CN1950091A - 含前列腺酰胺的可生物降解眼内植入物 - Google Patents
含前列腺酰胺的可生物降解眼内植入物 Download PDFInfo
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Abstract
生物相容性眼内植入物,含有前列腺酰胺组分和可生物降解的聚合物,其中该聚合物可有效促进前列腺酰胺组分在更长一段时间内释放到眼内。前列腺酰胺组分可与可生物降解的聚合物基质如两种可生物降解的聚合物结合。该植入物可被放入眼内以治疗或减轻眼病的至少一种症状,如青光眼。
Description
技术领域
本发明涉及治疗患者眼睛的装置和方法,更具体而言,涉及眼内植入物以及制备和使用该植入物的方法,该植入物能将治疗剂延长释放到放入植入物的眼内,例如通过降低或至少维持眼内压以治疗高眼压。
背景技术
降眼压药可用于治疗多种不同高眼压病症,如外科小梁切除术后或激光小梁切除术后的高眼压发作、青光眼及术前辅助用药。
青光眼是一种眼部疾病,其特征在于眼内压升高。根据病因学,青光眼可分为原发性的或继发性的。例如,成人所患的原发性青光眼(先天性青光眼)可为开角型青光眼、急性或慢性闭角型青光眼。继发性青光眼是由已有眼病如眼葡萄膜炎、眼内肿瘤或白内障恶化所引起的。
原发性青光眼的主要原因尚不清楚。眼内压的升高是由于房水排出受阻。在慢性开角型青光眼中,前房及其解剖学结构似乎正常,但是房水排出受阻。在急性或慢性闭角型青光眼中,前房变浅,滤角变窄,并且虹膜可在施累姆管(canal of Schlemm)的入口处阻塞小梁网。瞳孔扩大可使虹膜根部向该角推进,并可产生瞳孔阻滞,由此促成急性攻击。前房角窄的眼睛易诱发不同严重程度的急性闭角型青光眼。
继发性青光眼是由于后房的房水流入前房从而进入到施累姆管这一过程受到干扰引起的。前段的炎性疾病可通过在虹膜膨起引起完全的虹膜后粘连防止房水流失(aqueous escape),并且渗出物可堵住排出通道。其它常见原因有眼瘤、白内障恶化、视网膜中央静脉阻塞、眼创伤、手术操作以及眼内出血。
将所有类型一起考虑,所有40岁以上的人中约2%的人患青光眼,并且在快速失去视力前可发展数年时间。就没有指明外科手术的情况而言,局部使用的β肾上腺素受体拮抗剂通常为选择用于治疗青光眼的药物。
前列腺素在早期被认为是可能的升眼压药,但是过去二十年里积累的证据表明某些前列腺素是高度有效的降眼压药,并且在医学上非常适用于长期治疗青光眼(参见例如Starr,M.S.Exp.Eye Res.1971,11,pp.170-177;Bito,L.Z.Biological Protection with ProstaglandinsCohen,M.M.,ed.,Baco Raton,Fla.,CRC Press Inc.,1985,pp.231-252;Bito,L.Z.,Applied Pharmacology in the Medical Treatment ofGlaucomas Drance,S.M.and Neufeld,A.H.eds.,New York,Grune&Stratton,1984,pp.477-505)。这些前列腺素包括PGF2α、PGF1α、PGE2和这些化合物的某些脂溶性酯类(如C1到C5烷基酯,例如1-异丙酯)。
在美国专利No.4,599,353中,报道了某些前列腺素,特别是PGE2和PGF2α以及后一种化合物的C1到C5烷基酯,具有降眼压活性,并推荐其用于治疗青光眼。
尽管尚不清楚精确的机制,但是最近的实验结果表明前列腺素诱导的眼内压的降低是由于葡萄膜巩膜外流增加所引起的(Nilsson et al.,Invest.Ophthalmol.Vis.Sci.28(suppl),284(1987))。
已显示PGF2α的异丙酯的降低眼压潜能显著大于母体化合物,这归因于它更为有效地穿透角膜。该化合物在1987年被描述为“在所有报道的药剂中最有潜能的降眼压药”(参见例如Bito,L.Z.,Arch.Ophthalmol.105,1036(1987)和Siebold et al.,Prodrug 5,3(1989))。
尽管前列腺素似乎没有明显的眼内副作用,但是人的眼表面(结膜)充血以及异物感一直与这类化合物、特别是PGF2α及其药物前体如其1-异丙酯的局部眼部使用相关。前列腺素用于治疗与眼压升高相关的病症如青光眼的临床潜力受到这些副作用的极大限制。
某些前列腺素及其类似物和衍生物,如PGF2α衍生的拉坦前列素(销售商标为Xalatan),已被确定为可用于治疗高眼压和青光眼的化合物。但是,拉坦前列素(美国食品和药品管理局批准的用于该适应症的第一种前列腺素)是前列腺素的衍生物,具有不受欢迎的副作用:引起5-15%人眼的虹膜棕色色素增多。颜色发生改变是由于虹膜黑色素细胞中黑素体(色素颗粒)数量增加。参见例如Watson et al.,Ophthalmology 103:126(1996)。尽管仍不清楚该效应是否具有其它以及有害的临床后果,但是仅从美容观点来看,该副作用是不受欢迎的。
欧洲专利申请0,364,417公开了用于治疗青光眼或高眼压的某些苯基和苯氧基一、三和四去甲前列腺素。
在授权予阿勒根公司的一系列美国专利申请中,公开了降眼压活性增加、并且没有副作用或者副作用显著降低的前列腺素酯。系列号No.(USSN)386,835的美国专利申请(1989年7月27日提交)涉及某些11-酰基-前列腺素,如11-新戊酰、11-乙酰基、11-异丁酰基、11-戊酰以及11-异戊酰PGF2α。系列号No.357,394的美国专利申请(1989年5月25日提交)公开了降低眼内压的15-酰基前列腺素。同样,已知前列腺素的11,15-9,15-和9,11-二酯、例如11,15-二新戊酰PGF2α具有降眼压活性。参见1990年7月27日提交、系列号No.385,645的美国专利申请,现为美国专利No.4,494,274;系列号No.386,312的美国专利申请的延续案584,370,以及系列号No.386,834的美国专利申请的延续案即系列号No.585,284的美国专利申请,现为美国专利No.5,034,413,其中母案提交于1989年7月27日。
Woodward等人的美国专利No.5,688,819和6,403,649公开了某些环戊庚酸、2-环烷基化合物或芳烷基(arylalkyl)化合物作为降眼压药。这些化合物被正确鉴定为降压脂类,可有效治疗高眼压。
作为一个实例,已发现前列腺酰胺(prostamide)类似物比马前列胺(bimatoprost)可能通过增加眼睛的房水排出而有效降低眼内压(Woodward et al.,AGN 192024(Lumigan):A Synthetic ProstamideAnalog that Lowers Primate Intraocular Pressure by Virtue of ItsInherent Pharmacological Activity,ARVO 2002;(CD-ROM):POS;Chen et al.,Lumigan:A Novel Drug for Glaucoma Therapy,Optom InPract,3:95-102(2002);Coleman et al.,A 3-Month RandomizedControlled Trial of Bimatoprost(LUMIGAN)versus CombinedTimolol and Dorzolamide(Cosopt)in Patients with Glaucoma orOcular Hypertension,Ophthalmology 110(12):2362-8(2003);Brubaker,Mechanism of Action of Bimatoprost(LumiganTM),Surv Ophthalmol45(Suppl 4):S347-S351(2001);and Woodward et al.,ThePharmacology of Bimatoprost(LumiganTM),Surv Ophthalmol 45(Suppl 4)S337-S345(2001))。
