CN1882362A - 通过结膜下或眼周递送前体药物将活性药物递送至眼后部的方法 - Google Patents
通过结膜下或眼周递送前体药物将活性药物递送至眼后部的方法 Download PDFInfo
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Abstract
本发明涉及一种将活性药物持续递送至哺乳动物眼后部以治疗或预防侵害所述哺乳动物的疾病或症状的方法,其中所述疾病或症状可以通过所述活性药物向所述眼后部的作用而得以治疗或预防,所述方法将有效量的活性药物的酯前体药物在结膜下或眼周给药。优选地,活性药物的活性比前体药物高约10倍以上。本发明的其它方面还涉及通过酯前体药物的眼周或结膜下递送以治疗某种疾病的方法,以及用于眼周或结膜下给药的包含酯前体药物的某种药用产品。
Description
发明领域
本发明涉及药物递送的方法。更具体而言,本发明涉及将活性药物递送至哺乳动物眼后部的方法。
背景技术
目前认为许多疾病或症状可以通过将活性药物直接递送至眼后部而得以有效的治疗或预防。这类疾病或症状的实例包括视网膜色素变性、增生性玻璃体视网膜病变(PVR)、年龄相关性黄斑变性(ARMD)、糖尿病性视网膜病变、糖尿病性黄斑水肿、视网膜脱离、视网膜撕裂、葡萄膜炎或巨细胞病毒性视网膜炎。眼科领域的一个主要问题是难以实现向眼后部(例如葡萄膜、玻璃体、视网膜、脉络膜、视神经或视网膜色素上皮)的有效递送以治疗所述疾病。局部或全身给药时,血液—视网膜屏障严重限制了药物向眼后部的递送。此外,对于拟在眼后部发挥作用的药物而言,全身给药需要的药物剂量比靶向递送所需的药量多得多。其结果是产生非所需的全身性高药物浓度,而这对于毒性药物或具有不良副作用的药物而言尤其成问题。
目前的作法是通过眼内注射或植入进行直接的眼内给药来避开血液—视网膜屏障,该方法也被认为是最有效的递送方式。遗憾的是,诸如眼内注射或植入的侵入性技术可能导致视网膜脱离、晶状体的物理性损伤和外源性眼内炎。直接的眼内注射或植入还导致药物在晶状体和其它眼内组织处的高脉冲浓度(pulsed concentration),从而带来极大的危害,尤其是对于具有眼内毒性的药物而言。此外,已知多数用于治疗侵害眼后部的症状的药物会导致白内障。高亲脂性药物另外还具有易于分配至亲脂性晶状体上皮中的缺点,从而进一步加剧了其致白内障的特性。
此外,多数用于治疗侵害眼后部的疾病或症状的药物具有很短的眼内半衰期。这就需要频繁递送所述药物,或者通过控释递送系统递送所述药物。由于显而易见的原因,向眼内频繁注射药物是非常不利的,因此普遍采用控释或缓释递送。例如,在专利文献(US 6,378,526和US6,397,849)中已经报道了包含于可生物降解或生物相容聚合物中的活性药物的巩膜内注射,用以实现以眼后部为靶向的药物的控释或缓释。通常,所述聚合物以用于眼药控释的微粒形式使用。一般而言,所述微粒由包在聚合物中的药物组成(参见Joshi,“Microparticles forOphthalmic Drug Delivery”,Journal of Ocular Pharmacology,第10卷,第1期,1994,第29-45页)。所述药物通过不同的机理(例如聚合物的降解或溶解、侵蚀、扩散、离子交换或其组合)缓慢释放。Einmal及其同事(“A Novel Route of Ocular Drug Delivery:SuprachoroidalInjections Of A Sustained-Release System”,Proceed.Int’l.Symp.Rel.Bioact.Mater.,28,(2001),第293-294页)已进一步指出,载有氢氧化镁和地塞米松磷酸盐的聚原酸酯的脉络膜上注射能够使药物向脉络膜和视网膜持续递送。
前体药物的概念为本领域所公知,对于具有影响其治疗人类或动物疾病适用性的缺陷的药物而言,前体药物已经被用来改善所述药物的物理、化学和生物特性。前体药物可以用来,例如,改变药物的疏水性或亲脂性,从而使其更易穿过生物屏障,提高溶解性,使药物稳定从而能够到达其生理靶标,减少副作用的发生,改善药物的保质期或有助于制剂。一般而言,前体药物是给药后经过转变成为活性类型的生理活性药物的衍生物。所述转变可以是酶催化的,但前体药物对于生理环境中的水解或其它反应而言也可以是不稳定的。从总体上涉及前体药物的众多科学文献之中,援引了前述实例:Design of Prodrugs(Bundgaard H.编辑)1985 Elsevier Science Publishers B.V.(BiomedicalDivision),第1章;Design of Prodrugs:Bioreversiblederivativesfor various functional groups and chemical entities(HansBundgaard);Bundgaard等,Int.J.of Pharmaceutics 22(1984)45-56(Elsevier);Bundgaard等,Int.J.of Pharmaceutics 29(1986)19-28(Elsevier);Bundgaard等,J.Med.Chem.32(1989)2503-2507Chem.Abstracts 93,137935y(Bundgaard等);Chem.Abstracts 95,138493f(Bundgaard等);Chem.Abstracts 95,138592n(Bundgaard等);Chem.Abstracts 110,57664p(Alminger等);Chem.Abstracts115,64029s(Buur等);Chem.Abstracts 115,189582y(Hansen等);Chem.Abstracts 117,14347q(Bundgaard等);Chem.Abstracts 117,55790x(Jensen等);以及Chem.Abstracts 123,17593b(Thomsen等)。
发明内容
本发明涉及前体药物用于延长活性药物眼内作用持续时间的用途。当采用前体药物来延长活性药物的作用持续时间时,通常的一个显著缺陷在于,相对于活性药物的治疗有效量而言,必须施用大量的前体药物。换言之,当需要较长的作用持续时间时,大量的活性药物以前体药物的形式“储存”起来,因而全身的前体药物浓度较高。如果前体药物比活性药物的毒性更强或不良副作用更甚,这就尤其成问题,而且,当所需的作用持续时间延长时这还会更糟,因为需要更多的前体药物。本发明通过将前体药物按以下方式给药而减少了与前体药物眼内使用相关的所述显著缺陷:所述方式降低了实现眼内活性药物持续治疗浓度所需的前体药物的眼内药量。
我们已经出人意料地发现,事实上,与酯前体药物的直接的眼内给药相比,通过酯前体药物的结膜下或眼周给药可以更加有效地将活性药物递送至玻璃体和其它眼后部。换言之,将前体药物的结膜下或眼周给药与前体药物的眼内给药或直接给药于玻璃体内相比较而言,前一种情况下的眼内的前体药物与活性药物的比值显著低于后一种情况下的比值。因此,通过前体药物的结膜下或眼周给药代替前体药物的直接的眼内或玻璃体内给药,可以实现副作用(例如白内障)更少、与前体药物相关的毒性危险性更低的、治疗有效浓度的活性药物向眼后部的持续递送。同样地,本发明极大地改进了针对眼后部结构的具有低治疗指数(therapeutic indices)的化合物的药物疗法。
