CN104114154A - 包含聚乙烯基己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物(Soluplus)的眼用组合物 - Google Patents
包含聚乙烯基己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物(Soluplus)的眼用组合物 Download PDFInfo
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Abstract
本文描述了与聚乙烯基己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚(Soluplus)物的眼科用途和治疗用途有关的组合物和方法。
Description
相关申请案
本申请要2011年12月16日提交的美国临时申请序列号61/576,453的权益,其通过引用整体并入本文。
发明背景
局部应用制剂,例如应用于角膜、结膜、睑缘等的制剂,通常在眼科中用于治疗急性和慢性病状,因为它们可能比全身递送制剂更安全。然而,一些治疗活性剂可能在水溶液中的溶解性差,这可能限制局部眼用。对于一些治疗活性剂而言,可使用非离子型表面活性剂提高溶解性,但是可能需要进一步提高。
发明概述
一些实施方案包括包含聚乙烯基己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物(PCA-PVA-PEG)的局部眼用组合物。
一些实施方案包括溶解治疗活性剂的方法,包括提供包括治疗活性剂和PCA-PVA-PEG的组合物。在一些实施方案中,在室温下没有PCA-PVA-PEG,所述治疗活性剂可能并非可完全溶于所述组合物中。
一些实施方案包括溶解治疗活性剂的方法,包括使所述治疗活性剂与PCA-PVA-PEG合并,从而提高治疗活性剂的稳定性。
一些实施方案包括溶解治疗活性剂的方法,包括混合所述治疗活性剂和聚乙烯基己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物,以便形成本文所述的组合物。
一些实施方案包括溶解治疗活性剂的方法,包括合并所述治疗活性剂和聚乙烯基己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物,以便形成本文所述的组合物。
一些实施方案包括治疗影响眼睛的疾病的方法,包括向有需要的眼睛施用本文所述的组合物。
本发明的其它实施方案包括:
1)一种包含聚乙烯基己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物的局部眼用组合物。
2)根据第1条所述的组合物,其中所述聚乙烯基己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物的平均分子量为约10,000g/mol至约500,000g/mol。
3)根据第1或2条所述的组合物,进一步包含治疗活性剂。
4)根据第3条所述的组合物,其中所述治疗活性剂包含免疫抑制剂、α-肾上腺素能拮抗剂、类固醇、前列腺素EP2激动剂、毒蕈碱、前列腺素、α激动剂、抗生素、抗感染剂、抗炎剂、β阻滞剂或其组合。
5)根据第3条所述的组合物,其中所述治疗活性剂包括环孢霉素A、环孢霉素类似物、酚妥拉明(phentolamine)、睾酮(testosterone)、地塞米松(dexamethasone)、强的松龙(prednisolone)、比马前列素(bimatoprost)、拉坦前列素(latanoprost)、表8的化合物A、B、C、D、E、F、G和H、匹鲁卡品(pilocarpine)、溴莫尼定(brimonidine)、加替沙星(gatifloxacin)、酮咯酸(ketorolac)、类固醇、噻吗洛尔(timolol)或其组合。
6)根据第5条所述的组合物,其中所述组合物为溶液。
7)根据第6条所述的组合物,进一步包含辅助增溶剂。
8)根据第7条所述的组合物,其中所述辅助增溶剂包含山梨醇酐单硬脂酸酯、聚氧化乙烯-聚氧化丙烯嵌段共聚物、聚氧化乙烯甘油三蓖麻醇酸酯35、环糊精或其组合。
9)根据第6条所述的组合物,进一步包含渗透压剂。
10)根据第9条所述的组合物,其中所述渗透压剂包含丙二醇、甘油、甘露糖醇、氯化钠或其组合。
11)根据第10条所述的组合物,进一步包含缓冲剂。
12)根据第11条所述的组合物,其中所述缓冲剂包含磷酸盐、磷酸盐和柠檬酸盐、三乙醇胺、乳酸盐、硼酸盐、硼酸盐和柠檬酸盐或其组合。
13)根据第10条所述的组合物,进一步包含防腐剂。
14)根据第13条所述的组合物,其中所述防腐剂包含苯扎氯胺、稳定化氧氯复合物或其组合。
15)一种溶解治疗活性剂的方法,包括提供包含所述治疗活性剂和聚乙烯基己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物的组合物,其中在室温下没有聚乙烯基己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物,所述治疗活性剂并非可完全溶于所述组合物中。
16)一种溶解治疗活性剂的方法,包括混合所述治疗活性剂和聚乙烯基己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物,以便形成根据权利要求5所述的组合物。
17)一种稳定治疗活性剂的方法,包括使所述治疗活性剂与聚乙烯基己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物合并,从而提高所述治疗活性剂的稳定性。