比马前列胺是天然存在的前列腺酰胺的类似物(如结构衍生物)。比马前列胺的化学名为(Z)-7-[(1R,2R,3R,5S)-3,5-二羟基-2-[1E,3S)-3-羟基-5-苯基-1-戊烯基]环戊基]-5-N-乙庚酰胺((Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-[1E,3S)-3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]-5-N-ethylheptenamide),分子量为415.58,分子式为C25H37NO4。比马前列胺可为商品名为Lumigan的局部眼用溶液(Allergan,Inc.)。每毫升溶液含有0.3mg活性剂比马前列胺,0.05mg防腐剂苯扎氯铵(BAK),还含有非活性剂氯化钠、磷酸氢二钠、柠檬酸和纯水。
许多专利已公开了放入眼内的生物相容植入物,如美国专利No.4,521,210、4,853,224、4,997,652、5,164,188、5,443,505、5,501,856、5,766,242、5,824,072、5,869,079、6,074,661、6,331,313、6,369,116和6,699,493。
提供可植入眼内的药物递送系统(如眼内植入物)以及使用该系统的方法是有益的,该系统能以持续速率或可控速率并以具有很少副作用或没有负面副作用的量延长释放诸如降压药的治疗剂。
发明内容
本发明提供新型药物递送系统以及制备和使用该系统的方法,该系统能将药物延长释放或持续释放到眼内,例如以获得一种或多种所需治疗效果。药物递送系统为可放入眼内的植入物或植入元件的形式。本系统和方法有利提供一种或多种治疗剂的延长释放。因此,眼内放入植入物的患者将在更长或延长的时间内接受到治疗量的药剂,而不需要另外给予药剂。例如,患者具有基本恒定水平的具有治疗活性的药剂,该药剂在相对较长的一段时间内(例如在放入植入物后至少约一周,如约2个月至约6个月)可持续治疗眼睛。该延长的释放时间有助于获得成功的治疗结果。
本发明所公开的眼内植入物包括治疗组分以及与治疗组分结合的药物释放维持组分。根据本发明,治疗组分包括前列腺酰胺组分,如可有效降低高压眼内的眼内压或维持其降低水平的前列腺酰胺衍生物,或基本由其构成或由其构成。药物释放维持组分与治疗组分结合,以将一定量的前列腺酰胺组分持续释放到放入植入物的眼内。在植入物放入眼内后,在长于约一周的一段时间内,一定量的前列腺酰胺组分被释放到眼内,并且它可有效治疗或减轻眼睛的眼病的至少一种症状。优选地,本发明的眼内植入物可通过降低眼睛的眼内压或将眼内压维持在较低水平有效缓解高压眼。
在一个实施方案中,眼内植入物包括前列腺酰胺组分以及可生物降解的聚合物基质。前列腺酰胺组分与可生物降解的聚合物基质结合,该基质以一定速率释放药物,可从植入物有效持续释放一定量的前列腺酰胺组分,以有效治疗眼病。眼内植入物为可生物降解的或可生物蚀解的,并且提供在延长的时间内,如超过一周,例如约三个月或更长,以及长达约六个月或更长,将前列腺酰胺组分持续释放到眼内。
上述植入物的可生物降解的聚合物组分可为可生物降解的聚合物的混合物,其中至少一种可生物降解的聚合物为分子量小于64千道尔顿(kD)的聚乳酸聚合物。或者,上述植入物可包括第一种可生物降解的聚乳酸聚合物以及不同的第二种可生物降解的聚乳酸聚合物。另外,上述植入物可包括不同可生物降解的聚合物的混合物,并且每种可生物降解的聚合物的固有粘度为约0.2分升/克(dl/g)至约1.0dl/g。
本发明所公开的植入物的前列腺酰胺组分可包括有效治疗眼病的前列腺酰胺衍生物,如前列腺酰胺类似物。前列腺酰胺衍生物的一个合适的实例为比马前列胺或其盐。另外,本植入物的治疗组分可包括一种或多种其它的和不同的可有效治疗眼病的治疗剂。
制备本植入物的方法包括使前列腺酰胺组分与可生物降解的聚合物结合或混合。然后挤压或压缩该混合物以形成单一组合物。然后可将该单一组合物进行加工以形成单个的、适于放入患者眼内的植入物。
植入物可被放入眼部以治疗多种眼病。例如,植入物可有效降低高眼压,因此可有效减轻与眼内压升高相关的眼病的至少一种症状。
本发明的药盒可包括一种或多种本植入物以及使用该植入物的说明书。例如,该说明书会阐述如何将植入物给予患者以及用植入物治疗的病症类型。
本发明所描述的每一种特征以及两种或者多种该特征的每一种组合包含在本发明的范围内,前提是该组合中的特征并不是相互矛盾的。另外,任何特征或特征的组合可被特别排除在本发明的任何实施方案外。
本发明的其他方面以及优点将特别结合附图在下面的具体实施方式以及权利要求中阐述。
具体实施方式
如本发明所述,通过使用一种或多种眼内植入物控制并持续给予治疗剂可改善对不受欢迎的眼病的治疗。植入物可包括可药用的聚合组合物,并被制备成制剂,以在更长一段时间内释放一种或多种具有药学活性的药剂,如前列腺酰胺、诸如前列腺酰胺类似物的前列腺酰胺衍生物或其它降低眼内压的药剂。该植入物可有效地将治疗有效剂量的药剂直接提供给眼的某个区域,以治疗或预防一种或多种不受欢迎的眼病。因此,通过单次给药,治疗剂将被给予至所需眼区,并在更长一段时间内得以维持,而非使患者接受反复注射或反复局部滴加给予。
本发明所公开的眼内植入物包括治疗组分以及与治疗组分结合的药物释放维持组分。根据本发明,治疗组分包括前列腺酰胺组分,或基本由其组成或由其组成。药物释放维持组分与治疗组分结合,以将有效量的前列腺酰胺组分持续释放到放入植入物的眼内。在植入物放入眼内后,一定量的前列腺酰胺组分在超过约一周的时间内被释放到眼内,并有效治疗或减轻眼病的症状。
定义
就本说明书的目的而言,除非该词的上下文意表明该词具有不同的意思,否则我们使用在本部分所定义的下述术语。
本发明所使用的“眼内植入物”指具有一定结构、大小或形状的、可放入眼内的装置或元件。眼内植入物一般与眼睛的生理条件是生物相容的并且不会引起不良副作用。眼内植入物可被放入眼内,不干扰眼睛的视力。
本发明所使用的“治疗组分”指眼内植入物的一部分,包括用于治疗眼睛的医学病症的一种或多种治疗剂或治疗物。该治疗组分可为眼内植入物的独立部分,或被均匀分布于植入物之中。治疗组分的治疗剂一般为眼科学可接受的,并且在植入物放入眼内时以不引起不良反应的形式供给。
本发明所使用的“前列腺酰胺组分”指眼内植入物的一部分,包括一种或多种前列腺酰胺、一种或多种前列腺酰胺衍生物(如前列腺酰胺类似物)、其盐及其混合物。前列腺酰胺衍生物为由前列腺酰胺衍生,并含有该前列腺酰胺基本元件的化合物,以提供治疗效果。前列腺酰胺衍生物包括前列腺酰胺类似物,并可通过使用本领域普通技术人员已知的用于评估前列腺酰胺的有效性的常规方法被鉴定。例如,治疗有效的前列腺酰胺衍生物可通过下述方法得以鉴定:将前列腺酰胺衍生物用于眼内压升高的眼睛内,并评估在使用后眼内压是否降低。前列腺酰胺组分还可含有一种或多种前列腺素类似物。