本发明还涉及通过酯前体药物的眼周或结膜下递送以治疗某些疾病的方法,以及用于眼周或结膜下给药的包含酯类前体药物的某些药用产品。
附图说明
图1显示单次结膜下注射含1mg他扎罗汀(tazarotene)的悬浮液后,房水、玻璃体液和视网膜(N=4)中他扎罗汀的浓度(均数+标准偏差)。所述均数代表各时间点上在4只不同的眼中所测得的各组织中的他扎罗汀的平均浓度。
图2显示单次结膜下注射含1mg他扎罗汀的悬浮液后,房水、玻璃体液和视网膜(N=4)中他扎罗汀酸(tazarotenicacid)的浓度(均数+标准偏差)。所述均数代表各时间点上在4只不同的眼中所测得的各组织中的他扎罗汀酸的平均浓度。
图3显示单次结膜下注射含1mg他扎罗汀的溶液后,房水、玻璃体液和视网膜(N=4)中他扎罗汀的浓度(均数+标准偏差)。所述均数代表各时间点上在4只不同的眼中所测得的各组织中的他扎罗汀的平均浓度。
图4显示单次结膜下注射含1mg他扎罗汀的溶液后,房水、玻璃体液和视网膜(N=4)中他扎罗汀酸的浓度(均数+标准偏差)。所述均数代表各时间点上在4只不同的眼睛中所测得的各组织中的他扎罗汀酸的平均浓度。
图5显示单次结膜下注射含0.5mg他扎罗汀的丙交脂-乙交脂共聚物(poly(lactide-co-glycolide,PGLA)微球后,房水、玻璃体液和视网膜(N=4)中他扎罗汀的浓度(均数+标准偏差)。所述均数代表各时间点上在4只不同的眼中所测得的各组织中的他扎罗汀的平均浓度。
图6显示单次结膜下注射含0.5mg他扎罗汀的PGLA微球后,房水、玻璃体液和视网膜(N=4)中他扎罗汀酸的浓度(均数+标准偏差)。所述均数代表各时间点上在4只不同的眼中所测得的各组织中的他扎罗汀酸的平均浓度。
图7显示他扎罗汀玻璃体内给药的玻璃体内的他扎罗汀和他扎罗汀酸的浓度。
图8显示通过下列给药方式的玻璃体内的他扎罗汀和他扎罗汀酸的浓度比:1.结膜下悬浮液,2.结膜下油状物,3.结膜下微球,4.玻璃体内注射。
图9和10是说明前体药物可给药的位置的人眼示图。
具体实施方式
本发明涉及一种将活性药物持续递送至哺乳动物眼后部以治疗或预防侵害所述哺乳动物的疾病或症状的方法,其中所述症状可以通过所述活性药物对所述眼后部的作用而得以治疗或预防,所述方法包括将有效量的活性药物的酯前体药物在结膜下或眼周给药。优选地,活性药物的活性比前体药物高约10倍。还优选,活性药物不是血小板活化因子拮抗剂。
用语“眼后部”定义为包括有眼后部的一个特定部位、眼后部的一般区域,或者二者结合的眼区。优选地,活性药物所作用的眼后部包括葡萄膜、玻璃体、视网膜、脉络膜、视神经或视网膜色素上皮。与本发明相关的疾病或症状包括任何可以通过活性药物对眼后部的作用而得以预防或治疗的疾病或症状。在并非试图以任何方式限制本发明范围的情况下,可以通过活性药物对眼后部的作用而得以预防或治疗的部分疾病或症状的实例包括:黄斑病/视网膜变性,例如非渗出性年龄相关性黄斑变性(ARMD)、渗出性年龄相关性黄斑变性(ARMD)、脉络膜新生血管、糖尿病性视网膜病变、急性黄斑性视神经视网膜病变、中心性浆液性脉络膜视网膜病变、囊样黄斑水肿以及糖尿病性黄斑水肿;葡萄膜炎/视网膜炎/脉络膜炎,例如急性多病灶鳞状色素上皮病变、白塞氏病(Behcet′sdisease)、散弹状脉络膜视网膜病变、传染性(梅毒、莱姆关节炎、结核病、弓形体病)、中间葡萄膜炎(周围葡萄膜炎)、多病灶脉络膜炎、多发性一过性白点综合征(mewds)、眼类肉瘤病、后巩膜炎、匍行性脉络膜炎、视网膜下纤维化和葡萄膜炎综合征、伏格特-小柳综合征(Vogt-Koyanagi syndrome)和原田综合征(Harada syndrome);血管疾病/渗出性疾病,例如视网膜动脉阻塞性疾病、视网膜中央静脉阻塞、弥散性血管内凝血、视网膜静脉分枝阻塞、高血压性眼底改变、眼缺血综合征、视网膜动脉微动脉瘤(retinal arterial microaneurysms)、外层渗出性视网膜病变、旁中心凹毛细血管扩张(parafovealtelangiectasis)、单侧视网膜静脉阻塞、视乳头静脉炎、视网膜中央动脉阻塞、视网膜动脉分枝阻塞、颈动脉疾病(CAD)、霜样树枝状视网膜血管炎(frosted branch angiitis)、镰状细胞性视网膜病变以及其它血红蛋白病、血管样条纹症、家族性渗出性玻璃体视网膜病变、以及伊尔斯氏病(Eales disease);外伤性/手术性症状,例如交感性眼炎、葡萄膜炎性视网膜疾病、视网膜脱离、外伤、由激光引起的症状、由光动力治疗、光凝术引起的症状、手术过程中的低灌注、辐射性视网膜病变、以及骨髓移植视网膜病变;增生性病症,例如增生性玻璃体视网膜病变和视网膜前膜、以及增生性糖尿病性视网膜病变;传染性病症,例如眼组织胞浆菌病、眼弓蛔虫病、拟眼组织胞浆菌病综合征(POHS)、眼内炎、弓形体病、与HIV感染有关的视网膜疾病、与HIV感染有关的脉络膜疾病、与HIV感染有关的葡萄膜炎疾病、病毒性视网膜炎、急性视网膜坏死、进行性外侧视网膜坏死、真菌性视网膜疾病、眼梅毒、眼结核病、弥散性单侧亚急性视神经视网膜炎以及蝇蛆病;遗传性病症,例如视网膜色素变性、伴有视网膜营养不良的全身性病症、先天性静止性夜盲、锥体营养不良,Stargardt氏病和眼底黄色斑点症,Best氏病,视网膜色素上皮的图形样营养不良,性连锁视网膜劈裂症,Sorsby氏眼底营养不良,良性同心性黄斑病变(benign concentric maculopathy),Bietti氏晶状体营养不良以及弹性假黄色瘤;视网膜撕裂/裂孔,例如视网膜脱离,黄斑裂孔,以及巨型视网膜撕裂;肿瘤,例如肿瘤相关的视网膜疾病、视网膜色素上皮先天性肥大、后葡萄膜黑色素瘤(posterioruveal melanoma)、脉络膜血管瘤、脉络膜骨瘤、脉络膜转移瘤、视网膜和视网膜色素上皮混合型错构瘤(combined hamartoma of the retinaand retinal pigmented epithelium)、视网膜母细胞瘤、眼底血管增生性肿瘤(vasoproliferative tumors of the ocular fundus)、视网膜星形细胞瘤以及眼内淋巴样瘤;以及混杂的其它侵害眼后部的疾病,例如点状内脉络膜病变(punctate inner choroidopathy)、急性后部多病灶鳞状色素上皮病变(acute posterior multifocal placoidpigment epitheliopathy)、近视性视网膜变性以及急性视网膜色素上皮炎。优选的疾病或症状为视网膜色素变性、增生性玻璃体视网膜病变(PVR)、年龄相关性黄斑变性(ARMD)、糖尿病性视网膜病变、糖尿病性黄斑水肿、视网膜脱离、视网膜撕裂、葡萄膜炎或者巨细胞病毒性视网膜炎。
酯前体药物是具有前述含义的前体药物,也是一种酯。酯官能团的作用是使活性药物具有活化-灭活的特性。换言之,通过酯官能团的水解,由前体药物产生醇或酸形式的活性药物。