18)一种稳定治疗活性剂的方法,包括合并所述治疗活性剂和聚乙烯基己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物,以便形成根据权利要求5所述的组合物。
19)一种治疗影响眼睛的疾病的方法,包括向有需要的眼睛施用根据第11条所述的组合物,其中所述活性剂中的一种为比马前列素。
20)根据第19条所述的组合物,进一步包含所述活性剂溴莫尼定。
发明详述
聚氧乙基化表面活性剂例如聚山梨醇酯80、聚山梨醇酯20和聚氧乙烯硬脂酸酯40可能遭受不利,例如组合物中治疗活性剂的氧化降解,表面活性剂的降解,防腐剂效率降低和通过生物膜的治疗活性剂的生物利用渗透性降低。使用PCA-PVA-PEG可帮助减少或防止这些不良结果。
聚乙烯基己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物(PCA-PVA-PEG)包括包含至少一个己内酰胺嵌段、至少一个聚乙酸乙烯酯嵌段和至少一个聚乙二醇嵌段的聚合物,其中至少一个嵌段从另一类型的嵌段分支。例如,一些PCA-PVA-PEG可用以下结构表示。
在上面的结构中,a可为约10至约10,000,约100至约900,约100至约500,或约500至约900。
在上面的结构中,b可为约20至约20,000,约150至约1500,约200至约800,或约800至约1500。
在上面的结构中,c可为约30至约30,000,约300至约3000,约300至约1000,约1000至约2000,或约2000至约3000。
在一些实施方案中,PCA-PVA-PEG可能平均分子量为约1,000g/mol至约5,000,000g/mol,约10,000g/mol至约500,000g/mol,或约90,000g/mol至约140,000g/mmol。
在一些实施方案中,PCA-PVA-PEG可为CAS No.402932-23-4表示的聚合物,例如可从BASF获得的
PCA-PVA-PEG的使用可提高治疗活性剂,包括下面列出的任何治疗活性剂的溶解性和/或稳定性。PCA-PVA-PEG也可能对防腐剂有最小干扰,因此在一些组合物中可能允许使用较少的防腐剂。此外,PCA-PVA-PEG在一些组合物中可能具有抗菌特性,因此可包括在可能不需要传统防腐剂的自身防腐组合物中。PCA-PVA-PEG也可能与一些防腐剂例如稳定化氧氯复合物协同。
治疗活性剂包括官方美国药典、官方美国顺势疗法药典或官方国家处方集或对其任一个的任何补充中认可的任何化合物或物质;旨在用于人类或其它动物疾病的诊断、治愈、缓解、治疗或预防的任何化合物或物质;和除食物或水外,旨在影响人类或其它动物身体的结构或任何功能的任何物质。
一些治疗活性剂可能包括抗组胺、抗生素、β阻滞剂、类固醇、抗肿瘤剂、免疫抑制剂、抗病毒剂及其混合物。
抗组胺的实例可能包括但不限于氯雷他定(loradatine)、羟嗪(hydroxyzine)、苯海拉明(diphenhydramine)、氯苯那敏(chlorpheniramine)、溴苯那敏(brompheniramine)、赛庚啶(cyproheptadine)、特非那定(terfenadine)、氯马斯汀(clemastine)、曲普立啶(triprolidine)、卡比沙明(carbinoxamine)、二苯拉林(diphenylpyraline)、苯茚胺(phenindamine)、阿扎他定(azatadine)、曲吡那敏(tripelennamine)、右氯苯那敏(dexchlorpheniramine)、右溴苯那敏(dexbrompheniramine)、甲地嗪(methdilazine)和阿利吗嗪多西拉敏(trimprazine doxylamine)、非尼拉敏(pheniramine)、吡拉明(pyrilamine)、chiorcyclizine、松齐拉敏(thonzylamine)及其衍生物。
抗生素的实例可能包括但不限于头孢唑啉(cefazolin)、头孢拉啶(cephradine)、头孢克洛(cefaclor)、头孢匹林(cephapirin)、头孢唑肟(ceftizoxime)、头孢哌酮(cefoperazone)、头孢替坦(cefotetan)、头孢呋肟(cefutoxime)、头孢噻肟(cefotaxime)、头孢羟氨苄(cefadroxil)、头孢他啶(ceftazidime)、头孢氨苄(cephalexin)、头孢噻吩(cephalothin)、头孢孟多(cefamandole)、头孢西丁(cefoxitin)、头孢尼西(cefonicid)、头孢雷特(ceforanide)、头孢曲松(ceftriaxone)、头孢羟氨苄(cefadroxil)、头孢拉定(cephradine)、头孢呋辛(cefuroxime)、环孢霉素、氨苄青霉素(ampicillin)、阿莫西林(amoxicillin)、环青霉素(cyclacillin)、氨苄青霉素、青霉素G(penicillin G)、青霉素V钾(penicillin V potassium)、哌拉西林(piperacillin)、苯唑西林(oxacillin)、巴氨西林(bacampicillin)、氯唑西林(cloxacillin)、替卡西林(ticarcillin)、阿洛西林(azlocillin)、羧苄西林(carbenicillin)、甲氧西林(methicillin)、萘夫西林(nafcillin)、红霉素(erythromycin)、四环素(tetracycline)、强力霉素(doxycycline)、二甲胺四环素(minocycline)、氨曲南(aztreonam)、氯霉素(chloramphenicol)、盐酸环丙沙星(ciprofloxacin hydrochloride)、克林霉素(clindamycin)、甲硝哒唑(metronidazole)、庆大霉素(gentamicin)、林肯霉素(lincomycin)、托普霉素(tobramycin)、万古霉素(vancomycin)、硫酸多粘菌素B(polymyxin B sulfate)、甲磺酸粘菌素(colistimethate)、多粘菌素(colistin)、阿奇霉素(azithromycin)、沃格孟汀(augmentin)、磺酸甲噁唑(sulfamethoxazole)、甲氧苄啶(trimethoprim)、加替沙星、氧氟沙星(ofloxacin)及其衍生物。
