemicals,SigmaChemicals),或采用酰基卤和任选酯化催化剂,对不同的芳基链烷酸进行常规的酯化作用制得,例如US5,556,905中所描述的,在此引入作为参考,和对于酮对其不同的仲醇前体进行氧化。
本领域已知具有所需溶解度的邻苯二甲酸衍生物溶剂包括选自:1,4-环己烷二甲醇二苯甲酸酯,二甘醇二苯甲酸酯,一缩二丙二醇二苯甲酸酯,聚乙二醇二苯甲酸酯,丙二醇二苯甲酸酯,二甘醇和一缩二丙二醇苯甲酸酯掺和物,聚乙二醇(200)二苯甲酸酯,苯甲酸异癸酯,新戊二醇二苯甲酸酯,三苯甲酸甘油酯,季戊四醇四苯甲酸酯,苯甲酸枯基苯基酯,三甲基戊二醇二苯甲酸酯。
本领域已知具有所需溶解度的邻苯二甲酸衍生物溶剂包括选自:邻苯二甲酸烷基苄基酯,双-枯基苯基间苯二甲酸酯,二丁氧基乙基邻苯二甲酸酯,邻苯二甲酸二甲酯,邻苯二甲酸二甲酯,邻苯二甲酸二乙酯,邻苯二甲酸二丁酯,邻苯二甲酸二异丁酯,邻苯二甲酸丁辛酯,邻苯二甲酸二异庚基酯,邻苯二甲酸丁辛酯,邻苯二甲酸二异壬酯,邻苯二甲酸壬基十一基酯,邻苯二甲酸二辛酯,邻苯二甲酸二异辛酯,邻苯二甲酸二辛基酯,混合的醇邻苯二甲酸酯,双-(2-乙己基)邻苯二甲酸酯,直链庚基、壬基邻苯二甲酸酯,直链庚基、壬基、十一基邻苯二甲酸酯,直链壬基邻苯二甲酸酯,直链壬基十一基邻苯二甲酸酯,直链二壬基、二癸基邻苯二甲酸酯(邻苯二甲酸二异癸酯),邻苯二甲酸双十一基酯,邻苯二甲酸二十三基酯,邻苯二甲酸十一基十二基酯,邻苯二甲酸癸基十三基酯,二辛基与二癸基(50/50)邻苯二甲酸酯的掺合物,邻苯二甲酸丁基苄基酯,和邻苯二甲酸二环己酯。
溶剂优选包括上述芳基酸的低级烷基和芳烷基酯。代表性酸为苯甲酸和邻苯二甲酸,例如邻苯二甲酸、间苯二甲酸和对苯二甲酸。最优选的溶剂为苯甲酸衍生物,并可但不限于苯甲酸乙酯,苯甲酸乙酯,苯甲酸正-丙酯,苯甲酸异丙酯,苯甲酸丁酯,苯甲酸异丁酯,苯甲酸仲丁酯,苯甲酸叔丁酯,苯甲酸异戊酯和苯甲酸苄酯,特别优选苯甲酸苄酯。优选溶剂混合物以苯甲酸苄酯为主要溶剂,和苯甲酸苄酯与甘油三乙酸酯,柠檬酸三丁酯,柠檬酸三乙酯或N-甲基-2-吡咯烷酮形成的混合物。混合物中的苯甲酸苄酯优选占溶剂总重量的50%或更多,更优选为60%或更多,最优选为80%或更多。混合物特别优选为80/20重量的苯甲酸苄酯/甘油三乙酸酯和苯甲酸苄酯/N-甲基-2-吡咯烷酮混合物。
附加溶剂包括酒石酸二乙酯,马来酸二乙酯,水杨酸甲酯,对甲氧基苯甲醛,乙酸苯酯,水杨酸苄酯,乙酸苄酯,苯乙酸甲酯,苯甲醚和丙二酸二乙酯。
业已发现,上述水混溶度低于7%重量的溶剂可与一种或多种附加混溶溶剂(″复合溶剂″)混合。复合溶剂可与主要溶剂配伍,并且具有更高的水混溶性,所形成的混合物可显著限制埋植剂的水分吸收。这种混合物指“复合溶剂混合物”。所用的复合溶剂混合物的水溶解度高于主要溶剂本身,典型地为0.1%重量和高达(包括)50%重量,优选高达(包括)30%重量,最优选高达(包括)10%重量,但对限制本发明埋植剂的水分吸收无不良影响。复合溶剂混合物的水溶解度特别优选约0.1%-7%重量。
复合溶剂混合物中的复合溶剂可与主要溶剂或溶剂混合物混溶,它们包括但不限于:甘油三乙酸酯,甘油二乙酸酯,甘油三丁酸酯,柠檬酸三乙酯,柠檬酸三丁酯,乙酰基柠檬酸三乙酯,乙酰基柠檬酸三丁酯,甘油三乙酯,磷酸三乙酯,邻苯二甲酸二乙酯,酒石酸二乙基酯,矿物油,聚丁烯,硅流体,甘油,乙二醇,聚乙二醇,辛醇,乳酸乙酯,丙二醇,碳酸丙烯酯,碳酸乙烯酯,丁内酯,环氧乙烷,环氧丙烷,N-甲基-2-吡咯烷酮,2-吡咯烷酮,环亚甲基甘油醚,乙酸甲酯,乙酸乙酯,甲基乙基甲酮,二甲基甲酰胺,二甲亚砜,四氢呋喃,己内酰胺,癸基甲基亚砜,油酸,和1-月桂基氮杂环-庚-2-酮,及其混合物。
在一个特别优选实施方案中,溶剂选自苯甲酸的低级烷基和芳烷基酯,聚合物为含乳酸的聚合物,最优选为PLGA,平均分子量约为8,000-13,000,优选约10,000。最优选的溶剂为苯甲酸苄酯和苯甲酸的低级烷基酯,尤其是苯甲酸乙酯。含PLGA/苯甲酸苄酯的凝胶的持续释药时间约为1个月或更长。含PLGA/苯甲酸乙酯的凝胶可持续释药1周,苯甲酸苄酯和苯甲酸乙酯凝胶除了溶剂不同以外,其它组分基本相同。持续释药时间上的差异,对医师来说是一种有利的工具。例如,按在此描述的方法,制备的PLGA/苯甲酸乙酯/人生长激素(″hGH″)凝胶可提供持续释放约1周的hGH。这种给药模式,对于需要密切监测病情的儿科患者的治疗是有利的,并可视需要而停止或开始给予hGH,不存在每日注射所带来的不便。苯甲酸酯可单独或与其它混溶溶剂如甘油三乙酸酯混合使用。