本发明所使用的“药物释放维持组分”指眼内植入物的一部分,它可有效提供植入物治疗剂的持续释放。药物释放维持组分可为可生物降解的聚合物基质,或者可为覆盖含有治疗组分的植入物的核心区域的包被物。
本发明所使用的“与……结合”意味着“与……混合”、“分散在其中”、“与……偶联”、“覆盖”或“包围”。
本发明所使用的“眼部”或“眼区”一般指眼球的任何位置,包括眼睛的前段和后段,并且通常包括但不限于眼球内的任何功能(如视力)或结构组织,或部分或全部位于眼球的内侧或外侧的组织或细胞层。眼部中的眼球区域的具体实例包括前房、后房、玻璃体腔、脉络膜、脉络膜周隙、结膜、结膜下隙、巩膜上隙、角膜内隙(intracornealspace)、角膜上隙(epicorneal space)、巩膜、睫状环、外科手术诱导的无血管区、黄斑和视网膜。
本发明所使用的“眼病”为影响或涉及眼睛、眼睛的某部分或某区域的疾病、不适或病症。广义地说,眼睛包括眼球和构成眼球的组织和液体、眼周肌肉(如斜肌和直肌)以及眼球内或与眼球相邻的部分视神经。
“前端眼病”指影响或涉及前端(即眼睛的前面)眼部或眼区的疾病、不适或病症,这些部位为例如眼周肌肉、眼睑或位于晶状体囊后壁或睫状肌前端的眼球组织或液体。因此,前端眼部疾病主要影响或涉及结膜、角膜、前房、虹膜、后房(视网膜后但在晶状体囊的后壁前面)、晶状体或晶状体囊以及使前端眼部或眼区血管化或分布神经的血管和神经。
因此,前端眼病可包括疾病、不适或病症,例如无晶状体、假晶状体、散光、眼睑痉挛、白内障、结膜疾病、结膜炎、角膜疾病、角膜溃疡、干眼综合征、眼睑疾病、泪器疾病、泪管堵塞、近视、老视、瞳孔病症、折光病症以及斜视。青光眼也被认为是前端眼病,这是因为治疗青光眼的临床目标在于降低眼睛前房中的房水高压(即降低眼内压)。
后端眼病为主要影响或涉及后端眼部或眼区的疾病、不适或病症,这些部位为例如脉络膜或巩膜(位于穿过晶状体囊后壁的平面的后端)、玻璃体、玻璃体房、视网膜、视神经(即视盘)以及使后端眼部或眼区血管化或分布神经的血管和神经。
因此,后端眼病包括疾病、不适或病症,例如急性黄斑视神经视网膜病变(acute macular neuroretinopathy)、贝切特氏病、脉络膜新生血管、糖尿病性葡萄膜炎、组织胞浆菌病、感染(如真菌或病毒引起的感染)、黄斑变性(如急性黄斑变性、非渗出性年龄相关黄斑变性以及渗出性年龄相关黄斑变性)、水肿(如黄斑水肿、囊样黄斑水肿以及糖尿病性黄斑水肿)、多病灶脉络膜炎、影响到后端眼部或眼区的眼外伤、眼瘤、视网膜病症(如视网膜中央静脉阻塞、糖尿病性视网膜病变(包括增殖性糖尿病视网膜病变)、增殖性玻璃体视网膜病变(PVR)、视网膜动脉阻塞性疾病、视网膜剥离、葡萄膜炎视网膜病变(uveitic retinal disease))、交感性眼炎、伏格特-小柳-原田三氏(VKH)综合征、葡萄膜扩散(uveal diffusion)、由眼部激光治疗引起或受其影响的后端眼病、由下列因素引起或受其影响的后端眼病:光动力学疗法、光凝固法、放射性视网膜病变、视网膜外膜病变、视网膜分支静脉阻塞、前部缺血性视神经病、非视网膜病变糖尿病性视网膜功能障碍、色素性视网膜炎和青光眼。青光眼可被认为是后端眼病,这是因为治疗目标在于防止失明的出现或降低其出现的机率(即神经保护),该失明是由于视网膜细胞或视神经细胞受到损害或该细胞丢失引起的。
术语“可生物降解的聚合物”指体内降解的聚合物,其中该一种或多种聚合物随时间其蚀解与治疗剂的释放同时出现或出现在其后。具体而言,水凝胶(如甲基纤维素,通过聚合物溶胀释放药物起作用)被特别排除于术语“可生物降解的聚合物”之外。术语“可生物降解的”和“可生物蚀解的”为同义,并在本发明中交互使用。可生物降解的聚合物可为均聚物、共聚物或含两种以上不同聚合单位的聚合物。
本发明中所使用的术语“治疗(作动词)”、“治疗(作形容词)”或“治疗(作名词)”指减轻、消除或预防眼病、眼损伤或损害,或指促进损伤或损害的眼组织的治愈。治疗通常可有效减轻眼病、眼损伤或损害的至少一个症状。
本发明中所使用的术语“治疗有效量”指治疗眼病、减轻或预防眼损伤或损害、但是并不对眼睛或眼部某一区域引起明显负面或不良副作用所需要的药剂的水平或量。考虑到上文所述,诸如前列腺酰胺或前列腺酰胺衍生物的治疗剂的治疗有效量为有效减轻眼病的至少一种症状的量。
已开发出可在不同时间内释放所负载的药物的眼内植入物。这些植入物当被放入眼内、如放入到眼睛的玻璃体中时,可在更长一段时间内(如约1周或更长时间)提供治疗水平的前列腺酰胺组分。所公开的植入物可有效治疗眼病如与眼内压升高相关的眼病,更为特别地是可减轻青光眼的至少一种症状。
在本发明的一个实施方案中,眼内植入物含有可生物降解的聚合物基质。可生物降解的聚合物基质是一类药物释放维持组分。可生物降解的聚合物基质可有效形成可生物降解的眼内植入物。可生物降解的眼内植入物含有与可生物降解的聚合物基质结合的前列腺酰胺组分。从植入物放入如眼睛的玻璃体的眼部或眼区的时间开始,该基质以在超过约一周的时间内有效维持一定量的前列腺酰胺组分释放的速率降解。
植入物的前列腺酰胺组分包括一类或多类前列腺酰胺、前列腺酰胺衍生物及其盐以及其混合物。在某些植入物中,前列腺酰胺组分含有具有化学式(I)的化合物:
其中虚线键表示可为顺式构型或反式构型的单键或双键,A为具有二个到六个碳原子的亚烷基(alkylene)或亚烯基(alkenylene),该基团可被一个或多个氧化基团(oxid radical)中断,并可被一个或多个羟基、氧代基、烷氧基或烷羧基取代,其中所述烷基含有一到六个碳原子;B为有三到七个碳原子的环烷基,或为选自具有四到十个碳原子的烃芳基和杂芳基的芳基,其中杂原子选自氮原子、氧原子和硫原子;X选自-OR4和-N(R4)2,其中R4选自氢以及具有一到六个碳原子的低级烷基、
其中R5为具有一到六个碳原子的低级烷基;Z为=O或代表两个氢自由基(hydrogen radicals);R1和R2中有一个为=O、-OH或-O(CO)R6基,另一个为-OH或-O(CO)R6,或者R1为=O,R2为H,其中,R6为具有1到约20个碳原子的饱和或不饱和开链烃基或为-(CH2)mR7,其中m为0或1到10的整数,R7为具有三到七个碳原子的环烷基,或上述限定的烃芳基或杂芳基,或为其可药用的盐类,但是前提是当B未被含有杂原子的侧基取代,并且Z为=O时X不是-OR4。
本发明的化合物的可药用酸加成盐为由酸形成的盐类,该酸形成含有可药用阴离子的无毒加成盐,例如氢氯化物、氢溴化物、氢碘化物、硫酸盐或硫酸氢盐、磷酸盐或酸式磷酸盐、乙酸盐、马来酸盐、延胡索酸盐、草酸盐、乳酸盐、酒石酸盐、柠檬酸盐、葡萄糖酸盐、蔗糖盐以及对甲苯磺酸盐。
在更为具体的植入物中,前列腺酰胺组分的化合物具有如下化学式(II):
其中,y为0或1,x为0或1,并且x+y并不全为1,Y选自下列基团:烷基、卤素、硝基、氨基、巯基、羟基、烷氧基、烷羧基以及卤素取代的烷基,其中所述烷基包括一到六个碳原子,n为0或1到3的整数,并且R3为=O、-OH或-O(CO)R6。
在其它植入物中,前列腺酰胺组分的化合物具有如下化学式(III):
其中阴影线表示α构型,实心三角表示β构型。
在某些植入物中,前列腺酰胺组分的化合物具有如下化学式(IV):
其中Y1为Cl或三氟甲基,例如具有如下化学式(V)的化合物:
及其9-和/或11-和/或15酯。
在至少一类眼内植入物中,前列腺酰胺组分含有具有如下化学式(VI)的化合物:
具有化学式VI的化合物也被称为比马前列胺,为公众可得的商品名为Lumigan的局部眼用溶液(Allergan,Inc.,CA)。