β阻滞剂的实例可能包括醋丁洛尔(acebutolol)、阿替洛尔(atenolol)、拉贝洛尔(labetalol)、美托洛尔(metoprolol)、普萘洛尔(propranolol)、噻吗洛尔及其衍生物。
类固醇的实例可能包括皮质类固醇,例如可的松(cortisone)、强的松龙、氟米龙(flurometholone)、地塞米松、甲羟松(medrysone)、氯替泼诺(loteprednol)、氟扎可松(fluazacort)、氢化可的松(hydrocortisone)、泼尼松(prednisone)、倍他米松(betamethasone)、泼尼松、甲基强的松龙、己酸丙炎松(riamcinolone hexacatonide)、醋酸帕拉米松(paramethasone acetate)、双氟拉松(diflorasone)、醋酸肤轻松(fluocinonide)、肤轻松(fluocinolone)、去炎松(triamcinolone)、其衍生物及其混合物。
抗肿瘤剂的实例可能包括阿霉素(adriamycin)、环磷酰胺(cyclophosphamide)、放线菌素(actinomycin)、博来霉素(bleomycin)、柔红霉素(duanorubicin)、多柔比星(doxorubicin)、表柔比星(epirubicin)、丝裂霉素(mitomycin)、甲氨蝶呤(methotrexate)、氟尿嘧啶(fluorouracil)、卡铂(carboplatin)、卡莫司汀(carmustine)(BCNU)、甲基-洛莫司汀(methyl-CCNU)、顺铂(cisplatin)、依托泊苷(etoposide)、干扰素、喜树碱(camptothecin)及其衍生物、苯芥胆甾醇(phenesterine)、紫杉醇(taxol)及其衍生物、泰素帝(taxotere)及其衍生物、长春花碱(vinblastine)、长春新碱(vincristine)、它莫西芬(tamoxifen)、依托泊苷、哌泊舒凡(piposulfan)、环磷酰胺和氟他胺(flutamide)及其衍生物。
免疫抑制剂的实例可能包括环孢霉素、硫唑嘌呤(azathioprine)、他克莫司(tacrolimus)及其衍生物。
抗病毒剂的实例可能包括γ干扰素、齐多夫定(zidovudine)、盐酸金刚烷胺、利巴韦林(ribavirin)、阿昔洛韦(acyclovir)、伐昔洛韦(valciclovir)、双脱氧胞苷、膦甲酸、更昔洛韦(ganciclovir)及其衍生物。
在一些实施方案中,治疗活性剂可能包括免疫抑制剂、α-肾上腺素能拮抗剂、类固醇、前列腺素EP2激动剂、毒蕈碱、前列腺素、α激动剂、抗生素、抗感染剂、抗炎剂、β阻滞剂或其组合。在一些实施方案中,治疗活性剂可能包括环孢霉素A、环孢霉素类似物、酚妥拉明、睾酮、地塞米松、强的松龙、比马前列素、拉坦前列素、表8的化合物A、B、C、D、E、F、G和H、匹鲁卡品、溴莫尼定、加替沙星、酮咯酸、类固醇、噻吗洛尔或其组合。
眼科上可接受的液体或溶液应该为患者可耐受以供局部眼用。另外,眼科上可接受的液体可经包装供一次性使用,或含有防腐剂以防止多次使用中的污染。
对于眼科应用,可使用生理盐水溶液作为主要媒介物制备溶液或药剂。可用恰当的缓冲体系将眼用溶液保持在舒适pH下。所述制剂也可能含有常规、药学上可接受的防腐剂、稳定剂和表面活性剂。
眼科上可接受的液体可能包括缓冲液。所述缓冲液可能不同,并且可能包括适合维持理想pH范围的任何弱共轭酸-碱对。实例包括但不限于醋酸盐缓冲液、柠檬酸盐缓冲液、磷酸盐缓冲液、硼酸盐缓冲液、乳酸盐缓冲液、NaOH/三乙醇胺缓冲液或其组合,例如磷酸盐和柠檬酸盐或硼酸盐和柠檬酸盐。酸或碱,例如HCl和NaOH,根据需要可用于调节这些制剂的pH。所用缓冲液的量可能不同。在一些实施方案中,缓冲液的浓度可能在约1nM至约100mM范围内。
眼科上可接受的液体可能包括防腐剂。所述防腐剂可能不同,并且可能包括适合减少或防止多次使用的眼用液体受试物受相同容器污染的任何化合物或物质。可用于本文公开的药物组合物中的防腐剂包括但不限于阳离子防腐剂例如季铵化合物,包括苯扎氯胺、polyquad等;胍基防腐剂,包括PHMB;洗必泰(chlorhexidine)等;氯丁醇;汞防腐剂例如硫柳汞(thimerosal)、醋酸苯汞、硝酸苯汞;氧化防腐剂例如稳定化氧氯复合物(例如);和其它防腐剂例如苯甲醇。在一些实施方案中,防腐剂可包含苯扎氯胺、稳定化氧氯复合物或其组合。在一些实施方案中,防腐剂的浓度可能为约10ppm至约200ppm,约10ppm至约300ppm或约50ppm至约150ppm。