埋植剂优选制成粘性凝胶形式,凝胶中基本均匀分散有有益试剂、有益试剂与溶出度调节剂的混合物、或有益试剂与低水溶性试剂的混合物的压制微粒,无论是否将初始突释作为一个重要因素,该组合物均可用于有益试剂的全身和局部给药。典型地,压制微粒在凝胶载体中的负载量可为0.1-50%重量,优选1-20%重量。另外,使用苯甲酸酯可进一步控制水分的迁移,这样就提高了有益试剂的稳定性。较低的水分吸收,即植入后控制水分向凝胶组合物中的迁移,可使应用本发明的医师限制有益试剂因扩散而转移,同时,通过控制聚合物的生物溶蚀特性,可提高对有益试剂释药特性的控制。组合物优选在聚合物的内部负载有高于其水饱和度的有益试剂,这样,如果需要,可提供有益试剂的零级释放。另外,组合物优选提供玻璃转变温度低于37℃的粘性凝胶,这样在植入后的24小时或更长时间内凝胶可保持非刚性状态。
溶剂或溶剂混合物可溶解聚合物,以形成分散有有益试剂压制颗粒的粘性凝胶,其中有益试剂在释放前与施用环境隔离。本发明组合物提供具有低突释指数的埋植剂。采用在此描述的有益试剂压制微粒,可控制有益试剂微环境的水分吸收,采用对聚合物具有增溶或增塑作用的溶剂或复合溶剂混合物,基本上可限制埋植剂大环境本体的水分吸收。
有益试剂在最初24小时内的期望或必需达到的释放量,取决于整个释药期间的环境、有益试剂的治疗窗、剂量过大可能造成的副作用、有益试剂的成本和期望的起效类型如全身或局部。优选地,在植入后的最初24小时内可释放20%或更低量的有益试剂,所述百分率是基于整个给药持续期内所要给予有益试剂的总量。典型地,如果给药的持续时间相对较短,例如少于7-14天,或者有益试剂具有广泛的治疗窗但出现副作用的可能性较低,或有益试剂有局部作用,则在最初的24小时容许有较高的释放率。
本发明用于全身给药的组合物可提供凝胶组合物,其突释指数为8或更低、优选为6或更低、更优选为4或更低和最优选为2或更低。可采用与制备全身给药组合物相同的方法制备局部给予有益试剂的组合物。然而,经局部给予的有益试剂在受治疗者血浆中检测不到,因此以有益试剂在预定的初始期内释放的百分比来描述该系统的的特性,而不是采用在此定义的突释指数。最典型地,所述时间段可以是植入后的最初24小时,所述百分率为这段时间内(例如24小时)有益试剂的释放量与整个给药时间内预期给予的有益试剂总量;乘以100。在大多数应用中,本发明组合物的初始突释为20%或更低,优选15%或更低,最优选10%或更低。通常,埋植剂系统的初始突释优选为5%或更低。
溶剂或溶剂混合物的含量典型地约为粘性凝胶即聚合物和溶剂总重量的95-20%,优选约为70-30%和通常60-40%。聚合物与溶剂混合可制得粘性凝胶,该凝胶的粘度典型地约为1,000-2,000,000泊,优选地约5,000-50,000泊,混合1-2天后,于25℃下采用Haake Rheometer以1.0/秒的剪切率测定粘度。
可采用常规的低剪切设备例如Ross双行星式混合器混合聚合物和溶剂,尽管本领域技术人员可根据组合物的特定物理性质选择混合时间,但是时间可约为10分钟-12小时,通常约为1-4小时。聚合物/溶剂混合物经过温热例如高达40℃,可减少聚合物溶出的时间。
由于通常需要将埋植剂以注射用组合物给药,出于这种考虑,应将埋植剂制成具有足够低粘性的聚合物/溶剂/有益试剂组合物的粘性凝胶形式,以使其能通过小口径如18-20号针头。如果有必要,可采用在此描述的乳化剂对用于注射的凝胶的粘度加以调节。另外,这种组合物应具有足够的形稳性使之可定位于局部位置并必要时可清除掉。本发明特定的凝胶或凝胶样组合物满足这种需求。
如果聚合物组合物作为注射凝胶给药,聚合物的溶出水平需用凝胶的粘度加以平衡,确保有适当的力量使粘性凝胶通过针头给药,和潜在的突释效应。较高粘性的凝胶可使有益试剂的释放没有明显的突释效应,但是高粘性会使凝胶通过针头给药变得困难。在这些情况下,任选向组合物中加入乳化剂。
随着温度的升高,组合物的粘度通常会降低,这对于某些应用是有利的,因为加热凝胶降低其粘度可形成更容易注射的组合物。另外,可在注射前混合凝胶,以剪切(shear)凝胶并降低贮存中可能出现的粘度升高。
本发明贮库凝胶组合物的剪切稀化特性良好,通常可采用标准度量的针头注射给动物包括人,但不需要太大的给药压力。