在并非试图局囿于任何理论的情况下,本发明认为,相对于玻璃体而言的脉络膜和虹膜-睫状体中较高的酯酶活性,使得经结膜下或眼周注射而递送至玻璃体的活性药物和前体药物的比值高于通过将前体药物直接注射至玻璃体所能够达到的比值。本发明还认为,结膜下或眼周区可以作为酯前体药物的储库,从而使药物向眼后部持续递送,同时还可避免眼内或全身高浓度的前体药物。换言之,活性药物的靶向递送通过间接给药前体药物而得以实现。一般而言,如果不进行靶向递送,则前体药物的全身给药需要较高的前体药物全身浓度,以使眼后部中存在治疗有效量的活性药物。这种情况极有可能引起无法接受的副作用。在本发明中,活性药物的递送是靶向性的,但并非将前体药物给药于作用点或敏感的外围区域。而是将前体药物给药于与作用点足够近的区域,以实现治疗有效的靶向递送,但同时还要与眼部特别敏感的部位足够远,从而显著降低有害副作用。因此本发明使得眼后部在持续的一段时间内能够获得治疗浓度的活性药物,同时显著降低前体药物在哺乳动物的眼部敏感部位和全身的浓度。
酯前体药物可以是任何符合上述标准的酯。优选的前体药物是羧酸酯。在并非试图限制的情况下,本领域内已经公知角膜和虹膜-睫状体富含酯酶,因此可局部用于角膜以治疗疾病(其中药物在眼内起作用)的羧酸酯,是一种水解产物的前体药物。在本发明的一个优选实施方案中,水解生成活性药物的前体药物的酯基不是内酯或环状羧酸酯。在本发明另一个优选实施方案中,前体药物是基于磷或硫的酸的酯。
对本发明而言,在合适的检测中活性药物比前体药物的活性高约十倍。合适的检测是被本领域技术人员所认可的与待治疗或预防的疾病或症状相关的检测。另外,合适的检测还应当能够区分前体药物和活性药物,也就是说这两种化合物在检测中得到显著不同的结果。在并非试图以任何方式限制本发明范围的情况下,合适的检测是受体结合检测、活性检测或其它体外检测。就涉及生物受体的结合或活性而言,所述检测可以涉及单个受体或受体亚型,或者多个受体或受体亚型。
在并非试图限制的情况下,某些相关的受体靶点是类维生素A受体(retinoid receptor),包括RAR亚型α、β和γ,RXR亚型α、β和γ,VEGFR和其它酪氨酸激酶受体,α肾上腺素能受体、α2肾上腺素能受体和亚型2A、2B和2C,β肾上腺素能受体,胆碱能受体,毒蕈碱性受体,整联蛋白受体ανβ3和ανβ5,以及核受体的甾体激素受体亚家族。
在相关受体检测未知或已知没有相关受体的情况下,使用合适的功能性检测。所使用的功能性检测应当是在与所治疗或预防的症状或疾病的相关领域内获得认可的功能性检测。所述功能性检测还应当能够区分前体药物和活性药物,也就是说这两种化合物在检测中得到显著不同的结果。例如,在并非试图限制本发明范围的情况下,就抗生素而言,可以使用合适的效能试验,例如纸片扩散法,其中抑制圈表明前体药物的效能比活性药物低十倍。就神经毒素而言,可以将小鼠效能检测用作效能的量度。类似地,对于任何其受体结合检测不存在或不相关的疾病或症状以及活性药物而言,使用合适的功能性检测。在对于疾病可使用一种以上检测的情况下,前体药物只需在一种检测中比活性药物的活性高约十倍。
本发明的活性药物可以是任何类型的用于治疗侵害眼后部的疾病或症状的可通过酯前体药物在生物环境中水解而生成的药物。优选的活性药物为类维生素A(retinoid)、前列腺素、α2肾上腺素能激动剂、β肾上腺素受体拮抗剂、多巴胺能激动剂、胆碱能激动剂、酪氨酸激酶抑制剂、抗炎剂、皮质类固醇、NMDA拮抗剂、抗癌药和抗组胺剂。在本发明的一个优选实施方案中,活性药物是类维生素A。类维生素A定义为具有类维生素A样活性的化合物。具有类维生素A活性的化合物为本领域所公知,在美国和其它国家的众多专利中以及众多科学出版物中亦有所叙述。在并非试图以任何方式限制本发明范围的情况下,作为本发明中的活性药物的类维生素A的部分实例为13-顺-维A酸、13-顺-维生素A、全反式维A酸、全反式维生素A。一种特别有效的类维生素A,即本发明的一个更优选实施方案中的活性药物,是4,4-二甲基-6-[2’-(5”-羧基-2”-吡啶基)-乙炔基]-二氢苯并噻喃,也被称为他扎罗汀酸,其结构如下式I中所示。
结构式I
如前面所提及的,活性药物是前体药物的水解产物。由于酯水解产生酸和醇,因此活性药物可以是酸或醇水解产物。酸水解产物可以是羧酸或其它有机酸,例如基于硫或磷的酸。此外,酸组分可以进一步分解(breakdown)为其它组分(例如,酰氧基烷基前体药物)。由于多数酸在生理环境中发生去质子化,因此活性药物也可能是水解生成的一种有机酸的盐。所述有机酸的盐应当广义地解释为通过去质子化所生成的解离的阴离子、离子对、或任何未完全解离或牢固配对的形式。优选的活性药物是羧酸、羧酸盐或醇。
在本发明的一个优选实施方案中,前体药物为活性药物的酯,其中活性药物是羧酸或其盐。更优选的前体药物是由活性药物(羧酸或其盐)生成的酯和C1-6醇或酚所组成的前体药物。更优选的前体药物为活性药物(羧酸或其盐)的乙酯。在本发明的最优选实施方案中,前体药物为6-[(4,4-二甲基二氢苯并噻喃-6-基)乙炔基]烟酸乙酯,也被称为他扎罗汀,该化合物是前述他扎罗汀酸的乙酯。
在本发明的一个优选实施方案中,前体药物或活性药物会引起白内障。致白内障的活性药物或前体药物引起或加剧侵害眼部的医学症状(即白内障)。
在本发明的另一个实施方案中,前体药物包含在旨在增强所述活性药物持续递送的聚合微粒体系中。在并非试图以任何方式限制本发明范围的情况下,旨在增强药物持续递送的聚合微粒体系为本领域所公知,且本领域中已知有众多的制备所述包含有药物的聚合微粒体系的方法。在本发明的一个优选实施方案中,所述聚合微粒体系为丙交脂-乙交脂共聚物(PLGA)微球悬浮液。
前体药物在结膜下或眼周给药。参见图9,图中显示了视网膜色素上皮40、脉络膜45和巩膜(schlera)35。前体药物的给药可以通过结膜下5,巩膜10或脉络膜上15。参见图10,前体药物的给药还可以通过筋膜(tenon)下20,眼球后25或眼球周30。优选地,通过结膜下5给药。给药可以通过注射、植入或等同的方法实施。优选地,给药通过注射实施。
本发明的另一个实施方案涉及治疗或预防疾病或症状的方法,其中所述疾病或症状的治疗或预防通过活性药物对受侵害哺乳动物的眼后部的作用而实现,所述方法包括通过注射将有效量的活性药物的羧酸酯前体药物在结膜下或眼周给药,其中所述前体药物包含在旨在增强所述活性药物持续递送的聚合微粒体系中,其中所述活性药物的活性比前体药物高约10倍。
本发明的另一个实施方案涉及药用产品,所述产品包括
i)包含有效浓度的活性药物酯前体药物的组合物,其中通过所述活性药物对哺乳动物眼后部的作用可有效治疗或预防侵害所述眼后部的疾病或症状,且其中所述活性药物的活性比前体药物高约10倍;以及
ii)合适的包装材料,包括有关通过结膜下或眼周注射所述产品而将该产品用于治疗所述疾病或症状的说明书,其中所述说明书并未指出所述产品应通过玻璃体内或眼内注射给药,或者其中所述说明书指出或建议优选结膜下或眼周注射而非玻璃体内或眼内注射。
术语“包装材料”包括任何容纳含有羧酸酯前体药物的组合物的容器,以及所述容器周围的任何辅助包装。在并非试图以任何方式限制本发明范围的情况下,所述辅助包装可以包括盒、收缩包装(shrink wrap)、纸包装等等。所述辅助包装还包括由药用产品制造商所制备的或者为药用产品制造商制备的旨在协助医生或患者使用所述产品的任何材料。所述辅助包装不一定必须是实际出售或者随所述产品配售的。所涉及的说明书可以是书面的,通过图形、图样、图表等或其组合说明,并且就其最广义的含义而言,可以包含在包装材料上的任何部位。另外,所述说明书还可以语言或视觉的方式包含在记录媒体上,例如录音带或录像带、光盘或DVD。
本领域技术人员应认识的是,上述优选方案或实施方案可以多种方式相结合以形成独特的实施方案。本说明书中所提及的优选方案或实施方案的任何结合对于本领域的普通技术人员而言是显而易见的,因此均被认为是属于本发明范围之内的单独的实施方案。