眼科上可接受的液体可能包括辅助增溶剂,例如表面活性剂。所述表面活性剂可能不同,并且可能包括具表面活性或可形成胶束的任何化合物。表面活性剂可用于帮助溶解赋形剂或活性剂,将固体或液体分散在组合物中,增强湿润,改变液滴大小,稳定乳液或许多其它用途。表面活性剂的实例可能包括但不限于以下类别的表面活性剂:醇;氧化胺;嵌段聚合物;羧化醇或烷基酚乙氧基化物;羧酸/脂肪酸;乙氧基化醇;乙氧基化烷基酚;乙氧基化芳基酚;乙氧基化脂肪酸;乙氧基化脂肪酸酯或油(动物和植物);脂肪酸酯;脂肪酸甲酯乙氧基化物;甘油酯;乙二醇酯;羊毛脂基衍生物;卵磷脂和卵磷脂衍生物;木质素和木质素衍生物;甲酯;甘油一酸酯和衍生物;聚乙二醇;高分子表面活性剂;丙氧基化和乙氧基化脂肪酸、醇或烷基酚;蛋白质基表面活性剂;肌氨酸衍生物;山梨聚糖衍生物;蔗糖和葡萄糖酯及衍生物。在一些实施方案中,表面活性剂可能包括聚乙二醇(15)-羟基硬脂酸酯(CAS号70142-34-6,可作为来自于BASF的SOLUTOL HS)、聚氧化乙烯-聚氧化丙烯嵌段共聚物(CAS No.9003-11-6,可作为来自于BASF的F-68)、聚氧化乙烯40硬脂酸酯(POE40硬脂酸酯)、聚山梨醇酯80或聚氧化乙烯(80)单油酸山梨醇酐酯(CAS No.9005-65-6)、山梨醇酐单硬脂酸酯(CAS No.1338-41-6,可作为来自于Croda International PLC的SPANTM 60)或聚氧化乙烯甘油三蓖麻醇酸酯35(CAS No.61791-12-6,可作为来自于BASF的CREMOPHOR)、乙氧基化蓖麻油例如Cremophor EL(CAS号61791-12-6)。表面活性剂的量可能不同。在一些实施方案中,任何表面活性剂例如以上所列表面活性剂的量可为约0.001至约5%、约0.1%至约2%或约0.1%至约1%。
其它化合物,例如环糊精,可用作辅助增溶剂。环糊精的实例可能包括α-环糊精;β-环糊精;γ-环糊精;环糊精衍生物,例如醚和混合醚衍生物和带有糖残基的衍生物(例如羟乙基、羟丙基(包括2-和3-羟丙基)和二羟丙基醚)、其相应的混合醚和其它具有甲基或乙基的混合醚,例如α-、β-和γ-环糊精的甲基-羟乙基、乙基-羟乙基和乙基-羟丙基醚;β-和γ-环糊精的麦芽糖基、葡糖基和麦芽三糖基衍生物,其可能含有一个或多个糖残基,例如葡糖基或二葡糖基、麦芽糖基或二麦芽糖基,及其各种混合物,例如麦芽糖基和二麦芽糖基衍生物的混合物;包含阴离子官能团例如磺丁基醚衍生物、磺酸盐、磷酸盐等的环糊精衍生物,例如羟丙基-β-环糊精、羟丙基-γ-环糊精、磺丁基醚-β-环糊精和磺丁基醚-γ-环糊精以及羟乙基-β-环糊精、羟乙基-γ-环糊精、二羟丙基-β-环糊精、葡糖基-β-环糊精、二葡糖基-β-环糊精、麦芽糖基-β-环糊精、麦芽糖基-γ-环糊精、麦芽三糖基-β-环糊精、麦芽三糖基-γ-环糊精和二麦芽糖基-β-环糊精及其混合物例如麦芽糖基-β-环糊精/二麦芽糖基-β-环糊精。环糊精可能以约0.01%至约30%、约0.01%至约10%或约1%至约10%的浓度存在。
在一些实施方案中,辅助增溶剂可包含山梨醇酐单硬脂酸酯、聚氧化乙烯-聚氧化丙烯嵌段共聚物、聚氧化乙烯甘油三蓖麻醇酸酯35、环糊精或其组合。
眼科上可接受的液体可能包括媒介物。适合媒介物的实例包括但不限于聚乙烯醇、聚烯吡酮、羟丙基甲基纤维素、聚羟亚烃(poloxamer)、羧甲基纤维素、羟乙基纤维素和丙烯酸酯(例如)。
眼科上可接受的液体可能包括渗透压剂。所述渗透压剂可能不同,并且可能包括对调节眼用液体的渗透压有用的任何化合物或物质。实例包括但不限于盐(特别是氯化钠或氯化钾)、有机化合物(例如丙二醇、甘露糖醇或甘油)或任何其它适合的眼科上可接受的渗透压调节剂。在一些实施方案中,渗透压剂可包含丙二醇、甘油、甘露糖醇、氯化钠或其组合。
渗透压剂的量可能根据是否需要等渗、高渗或低渗液体而改变。在一些实施方案中,例如以上所列渗透压剂的量可能至少约0.0001%至约1%,约2%或约5%。
眼科上可接受的液体可能包括抗氧化剂。所述抗氧化剂可能不同,并且可能包括对减少眼科上可接受的液体中存在的任何化合物的氧化有用的任何化合物或物质。实例包括但不限于焦亚硫酸钠、硫代硫酸钠、乙酰半胱氨酸、丁羟茴醚和丁羟甲苯。
眼科上可接受的液体可能包括螯合剂。所述螯合剂可能不同,并且可能包括能够螯合金属的任何化合物或物质。虽然也可用其它螯合剂代替或连同一起使用,但是有用的螯合剂为依地酸二钠。
组合物可为水溶液或乳液或一些其它可接受的液体形式。对于乳液,可使用一种或多种油形成乳液。适合的油包括但不限于大茴香油、蓖麻油、丁香油、肉桂油、桂皮油、扁桃仁油、玉米油、花生油、棉籽油、红花油、玉米油、亚麻籽油、菜籽油、大豆油、橄榄油、藏茴香油、迷迭香油、花生油、薄荷油、向日葵油、桉油、芝麻油等。
一些眼科上可接受的组合物可包含软膏或乳膏媒介物,其可包括聚合物增稠剂、水、防腐剂、活性表面活性剂或乳化剂、抗氧化剂和溶剂或混合溶剂体系。
可使用适合眼科应用的聚合物增稠剂,例如制药行业常用的亲水性增稠剂。例如,亲水性增稠剂可包含交联或非交联丙烯酸或丙烯酸酯聚合物,例如(B.F.Goodrich,Cleveland,OH),包括CARBOPOL这些聚合物可溶于水并且在用碱例如氢氧化钠、氢氧化钾、三乙醇胺或其它胺碱中和后可形成清澈或稍微混浊的凝胶。其它市场上可购买的增稠剂可包括(KingstonTechnologies,Dayton,NJ)、(Aqualon,Wilmington,DE)、(Aqualon,Wilmington,DE)或(ISPTechnologies,Wayne,NJ)。为可分散于水中并且在完全水合后可形成均匀凝胶的纤维素聚合物。其它有用的胶凝聚合物可包括羟乙基纤维素、羟丙基纤维素、纤维素胶、MVA/MA共聚物、MVE/MA癸二烯交联聚合物、PVM/MA共聚物等。
可使用有效量的聚合物增稠剂,例如组合物的约0.2%至约4%重量/重量。的有用重量/重量百分比范围可为约0.1%至约5%、约0.1%至约2%或约0.5%至约2%,和的有用重量/重量百分比范围可为约0.5%至约4%,并且或的有用重量/重量百分比范围可为约0.5%至约4%。