因此,植入物可含有治疗组分,该治疗组分含有比马前列胺、其盐或其混合物,或基本由上述物质组成或由上述物质组成。
前列腺酰胺组分可为微粒或粉剂形式,可被可生物降解聚合物基质所包埋。通常,前列腺酰胺颗粒的有效平均尺寸小于约3000纳米。在某些植入物中,该颗粒的有效平均颗粒尺寸数量级约小于3000纳米。例如,颗粒的有效平均颗粒尺寸小于约500纳米。在其它植入物中,颗粒的有效平均颗粒尺寸小于约400纳米,在另外一些实施方案中,尺寸小于约200纳米。
植入物的前列腺酰胺组分优选以重量计占植入物的约10%到90%。更优选地,前列腺酰胺组分以重量计占植入物的约20%到约80%。在一优选的实施方案中,前列腺酰胺组分以重量计占植入物的约20%(如15%-25%)。在另一实施方案中,前列腺酰胺组分以重量计占植入物的约50%。
用于植入物的合适的聚合材料或组合物,包括与眼睛相容(即生物相容)的材料,以不显著干扰眼睛的功能或生理。该材料优选至少部分可生物降解或可生物蚀解,更优选基本完全可生物降解或可生物蚀解。
有用的聚合材料的实例包括但不限于诸如来源于和/或包括有机酯类和有机醚类的材料,在该材料降解时,会产生生理上可接受的包括单体在内的降解产物。另外,也可以使用来源于和/或包括酸酐、酰胺、原酸酯等自身或者它们与其它单体结合的聚合材料。聚合材料可为加聚物或缩聚物,优选缩聚物。聚合材料可交联,也可不交联,例如至多轻度交联,如小于约5%或小于约1%的聚合材料交联在一起。多数情况下,除了碳和氢,聚合物还包括氧和氮中的至少一种,优选氧。氧可以氧基形式,如羟基或醚、羰基,如非氧代羰基(如羧酸酯)等等。氮可以酰胺、氰基和氨基的形式存在。Heller,BiodegradablePolymers in Controlled Drug Delivery,In:CRC Critical Reviews inTherapeutic Drug Carrier Systems,Vol.1,CRC Press,Boca Raton,FL1987,pp 39-90中描述的聚合物可用于本发明植入物,该文章描述了用于控释给药的包埋。
所研究的还有羟基脂族羧酸(hydroxyaliphatic carboxylic acid)的聚合物(均聚物或共聚物)和多糖。所研究的聚酯包括D-乳酸、L-乳酸、外消旋乳酸、羟乙酸的聚合物、聚已酸内酯及其组合物。一般而言,通过采用L-乳酸酯或D-乳酸酯能得到缓慢蚀解的聚合物或聚合材料,而外消旋乳酸酯显著提高了蚀解作用。
有用的多糖包括但不限于藻酸钙以及功能化的纤维素,特别是羧甲基纤维素酯,其特征为水不溶性,例如分子量为约5kD到500kD。
所研究的其他聚合物包括但不限于生物相容以及可生物降解和/或生物蚀解的聚乙烯醇、聚酯、聚醚及其组合物。
用于本发明的聚合物或聚合材料的某些优选特征可包括生物相容性,与治疗组分的相容性、聚合物在制备本发明的药物递送系统中使用简便、在生理环境下的半衰期至少约6小时,优选超过约1天,不显著提高玻璃体的粘度以及在水中的不可溶性。
所包括的用于形成基质的可生物降解聚合材料易受酶学不稳定性或水解不稳定性的作用。水溶性聚合物可与水解的或生物降解的不稳定交联物发生交联以提供有用的水不溶性聚合物。稳定程度变化范围较大,这取决于单体的选择、使用了均聚物还是共聚物、是否使用了聚合物的混合物,以及该聚合物是否包括末端酸性基团。
与控制聚合物的生物降解性并由此延长植入物的释放同等重要的是植入物中所使用的聚合组合物的相对平均分子量。不同分子量的相同或不同聚合组合物可包含在该植入物中以调节释放模式。在某些植入物中,聚合物的相对平均分子量为约9至约64kD,通常为约10至约54kD,更通常为约12至约45kD。
在某些植入物中,使用了羟乙酸和乳酸的共聚物,此时生物降解的速率受到羟乙酸与乳酸的比率的调节。降解最快的共聚物其羟乙酸和乳酸的量几乎相等。均聚物或比率不同的共聚物更容易对抗降解。羟乙酸与乳酸的比率还会影响植入物的脆性,此时更为柔韧的植入物是更大的几何形状所需要的。聚乳酸聚羟乙酸(PLGA)共聚物的聚乳酸百分比可为0-100%,优选约15-85%,更优选约35-65%。在某些植入物中使用了50/50PLGA共聚物。
眼内植入物的可生物降解聚合物基质可含有两种或多种可生物降解的聚合物的混合物。例如,植入物可含有第一种可生物降解的聚合物和不同的第二种可生物降解的聚合物的混合物。一种或多种可生物降解的聚合物可具有末端酸性基团。
药物从可蚀解聚合物释放是几种机制或其组合的结果。这些机制中的一些包括从植入物的表面脱附、溶解、通过水化聚合物的孔道扩散以及蚀解。蚀解可为整体或表面或其组合。如上所述,在眼内植入物被植入眼内后,其基质以有效维持一定量的前列腺酰胺组分释放的速率将药物释放超过一周。在某些植入物中,植入后治疗量的前列腺酰胺组分释放不超过约30-35天。例如,植入物可包括比马前列胺,并且在植入物放置到眼内后,其基质以有效维持治疗有效量的比马前列胺释放约1个月的速率降解。作为另一个实例,植入物可含比马前列胺,并且基质以有效维持治疗有效量的比马前列胺释放超过四十天(如约六个月)的速率释放药物。
可生物降解的眼内植入物的一个实例包括与可生物降解的聚合物基质结合的前列腺酰胺组分,该聚合物基质含不同的可生物降解聚合物的混合物。至少有一种可生物降解的聚合物为分子量约为63.3kD的聚丙交酯。第二种可生物降解的聚合物为分子量约为14kD的聚丙交酯。从植入物放入眼内后,该混合物可有效维持治疗有效量的前列腺酰胺组分释放超过约一个月的一段时间。
可生物降解的眼内植入物的另一实例含有与可生物降解的聚合物基质结合的前列腺酰胺组分,该聚合物基质含有不同的可生物降解的聚合物的混合物,每一种可生物降解的聚合物的固有粘度为约0.16dl/g到约1.0dl/g。例如,一种可生物降解的聚合物的固有粘度可为约0.3dl/g。第二种可生物降解的聚合物的固有粘度可为约1.0dl/g。其它植入物可含有固有粘度介于约0.2dl/g到0.5dl/g之间的可生物降解的聚合物。上文所鉴定的固有粘度可在0.1%氯仿中于25℃测定。
一个特殊的植入物含有与两种不同聚丙交酯聚合物的组合物结合的比马前列胺。比马前列胺以重量计占植入物的约20%。一种聚丙交酯聚合物的分子量为约14kD,固有粘度为约0.3dl/g;另一种聚丙交酯聚合物的分子量为约63.3kD,固有粘度为约1.0dl/g。这两种聚丙交酯聚合物在植入物中的比率为1∶1。该植入物可有效释放比马前列胺超过2个月。该植入物为通过挤压法生产的棒状或丝状形式。
前列腺酰胺组分从含有可生物降解聚合物基质的眼内植入物的释放可包括初始突然释放,然后所释放的前列腺酰胺组分的量逐渐增加,或者该释放可包括初始前列腺酰胺的释放的延滞,然后释放增加。植入物基本完全降解时,已被释放的前列腺酰胺组分的百分比为约100。与现有的植入物相比,本发明所公开的植入物直到被放入眼内约一周后才完全释放,或者说释放约100%的前列腺酰胺组分,。
在植入物的有效期间内以相对稳定的速率从植入物释放前列腺酰胺组分是合乎需要的。例如,在植入物的有效期间内以每天约0.01μg到约2μg的量释放前列腺酰胺组分。但是,释放速率可根据可生物降解聚合物基质的制备方法升高或降低。另外,前列腺酰胺组分的释放曲线可包括一个或多个线性部分和/或一个或多个非线性部分。优选地,一旦植入物开始降解或蚀解,释放速率大于0。