以下实施例中叙述了进行和使用本发明的最佳方式。提出所述实施例的目的仅仅是说明和指导如何进行和使用本发明,而并非试图以任何方式限制本发明的范围。
实施例A
他扎罗汀和他扎罗汀酸与维A酸受体(RAR)家族的受体(RARα、RARβ、RARγ)的结合按以下方式确定。
所有的结合检测以类似的方式实施。全部三种受体亚型均来自于在杆状病毒中表达的表达受体类型(RARα、RARβ和RARγ)。所述化合物的贮存液制备成10mM乙醇溶液,并稀释为一系列1∶1的DMSO∶乙醇稀释液。检测缓冲液由针对所有六种受体检测的下列各项组成:8%甘油,120mM KCl,8mM Tris,5mM CHAPS,4mM DTT和0.24mM PMSF,室温下pH为7.4。
所有的受体结合检测均以相同的方式实施。最终检测体积为250μl,并依据被检测受体含有10-40μg的提取蛋白,以及5nM[3H]全反式维A酸或10nM[3H]9-顺式维A酸和浓度在0-105M的范围内变化的竞争性配体。将所述检测安排在96孔微型管系统中进行。在4℃时进行培育直至达到平衡。非特异性结合定义为存在1000nM适当的未标记的维A酸异构体时所剩余的结合。在培育期结束时,在适当的洗涤缓冲液中加入50mul 6.25%的羟基磷灰石(hydroxyapitite)。所述洗涤缓冲液由100mM KCl、10mM Tris以及5mM CHAPS(RARα、RARβ和RARγ)或0.5%Triton X-100(RARα、RARβ和RARγ)组成。将混合物旋涡搅拌并在4℃下培育10分钟,离心并除去上清液。用合适的洗涤缓冲液将羟基磷灰石再洗涤3次。受体配体络合物被羟基磷灰石所吸附。通过羟基磷灰石小球的液体闪烁计数来确定受体配体络合物的量。
在针对非特异性结合进行矫正之后,确定IC50值。所述IC50值定义为特异性结合减少50%所需的竞争性配体的浓度。所述IC50值从数据的重对数(loglogit)图中绘图确定。Kd值通过对所述IC50值、标记配体的浓度和标记配体的Kd值应用Cheng-Prussof方程式来确定。
配体结合检测的结果以Kd数表示。(参见Chena等,BiochemicalPharmacology第22卷第3099-3108页,所述文献通过援引的方式特此纳入本说明书中。)所有受体对他扎罗汀的受体亲和力(KD以nM为单位)大于104。他扎罗汀酸(即他扎罗汀的母体化合物)分别以901±123nM、164±48nM和353±37nM的KD值与RARα、RARβ和RARγ结合。他扎罗汀酸的结合数据以均数和标准偏差表示。由于他扎罗汀酸比他扎罗汀的活性高约十倍(即结合常数低约十倍以上),因此所述数据证实他扎罗汀是活性药物他扎罗汀酸的前体药物。
实施例1
微球的制备
根据下表的用量,制备装填有10%w/w他扎罗汀的75∶25的丙交脂-乙交脂共聚物微球。
配方:每批五克
组分 用途 用量
I相
聚乙烯醇(PVA) 稳定剂 47.5克
净化水 溶剂 1600mL
II相
他扎罗汀 活性物 0.5(10%)
聚(丙交脂-共-乙交 聚合物/载体 4.50克
脂)
二氯甲烷 溶剂 300mL
I相
80℃下在五升烧杯中用高剪切叶轮搅拌机(high shear impeller)制备3.0%的PVA溶液,搅拌速率400至500rpm。一旦PVA溶解,则将搅拌速率降至200RPM以使起泡减到最小。
II相
然后室温下将丙交脂-乙交脂共聚物(PLGA)溶于二氯甲烷中。一旦PLGA溶解,则同样在室温下加入他扎罗汀并使之溶解。
然后应用溶剂蒸发技术制备微球。室温下剧烈搅拌I相溶液,同时缓慢加入II相溶液。然后搅拌所述乳状液48小时以除去二氯甲烷。然后冲洗微球,最后冷冻干燥。于-50℃下冷冻所述微球,然后于4mbar最低压力(400Pa)下冷冻干燥至少12小时。
然后于0℃下通过2.5至4.0mRad剂量的γ辐射对所述冷冻干燥的微球灭菌。通过采用冰袋(cold pack)使纸箱中的温度维持在0℃。
实施例2
室温下,通过将他扎罗汀加至pH7.4的等渗磷酸盐缓冲液(IPBS)中来制备他扎罗汀的水性悬浮液。将二十微升的多乙氧基醚80加至所述混合物中。最后,室温搅拌使他扎罗汀分散,得到含20mg/mL他扎罗汀的IPBS的均匀悬浮液。
实施例3
室温下,通过向橄榄油中简单加入他扎罗汀来制备他扎罗汀的橄榄油溶液。使所述混合物在室温下旋涡搅拌直至他扎罗汀溶解。最终的他扎罗汀浓度为20mg/mL。
实施例4
对由他扎罗汀的眼内和结膜下给药所产生的他扎罗汀和他扎罗汀酸的总体分配(general disposition)进行评价。通过眼内注射1.25μg他扎罗汀对患有白化病的兔子用药。注射在玻璃体中部实施。用药后,于用药后0.5、1、2、4、8、12和24小时测定他扎罗汀和他扎罗汀酸的玻璃体、视网膜和房水浓度。参见图7,数据清楚显示,他扎罗汀酸由玻璃体内的他扎罗汀生成,其在玻璃体内的浓度渐近地达到约10ng/ml。数据显示,直接眼内植入后所能获得的他扎罗汀酸的最大玻璃体内浓度是10ng/ml。在进行1.25μg他扎罗汀酸的中部玻璃体用药后,他扎罗汀酸通过明显的一级过程以4.24小时的半衰期从玻璃体中清除。
他扎罗汀还于结膜下区用药。对三种剂型进行评价:实施例2中所述的他扎罗汀水性悬浮液(50μl溶液,1mg他扎罗汀),实施例3中所述的他扎罗汀橄榄油溶液(50μl mg溶液,1mg他扎罗汀),以及实施例1中所述的他扎罗汀丙交脂-乙交脂共聚物微球悬浮液。用药后,于用药后2、8、24、48、96、168和336小时测定他扎罗汀和他扎罗汀酸的玻璃体、视网膜和房水浓度(参见图1-8)。所述测量结果显示,结膜下给药在眼组织中获得了显著水平的他扎罗汀和他扎罗汀酸。更为重要的是,他扎罗汀与他扎罗汀酸的比值显著低于通过将他扎罗汀直接注射至玻璃体内所得到的比值,如图8所示,这表明通过所述给药方法能够获得较高的前体药物到活性药物的转化率。表1中概括给出玻璃体浓度数据。表1中,平均玻璃体浓度是指,用药后零至一百六十八小时所观察到的平均玻璃体浓度。各时间点的平均玻璃体浓度用于计算针对给定的给药途径和剂型的168小时内的总的玻璃体平均浓度。图1-7中概括绘出玻璃体浓度时间概图。总而言之,数据清楚显示,与玻璃体内递送相比,他扎罗汀酸的结膜下递送是更为有效的递送。同样重要的是,本发明注意到类维生素A他扎罗汀和他扎罗汀酸的浓度在336小时(2周)内维持在较低的有效水平上。
表1.玻璃体内和结膜下用药后他扎罗汀和他扎罗汀酸的玻璃体浓度
剂型 | 他扎罗汀平均玻璃体浓度 | 他扎罗汀酸平均玻璃体浓度 | 他扎罗汀/他扎罗汀酸比值 |
玻璃体内注射(1.25μg) | 417.0 | 9.9 | 42.0 |
结膜下悬浮液(1mg) | 42.0 | 2.5 | 16.8 |
结膜下微球(1mg) | 21.9 | 1.4 | 16.1 |
结膜下油溶液(1mg) | 96.2 | 5.43 | 17.7 |
实施例5
用包括于实施例1的丙交脂-乙交脂共聚物微球悬浮液中的一剂他扎罗汀(1mg)对患有视网膜色素变性的患者进行结膜下注射。在疗程中观察到视力维持或视力丧失的进行减慢。
实施例6
用包括于实施例1的丙交脂-乙交脂共聚物微球悬浮液中的一剂他扎罗汀(1mg)对患有增生性玻璃体视网膜病变的患者进行结膜下注射。通过治疗,预防了牵拉性视网膜脱离,或减缓了牵拉性视网膜脱离的速率。
实施例7