防腐剂用于眼用软膏或乳膏中并且可包含总组合物的约0.1%至约10%、约1%至约5%、约0.05%至约0.5%或约0.05%至约0.1%重量/重量。使用防腐剂可帮助减少或防止微生物生长。一些有用的防腐剂可包括苯甲醇、尼泊金甲酯(methylparaben)、尼泊金丙酯(propylparaben)、尼泊金丁酯(butylparaben)、氯二甲酚、苯甲酸钠、DMDM乙内酰脲、3-碘-2-丙基丁基氨基甲酸酯、山梨酸钾、二葡萄糖酸洗必泰等。
眼用组合物可应用于局部用乳膏中。局部用乳膏可为水包油乳液或油包水乳液。油相可包括但不限于脂肪醇、酸或酯例如肉豆蔻酸异丙酯、鲸蜡醇十六酸酯、鲸蜡醇、硬脂醇、硬脂酸、硬脂酸异丙酯、硬脂酸甘油酯、矿物油、白凡士林或其它单独或组合的油。油相可为约1%至约50%、约1%至约3%、约10%至约30%、约10%至约25%、约10%至约20%、约20%至约30%或约10%至约15%重量/重量。
眼用组合物,例如本文所述的眼用组合物可用于治疗或预防眼部疾病或病状,例如下列其中之一:
黄斑病/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、糖尿病性视网膜病、急性黄斑神经视网膜病变、中心性浆液性脉络膜视网膜病变、黄斑囊样水肿、糖尿病性黄斑水肿。
葡萄膜炎/视网膜炎/脉络膜炎:急性多灶性鳞状色素上皮病变、白塞氏病(Behcet’s disease)、鸟枪弹样视网膜脉络膜病变、传染病(梅毒、莱姆关节炎(lyme)、结核、弓形虫病)、中间葡萄膜炎(睫状体平坦部炎)、多灶性脉络膜炎、多发性一过性白点综合征(MEWDS)、眼结节病、后巩膜炎、匐行性脉络膜炎、视网膜下纤维增生和葡萄膜炎综合征、伏格特-小柳-原田三氏综合征(Vogt-Koyanagi-Haradasyndrome)。
血管病/渗出性疾病:视网膜动脉阻塞性疾病、视网膜中央静脉阻塞、弥散性血管内凝血病、视网膜分支静脉阻塞、高血压眼底变化、眼部缺血综合征、视网膜微动脉瘤、柯氏症(Coat’s disease)、旁中心凹毛细管扩张、半侧性视网膜静脉阻塞、视乳头静脉炎、视网膜中央动脉阻塞、视网膜分支动脉阻塞、颈动脉疾病(CAD)、霜样树枝状视网膜血管炎、镰状红细胞性视网膜病变和其它血红蛋白病、血管样条纹症、家族性渗出性玻璃体视网膜病变、伊尔斯氏病(Eales disease)。
外伤/手术性:交感性眼炎、葡萄膜炎性视网膜病、视网膜脱离、外伤、激光、PDT、光凝固、手术过程中灌注不足、辐射性视网膜病变、骨髓移植视网膜病变。
增生性病症:增殖性玻璃体视网膜病变和视网膜前膜、增生性糖尿病视网膜病变、早产儿视网膜病变(晶状体后纤维增生症)。
传染病: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、弓形体病、HIV感染相关的视网膜疾病、HIV感染相关的脉络膜疾病、HIV感染相关的葡萄膜炎疾病、病毒性视网膜炎、急性视网膜坏死、进行性外层视网膜坏死、真菌视网膜疾病、眼部梅毒、眼结核、弥漫性单侧亚急性视神经视网膜炎、蝇蛆病。
遗传病:色素性视网膜炎、视网膜营养不良相关的系统性疾病、先天性静止性夜盲、视锥营养不良、眼底黄色斑点症、贝斯特氏病(Best’s disease)、视网膜色素上皮细胞的模式营养不良、X-连锁视网膜劈裂症、Sorsby眼底营养不良(Sorsby’s fundus dystrophy)、良性同心性黄斑病变、Bietti结晶性营养不良(Bietti’s crystalline dystrophy)、弹性假黄瘤、奥-韦氏综合征(Osler Weber syndrome)。
视网膜撕裂/裂孔:视网膜脱离、黄斑裂孔、巨大视网膜撕裂。
肿瘤:肿瘤相关的视网膜疾病、实体瘤、肿瘤转移、良性瘤(例如血管瘤、神经纤维瘤、沙眼和化脓性肉芽肿)、RPE先天性肥大、后葡萄膜黑素瘤、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联合错构瘤、成视网膜细胞瘤、眼底血管增生性肿瘤、视网膜星形细胞瘤、眼内淋巴瘤。
其它:点状内层脉络膜病变、急性后部多病灶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、眼部炎症和免疫病症、眼部血管功能障碍、角膜移植排斥、新生血管性青光眼等。
实施例1
表1汇总了在一定稳定范围内比马前列素在具有5种不同增溶剂的媒介物中的溶解性。在室温(RT)和更高温度下,比马前列素在含有PCA-PVA-PEG的媒介物中的溶解性高于其它增溶剂。
表1:不同温度下在5种不同制剂媒介物中的比马前列素溶解性。在室温和更高温度下,PCA-PVA-PEG显示出对比马前列素最高的增溶作用。
*仅在第1周测量;**在第8周测量
实施例2
支持BAK功效提高的数据
进行防腐剂滴定研究以比较在使用不同增溶剂的制剂中BAK的功效。通常,看到在表面活性剂的存在下,BAK的防腐功效显著降低。因此,为达到USP<51>和欧洲药典5.1.3章中定义的眼科产品防腐剂标准,可能需要更高水平的BAK。看来在用PCA-PVA-PEG作为增溶剂时,与表2中汇总的所有其它表面活性剂相比,在较低BAK水平下达到防腐剂标准。事实上,含有PCA-PVA-PEG的制剂以低至50ppm BAK达到PhEurA标准,这与不含增溶剂的制剂相似。
表2:含不同增溶剂的制剂的防腐剂滴定至失败的结果汇总
1APET标准如USP<51>和欧洲药典(Ph Eur)5.1.3所定义。
实施例3:PCA-PVA-PEG自身防腐体系中的用途
含PCA-PVA-PEG的制剂即使没有使用任何防腐剂也展现出抗菌活性。表3中连同APET试验结果一起列出了评估的制剂。发现含1%PCA-PVA-PEG和磷酸盐-柠檬酸盐缓冲液的制剂(制剂1)达到对所有生物的USP标准。将磷酸盐缓冲液更换为硼酸盐缓冲液并且去除EDTA使制剂(制剂3-5)在0.5%-1%的PCA-PVA-PEG浓度下达到对所有生物的PhEurB标准。