所用乳化剂的含量,典型地为可注射贮库凝胶组合物即聚合物、溶剂、乳化剂和有益试剂总重量的5-80%,优选约20-60%和通常为30-50%。乳化剂包括,例如不能与聚合物溶剂或溶剂混合物完全混溶的溶剂。示例乳化剂为水、醇、多元醇、酯,羧酸、酮、醛及其混合物。乳化剂优选为醇、丙二醇、乙二醇、甘油、水,和溶液及其混合物。特别优选为水、乙醇、和异丙醇和溶液及其混合物。乳化剂的类型对分散液滴的大小有影响。例如,与21℃下含有0.9%重量氯化钠的等渗盐水溶液提供的液滴的平均直径相比,乙醇提供的液滴要大10倍。
本发明埋植剂系统优选为粘性凝胶形式,因此埋植剂的给药并不限于注射,尽管这种给药方式通常是优选的。当埋植剂以留置型制品给药时,可将其制备成适于术后留于体腔内的形式,或者制备成可涂布或palleting于存留组织或骨上的流动性凝胶。这种用法使凝胶中有益试剂的载药量比注射用组合物要高。
在室温下,采用任何常规的低剪切装置如Ross双行星式混合器,在聚合物与溶剂形成的粘性凝胶中制备有益试剂颗粒的混悬体或分散体。采用这种方法,可使有益试剂有效地分散且基本不会降解。
典型地将有益试剂溶解或分散于组合物中,含量约为聚合物、溶剂和有益试剂总重量的1-50%,优选约5-30%和通常为10-20%。根据组合物中有益试剂的含量,可以获得不同的释放特性和突释指数。具体地说,给定聚合物和溶剂后,通过调节这些组分和有益试剂的含量,所得的释放特性主要取决于聚合物的降解,而不是有益试剂从组合物中的扩散或反之亦然。因此,当有益试剂负载率较低时,所得的释放特性通常反映了聚合物的降解,即释放速率随时间增加。当载药率较高时,所得的释放特性通常反映了有益试剂的扩散,即释放速率随时间降低。当为中等载药率时,所得的复合释放特性可表现为基本恒速。为了使突释最小化,所负载的有益试剂优选占整个凝胶组合物即聚合物、溶剂和有益试剂的30%或更低,更优选载药量为20%或更低。
对有益试剂的释放速率和负载加以调节,可在预期的缓释给药期间提供治疗有效量的有益试剂。聚合物凝胶中含有水过饱和浓度的有益试剂,可提供分散有有益试剂的药物贮库。有益试剂的释放取决于特定环境,例如给予有益试剂后,可在7-90天内以约0.01微克/天-100毫克/天,优选0.1-10毫克/天的释放速率释放。如果在短期内给药,可给予更高的速度。通常,如果能耐受较大的突释,则可能达到更高的释放速率。与采用注射的埋植剂相比,采用手术植入的凝胶组合物,或者与外科手术联用治疗疾病状态或其它病症的“留置”型贮库,可提供更高的剂量。此外,调节埋植凝胶剂或注射用凝胶剂的体积,可控制有益试剂的剂量。
凝胶组合物中还可含有其它组分,它们可是预期的或可向组合物提供有益性能的组分,例如聚乙二醇、润湿剂、稳定剂、致孔剂等。US5,654,010和5,656,297描述了多种稳定剂,在此引入作为参考。虽然通常认为本发明组合物应避免使用有益试剂的稳定剂,然而有些情况下此类试剂与本发明组合物组分的联用是有益的。
致孔剂,包括与体液接触时可溶解、分散或降解而在聚合物骨架中生产孔或通道的生物相容材料。典型地,水溶性有机物和无机物例如糖(如蔗糖,葡萄糖),水溶性盐(例如氯化钠,磷酸钠,氯化钾,和碳酸钠),水溶性溶剂例如N-甲基-2-吡咯烷酮和聚乙二醇和水溶性聚合物(例如羧甲基纤维素,羟甲基纤维素等)等,通常可用作致孔剂。此类材料的量约占聚合物重量的0.1%-100%,但是典型地低于聚合物重量的50%、更典型地低于10-20%。
为进一步理解本发明的不同方面,可参考图1中制备本发明组合物的总流程图。本发明特别以hGH(人生长激素激素)或溶菌酶为有益试剂、硬脂酸为低水溶性试剂、和PLGA为生物相容载体为代表性实例,描述了制备过程。然而,所述过程应理解为也适用采用了在此描述的其它材料的本发明组合物,对于所属领域技术人员来说,其中所作的适宜修改应是显而易见的。
图1中的生产流程图描画了生产终产品的许多步骤,终产品即预填充的注射器,其中含有疏水性试剂/活性剂/聚合物的注射用贮库组合物。结合下面的的描述可更好地理解流程图。
步骤1中,将贮存于位置A的适于批量处理量疏水性试剂如硬脂酸转移到位置B的研磨或磨设备中。研磨是任选步骤,是否研磨取决于所用疏水性试剂原料的粒径。在步骤2中,将研磨后的疏水性试剂转移到灭菌位置C,在此采用常规的辐射灭菌装置对粉碎的疏水性试剂灭菌。可采用钴-60或铯-137放射的ν射线。钴-60放射源的放射剂量约16千戈瑞(KGy)比较适宜。