用包括于实施例1的丙交脂-乙交脂共聚物微球悬浮液中的一剂他扎罗汀(1mg)对患有年龄相关性黄斑变性的患者进行结膜下注射。疗程中观察到视力维持或视力丧失的进行减慢。治疗过程中,症状的消退或症状进行的减慢得以实现。
实施例8
用包括于实施例1的丙交脂-乙交脂共聚物微球悬浮液中的一剂全反式棕榈酸视黄酯(1mg)对患有视网膜色素变性的患者进行结膜下注射。疗程中观察到视力维持或视力丧失进行的减慢。
Claims (20)
1.一种将活性药物持续递送至哺乳动物眼后部以治疗或预防侵害所述哺乳动物的疾病或症状的方法,其中所述疾病或症状可以通过所述活性药物对所述眼后部的作用而得以治疗或预防,所述方法包括将有效量的活性药物的酯前体药物在结膜下或眼周给药,并且其中活性药物的活性比前体药物高约10倍。
2.权利要求1的方法,其中活性药物或前体药物会导致白内障。
3.权利要求1的方法,其中活性药物为羧酸或羧酸盐。
4.权利要求1的方法,其中活性药物选自类维生素A、前列腺素、α2肾上腺素能激动剂、β肾上腺素受体拮抗剂、多巴胺能激动剂、胆碱能激动剂、酪氨酸激酶抑制剂、抗炎剂、皮质类固醇、NMDA拮抗剂、抗癌药和抗组胺剂。
5.权利要求1的方法,其中活性药物为醇。
6.权利要求1的方法,其中活性药物为类维生素A。
7.权利要求1的方法,其中活性药物为他扎罗汀酸。
8.权利要求1的方法,其中前体药物为他扎罗汀。
9.权利要求1的方法,其中前体药物为基于磷或硫的酸的酯。
10.权利要求1的方法,其中前体药物包含在旨在增强所述活性药物持续递送的聚合微粒体系中。
11.权利要求10的方法,其中所述聚合微粒体系为丙交脂-乙交脂共聚物微球悬浮液。
12.权利要求1的方法,其中所述眼后部包括葡萄膜、玻璃体、视网膜、脉络膜、视神经或视网膜色素上皮。
13.权利要求1的方法,其中所述疾病或症状为视网膜色素变性、增生性玻璃体视网膜病变(PVR)、年龄相关性黄斑变性(ARMD)、糖尿病性视网膜病变、糖尿病性黄斑水肿、视网膜脱离、视网膜撕裂、葡萄膜炎或巨细胞病毒性视网膜炎。
14.权利要求1的方法,其中前体药物通过注射给药。
15.权利要求1的方法,其中前体药物通过结膜下、巩膜、脉络膜上、筋膜下、眼球后或眼球周给药。
16.权利要求1的方法,其中前体药物通过结膜下给药。
17.一种治疗或预防疾病或症状的方法,其中所述疾病或症状的治疗或预防通过活性药物对受侵害哺乳动物眼后部的作用而实现,所述方法包括通过注射将有效量的活性药物的羧酸酯前体药物在结膜下或眼周给药,其中前体药物包含在旨在增强所述活性药物持续递送的聚合微粒体系中,并且其中活性药物的活性比前体药物高约10倍,并且其中所述活性药物不是血小板活化因子拮抗剂。
18.一种药用产品,包括
i)包含有效浓度的活性药物酯前体药物的组合物,其中通过所述活性药物对哺乳动物眼后部的作用可有效治疗或预防侵害所述眼后部的疾病或症状,并且其中活性药物的活性比前体药物高约10倍;以及
ii)合适的包装材料,包括有关通过结膜下或眼周注射所述产品而将该产品用于治疗所述疾病或症状的说明书,其中所述说明书并未指出所述产品应通过玻璃体内或眼内注射给药,或者其中所述说明书指出或建议优选结膜下或眼周注射而非玻璃体或眼内注射。
19.权利要求1的方法,其中活性药物不是血小板活化因子拮抗剂。
20.权利要求18的药用产品,其中活性药物不是血小板活化因子拮抗剂。
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Families Citing this family (53)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050250737A1 (en) * | 2003-11-12 | 2005-11-10 | Allergan, Inc. | Therapeutic ophthalmic compositions containing retinal friendly excipients and related methods |
US20050101582A1 (en) | 2003-11-12 | 2005-05-12 | Allergan, Inc. | Compositions and methods for treating a posterior segment of an eye |
CN1889954A (zh) * | 2003-12-02 | 2007-01-03 | 阿勒根公司 | 用类维生素a预防和/或减轻光受体变性的方法 |
US8871224B2 (en) * | 2003-12-09 | 2014-10-28 | Allergan, Inc. | Botulinum toxin therapy for skin disorders |
WO2005087210A2 (en) * | 2004-03-17 | 2005-09-22 | Lars Michael Larsen | Prevention of retinopathy by inhibition of the visual cycle |
US20050220734A1 (en) * | 2004-04-02 | 2005-10-06 | Allergan, Inc. | Therapy for melanin related afflictions |
AU2005240078A1 (en) * | 2004-04-30 | 2005-11-17 | Allergan, Inc. | Retinoid-containing sustained release intraocular drug delivery systems and related methods of manufacturing |
WO2005107708A1 (en) | 2004-04-30 | 2005-11-17 | Allergan, Inc. | Biodegradable intravitreal tyrosine kinase inhibitors implants |
US7771742B2 (en) | 2004-04-30 | 2010-08-10 | Allergan, Inc. | Sustained release intraocular implants containing tyrosine kinase inhibitors and related methods |
AU2011211380B9 (en) * | 2004-04-30 | 2014-05-08 | Allergan, Inc. | Biodegradable intravitreal tyrosine kinase inhibitor implants |
US8246949B2 (en) * | 2004-10-27 | 2012-08-21 | Aciont, Inc. | Methods and devices for sustained in-vivo release of an active agent |
WO2007130134A2 (en) * | 2005-12-02 | 2007-11-15 | (Osi) Eyetech, Inc. | Controlled release microparticles |
US20070202186A1 (en) | 2006-02-22 | 2007-08-30 | Iscience Interventional Corporation | Apparatus and formulations for suprachoroidal drug delivery |