表3:APET试验中PCA-PVA-PEG水平和硼酸缓冲液的影响
实施例4:PCA-PVA-PEG对作为防腐剂的Purite抗菌功效的协
同效应
由于缺乏对细菌的充分杀伤,Purite防腐制剂通常在6h时间点达到APET的PhEurB标准并且在第7天时间点发霉。Purite与PCA-PVA-PEG()的组合,看来这些制剂满足PhEurA标准(表4)。据观察,0.5%与100ppm Purite的组合足以满足APET的PhEurA标准(表5)。更重要的是,在6h时间点(对于细菌而言)和第7天时间点(对真菌而言),对所有生物观察到优等对数杀伤比。
Purite、硼酸和PCA-PVA-PEG的组合将在非处方(OTC)产品中实用。在Allergan产品例如REFRESHREFRESHDRY和下一代乳液中添加0.5%PCA-PVA-PEG将使这些产品满足APET试验的PhEurA标准。类似地,对于药物产品例如ALPHAGAN添加PCA-PVA-PEG和满足PhEurA标准将使这种产品适合在欧盟申请。
表4:与Purite组合的PCA-PVA-PEG和硼酸对APET的影响
表5:不同水平的PCA-PVA-PEG与Purite对APET的影响
实施例5 PCA-PVA-PEG制剂的细胞毒性试验
在体外人角膜上皮细胞中评估了含有范围从0.25%至2%浓度的PCA-PVA-PEG的制剂。在37℃下用所述制剂培育细胞16h并测量细胞活力。发现所有PCA-PVA-PEG制剂无细胞毒性。用含PCA-PVA-PEG的制剂处理的细胞的活力比得上未用PCA-PVA-PEG或用聚山梨醇酯80处理的细胞。
表6:含PCA-PVA-PEG的制剂的细胞毒性试验
实施例6:显示含PCA-PVA-PEG的制剂中药物稳定性提高的数
据
评估使用聚山梨醇酯80(PS80)或PCA-PVA-PEG作为增溶剂的制剂中环孢霉素类似物的稳定性。用PCA-PVA-PEG或作为增溶剂时,观察到化合物的稳定性提高。表8中示出了化合物H的实例。在含有pH 7.2的柠檬酸盐-磷酸盐缓冲液的媒介物中并且使用1%浓度的PS80、或PCA-PVA-PEG作为增溶剂制备所述制剂。样品储存在40℃条件下并且在4周后分析。用或PCA-PVA-PEG,药物回收率与用PS80相比高2倍。化合物H易受氧化降解。据信,和PCA-PVA-PEG均可能通过减少氧化提高这些类型的化合物的稳定性。
表7:40℃下0.01%化合物H在MP500瓶中的稳定性
媒介物的其它化合物:pH~7.2的柠檬酸盐/磷酸盐缓冲液和NaCl
实施例7:可用PCA-PVA-PEG配制供眼用的API和制剂的类
别实例
PCA-PVA-PEG可用作具有多种活性物的制剂的增溶剂或添加剂。这些包括但不限于表8所列实例。表9列出了可用PCA-PVA-PEG制备的溶液制剂的实例。也可用于除水溶液外的制剂中。这些包括但不限于表10所列实例。
表8:可使用PCA-PVA-PEG配制的API的实例
表9:使用PCA-PVA-PEG的溶液制剂的实例
表10.含PCA-PVA-PEG、有非水组分的制剂的实例
表10.含PCA-PVA-PEG、有非水组分的制剂的实例(续)
表11-17中有的制剂媒介物组成的实例。表11-17中公开的所有制剂均可能包括来自表8的活性剂。
表11:具有硼酸缓冲液(无防腐剂)的含的制剂媒介物
表12:具有硼酸缓冲液和作为防腐剂的含的制剂媒介物
表13:具有柠檬酸盐-磷酸盐缓冲液(无防腐剂)的含的制剂媒介物
表14:具有柠檬酸盐-磷酸盐缓冲液和作为防腐剂的苯扎氯胺(BAK),含的制剂媒介物
表15:具有柠檬酸盐-磷酸盐缓冲液、作为防腐剂的苯扎氯胺(BAK)和EDTA,含的制剂媒介物
表16:具有Soluplus(无防腐剂)的乳液媒介物的实例
表17:具有Soluplus的乳液媒介物(用Purite、苯扎氯胺或组合防腐)的实例。表6中具有下列成分作为防腐剂的任何媒介物
实施例8
一些局部眼用组合物包含聚乙烯基己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物。
实施例9
在实施例8的一些组合物中,聚乙烯基己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物的平均分子量为约10,000g/mol至约500,000g/mol。
实施例10
在实施例8或9的一些组合物进一步包含治疗活性剂。
实施例11
在实施例10的一些组合物中,所述治疗活性剂包含免疫抑制剂。
实施例12
在实施例10的一些组合物中,所述治疗活性剂包含α-肾上腺素能拮抗剂。
实施例13
在实施例10的一些组合物中,所述治疗活性剂包含前列腺素EP2激动剂。
实施例14
在实施例10的一些组合物中,所述治疗活性剂包含毒蕈碱。
实施例15
在实施例10的一些组合物中,所述治疗活性剂包含前列腺素。
实施例16
在实施例10的一些组合物中,所述治疗活性剂包含α激动剂。
实施例17
在实施例10的一些组合物中,所述治疗活性剂包含抗生素。
实施例18
在实施例10的一些组合物中,所述治疗活性剂包含抗感染剂。
实施例19
在实施例10的一些组合物中,所述治疗活性剂包含抗炎剂。
实施例20
在实施例10的一些组合物中,所述治疗活性剂包含β阻滞剂。
实施例21
在实施例10的一些组合物中,所述治疗活性剂包含环孢霉素A。
实施例22
在实施例10的一些组合物中,所述治疗活性剂包含环孢霉素类似物。
实施例23
在实施例10的一些组合物中,所述治疗活性剂包含酚妥拉明。
实施例24
在实施例10的一些组合物中,所述治疗活性剂包含睾酮。
实施例25
在实施例10的一些组合物中,所述治疗活性剂包含地塞米松。
实施例26
在实施例10的一些组合物中,所述治疗活性剂包含强的松龙。
实施例27