在步骤3中,将灭菌的疏水性试剂粉末转移到位置J的混合室,通过步骤4,这里也可接收来自位置1的灭菌活性剂,例如人生长激素或溶菌酶。小量混合可采用手工操作,大规模生产可采用V型混合器或其它常规混合设备。在步骤5中,将混合后的蛋白质/疏水性试剂掺合物转移到压缩位置K,在此用常规方法将粉末掺合物压片、滚压式压缩或挤压。然后将压制的材料转移到位置L的研磨机或磨中研磨成微粒,并在位置M过筛。一般,通过70目筛却被400目筛截留的微粒可用于制备微粒/聚合物分散组合物。70目筛中收集的微粒可回收到位置L的研磨机中,在步骤7中,将通过400目筛的微粒弃去或回收。在步骤6中,将收集的经整粒的颗粒转移到位置N的混合容器中,下面制备的聚合物和溶剂灭菌混合物也将转移到这里。
通过步骤8和9,分别将贮藏在位置D的一定量的溶剂如苯甲酸苄酯,和贮藏在位置E的一定量的聚合物如PLGA转移到位置F混合容器中。混合容器可为任何适宜的常规混合装置,例如V型搅拌器或Wharing搅拌器。通常,最初的混合可在室温下混合几小时。将初混合的材料转移到位置G的控温混合容器中,升温如35-40℃连续混合,直至聚合物溶液均质。通过步骤11,将混合的聚合物/溶剂凝胶转移到位置H,在此采用适于疏水性试剂的方法进行灭菌,然后经步骤12转移到位置N的混合容器中。在此混合聚合物/溶剂和蛋白质/疏水性试剂微粒,将微粒均匀分散到聚合物载体组合物中。
通过步骤14,将在位置O消毒的注射器转移到无菌生产区位置P,在此将所需体积的蛋白质/疏水性试剂/聚合物凝胶组合物无菌填充到注射器中。经步骤15,将填充后的注射器转移到初级封装位置Q,然后经步骤16将封装的注射器从无菌生产区转移到二次包装和贴签位置R。经步骤17,将贴签和批量包装的注射器转移到最终贮藏和出货的位置S。
在上述常规步骤个别情况下,如果未得到硬脂酸与有益试剂紧密混合的适宜粉末,可将适量的硬脂酸(Sigma-Aldrich化学公司)用研钵和研棒或自动研磨机或磨研磨或碾磨成粉末。硬脂酸颗粒的粒径越小越易于与有益试剂混合。硬脂酸优选为硬脂酸和棕榈酸的混合物,其中硬脂酸至少占40%,和硬脂酸和棕榈酸至少占90%。优选硬脂酸/棕榈酸混合物中硬脂酸的含量较高。硬脂酸粉末用16kGy剂量的钴60以1千戈每小时(kGy/小时)的速度灭菌。另外,可将硬脂酸先熔化、再微孔过滤灭菌。
按下面的实施例1制备凝胶载体,并在与硬脂酸/hGH压制微粒混合前灭菌。按下面的实施例2和3分别制备冻干hGH和溶菌酶颗粒。典型地,将等量的蛋白质和硬脂酸,例如各占整个组合物重量的10%,以干粉形式混合。小量混合可采用手工操作,大规模生产可采用V型混合器或其它常规混合设备。然后,采用13mm直径冲模的Carve压片机以10,000-12,000psi压制5分钟,将有益试剂和硬脂酸混合物造粒。在大生产中,可用其它常规压片机取代Carver压片机。
将蛋白质/硬脂酸混合物压制后,用研钵和研棒或大型磨设备将其粒化或碾磨成粉末。粉状混合物过212微米筛并用53微米筛收集。上述筛相当于#70和#400筛。通过400目筛颗粒弃去或回收利用。
在另一方法中,在将有益试剂/硬脂酸冻干为冻干颗粒前,先将硬脂酸加到有益试剂溶液中,例如实施例2制备的hGH的渗滤溶液中。然后压制冻干颗粒,并按上述粒化和过筛,得到有益试剂/硬脂酸混合物的压制微粒。
从400目筛中收集有益试剂/硬脂酸混合物的压制微粒,并用Lightning overhead搅拌器与凝胶载体混合约5-10分钟,或至混合物接近或达到均匀。具体所用时间并不是关键的,这部分取决于所以混合设备的性质。例如,若大批量生产中采用Ross或双行星式搅拌器,则混合时间就需要长一些。。
将益试剂/硬脂酸的压制微粒与凝胶载体混合后,在无菌灌注条件下,将混合物填装到灭菌注射器中,这样得到的无菌包装的最终产品可直接使用,无需对施用部位进一步灭菌。
采用下面实施例所述比例的材料,可制备分散有有益试剂/硬脂酸压制微粒的粘性凝胶,含它的产品可直接到注射到受治疗者的施用部位中。另外,采用较少量的溶剂,可在受治疗者体外形成含有粘性凝胶的埋植剂或刚性埋植剂,然后用适宜的外科手术即可将其植入。实施例1-制备凝胶载体
