CN100355455C - 用于眼内使用的非聚合亲脂性药物植入组合物 - Google Patents
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Abstract
本发明公开了固体或半固体眼内植入组合物。该组合物含有亲脂化合物但是不含聚合物成分。
Description
发明背景
本发明涉及药物植入组合物。具体地,本发明涉及低分子量的亲脂性化合物在眼内使用的植入组合物中的用途。
公知各种固体和半固体药物递送植入物,包括非侵蚀性的、非降解的植入物如使用乙烯-醋酸乙烯制备的植入物,和易侵蚀和生物可降解的植入物如使用聚酐和聚交酯制备的植入物。药物递送植入物、尤其是眼科药物递送植入物通常的特征是含有至少一种聚合物成分。在许多情况中,药物递送植入物含有一种以上聚合物成分。
例如,美国专利No.5,773,019公开了用于将药物递送至眼的可植入控释装置,其中该可植入装置具有含有有效量的低溶解性药物的内核,该内核被非生物可侵蚀的、低溶解性药物可透过的聚合物包衣层覆盖。
美国专利No.5,378,475公开了缓释药物递送装置,其具有包含药物的内核或贮库、基本上对药物的通过不可渗透的第一包衣层和药物可渗透的第二包衣层。第一包衣层覆盖至少一部分内核但至少一小部分内核不被第一包衣层包衣。第二包衣层基本上完全覆盖第一包衣层和内核的未包衣部分。
美国专利No.4,853,224公开了生物可降解的眼植入物,其包含微囊化药物以植入眼前房和/或后房。聚合物包封剂或脂质包封剂是胶囊的主要成分。公开了许多类型的聚合物,但是没有公开不含生物可降解聚合物的植入物。
美国专利No.5,164,188公开了生物可降解的植入物在眼脉络膜中的用途。植入物通常被制成胶囊。该胶囊大部分是聚合物包封剂。也可使用能够置于脉络膜上的给定区域而不迁移的材料“如氧化纤维素、明胶、硅酮等”。
美国专利No.6,120,789公开了非聚合组合物用于在动物中原位形成固体基质的用途,和该组合物作为医学装置或作为生物活性剂的缓释递送系统的用途等。该组合物由生物相容的、非聚合物材料和药学上可接受的有机溶剂组成。非聚合型组合物是生物可降解的和/或生物可侵蚀的,并且基本上不溶于水性液体或体液。有机溶剂溶解非聚合物材料,并且在水或其他水性介质中的溶解性为可混溶至可分散。当置于动物中的植入位点时,非聚合组合物最终转化成固体结构。该植入物通过增强细胞生长和组织再生、伤口和器官修复、神经再生、软组织和硬组织再生等而可用于治疗组织缺陷。该组合物可包括生物学活性剂(生物活性剂),例如抗炎剂、抗病毒剂、可用于治疗和预防植入位点感染的抗菌剂或抗真菌剂、生长因子、激素等。所得植入物提供了向动物递送生物学活性剂的系统。根据’789专利,适宜的有机溶剂为生物相容的、药学上可接受的有机溶剂,并且将至少部分溶解非聚合物材料。有机溶剂在水中的溶解性为可混溶至可分散。溶剂能够从组合物原位扩散、分散或浸出至植入位点的水性组织液如血清、淋巴、脑脊液(CSF)、唾液等中。根据’789专利,溶剂的Hildebrand(HLB)溶解度比值优选地为约9-13(cal/cm3)1/2并且优选溶剂的极性程度可有效提供至少约5%的水中溶解度。
易侵蚀的或生物可降解的植入物中的聚合物成分必须侵蚀或降解以转运通过眼组织并清除。4000或更低的低分子量分子可以转运通过眼组织并被清除,而无需生物降解或侵蚀。
发明概述
本发明提供了眼内植入组合物,其包含一种或多种低分子量亲脂化合物和药物,但是不含聚合物成分和与水混溶或可分散于水中的有机溶剂。该组合物在≤37℃——平均人眼温度的温度下是固体或半固体。该植入物可置于眼的任何地方,包括结膜穹窿,但是特别适于植入眼内。
附图简述
图1显示了含有所示单酸甘油酯掺合物的植入组合物中地塞米松的释放。
图2显示了含有所示单酸甘油酯的植入组合物中地塞米松的释放。
图3显示了含有甘油单硬脂酸酯和不同量的表面活性剂的植入组合物中地塞米松的释放。
发明详述
除非特别指出,所有以百分数表示的成分的量以%w/w给出。
如此处所用的“植入物”指含有一种或多种药物的固体或半固体物质,并且包括但不限于珠、小丸(pellet)、棒剂、膜剂和微粒剂。微粒剂可悬浮于水性或非水性液态载体中。
本发明的植入组合物不含聚合物成分和与水混溶或可分散于水中的有机溶剂,包含药物和一种或多种分子量为150-4000的亲脂化合物,其中该亲脂化合物具有下式:
其中:R1为-H、-OH、-COOH、-CnH2n+1-2m、-COOCnH2n+1-2m、-COO(CH2CH2O)nCH2CH2OH、-CH2R3或
R2、R3和R4独立地为-H、-OH、-COOH、-CnH2n+1-2m、-OOCCnH2n+1-2m、-COOCnH2n+1-2m、-COO(CH2CH2O)nCH2CH2OH、-CnH2n+1-2mCOO(CH2CH2O)nCH2CH2OH、-OOCCnH2n+1-2mCOOCn’H2n’+1-2m’、-COO-Na+、-COO-K+、-SO3H、-SO3 -Na+、-SO3 -K+、-NH2、-Cl、
n、n’和n”独立地为0-50;且
m、m’和m”独立地为0-10。
优选地,用于本发明的亲脂化合物的分子量≤2000、最优选≤1000。如果本发明的植入物仅含有一种式(I)的亲脂化合物,则亲脂化合物的熔点必须≥34℃、优选≥37℃。如果植入物含有两种或多种式(I)的亲脂化合物,则至少一种式(I)亲脂化合物的熔点<34℃,仅仅混合物的熔点必须≥34℃、优选≥37℃。亲脂化合物在37℃下不溶于水(即在37℃下水中溶解度<0.5mg/ml)。
优选式(I)的亲脂化合物,其中R1为-CnH2n+1-2m、-COOCnH2n+1-2m、-COO(CH2CH2O)nCH2CH2OH、-CH2R3或
R2、R3和R4独立地为-H、-OH、-COOH、-CnH2n+1-2m、-OOCCnH2n+1-2m、-COOCnH2n+1-2m、-COO(CH2CH2O)nCH2CH2OH、-CnH2n+1-2mCOO-(CH2CH2O)nCH2CH2OH或-OOCCnH2n+1-2mCOOCn’H2n’+1-2m’;
n、n’和n”独立地为0-40;且
m、m’和m”独立地为0-5。
最优选式(I)的亲脂化合物,其中R1为
R2、R3和R4独立地为-H、-OH、-COOH、-CnH2n+1-2m或-OOCCnH2n+1-2m;
n、n’和n”独立地为0-30;且
m、m’和m”独立地为0-3。
特别优选的式(I)亲脂化合物为甘油单月桂酸酯、甘油二月桂酸酯、甘油单肉豆蔻酸酯、甘油二肉豆蔻酸酯、甘油单棕榈酸酯、甘油二棕榈酸酯、甘油单硬脂酸酯、甘油二硬脂酸酯、甘油单油酸酯、甘油二油酸酯、甘油单亚油酸酯、甘油二亚油酸酯、甘油单花生酸酯(glyceryl monoarachidate)、甘油二花生酸酯、甘油单山嵛酸酯和甘油二山嵛酸酯。
如此处所用的“与水混溶或可分散于水中的有机溶剂”指生物相容的、药学上可接受的并且在水中溶解性为可混溶至可分散的有机溶剂。这些从本发明权利要求的组合物排除的有机溶剂和美国专利No.6,120,789中描述的组合物中必需的有机溶剂相同。
本发明的亲脂化合物可通过本领域公知的方法制备并且许多这些化合物市售可得。例如,供应商包括NuChek Prep(Elysian,明尼苏达);QuestInternational(Hoffman Estates,伊利诺斯),其生产商标为Myvaplex和Myvacet的这类化合物;和Gattefossa(Saint-Priest,法国),其生产商标为Gelucire和Geleol的这类化合物。适宜的亲脂化合物包括但不限于以下市售可得的产品。
二甘醇单硬脂酸酯(Hydrine;m.p.=45.5-48.5℃);
丙二醇单和二硬脂酸和棕榈酸酯(Monosteol;m.p.=34.0-37.5℃;“单硬脂酸丙二醇酯);
甘油单硬脂酸酯(Geleol;m.p.=70℃);
甘油单亚油酸酯(Maisine35-1;m.p.=-6.5℃);
甘油单油酸酯(Peceol;m.p.=16℃);
单酸甘油酯混合物,如所售的Myverol18-85(m.p.=46℃);
甘油单硬脂酸酯(85-90%)和甘油单棕榈酸酯(10-15%)的混合物(Myvaplex600P;m.p.=69℃);
饱和C12-C18饱和脂肪酸的甘油酯(Gelucire43/01;m.p.=42-46℃);
饱和C8-C18饱和脂肪酸的甘油酯(Gelucire33/01;m.p.=33-37℃);和
饱和C12-C18饱和脂肪酸的甘油酯(Gelucire39/01;m.p.=37.5-41℃)。
本发明的植入组合物包含一种或多种式(I)亲脂化合物,其总浓度为至少10%、优选至少30%、最优选至少50%。