植入物可为均一的,即具有均匀分布在聚合基质中的一种或多种活性剂,或者植入物可为胶囊式的,此时活性剂部分被聚合基质包裹。由于制作简单,通常优选均一式而非胶囊式植入物。但是,由于胶囊式植入物所提供的可控性更大、储药型植入物在某些情况下是有益的,此时药物的治疗水平下降到一窄窗内。另外,包括前列腺酰胺组分在内的治疗组分可以非均一形式分布在基质中。例如,植入物可包括相对于植入物的第二部分前列腺酰胺组分的浓度更高的部分。
本发明所公开的眼内植入物可通过注射针给予,其大小介于约5μm到约10mm之间,或介于约10μm到约1mm之间,也可通过外科手术植入,其大小大于1mm或大于2mm,如3mm或最高达10mm。就注射针注射式植入物而言,该植入物可具有任何合适的长度,只要这样植入物的直径使得植入物可在注射针中移动。例如,长度为约6mm到约7mm的植入物可被注射到眼内。通过注射针给予的植入物应该具有小于注射针内径的直径。在某些植入物中,直径小于约500μm。人的玻璃体腔能容纳相对较大的不同几何形状的植入物,例如其长度为1到10mm。植入物可为圆柱形药片(如棒剂),大小约为2mm×0.75mm(直径)。或者植入物可为长度为约7mm到约10mm并且直径为约0.75mm到约1.5mm的圆柱形药片。
植入物至少还有几分柔韧度,这样有助于将植入物嵌入眼内(如玻璃体内),并有助于容纳植入物。植入物的总重量通常为约250-5000μg,更优选约500-1000μg。例如,植入物可为约500μg或约1000μg。对除人外的个体而言,植入物的大小以及总重量可更大也可更小,这取决于个体类型。例如,人的玻璃体容积约为3.8ml,而马的约为30ml,大象的约为60-100ml。对其它动物而言,大小适用于人的植入物可相应增大或缩小,例如就用于马的植入物而言可增大约8倍,或者,例如就用于大象的植入物而言可增大约26倍。
因此,可以制备植入物,其中心可为一种材料,表面可为具有相同或不同组成的一层或多层,并且各层可交联,或者分子量不同、密度或孔隙率不同等等。例如,在需要快速释放大量初始药物时,中心可为聚乳酸-聚羟乙酸共聚物包被的聚乳酸,以提高初始降解速率。或者,中心可为聚乳酸包被的聚乙烯醇,这样一旦聚乳酸外壳降解,中心将溶解并快速流出眼睛。
植入物可为任何几何形状,包括纤维状、片层状、薄膜状、微球状、球状、圆盘状、斑状等。植入物大小的上限可由下述因子决定:植入物的耐受性、嵌入的尺寸限制、操作简易性等。使用片层或薄膜时,为操作简单,它们的大小至少约为0.5mm×0.5mm,通常约为3-10mm×5-10mm,厚度约为0.1-1.0mm。使用纤维时,纤维直径一般为约0.05到3mm,并且纤维的长度一般为约0.5-10mm。球形直径为约0.5μm到4mm,并且其体积与其它形状颗粒相当。
植入物的大小以及形式还可用于控制释放速率、治疗时间以及植入部位的药物浓度。较大植入物可递送成比例增多的剂量,但根据表面质量比,可能具有较慢的释放速率。选择特定尺寸和几何形状的植入物以适合植入部位。
前列腺酰胺组分、聚合物以及任何其它改性剂的比例可通过制备不同比例的几种植入物通过经验决定。USP批准的溶解或释放检验的方法可用于测量释放速率(USP 23;NF 18(1995)pp.1790-1798)。例如,使用无限沉降法(infinite sink method),将已知重量的植入物样本加入已知体积的溶液中(含有溶于水的0.9%NaCl),其中溶液体积为在释放后药物浓度小于饱和度的5%。将混合物保持在37℃并缓慢搅拌保持植入物悬浮。溶解药物出现率的时间函数可通过本领域已知的各种方法追踪,如分光光度计法、HPLC、质谱法等等,直到吸光度变得恒定或者超过90%的药物已被释放。
除了包含在本发明所公开的眼内植入物的前列腺酰胺或前列腺酰胺衍生物外,眼内植入物还可含有一种或多种其它眼科学上可接受的治疗剂。例如,植入物可含有一种或多种抗组胺、一种或多种抗生素、一种或多种β阻断剂、一种或多种类固醇、一种或多种抗肿瘤药、一种或多种免疫抑制剂、一种或多种抗病毒剂、一种或多种抗氧化剂及其混合物。
可用于本系统的药理剂或治疗剂包括但不限于在美国专利NO.4,474,451第4-6栏以及NO.4,327,725第7-8栏所公开的药理剂或治疗剂。
抗组胺的实例包括但不限于loradatine、羟嗪、苯海拉明、氯苯那敏、溴苯那敏、赛庚啶、特非那定、氯马斯汀、曲普利定、氯苯吡醇胺、二苯拉林、苯茚胺、阿扎他定、曲吡那敏、右氯苯那敏、右溴苯那敏、甲吡吩嗪以及trimprazine、多西那敏、非尼拉敏、新安替根、chiorcyclizine、松齐拉敏、及其衍生物。
抗生素的实例包括但不限于头孢唑啉、头孢拉定、头孢克洛、头孢砒硫、头孢唑肟、头孢哌酮、头孢替坦、cefutoxime、头孢氨噻、头孢羟氨苄、头孢他啶、头孢氨苄、头孢噻吩、头孢羟唑、头孢西丁、头孢尼西、头孢雷特、头孢曲松、头孢羟氨苄、头孢拉定、头孢氨呋肟、氨苄青霉素、阿莫西林、环青霉素、氨苄青霉素、青霉素G、青霉素V钾、哌拉西林、苯唑西林、巴氨西林、氯唑西林、替卡西林、阿洛西林、羧苄西林、甲氧苯青霉素、萘夫西林、红霉素、四环素、多西环素、米诺环素、氨曲南、氯霉素、盐酸环丙沙星、氯林肯霉素、甲硝唑、艮他霉素、林可霉素、妥布拉霉素、万古霉素、硫酸多粘菌素B、粘菌素M、粘菌素、阿奇霉素、奥格门汀、磺胺甲噁唑、甲氧苄啶及其衍生物。
β阻断剂的实例包括醋丁洛尔、阿替洛尔、拉贝洛尔、美托洛尔、普萘洛尔(propranolol)、噻吗洛尔及其衍生物。
类固醇的实例包括皮质类固醇,如可的松、泼尼松龙、氟甲松龙(flurometholone)、地塞米松、甲羟松、氯替泼诺、氟噁米松、氢化可的松、泼尼松、倍他米松、泼尼松、甲基氢化泼尼龙、已酸丙炎松、醋酸对氟米松、二氟拉松、醋酸氟轻松(fluocinonide)、氟轻松(fluocinolone)、去炎松、其衍生物及其混合物。
抗肿瘤药的实例包括阿霉素、环磷酰胺、放线菌素、博莱霉素、柔红霉素(duanorubicin)、羟基红比霉素、表阿霉素、丝裂霉素、甲氨蝶呤、氟尿嘧啶、卡铂、卡莫斯汀(BCNU)、司莫司汀、顺铂、依托泊苷、干扰素、喜树碱及其衍生物、苯芥胆甾醇、紫杉醇及其衍生物、泰索帝(taxotere)及其衍生物、长春碱、长春新碱、他莫西芬、依托泊苷、哌泊舒凡、环磷酰胺和氟他胺、及其衍生物。
免疫抑制剂的实例包括环孢霉素A(cyclosporine)、硫唑嘌呤、他克莫司及其衍生物。
抗病毒剂的实例包括γ干扰素、齐多夫定、盐酸金刚烷胺、利巴韦林、阿昔洛韦、缬昔洛韦、二脱氧胞苷、膦甲酸(phosphonoformicacid)、更昔洛韦及其衍生物。
抗氧化剂的实例包括抗坏血酸、α-生育酚、甘露醇、还原谷胱甘肽、各种类胡萝卜素、半胱氨酸、尿酸、牛磺酸、酪氨酸、超氧化歧化酶、叶黄素、玉米黄素、隐黄素(cryotpxanthin)、虾青素(astazanthin)、番茄红素、N-乙酰半胱氨酸、肌肽、γ-谷氨酰半胱氨酸、橡素(quercitin)、乳铁蛋白、二氢硫辛酸、柠檬酸盐、银杏叶提取物、茶叶儿茶素、越桔提取物、维生素E或维生素E的酯类、棕榈酸视黄酯及其衍生物。
其它治疗剂包括角鲨胺(squalamine)、碳酸酐酶抑制剂、α2肾上腺素能受体激动剂、抗寄生虫药、抗真菌药及其衍生物。
用于植入物的活性药剂的量(分别或者其组合)随着所需要的有效剂量以及所需要的从植入物释放的速率的变化而有很大变化。通常药剂至少约为植入物的1%(重量)、更通常至少为约10%(重量),并且通常不超过植入物的约80%(重量),更通常不超过约40%(重量)。
本发明中的一些植入物可包括前列腺酰胺组分,该组分含有两种或多种不同前列腺酰胺衍生物的组合物。一种植入物可含有比马前列胺以及拉坦前列素的组合物。另一种植入物可含有比马前列胺和曲伏前列素的组合物。