于Mettler PJ3000顶装式天平上配衡一玻璃容器。称取聚(D,L-交酯-共聚-乙醇酸交酯)50∶50RESOMERRG502(PLGA-502)置于玻璃容器中。配衡含有PLGA-502的玻璃容器并加入相应的溶剂。联用的各种聚合物/溶剂的百分重量见表1。用不锈钢方形尖的软膏刀手工搅拌聚合物/溶剂混合物,得到一含有白色聚合物颗粒的粘性琥珀色糊状物。密封含有聚合物/溶剂混合物的容器并置于恒温37-39℃的恒温箱中。当聚合物/溶剂混合物变为澄明琥珀色的均匀凝胶后,将其从恒温箱中取出。孵育时间间隔可为1-4天,这取决于溶剂与聚合物的类型及他们之间的比例。采用以下聚合物和溶剂或混合物制备其他贮库型凝胶载体:聚合物为聚(D,L-交酯-共聚-乙醇酸交酯)50∶50RESOMERL104,PLGA-L104,代号33007,聚(D,L-交酯-共聚-乙醇酸交酯)50∶50 RESOMERRG206,PLGA-206,代号8815,聚(D,L-交酯-共聚-乙醇酸交酯)50∶50 RESOMERRG502,PLGA-502,代号0000366,聚(D,L-交酯-共聚-乙醇酸交酯)50∶50RESOMERRG502H,PLGA-502H,代号260187,聚(D,L-交酯-共聚-乙醇酸交酯)50∶50 RESOMERRG503,PLGA-503,代号0080765,聚(D,L-交酯-共聚-乙醇酸交酯)50∶50 RESOMERRG506,PLGA-506,代号95051,聚(D,L交酯-共聚-羟基乙酸)50∶50 RESOMERRG755,PLGA-755,代号95037,(Boehringer Ingelheim化学公司,Petersburg,VA);溶剂为三乙酸甘油酯(Eastman化学公司,Kingsport,TN),苯甲酸苄酯(″BB″),苯甲酸乙酯(″EB″),苯甲酸甲酯(″MB″),甘油三乙酸酯(″TA″),和柠檬酸三乙酯(″TC″)(Aldrich化学公司,St Louis,MO)。当联用溶剂时,例如20%甘油三乙酸酯和80%苯甲酸苄酯,可将溶剂直接加到已称重的干燥聚合物中。典型聚合物的分子量为14,400-39,700(Mw)[6,400-12,200(Mn)]。代表性凝胶载体如表1所示。实施例2-制备hGH颗粒
如下制备人生长激素(hGH)颗粒(任选含有醋酸锌):
用Concentration/Dialysis Selector渗滤装置,将hGH的水溶液(5mg/ml)(BresaGen公司,Adelaide,澳大利亚)浓缩成10mg/ml。然后用5倍体积的Tris或磷酸缓冲液(pH7.6)洗涤经渗滤的hGH。采用常规技术经喷雾干燥或冻干形成hGH颗粒。采用参数如下设置的Yamato微型喷雾干燥器,喷雾干燥含有hGH(5mg/ml)磷酸缓冲液(5或50mM)(当制备Zn络合颗粒时,任选含不同浓度的醋酸锌(0-30mM):
所得hGH颗粒的粒径为2-100微米。
喷雾干燥器参数 | 设定值 |
雾化空气 | 2psi |
入口温度 | 120℃ |
抽吸器刻度 | 7.5 |
溶液泵 | 2-4 |
主气阀 | 40-45psi |
采用DurastopμP冻干机按下述冷冻和干燥循环,从含有hGH(5mg/mL)的Tris缓冲液(5或50mM:pH7.6)制备冻干颗粒:
冷冻循环 | 以2.5℃/min持续下降至-30℃,并保持30min |
以2.5℃/min从-30℃持续下降至-50℃,并保持30min | |
干燥循环 | 以0.5℃/min持续上升至10℃,并保持960min |
以0.5℃/min持续上升至20℃,并保持480min | |
以0.5℃/min持续上升至25℃,并保持300min | |
以0.5℃/min持续上升至30℃,并保持300min | |
以0.5℃/min持续下降至50℃,并保持5000min |
所得hGH颗粒的粒径为2-100微米。实施例3
按实施例2的方法,将50%蔗糖和50%鸡溶菌酶(干重)喷雾干燥制备溶菌酶颗粒。将这些颗粒分别与硬脂酸、棕榈酸和肉豆蔻酸混合,按上述方法制备含有溶菌酶与相应脂肪酸混合物的压制微粒,其粒径约为40μm和200μm。两批硬脂酸的平均粒径分别为65μm和85μm;两批棕榈酸平均粒径分别为80μm和76μm;一批肉豆蔻酸的平均粒径为74μm。表1:凝胶载体
药物负载
溶剂/聚合物 | 溶剂 | 聚合物 | 溶剂用量 | 聚合物用量 | 凝胶重量 | 比率 |
50/50 | BB | PLGA-502 | 5g | 5g | 10g | 1.0 |
50/50 | TA/BB混合物 | PLGA-502 | 5g | 5g | 10g | 1.0 |
60/40 | TA/BB混合物 | PLGA-502 | 6g | 4g | 10g | 1.5 |
70/30 | TA/BB混合物 | PLGA-502 | 7g | 3g | 10g | 2.3 |
80/20 | TA/BB混合物 | PLGA-502 | 8g | 2g | 10g | 4.0 |
50/50 | EB | PLGA-502 | 5g | 5g | 10g | 1.0 |