US8197435B2 (en) | 2006-05-02 | 2012-06-12 | Emory University | Methods and devices for drug delivery to ocular tissue using microneedle |
CN101074935B (zh) * | 2006-05-19 | 2011-03-23 | 清华大学 | 探测器阵列及设备 |
EP1864667B1 (en) | 2006-06-01 | 2013-09-04 | Novagali Pharma S.A. | Use of prodrugs for ocular intravitreous administration |
US10123970B2 (en) | 2009-05-20 | 2018-11-13 | Sun Pharmaceutical Industries Limited | Topical retinoid solutions |
US10022348B2 (en) | 2009-05-20 | 2018-07-17 | Sun Pharmaceutical Industries Limited | Topical solution of isotretinoin |
US8889193B2 (en) | 2010-02-25 | 2014-11-18 | The Johns Hopkins University | Sustained delivery of therapeutic agents to an eye compartment |
WO2012039979A2 (en) | 2010-09-10 | 2012-03-29 | The Johns Hopkins University | Rapid diffusion of large polymeric nanoparticles in the mammalian brain |
BR112013009205A2 (pt) | 2010-10-15 | 2016-07-26 | Iscience Interventional Corp | dispositivo para colocação na esclera de um olho, método para acessar o espaço supracoroidal de um olho, para acessar o espaço subretinal de um olho e para colocar um orifício dentro de um trato escleral em um olho. |
WO2012109363A2 (en) | 2011-02-08 | 2012-08-16 | The Johns Hopkins University | Mucus penetrating gene carriers |
CN104936620B (zh) | 2012-01-19 | 2019-08-09 | 约翰霍普金斯大学 | 增强粘膜渗透的纳米粒子调配物 |
CN104363924B (zh) | 2012-03-16 | 2018-04-17 | 约翰霍普金斯大学 | 用于递送hif‑1抑制剂的控制释放调配物 |
CA2867203C (en) | 2012-03-16 | 2016-09-20 | The Johns Hopkins University | Non-linear multiblock copolymer-drug conjugates for the delivery of active agents |
US9827191B2 (en) | 2012-05-03 | 2017-11-28 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
KR102140989B1 (ko) | 2012-05-03 | 2020-08-04 | 칼라 파마슈티컬스, 인크. | 개선된 점막 수송을 나타내는 제약 나노입자 |
CA2871745C (en) | 2012-05-03 | 2023-01-24 | Kala Pharmaceuticals, Inc. | Pharmaceutical nanoparticles showing improved mucosal transport |
US11596599B2 (en) | 2012-05-03 | 2023-03-07 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
US9889208B2 (en) | 2012-05-04 | 2018-02-13 | The Johns Hopkins University | Lipid-based drug carriers for rapid penetration through mucus linings |
AU2013342275B2 (en) | 2012-11-08 | 2017-11-09 | Clearside Biomedical, Inc. | Methods and devices for the treatment of ocular diseases in human subjects |
US10568975B2 (en) | 2013-02-05 | 2020-02-25 | The Johns Hopkins University | Nanoparticles for magnetic resonance imaging tracking and methods of making and using thereof |
CA3121759C (en) | 2013-05-03 | 2024-01-02 | Clearside Biomedical, Inc. | Apparatus and methods for ocular injection |
WO2014197317A1 (en) | 2013-06-03 | 2014-12-11 | Clearside Biomedical, Inc. | Apparatus and methods for drug delivery using multiple reservoirs |
US10010447B2 (en) | 2013-12-18 | 2018-07-03 | Novartis Ag | Systems and methods for subretinal delivery of therapeutic agents |
US20150209342A1 (en) | 2014-01-28 | 2015-07-30 | Allergan, Inc. | Topical retinoid formulations, processes for making and methods of use |
WO2015127368A1 (en) | 2014-02-23 | 2015-08-27 | The Johns Hopkins University | Hypotonic microbicidal formulations and methods of use |