在实施例10的一些组合物中,所述治疗活性剂包含比马前列素。
实施例28
在实施例10的一些组合物中,所述治疗活性剂包含拉坦前列素。
实施例29
在实施例10的一些组合物中,所述治疗活性剂包含表8的化合物A或B。
实施例30
在实施例10的一些组合物中,所述治疗活性剂包含匹鲁卡品。
实施例31
在实施例10的一些组合物中,所述治疗活性剂包含溴莫尼定。
实施例32
在实施例10的一些组合物中,所述治疗活性剂包含表8的化合物C。
实施例33
在实施例10的一些组合物中,所述治疗活性剂包含表8的化合物D。
实施例34
在实施例10的一些组合物中,所述治疗活性剂包含表8的化合物E。
实施例35
在实施例10的一些组合物中,所述治疗活性剂包含表8的化合物F或G。
实施例36
在实施例10的一些组合物中,所述治疗活性剂包含加替沙星。
实施例37
在实施例10的一些组合物中,所述治疗活性剂包含酮咯酸。
实施例38
在实施例10的一些组合物中,所述治疗活性剂包含类固醇。
实施例39
在实施例10的一些组合物中,所述治疗活性剂包含噻吗洛尔。
实施例40
在实施例8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38或39的一些组合物中,所述组合物为溶液。
实施例41
实施例40的一些组合物进一步包含辅助增溶剂。
实施例42
在实施例41的一些组合物中,所述辅助增溶剂包含山梨醇酐单硬脂酸酯。
实施例43
在实施例41的一些组合物中,所述辅助增溶剂包含聚氧化乙烯-聚氧化丙烯嵌段共聚物。
实施例44
在实施例41的一些组合物中,所述辅助增溶剂包含聚氧化乙烯甘油三蓖麻醇酸酯35。
实施例45
在实施例41的一些组合物中,所述辅助增溶剂包含环糊精。
实施例46
实施例40、41、42、43、44或45的一些组合物进一步包含渗透压剂。
实施例47
在实施例46的一些组合物中,所述渗透压剂包含丙二醇。
实施例48
在实施例46的一些组合物中,所述渗透压剂包含甘油。
实施例49
在实施例46的一些组合物中,所述渗透压剂包含甘露糖醇。
实施例50
在实施例46的一些组合物中,所述渗透压剂包含氯化钠。
实施例51
实施例40、41、42、43、44、45、46、47、48、49或50的一些组合物进一步包含缓冲液。
实施例52
在实施例51的一些组合物中,所述缓冲液包含磷酸盐。
实施例53
在实施例51的一些组合物中,所述缓冲液包含磷酸盐和柠檬酸盐。
实施例54
在实施例51的一些组合物中,所述缓冲液包含三乙醇胺。
实施例55
在实施例51的一些组合物中,所述缓冲液包含乳酸盐。
实施例56
在实施例51的一些组合物中,所述缓冲液包含硼酸盐。
实施例57
在实施例51的一些组合物中,所述缓冲液包含硼酸盐和柠檬酸盐。
实施例58
实施例40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56或57的一些组合物进一步包含防腐剂。
实施例59
在实施例58的一些组合物中,所述防腐剂包含苯扎氯胺。
实施例60
在实施例58的一些组合物中,所述防腐剂包含稳定化氧氯复合物。
实施例61
一种溶解治疗活性剂的方法,包括混合所述治疗活性剂和聚乙烯基己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物,以便形成根据实施例10-60中任一项所述的组合物。
实施例62
一种稳定治疗活性剂的方法,包括使所述治疗活性剂与聚乙烯基己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物合并,从而提高所述治疗活性剂的稳定性。
实施例63
一种稳定治疗活性剂的方法,包括合并所述治疗活性剂和聚乙烯基己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物,以便形成根据实施例10-60中任一项所述的组合物。
实施例64
一种治疗影响眼睛的疾病的方法,包括向有需要的眼睛施用根据任何实施例8-60所述的组合物。
实施例65
患有眼压升高的65岁白种人男性每天在每只眼用一滴表18的制剂2,60天。患者几乎立刻体验到IOP显著下降,这持续了整整60天的治疗,其中患者的眼压水平降到可接受的水平。
表18
实施例66
患有眼压升高和开角型青光眼的71岁非裔美国女性每天在每只眼用一滴来自表19的制剂4。30天后,只要她继续每天应用表19的制剂4,她的青光眼症状明显改善并且她的眼压下降到正常水平并且没有显著副作用。
表19
41岁白种人女性患有干眼病症状,每天在每只眼睛用两次表20中的制剂2。应用2天后,干眼病症状显著改善。
表20
除非另外指出,说明书和权利要求中使用的表示成分的量、性质(例如分子量)、反应条件等的所有数字应理解为在所有情况下被术语“约”修饰。相应地,除非指出相反,说明书和所附权利要求中提出的数字参数是可能根据设法获得的所需性质改变的近似值。至少,而不是试图限制权利要求范围的等同原则的应用,每个数字参数至少应根据报道的有效位的数字和应用普通舍入技术解释。
除非本文另外指出或与上下文明显矛盾,术语“一”、“一种”、“所述”和描述本发明的上下文(特别是下列权利要求的上下文)中使用的类似所指物应解释为包括单数和复数。除非本文另外指出或与上下文明显矛盾,本文描述的所有方法可按任何适合顺序进行。使用本文提供的任何和所有实施例或示例性语言(例如,“例如”)仅仅旨在更好地说明本发明而不构成对任何权利要求范围的限制。说明书中的语言不得解释为指示本发明实践所必需的任何未要求保护的要素。
对本文所述替代要素或实施方案的分组不得解释为限制。可能提到每个组成员并且单独地或与本文出现的组的其它成员或其它要素以任何组合一起要求保护。预计出于方便和/或专利性原因,可将组的一个或多个成员包括在组中或从中删除。当出现任何此类包括或删除时,将说明书视为包含经修改的组,从而完成所附权利要求中使用的所有马库什组(Markush groups)的书面描述。