50/50 | TA/BB混合物 | PLGA-502 | 5g | 5g | 10g | 1.0 |
50/50 | BB | PLGA-502 | 25g | 25g | 50g | 1.0 |
55/45 | BB | PLGA-502 | 27.5g | 22.5g | 50g | 1.2 |
50/50 | BB | PLGA-502 | 50g | 50g | 100g | 1.0 |
50/50 | TA/BB混合物 | PLGA-502 | 50g | 50g | 100g | 1.0 |
50/50 | BB | PLGA-502H | 5g | 5g | 10g | 1.0 |
50/50 | BB | PLGA-503 | 50g | 50g | 100g | 1.0 |
将上述制备的含有有益试剂/硬脂酸的压制微粒以10-20%重量加到凝胶载体中,并手工混合物至干燥粉末完全变湿。然后,采用带有方形尖金属软膏刀的Caframo机械搅拌器,以常规混合方法将乳状淡黄色颗粒/凝胶混合物混合完全。将所得的均匀凝胶制剂转移到3、10或30cc的一次性注射器,以备贮存或调剂。
按上述方法制备一定量的植入用凝胶,进行有益试剂的体外释放试验作为时间的函数,并测定大鼠血浆中有益试剂浓度随时间的变化,以研究其体内释放。
如图2所示,当用转速为100rpm的含有磷酸缓冲液的USP溶出流室法测量时,未与硬脂酸或棕榈酸形成压制混合物的溶菌酶,其从凝胶载体中的释放更加快且释放量更大。与从含有硬脂酸或棕榈酸的溶菌酶混合物压制微粒的凝胶载体中的释放相比,未压制溶菌酶的释放百分比要高3-4倍。如图3所示,微粒溶出试验也证实了压制微粒的有益作用,其中未与硬脂酸或棕榈酸形成混合物压制微粒的溶菌酶颗粒基本上完全溶出。图4中的未压制溶菌酶颗粒及溶菌酶与硬脂酸、肉豆蔻酸和棕榈酸的压制微粒结果也类似。
图5为溶菌酶在体内从凝胶中的释放,凝胶为上述制备的含有10%重量冻干hGH颗粒和hGH/硬脂酸压制颗粒的PLGA 502/苯甲酸苄酯(50-50),其中一种情况下硬脂酸与hGH等量(记为″低″),另一种情况下硬脂酸的量是hGH的两倍(记为″高″)。以大鼠血清中的hGH浓度(相对于体重)对植入天数作图。从图中可知,未压制的hGH颗粒在植入后表现有非常高的初始突释,以致于大多数蛋白质在植入1天内就从埋植剂中释放出来。与此形成明显对照的是,含有硬脂酸的hGH制剂均表现有非常低的蛋白质初始突释,并且可使hGH从埋植剂中缓释超过14天。
图6说明了联用硬脂酸的有益效果,它可控制hGH颗粒的微环境,并可控制采用苯甲酸酯即苯甲酸乙酯和苯甲酸苄酯的PLGA埋植剂的大环境,这样就在植入后控制了水分向埋植剂中透入的总量。以苯甲酸乙酯或苯甲酸苄酯为聚合物溶剂制备的PLGA-502埋植剂,其中hGH从hGH/硬脂酸压制颗粒中的释放表现为较低的初始突释并具有缓释效果。
采用以下技术特征和/或特性,也可单独或结合一种或多种其它技术特征和/或特性,可对本发明加以描述和特征化:
一种含有生物相容载体和微粒的组合物,其中微粒含有活性剂与任选溶出度调节剂或低水溶性试剂的压制混合物,所述微粒分散于载体中;一种含有生物相容载体和微粒的组合物,其中微粒含有活性剂与溶出度调节剂的压制混合物,所述微粒分散于载体中;一种含有生物相容载体和微粒的组合物,其中微粒含有活性剂与低水溶性试剂的压制混合物,所述微粒分散于载体中;一种组合物,其中低水溶性试剂为疏水性的且载体为生物相容性的;一种组合物,其中疏水性试剂包括药用油,脂肪,脂肪酸,脂肪酸酯,蜡或其疏水性衍生物;一种组合物,其中疏水性试剂包括C16-C24脂肪酸,或酯或及其药用盐,或上述物质的混合物;一种组合物,其中疏水性试剂包括硬脂酸和棕榈酸的混合物;一种组合物,其中硬脂酸和棕榈酸至少占疏水性试剂中脂肪酸重量的90%,和硬脂酸至少占疏水性试剂中脂肪酸重量的40%;一种组合物,其中硬脂酸和棕榈酸至少占疏水性试剂中脂肪酸重量的96%,和硬脂酸至少占疏水性试剂中脂肪酸重量的90%;一种组合物,微粒包括粉末;一种组合物,其中粉末的粒径可使其90%通过50目筛并被400目筛截留;一种组合物,其中粉末的粒径可使其通过70目筛并被400目筛截留;一种组合物,其中微粒的粒径为0.1-500微米;一种组合物,其中微粒的粒径为0.1-500微米;一种组合物,其中微粒的粒径为30-400微米;一种组合物,其中活性剂为水溶性的;一种组合物,其中活性剂选自DNA,cDNA,蛋白质,肽及其片段和衍生物;一种组合物,其中载体包括聚合物选自聚乳酸,聚羟基乙酸和聚(