RU2710491C2 (ru) | 2014-06-20 | 2019-12-26 | Клиасайд Байомедикал, Инк. | Устройство для инъекции лекарственного средства в глазную ткань и способ инъекции лекарственного средства в глазную ткань |
CA2974715C (en) | 2015-01-27 | 2020-05-05 | The Johns Hopkins University | Hypotonic hydrogel formulations for enhanced transport of active agents at mucosal surfaces |
EP3340982B1 (en) | 2015-08-26 | 2021-12-15 | Achillion Pharmaceuticals, Inc. | Compounds for treatment of immune and inflammatory disorders |
AR106018A1 (es) | 2015-08-26 | 2017-12-06 | Achillion Pharmaceuticals Inc | Compuestos de arilo, heteroarilo y heterocíclicos para el tratamiento de trastornos médicos |
WO2017139375A1 (en) | 2016-02-10 | 2017-08-17 | Clearside Biomedical, Inc. | Ocular injection kit, packaging, and methods of use |
CA3062845A1 (en) | 2016-05-02 | 2017-11-09 | Clearside Biomedical, Inc. | Systems and methods for ocular drug delivery |
CN109562113A (zh) | 2016-05-10 | 2019-04-02 | C4医药公司 | 用于靶蛋白降解的螺环降解决定子体 |
EP3455218A4 (en) | 2016-05-10 | 2019-12-18 | C4 Therapeutics, Inc. | C3 CARBON-BASED GLUTARIMIDE DEGRONIMERS FOR TARGET PROTEIN REDUCTION |
CN109562107A (zh) | 2016-05-10 | 2019-04-02 | C4医药公司 | 用于靶蛋白降解的杂环降解决定子体 |
WO2018005552A1 (en) | 2016-06-27 | 2018-01-04 | Achillion Pharmaceuticals, Inc. | Quinazoline and indole compounds to treat medical disorders |
KR20190025943A (ko) | 2016-07-01 | 2019-03-12 | 쥐원 쎄라퓨틱스, 인크. | 피리미딘-기재 항증식제 |
CA3072847A1 (en) | 2016-08-12 | 2018-02-15 | Clearside Biomedical, Inc. | Devices and methods for adjusting the insertion depth of a needle for medicament delivery |
EP3650045A4 (en) * | 2017-07-04 | 2021-07-07 | Daiichi Sankyo Company, Limited | MEDICINAL PRODUCTS FOR RETINA DEGENERATIVE DISEASE ASSOCIATED WITH PHOTORECEPTOR DEGENERATION |
CN111902141A (zh) | 2018-03-26 | 2020-11-06 | C4医药公司 | 用于ikaros降解的羟脑苷脂结合剂 |
JP2021535112A (ja) | 2018-08-20 | 2021-12-16 | アキリオン ファーマシューティカルズ,インコーポレーテッド | 補体d因子の医学的障害の治療のための医薬化合物 |
EP3866773A4 (en) | 2018-10-16 | 2022-10-26 | Georgia State University Research Foundation, Inc. | CARBON MONOXIDE PRODRUGS FOR THE TREATMENT OF MEDICAL CONDITIONS |
Family Cites Families (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4997652A (en) * | 1987-12-22 | 1991-03-05 | Visionex | Biodegradable ocular implants |
US4853224A (en) * | 1987-12-22 | 1989-08-01 | Visionex | Biodegradable ocular implants |
US5164188A (en) * | 1989-11-22 | 1992-11-17 | Visionex, Inc. | Biodegradable ocular implants |
US5275820A (en) * | 1990-12-27 | 1994-01-04 | Allergan, Inc. | Stable suspension formulations of bioerodible polymer matrix microparticles incorporating drug loaded ion exchange resin particles |
US5384333A (en) * | 1992-03-17 | 1995-01-24 | University Of Miami | Biodegradable injectable drug delivery polymer |
US5178635A (en) * | 1992-05-04 | 1993-01-12 | Allergan, Inc. | Method for determining amount of medication in an implantable device |
WO1995003009A1 (en) * | 1993-07-22 | 1995-02-02 | Oculex Pharmaceuticals, Inc. | Method of treatment of macular degeneration |
US5443505A (en) * | 1993-11-15 | 1995-08-22 | Oculex Pharmaceuticals, Inc. | Biocompatible ocular implants |