本文描述了某些实施方案,包括发明人已知实施本发明的最佳模式。当然,对于本领域的普通技术人员而言,对这些所述实施方案的变更将在阅读前面的描述后变得显而易见。发明人期望技术人员酌情采用此类变更,并且发明人希望本发明不像本文具体描述那样实践。相应地,在适用法律允许的情况下权利要求包括权利要求中叙述的主题的修改或等效内容。而且,除非另外指出或与上下文明显矛盾,在其所有可能变更中考虑到了上述要素的组合。
最后,应理解本文公开的实施方案说明了权利要求的原理。可能采用的其它修改在权利要求范围之内。因此,举例而言而非限制,可根据本文的教导利用替代实施方案。相应地,权利要求不限于明确示出和描述的实施方案。
Claims (20)
1.一种局部眼用组合物,包含聚乙烯基己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物。
2.根据权利要求1所述的组合物,其中所述聚乙烯基己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物的平均分子量为约10,000g/mol至约500,000g/mol。
3.根据权利要求1或2所述的组合物,进一步包含治疗活性剂。
4.根据权利要求3所述的组合物,其中所述治疗活性剂包括免疫抑制剂、α-肾上腺素能拮抗剂、类固醇、前列腺素EP2激动剂、毒蕈碱、前列腺素、α激动剂、抗生素、抗感染剂、抗炎剂、β阻滞剂或其组合。
5.根据权利要求3所述的组合物,其中所述治疗活性剂包括选自由环孢霉素A、环孢霉素类似物、酚妥拉明、睾酮、地塞米松、强的松龙、比马前列素、拉坦前列素、表8的化合物A、B、C、D、E、F、G或H、匹鲁卡品、溴莫尼定、加替沙星、酮咯酸、类固醇、噻吗洛尔或其组合组成的治疗活性剂。
6.根据权利要求5所述的组合物,其中所述组合物为溶液。
7.根据权利要求6所述的组合物,进一步包含辅助增溶剂。
8.根据权利要求7所述的组合物,其中所述辅助增溶剂包含山梨醇酐单硬脂酸酯、聚氧化乙烯-聚氧化丙烯嵌段共聚物、聚氧化乙烯甘油三蓖麻醇酸酯35、环糊精或其组合。
9.根据权利要求6所述的组合物,进一步包含渗透压剂。
10.根据权利要求9所述的组合物,其中所述渗透压剂包含丙二醇、甘油、甘露糖醇、氯化钠或其组合。
11.根据权利要求10所述的组合物,进一步包含缓冲剂。
12.根据权利要求11所述的组合物,其中所述缓冲剂包含磷酸盐、磷酸盐和柠檬酸盐、三乙醇胺、乳酸盐、硼酸盐、硼酸盐和柠檬酸盐或其组合。
13.根据权利要求10所述的组合物,进一步包含防腐剂。
14.根据权利要求13所述的组合物,其中所述防腐剂包含苯扎氯胺、稳定化氧氯复合物或其组合。
15.一种溶解治疗活性剂的方法,包括提供包含治疗活性剂和聚乙烯基己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物的组合物,其中在室温下没有聚乙烯基己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物,所述治疗活性剂并非可完全溶于所述组合物中。
16.一种溶解治疗活性剂的方法,包括混合所述治疗活性剂和聚乙烯基己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物,以便形成根据权利要求5所述的组合物。
17.一种稳定治疗活性剂的方法,包括使所述治疗活性剂与聚乙烯基己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物合并,从而提高所述治疗活性剂的稳定性。
18.一种稳定治疗活性剂的方法,包括合并所述治疗活性剂和聚乙烯基己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物,以便形成根据权利要求5所述的组合物。
19.一种治疗影响眼睛的疾病的方法,包括向有需要的眼睛施用根据权利要求11所述的组合物,其中所述活性剂中的一种为比马前列素。
20.根据权利要求19所述的方法,进一步包含所述活性剂溴莫尼定。
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CN110193084A (zh) * | 2019-07-02 | 2019-09-03 | 付纪军 | 一种含聚乙烯己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物的药物制剂及其制备方法 |
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CA2859583C (en) | 2020-02-18 |
WO2013090842A3 (en) | 2013-10-10 |
US9579385B2 (en) | 2017-02-28 |
JP2015500347A (ja) | 2015-01-05 |
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EP2790673A2 (en) | 2014-10-22 |
CA2859583A1 (en) | 2013-06-20 |
WO2013090842A2 (en) | 2013-06-20 |
HK1203148A1 (zh) | 2015-10-23 |
US20130157963A1 (en) | 2013-06-20 |
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