乳酸-共聚-羟基乙酸)和溶剂包括苯甲酸的烷基或芳烷基酯;一种组合物,其中活性剂为人生长激素,α-、β-或ν-干扰素,红细胞生成素,glugacon,降钙素,肝素,白介素-1,白介素-2,因子VIII,因子IX,促黄体激素,松弛素,促卵泡成熟激素,心钠素或人粒细胞集落刺激因子;一种组合物,其中聚合物为聚(乳酸-共聚-羟基乙酸)和溶剂为苯甲酸苄酯;一种组合物,其中聚合物为聚(乳酸-共聚-羟基乙酸)和溶剂为苯甲酸乙酯;一种组合物,包括聚合物选自聚乳酸,聚羟基乙酸,和聚(乳酸-共聚-羟基乙酸),溶剂选自苯甲酸的烷基或芳烷基酯的生物溶蚀凝胶,和含有活性剂与低水溶性试剂压制混合物的微粒,其中低水溶性试剂选自药用油,脂肪,脂肪酸,脂肪酸酯,蜡,及其衍生物,或上述物质的混合物,所述微粒分散于凝胶中;一种制备分散有活性剂的埋植载体的方法,包括形成活性剂与任选溶出度调节剂或低水溶性试剂混合物的压制物,磨碎压制物形成含活性剂和任选混合有溶出度调节剂或低水溶性试剂的压制微粒,然后将压制微粒分散于载体中;一种制备方法,其中活性剂为水溶性的且低水溶性试剂是疏水性的;一种制备方法,其中活性剂为蛋白质或多肽且疏水性试剂为硬脂酸、棕榈酸或肉豆蔻酸;一种制备方法,其中蛋白质为人生长激素且疏水性试剂为硬脂酸;一种制备方法,其中活性剂选自cDNA,DNA,蛋白质,肽及其片段和衍生物;一种制备方法,其中活性剂选自人生长激素,α-、β-或ν-干扰素,红细胞生成素,glugacon,降钙素,肝素,白介素-1,白介素-2,因子VIII,因子IX,促黄体激素,松弛素,促卵泡成熟激素,心钠素或人粒细胞集落刺激因子。
上述示例性实施方案旨在说明而非对本发明加以限制。根据在此公开的内容,本领域技术人员有可能对本发明的多处细节加以改变。所有此类变化和改变均在本发明的范畴和精神中。
Claims (35)
1.一种含有载体和微粒的组合物,其中微粒含有活性剂与低水溶性试剂的压制混合物,所述微粒分散于载体中。
2.如权利要求1的组合物,其中低水溶性试剂为疏水性且载体为生物相容性凝胶。
3.如权利要求1的组合物,其中疏水性试剂选自药用油、脂肪、脂肪酸、脂肪酸酯、蜡及其疏水性的混合物和衍生物。
4.如权利要求3的组合物,其中疏水性试剂选自C6-C24脂肪酸、酯及其药用盐,和上述物质的混合物。
5.如权利要求4的组合物,其中疏水性试剂包括硬脂酸和棕榈酸的混合物。
6.如权利要求5的组合物,其中硬脂酸和棕榈酸至少占疏水性试剂中脂肪酸重量的90%,和硬脂酸至少占疏水性试剂中脂肪酸重量的40%。
7.如权利要求6的组合物,其中硬脂酸和棕榈酸至少占疏水性试剂中脂肪酸重量的96%,和硬脂酸至少占疏水性试剂中脂肪酸重量的90%。
8.如权利要求1的组合物,其中微粒包括粉末。
9.如权利要求1的组合物,其中粉末的粒径可使其90%通过50目筛并被400目筛截留。
10.如权利要求1的组合物,其中活性剂为水溶性的。
11.如权利要求10的组合物,其中活性剂选自DNA、cDNA、蛋白质、肽和及其片断和衍生物。
12.如权利要求10的组合物,其中载体包括选自聚乳酸、聚羟基乙酸和聚(乳酸-共聚-羟基乙酸)的聚合物和包括烷基或芳烷基苯甲酸酯的溶剂。
13.如权利要求12的组合物,其中活性剂为选自人生长激素、α-、β-或ν-干扰素、红细胞生成素、glugacon、降钙素、肝素、白介素-1、白介素-2、因子VIII、因子IX、促黄体激素、松弛素、促卵泡成熟激素、心钠素和人粒细胞集落刺激因子。
14.如权利要求13的组合物,其中聚合物为聚(乳酸-共聚-羟基乙酸)和溶剂为苯甲酸苄酯。
15.如权利要求14的组合物,其中聚合物为聚(乳酸-共聚-羟基乙酸)和溶剂为苯甲酸乙酯。
16.一种组合物,包括:(a)含有选自聚乳酸、聚羟基乙酸、和聚(乳酸-共聚-羟基乙酸)聚合物的生物溶蚀型凝胶;(b)选自烷基或芳烷基苯甲酸酯的溶剂;和(c)分散于凝胶中的微粒,所述微粒含有活性剂与低水溶性试剂的压制混合物,其中低水溶性试剂选自药用油、脂肪、脂肪酸、脂肪酸酯、蜡,及其衍生物,和上述物质的混合物。
17.如权利要求16的组合物,其中低水溶性试剂为疏水性的。
18.如权利要求17的组合物,其中疏水性试剂选自C16-C24脂肪酸、酯及其药用盐,和上述物质的混合物。
19.如权利要求18的组合物,其中疏水性试剂包括硬脂酸和棕榈酸的混合物。
20.如权利要求19的组合物,其中硬脂酸和棕榈酸至少占疏水性试剂中脂肪酸重量的90%,和硬脂酸至少占疏水性试剂中脂肪酸重量的40%。