如本发明所述,本植入物可含有其它治疗剂。例如,一种植入物可含有比马前列胺和β肾上腺素能受体拮抗剂的组合物。更具体而言,植入物可含有比马前列胺和Timolol的组合物。或者,植入物可含有比马前列胺和碳酸酐酶抑制剂的组合物。例如,植入物可含有比马前列胺和多佐胺(Trusopt)的组合物。
除了治疗组分外,本发明所公开的眼内植入物可包括有效量的缓冲剂、防腐剂等。合适的水溶性缓冲剂包括但不限于强碱和碱土金属的碳酸盐、磷酸盐、碳酸氢盐、柠檬酸盐、硼酸盐、乙酸盐、琥珀酸盐等,如磷酸钠、柠檬酸钠、硼酸钠、乙酸钠、碳酸氢钠、碳酸钠等。这些药剂的量优选足以将系统的pH维持在约2到约9,更优选约4到约8。因此,这种缓冲剂以重量计可约为植入物总重的5%。合适的水溶性防腐剂包括亚硫酸氢钠、硫酸氢钠、硫代硫酸钠、抗坏血酸、苯扎氯胺、三氯叔丁醇、硫柳汞、醋酸苯汞、硼酸苯汞、硝酸苯汞、对羟苯甲酸酯、对羟基苯甲酸甲酯、聚乙烯醇、苯甲醇、苯基乙醇等及其混合物。这些药剂可以重量计0.001到约5%、优选以重量计0.01到约2%的量存在。在至少一种本发明的植入物中,如当前列腺酰胺组分基本由比马前列胺组成时,植入物中具有防腐剂苯扎氯铵。
在某些情况下,可利用采用相同或不同药理剂的植入物的混合物。通过这种途径,可实现释放曲线的叠加,单次给药实现两阶段或三阶段释放,此时释放模式可有很大不同。
另外,如在美国专利No.5,869,079中所描述的释放调节剂可包含在本植入物中。所使用的释放调节剂的量取决于所需释放模式、调节剂的活性,还取决于没有调节剂时前列腺酰胺组分的释放模式。诸如氯化钠和氯化钾的电解质也可包括在本植入物中。当缓冲剂或增强剂为亲水性时,它们还可起到释放加速剂的作用。亲水性添加剂通过加快围绕在药物颗粒周围的材料的溶解起到提高释放速率的作用,这增加了所暴露的药物的表面面积,由此提高药物生物蚀解的速率。相似地,疏水性缓冲剂或增强剂溶解更缓慢,减慢了药物颗粒的暴露,由此减慢药物生物蚀解的速率。
在某些植入物被植入眼内后,含比马前列胺和可生物降解的聚合物基质的植入物能释放或递送量约为0.1mg到约0.5mg的比马前列胺达约3-6个月。植入物可被制备为棒状或薄片。棒状植入物可来自从720μm喷嘴压出的细丝并被剪成1mg大小。薄片状植入物可为圆盘状,直径约为2.5mm,厚度约为0.127mm,重量约为1mg。
可使用各种技术生产本发明所描述的植入物。有用的技术包括但不必限于溶剂蒸发法、相分离法、界面法、成形法、注射成形法、挤压法、共挤压法、刻压法(carver press method)、模切法(die cuttingmethod)、热压缩法(heat compression)及其组合方法等。
具体的方法在美国专利No.4,997,652中有描述。可使用挤压法避免在制造中使用溶剂。在使用挤压法时,选择聚合物和药物使得在制造所需温度条件下稳定存在,通常至少为约85℃。挤压法使用的温度为约25℃到约150℃,更优选约65℃到约130℃。可通过将温度设为约60℃到约150℃(如约130℃)将药物/聚合物混合0到1小时、0到30分钟或5-15分钟,以生产植入物。例如,时间可为约10分钟,优选约0到5min。然后在温度约60℃到约130℃(如约75℃)挤压植入物。
另外,可共挤压植入物,这样在制造植入物的过程中在核心区外形成了包被层。
压缩法可用于制备植入物,通常用于生产与挤压法所生产的植入物相比具有较快释放速率的植入物。压缩法可使用的压力约为50-150psi,更优选约70-80psi,更优选约76psi,并且使用的温度为约0℃到约115℃,更优选约25℃。
通过多种方法,包括在巩膜切一个2-3mm的切口,然后通过镊子或套针放置,可将本发明的植入物放入眼内,例如可放入眼睛的玻璃体腔内。美国专利公布文本No.2004/0054374公开了可用来将植入物放入眼内的装置的一个实例。放置方法可影响治疗组分或药物释放动力学。例如,与用镊子放置相比,用套针递送植入物可使得植入物被放置到玻璃体的较深处,这使得植入物更接近玻璃体的边缘。植入物的位置可影响元件周围的治疗组分或药物的浓度梯度,由此影响释放速率(如放置到更接近玻璃体边缘的元件可减缓释放速率)。
本发明的植入物被制成释放一定量的有效治疗眼病(如通过减轻至少一种眼病症状)的前列腺酰胺组分。更具体而言,植入物可用于治疗青光眼的方法中,如开角型青光眼、高眼压、接受开放虹膜切开术的慢性闭角型青光眼、假表皮脱落性青光眼以及色素性青光眼。通过将含有前列腺酰胺组分的植入物植入眼睛的玻璃体,认为前列腺酰胺组分可有效提高房水流动由此降低眼内压。
还可制备本发明所公开的植入物以释放上述前列腺酰胺组分或其它治疗剂,由此预防或治疗下列疾病或病症:
黄斑病变/视网膜变性: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)、脉络膜新生血管形成、糖尿病视网膜病变、急性黄斑视神经视网膜病变、中心性浆液性脉络膜视网膜病变、囊样黄斑水肿、糖尿病性黄斑水肿。
葡萄膜炎/视网膜炎/脉络膜炎:急性多病灶鱼鳞板状色素上皮病、贝切特病、鸟枪弹样视网膜脉络膜病变(BirdshotRetinochoroidopathy)、感染性疾病(梅毒、莱姆病、肺结核、弓形虫病)、中间葡萄膜炎(扁平部睫状体炎)、多病灶脉络膜炎、多发性一过性白点综合征(MEWDS)、眼部类肉瘤、后巩膜炎、匐行性脉络膜炎、视网膜下纤维化以及葡萄膜炎综合征、伏格特-小柳-原田三氏综合征。
血管病变/渗出性病变:冠茨病、旁中心凹毛细血管扩张、乳头视网膜炎、霜样树枝状血管炎(Frosted Branch Angitis)、镰刀细胞视网膜病变(Sickle Cell Retinopathy)和其它血红蛋白病变、血管样纹、家族性渗出性玻璃体视网膜病变。
创伤/外科手术:交感神经眼炎、葡萄膜视网膜疾病(UveiticRetinal Disease)、视网膜剥离、创伤、激光、PDT、光凝固法、外科手术期间血液灌流不足、辐射性视网膜病变、骨髓移植视网膜病变。
增生性病变:增生性玻璃体视网膜病变(Proliferative VitrealRetinopathy)和视网膜前膜(Epiretinal Membrane)、增生性糖尿病性视网膜病变。
感染性疾病:眼组织胞浆菌病、眼弓蛔虫病、眼假组织胞浆菌病综合征(POHS)、眼内炎、弓形虫病、与HIV感染相关视网膜疾病、与HIV感染相关脉络膜疾病、与HIV感染相关葡萄膜炎性疾病、病毒性视网膜炎、急性视网膜坏死、进行性外部视网膜坏死(ProgressiveOuter Retinal Necrosis)、真菌性视网膜疾病、眼梅毒、眼内结核、弥散性单侧亚急性视神经视网膜炎、蝇蛆病。
遗传性疾病:与视网膜营养不良相关的全身性病变(SystemicDisorders with Accosiated Retinal Dystrophies)、先天性静止性夜盲、锥体营养不良、黄点状眼底、贝斯特病、视网膜色素上皮细胞模式性营养不良(Pattern Dystrophy of the Retinal Pigmented Epithelium)、X连锁视网膜劈裂症(X-Linked Retinoschisis)、索斯比氏眼底营养不良、良性同心性黄斑病变(Benign Concentric Maculopathy)、比蒂氏结晶型营养不良(Bietti′s Crystalline Dystrophy)、弹性假黄色瘤。
视网膜撕裂/视网膜裂孔:视网膜剥离、黄斑裂孔、巨型视网膜撕裂。