US5420120A (en) * | 1993-12-17 | 1995-05-30 | Alcon Laboratories, Inc. | Anti-inflammatory glucocorticoid compounds for topical ophthalmic use |
WO1995026734A1 (en) * | 1994-04-04 | 1995-10-12 | Freeman William R | Use of phosphonylmethoxyalkyl nucleosides for the treatment of raised intraocular pressure |
ATE209907T1 (de) * | 1994-04-08 | 2001-12-15 | Atrix Lab Inc | Flüssige mittel zur wirkstoffabgabe |
US5824685A (en) * | 1995-02-01 | 1998-10-20 | The Johns Hopkins University School Of Medicine | Method of preventing proliferation of retinal pigment epithelium by retinoic acid receptor agonists |
US5718922A (en) * | 1995-05-31 | 1998-02-17 | Schepens Eye Research Institute, Inc. | Intravitreal microsphere drug delivery and method of preparation |
US5675033A (en) * | 1995-06-06 | 1997-10-07 | Allergan | 2,4-pentadienoic acid derivatives having retinoid-like biological activity |
ES2325141T3 (es) * | 1998-07-17 | 2009-08-26 | Pacira Pharmaceuticals, Inc. | Composiciones biodegradables para la liberacion controlada de sustancias encapsuladas. |
US6017938A (en) * | 1998-07-28 | 2000-01-25 | Bershad; Susan | Short contact treatment for acne |
US6378526B1 (en) * | 1998-08-03 | 2002-04-30 | Insite Vision, Incorporated | Methods of ophthalmic administration |
US6416777B1 (en) * | 1999-10-21 | 2002-07-09 | Alcon Universal Ltd. | Ophthalmic drug delivery device |
US6489335B2 (en) * | 2000-02-18 | 2002-12-03 | Gholam A. Peyman | Treatment of ocular disease |
US20030018044A1 (en) * | 2000-02-18 | 2003-01-23 | Peyman Gholam A. | Treatment of ocular disease |
CA2410052A1 (en) * | 2000-06-02 | 2001-12-13 | Zycos Inc. | Delivery systems for bioactive agents |
AR030346A1 (es) * | 2000-08-14 | 2003-08-20 | Alcon Inc | Metodo de tratamiento de desordenes neurodegenerativos de la retina y cabeza de nervio optico |
JP4061015B2 (ja) * | 2000-10-30 | 2008-03-12 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | レチノイン酸レセプターアゴニスト作用を有する薬剤含有組成物 |
US6673802B2 (en) * | 2000-12-01 | 2004-01-06 | Osi Pharmaceuticals, Inc. | Compounds specific to adenosine A3 receptor and uses thereof |
EP1383504A1 (en) * | 2001-04-26 | 2004-01-28 | Control Delivery Systems, Inc. | Sustained release drug delivery system containing codrugs |
GB0122318D0 (en) * | 2001-09-14 | 2001-11-07 | Novartis Ag | Organic compounds |
US7381426B2 (en) * | 2002-01-24 | 2008-06-03 | Southwest Research Institute | Targeted delivery of bioactive factors to the systemic skeleton |
CA2689424A1 (en) * | 2002-09-29 | 2004-04-08 | Surmodics, Inc. | Methods for treatment and/or prevention of retinal disease |
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RU2006104983A (ru) | 2006-06-27 |
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US20050009910A1 (en) | 2005-01-13 |
JP2007528851A (ja) | 2007-10-18 |
AU2004260645B2 (en) | 2010-03-11 |
US20120157499A1 (en) | 2012-06-21 |
NZ582376A (en) | 2012-02-24 |
CA2531753A1 (en) | 2005-02-10 |
MXPA06000408A (es) | 2006-03-17 |
ZA200510129B (en) | 2007-02-28 |
AU2004260645A1 (en) | 2005-02-10 |
KR20060033008A (ko) | 2006-04-18 |
IL172583A (en) | 2011-02-28 |
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