21.如权利要求20的组合物,其中硬脂酸和棕榈酸至少占疏水性试剂中脂肪酸重量的96%,和硬脂酸至少占疏水性试剂中脂肪酸重量的90%。
22.如权利要求21的组合物,其中微粒包括粉末。
23.如权利要求22的组合物,其中粉末的平均粒径约为30微米-500微米。
24.如权利要求23的组合物,其中活性剂为水溶性的。
25.如权利要求24的组合物,其中活性剂选自DNA、cDNA、蛋白质、肽及其片断和衍生物。
26.如权利要求24的组合物,其中凝胶包括聚(乳酸-共聚-羟基乙酸)。
27.如权利要求24的组合物,其中活性剂选自人生长激素、α-、β-或ν-干扰素、红细胞生成素、glugacon、降钙素、肝素、白介素-1、白介素-2、因子VIII、因子IX、促黄体激素、松弛素、促卵泡成熟激素、心钠素和人粒细胞集落刺激因子。
28.如权利要求27的组合物,其中溶剂为苯甲酸苄酯和活性剂为人生长激素。
29.如权利要求27的组合物,其中溶剂为苯甲酸乙酯和活性剂为人生长激素。
30.制备埋植组合物的方法,所述组合物包括分散有活性剂的生物溶蚀型载体,该方法包括制备活性剂与低水溶性试剂混合物的压制物,将压制物破碎成含有活性剂与低水溶性试剂混合物的压制微粒,然后将压制微粒分散于载体中。
31.如权利要求30的方法,其中活性剂是水溶的且低水溶性试剂为疏水性的。
32.如权利要求31的方法,其活性剂选自蛋白质和多肽,和疏水性试剂选自硬脂酸、棕榈酸和豆蔻酸。
33.如权利要求32的方法,其中蛋白质为人生长激素且疏水性试剂为硬脂酸。
34.如权利要求31的方法,其中活性剂选自cDNA、DNA、蛋白质、肽及其片段和衍生物。
35.如权利要求31的方法,其中活性剂选自人生长激素、α-、β-或ν-干扰素、红细胞生成素、glugacon、降钙素、肝素、白介素-1、白介素-2、因子VIII、因子IX、促黄体激素、松弛素、促卵泡成熟激素、心钠素和人粒细胞集落刺激因子。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105848628A (zh) * | 2013-12-31 | 2016-08-10 | Pb&B公司 | 用于身体重构和身体成形的受控释放脂肪酸组合物 |
CN105848628B (zh) * | 2013-12-31 | 2020-09-18 | Pb&B公司 | 用于身体重构和身体成形的受控释放脂肪酸组合物 |
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MXPA01012471A (es) | 2002-07-30 |
HUP0201626A3 (en) | 2004-05-28 |
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CA2372994C (en) | 2010-03-23 |
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CZ20014338A3 (cs) | 2002-03-13 |
US20060233841A1 (en) | 2006-10-19 |
NO20015888L (no) | 2002-01-31 |
KR100844295B1 (ko) | 2008-07-07 |
WO2000074650A2 (en) | 2000-12-14 |
KR20020011995A (ko) | 2002-02-09 |
AU5462900A (en) | 2000-12-28 |
CN100370967C (zh) | 2008-02-27 |
WO2000074650A3 (en) | 2001-07-05 |
HK1060856A1 (en) | 2004-08-27 |
JP2003501375A (ja) | 2003-01-14 |
NZ515911A (en) | 2004-02-27 |
HUP0201626A2 (hu) | 2002-12-28 |
EP1183010A2 (en) | 2002-03-06 |
ZA200109970B (en) | 2002-12-04 |
IL146814A0 (en) | 2002-07-25 |
NO20015888D0 (no) | 2001-12-03 |
NZ530701A (en) | 2005-09-30 |
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