肿瘤:与肿瘤相关的视网膜病变、先天性视网膜色素上皮细胞肥大、后葡萄膜黑色素瘤(Posterior Uveal Melanoma)、脉络膜血管瘤、脉络膜骨瘤、脉络膜转移、视网膜和视网膜色素上皮细胞的混合性错构瘤(Combined Hamartoma of the Retina and Retinal PigmentedEpithelium)、视网膜母细胞瘤、眼底血管增生肿瘤(VasoproliferativeTumors of the Ocular Fundus)、视网膜星形细胞瘤、眼内淋巴瘤。
杂症:点状内脉络膜病变、急性后极部多发性鳞状色素上皮病变,近视性视网膜变性、急性视网膜色素上皮炎等等。
在一个实施方案中,植入物(如本发明公开的植入物)可给予人或动物(优选人或动物活体)患者眼睛的后段。在至少一个实施方案中,给予植入物无需接近眼睛的视网膜下隙。例如,治疗患者的方法可包括将植入物直接放入眼睛的后房。在其它实施方案中,治疗患者的方法可包括通过下述注射方法中的至少一种将植入物给予患者:玻璃体内注射、结膜下注射、Tenon囊下注射、眼球后注射以及脉络膜上注射。
在至少一个实施方案中,降低患者眼睛的眼内压的方法包括通过下述注射方法中的至少一种将一个或多个含上述前列腺酰胺组分的植入物给予患者:玻璃体内注射、结膜下注射、Tenon囊下注射、眼球后注射以及脉络膜上注射。注射器装置包括尺寸合适的注射针,例如22号注射针、27号注射针或30号注射针,它们可有效用于将组合物注射到人或动物眼睛的后段。由于前列腺酰胺组分可从植入物延长释放,通常不需要反复注射。
另外,就治疗眼病的二联疗法而言,该方法可包括一步或多步将其它治疗剂给予眼睛,例如通过局部给予含噻吗洛尔、多佐胺以及拉坦前列素等的组合物。
本发明的另一方面,提供了治疗眼睛的眼病的药盒,包括:a)含有释放时间更长的植入物的容器,该植入物含有含前列腺酰胺组分如比马前列胺(Lumigan)的治疗组分和药物释放维持组分;以及b)使用说明书。说明书可包括如何处理植入物、如何将植入物嵌入眼部的步骤以及使用植入物所期望得到的结果。
在某些植入物中,植入物含基本由比马前列胺、其盐及其混合物组成的治疗组分和可生物降解的聚合物基质。可生物降解的聚合物基质基本由PLA、PLGA或其组合物组成。当植入物被放入眼内时,植入物在放入眼内后约1天内释放约40%到约60%比马前列胺,以提供负载剂量的比马前列胺。然后,植入物每天释放约1%到约2%比马前列胺,以提供持续的治疗效果。该植入物可有效降低眼内压并维持降低的眼内压,如维持小于约15mm Hg的眼内压几个月,并且可能维持一年或两年。
可制成本发明所公开的其它植入物,这样在被放入眼睛的两天内从植入物释放的前列腺酰胺组分的量小于植入物内前列腺酰胺组分的总量的约95%。在某些植入物中,直到植入物被放入眼内约一周后才有95%的前列腺酰胺组分被释放。在某些植入物中,在植入物放入眼内约1天里释放约50%的前列腺酰胺组分,并且约2%在植入物被放入眼内后释放约1个月。在其它植入物中,在植入物被放入眼内后约1天内释放约50%的前列腺酰胺组分,约1%在植入物被放入眼内后释放约两个月。
实施例1 含比马前列胺和可生物降解的聚合物基质的植入物的制备和检验
通过组合比马前列胺和可生物降解的聚合物组合物制备了可生物降解的植入物。将800mg聚乳酸(PLA)与200mg比马前列胺组合。然后将组合物溶于25毫升二氯甲烷。将混合物45℃在真空放置过夜以蒸发二氯甲烷。所得到的混合物为铸塑板形式。剪切铸塑板并在有干冰的高剪切力的碾磨器中碾磨,直到颗粒可通过孔径约为125μm的筛网。使用高压液相色谱法(HPLC)分析微粒中的比马前列胺的百分比。使用透析法表征从微粒中释放的比马前列胺的释放百分率。HPLC分析了所回收的颗粒中残留的比马前列胺的百分率。
表1描述了释放模式。
时间点 | 消耗时间(天) | 释放百分率 | 百分率/天 |
起点 | 0 | - | - |
1 | 1.03 | 47.51 | 47.51 |
2 | 2.03 | 47.92 | 0.41 |
3 | 3.03 | 49.99 | 2.07 |
4 | 4.03 | 50.09 | 0.10 |
5 | 7.04 | 50.90 | 0.82 |
比马前列胺的负载百分比为14.93%。残留在回收的释放颗粒中的比马前列胺的百分比为4.94%。
实施例2 挤压法和压缩法制造含比马前列胺的可生物降解的眼内植入物
在研钵中将比马前列胺与可生物降解的聚合组合物组合。然后在设定为约96RPM的振荡器上将组合物混合约15分钟。从研钵壁上刮下粉状混合物,然后再混合15分钟。在特定温度下将混合粉状混合物总共加热30分钟,达到半融状态,形成聚合物/药物熔融物。
按照如下步骤制造棒剂:使用9号聚四氟乙烯(PTFE)管将聚合物/药物熔融物作成颗粒状,将颗粒装入桶中并在特定核心挤压温度下将材料挤压形成细丝。然后将细丝剪切成约1mg大小的植入物或药物递送系统。该棒剂大小为约2mm长×0.72mm直径。棒剂植入物重为约900μg到1100μg。
按照如下步骤形成薄片:用刻压机在特定温度下将聚合物熔融物压平,然后将压平的材料剪切成薄片,每个重约1mg。该薄片的直径约为2.5mm,厚度约为0.13mm。薄片植入物重约为900μg到1100μg。
在37℃将每一植入物放入装有10ml磷酸盐缓冲液的24ml螺旋盖小瓶中进行体外释放检验。在第1、4、7、14、28天以及此后每两个星期,取出1mL等份并换上相同体积的新鲜培养基。
用HPLC进行药物分析,该HPLC由Waters 2690 SeparationModule(或2696)以及Waters 2996 Photodiode Array Detector组成。30℃加热的Ultrasphere(C-18(2),5μm;4.6×150mm柱)用于分离,检测器设为约264nm。流动相为(10∶90)MeOH缓冲的流动相,流速为1mL/min,并且每个样本的总运行时间为12min。缓冲的流动相可含有(68∶0.75∶0.25∶31)13mM 1-庚烷磺酸钠盐-冰醋酸-三乙胺-甲醇。通过计算在一定体积的介质中的药物随着时间变化而释放的量(μg/天)测定释放速率。
可用于植入物的聚合物可从Boehringer Ingelheim获得。聚合物的实例包括RG502、RG752、R202H、R203和R206以及Purac PDLG(50/50)。RG502为(50∶50)聚(D,L-丙交酯-共-乙交酯),RG752为(75∶25)聚(D,L-丙交酯-共-乙交酯),R202H为具有酸性末端基团或末端酸性基团的100%聚(D,L-丙交酯),R203和R206均为100%聚(D,L-丙交酯)。Purac PDLG(50/50)为(50∶50)聚(D,L-丙交酯-共-乙交酯)。RG502、RG752、R202H、R203、R206和Purac PDLG的固有粘度分别为0.2、0.2、0.2、0.3、1.0和0.2dL/g。RG502、RG752、R202H、R203、R206和Purac PDLG的平均分子量分别为11700、11200、6500、14000、63300和9700道尔顿。
实施例3 治疗青光眼的比马前列胺/PLA/PLGA眼内植入物
一位双眼患青光眼的72岁女性每只眼内被放入含比马前列胺和PLA与PLGA的组合物的眼内植入物。植入物重约1mg,含约500mg比马前列胺。使用注射器将一个植入物放入每只眼睛的玻璃体内。约两天后,患者报告说眼部不适得到显著缓解。检查表明眼内压降低,在8:00AM所测量的平均眼内压从28mm Hg降低到14.3mm Hg。患者每月被监测一次,持续了约六个月。低于15mm Hg的眼内压水平保持了六个月,并且患者报告说眼部不适得到缓解。
实施例4 降低高眼压的比马前列胺/PLA眼内植入物
一位62岁男性左眼眼内压为33mm Hg。使用套针将含400mg比马前列胺以及600mg PLA的植入物嵌入左眼的玻璃体内。每天监测患者的眼内压,持续一周,然后每月检查一次。在植入后一天,眼内压降低到18mm Hg。到植入后第7天,眼内压相对稳定,为14mmHg。患者在两年里未出现任何眼内压升高的其它征兆。
本发明所引用的全部参考文献、文章、出版物和专利以及专利申请通过援引全文纳入本发明。
尽管本发明就不同具体实施例和实施方案进行了描述,但是应该理解的是:本发明并不受限于此,并在权利要求的范围内可有所改变。
Claims (48)
1.一种可生物降解的眼内植入物,含有前列腺酰胺组分和可生物降解的聚合物基质,在植入物放入眼内后,该基质以有效维持治疗有效量的前列腺酰胺组分释放至少约一周的速率释放药物。
2.权利要求1的植入物,其中所述前列腺酰胺组分包括单一类型的前列腺酰胺衍生物。
3.权利要求1的植入物,其中所述前列腺酰胺组分包括至少一种选自比马前列胺、其盐及其混合物的前列腺酰胺衍生物。
4.权利要求1的植入物,其中所述前列腺酰胺组分基本由比马前列胺组成。
5.权利要求1的植入物,其中所述前列腺酰胺组分含有两种或多种不同前列腺酰胺衍生物的组合物。
6.权利要求5的植入物,其中所述前列腺酰胺组分含有比马前列胺和拉坦前列素的组合物。
7.权利要求5的植入物,其中所述前列腺酰胺组分含有比马前列胺和曲伏前列素的组合物。
8.权利要求1的植入物,其中所述前列腺酰胺组分含有比马前列胺,并且植入物还含有β肾上腺能受体拮抗剂。
9.权利要求8的植入物,其中所述β肾上腺能受体拮抗剂为噻吗洛尔。
10.权利要求1的植入物,其中所述前列腺酰胺组分含有比马前列胺,并且该植入物还含有碳酸酐酶抑制剂。
11.权利要求10的植入物,其中所述碳酸酐酶抑制剂为多佐胺。
12.权利要求1的植入物,其中所述前列腺酰胺组分分散在可生物降解的聚合物基质中。
13.权利要求1的植入物,其中所述前列腺酰胺组分含有以重量计占植入物约0.1%到约90%的量的比马前列胺。
14.权利要求1的植入物,其中所述前列腺酰胺组分含有具有化学式(I)的化合物:
其中虚线键表示可为顺式构型或反式构型的单键或双键,A为具有二个到六个碳原子的亚烷基或亚烯基,该基团可被一个或多个氧化基团中断,并可被一个或多个羟基、氧代基、烷氧基或烷羧基取代,其中所述烷基含有一到六个碳原子;B为有三到七个碳原子的环烷基,或为选自具有四到十个碳原子的烃芳基和杂芳基的芳基,其中杂原子选自氮原子、氧原子和硫原子;X选自-OR4和-N(R4)2,其中R4选自氢以及具有一到六个碳原子的低级烷基、
其中R5为具有一到六个碳原子的低级烷基;Z为=O或代表两个氢自由基;R1和R2中有一个为=O、-OH或-O(CO)R6基,另一个为-OH或-O(CO)R6,或者R1为=O,R2为H,其中,R6为具有1到约20个碳原子的饱和或不饱和开链烃基或为-(CH2)mR7,其中m为0或1到10的整数,R7为具有三到七个碳原子的环烷基,或上述限定的烃芳基或杂芳基,或为其可药用的盐类,但是前提是当B未被含有杂原子的侧基取代,并且Z为=O时,X不是-OR4。
15.权利要求14的植入物,其中所述前列腺酰胺组分的化合物具有如下化学式(II):
其中,y为0或1,x为0或1,并且x+y并不全为1,Y选自下列基团:烷基、卤素、硝基、氨基、巯基、羟基、烷氧基、烷羧基以及卤素取代的烷基,其中所述烷基含有一到六个碳原子,n为0或1到3的整数,并且R3为=O、-OH或-O(CO)R6。
17.权利要求16的植入物,其中所述化合物具如如下化学式(IV):
其中Y1为Cl或三氟甲基。
19.权利要求1的植入物,其中所述基质含有两种不同的可生物降解的聚合物的混合物,每一种聚合物选自聚乳酸、聚羟乙酸、聚丙交酯-共-乙交酯、其衍生物及其混合物。
20.权利要求19的植入物,其中所述基质含有两种不同聚乳酸的混合物。
21.权利要求19的植入物,其中所述基质含有聚乳酸和聚丙交酯-共-乙交酯的混合物。
22.权利要求1的植入物,其中所述基质含有不同的可生物降解聚合物的混合物,每种可生物降解聚合物具有不同的固有粘度。
23.权利要求1的植入物,其中所述基质含有不同的可生物降解聚合物的混合物,每种聚合物具有不同分子量。
24.权利要求1的植入物,其中,从植入物放入眼睛的玻璃体内开始,所述基质以有效维持一定量的前列腺酰胺组分从植入物释放超过一个月的速率释放药物。
25.权利要求1的植入物,其中所述前列腺酰胺组分含有比马前列胺,并且基质以有效维持治疗有效量的比马前列胺释放约3个月的速率释放药物。
26.权利要求1的植入物,其中所述前列腺酰胺组分的治疗有效量为有效刺激放入植入物的眼内的房水排出的量。
27.权利要求1的植入物,还含有前列腺素类似物。
28.权利要求27的植入物,其中前列腺素类似物为乌诺前列酮。
29.权利要求1的植入物,还含有除前列腺酰胺衍生物之外的降低眼内压的药物。
30.权利要求1的植入物,其中所述植入物被构造成可放入眼睛的玻璃体内。
31.权利要求1的植入物,通过挤压法形成。
32.一种制备可生物降解的眼内植入物的方法,包括如下步骤:挤压前列腺酰胺组分和可生物降解的聚合物组分的混合物,形成可生物降解的材料,该材料以有效维持一定量的前列腺酰胺组分从放入眼内的植入物中释放的速率释放药物。
33.权利要求32的方法,其中所述前列腺酰胺组分含有至少一种选自比马前列胺、其盐及其混合物的前列腺酰胺衍生物。
34.权利要求32的方法,其中所述前列腺酰胺组分基本由比马前列胺组成。
35.权利要求32的方法,还包括在挤压步骤前将前列腺酰胺组分与聚合物组分混合的步骤。
36.权利要求32的方法,其中所述前列腺酰胺组分和聚合物组分为粉剂形式。
37.权利要求32的方法,其中所述聚合物组分含有两种不同的可生物降解的聚合物的混合物,每一种聚合物选自聚乳酸、聚羟乙酸、聚丙交酯-共-乙交酯、其衍生物及其混合物。
38.权利要求32的方法,其中所述聚合物组分含有两种不同的可生物降解的聚合物的混合物,每种可生物降解的聚合物具有不同的固有粘度。
39.一种药剂,为可生物降解的眼内植入物,用于通过将可生物降解的眼内植入物放入患者眼内治疗患者眼睛的眼病,该植入物含有前列腺酰胺组分和可生物降解的聚合物基质,该基质以有效维持一定量的前列腺酰胺组分从植入物释放的速率释放药物,以提供预防或减轻眼病症状有效量的前列腺酰胺组分。
40.权利要求39的药剂,其中所述药剂可有效治疗青光眼。
41.权利要求39的药剂,其中植入物放入眼内可有效降低眼的眼内压。
42.权利要求39的药剂,其中植入物被放入眼的后端。
43.权利要求39的药剂,其中所述植入物被使用套针放入眼内。
44.权利要求39的药剂,其中所述植入物使用注射器放入眼内。
45.权利要求39的药剂,其中除了将前列腺酰胺组分给予患者,还将其他治疗剂给予患者。
46.权利要求39的药剂,其中所述前列腺酰胺组分含有至少一种选自比马前列胺、其衍生物、其盐及其混合物的前列腺酰胺。
47.权利要求39的药剂,其中植入物放入眼内可有效增加房水排出。
48.权利要求47的药剂,其中,在植入物被放入眼内后,前列腺酰胺组分可有效释放至少两周。
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2004
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