本发明的植入组合物包含药学有效量的眼科药物。如果必须或需要,本发明的植入物可包括一种以上的药物。公知许多类型的眼科药物,包括但不限于:抗青光眼剂如β-阻滞剂,包括噻吗洛尔、倍他洛尔、左旋倍他洛尔、卡替洛尔,缩瞳药,包括匹鲁卡品,碳酸酐酶抑制剂、前列腺素类似物、seretonergics、蕈毒碱类药物(muscarinics)、多巴胺能激动剂、肾上腺素能激动剂,包括阿拉可乐定和溴莫尼定;抗感染剂,包括喹诺酮类如环丙沙星,和氨基苷类如托普霉素和庆大霉素;非甾族和甾族抗炎剂如舒洛芬、双氯芬酸、酮洛酸、双甲丙酰龙、地塞米松和四氢可的松;生长因子如VEGF;免疫抑制剂;神经保护剂;血管生成抑制剂和抗过敏剂,包括奥洛他定。眼科药物可以以药学上可接受的盐形式存在,如噻吗洛尔马来酸盐、溴莫尼定酒石酸盐或双氯芬酸钠。本发明的组合物还可包含眼科药物的组合,如(I)选自倍他洛尔和噻吗洛尔的β-阻滞剂,和(ii)选自以下的前列腺素:拉坦前列素、15-酮拉坦前列素、氟前列醇异丙酯(特别是1R-[1α(Z),2β(1E,3R*),3α,5α]-7-[3,5-二羟基-2-[3-羟基-4-[3-(三氟甲基)-苯氧基]-1-丁烯基]环-戊基-]-5-庚烯酸1-甲基乙基酯)、[2R(1E,3R),3S(4Z),4R]-7-[四氢-2-[4-(3-氯苯氧基)-3-羟基-1-丁烯基]-4-羟基-3-呋喃基]-4-庚烯酸异丙酯和(5Z)-(9R,11R,15R)-9-氯-15-环己基-11,15-二羟基-3-氧杂-16,17,18,19,20-五降-5-前列腺烯酸(prostenoic acid)异丙酯的组合。本发明植入组合物中所含药物的总量优选不大于50%。
除了式(I)的亲脂化合物和眼科药物外,本发明的植入组合物任选包含一种或多种赋形剂。公知用于固体和半固体药物组合物的许多赋形剂。适宜的赋形剂的实例包括但不限于表面活性剂、防腐剂和稳定剂。
适宜的表面活性剂包括泰洛沙泊、聚山梨酯20、聚山梨酯60和聚山梨酯80表面活性剂。优选的表面活性剂为聚山梨酯80。
适宜的防腐剂包括季铵防腐剂如聚夸特宁-1(polyquaternium-1)和苯扎卤铵。优选的苯扎卤铵为苯扎氯铵(“BAC”)和苯扎溴铵。
适宜的稳定剂包括螯合剂如乙二胺四乙酸二钠,和抗氧化剂如抗坏血酸和柠檬酸。
植入组合物可制成适于植入眼中的形状。例如,这些形状包括但不限于圆柱形、圆锥形和球形。备选地,植入组合物的形状和大小可以使得它们可悬浮于液态载体中并被注射或存放在眼中。本发明植入物的大小和形状将依赖于许多因素,包括所选药物、目标疾病和所选植入位置。本发明的植入物可以植入眼的任何地方,包括结膜穹窿、泪点(punctum)和泪小管、眼前节和眼后节,以及眼球筋膜下(sub-Tenon’s)腔、脉络膜上腔和结膜下腔。
尽管植入组合物优选作为固体和半固体施用,但是在一个实施方案中,该组合物被加温并以半固体或液体状态经插管施用。在施用位点冷却至室温后,组合物将形成半固体或固体植入物。
以下实施例旨在阐明但不限制本发明。
实施例1:安慰剂小丸剂
将0.25g聚山梨酯80和4.75g单酸甘油酯Myverol 18-35加入闪烁管中。通过在水浴中加热将单酸甘油酯熔化。然后将聚山梨酯80和单酸甘油酯通过涡流混合。通过在圆柱形模子中冷却溶液以制备小丸剂。以单酸甘油酯Myverol 18-50、Myverol 18-85和Myaplex 600P重复该步骤。
为了阐明所实施的材料和式(I)间的关系,Myverol 18-35、Myverol18-50和Myverol 18-85含有(根据其生产商)以下所示比例的以下成分:
Myverol 18-35
单酸甘油酯成分
简写
Wt.%
甘油单月桂酸酯 C12.0 0.3
甘油单肉豆蔻酸酯 C14.0 1.1
甘油单棕榈酸酯 C16.0 44.1
甘油单硬脂酸酯 C18.0 4.5
甘油单油酸酯 C18.1 39.3
甘油单亚油酸酯 C18.2 10.2
甘油单花生酸酯 C20.0 0.3
Myverol 18-50
单酸甘油酯成分
简写
Wt.%
甘油单肉豆蔻酸酯 C14.0 0.1
甘油单棕榈酸酯 C16.0 10.8
甘油单硬脂酸酯 C18.0 12.6
甘油单油酸酯 C18.1 73.9
甘油单亚油酸酯 C18.2 1.9
甘油单花生酸酯 C20.0 0.3
甘油单山嵛酸酯 C22.0 0.3
Myverol 18-85
单酸甘油酯成分
简写
Wt.%
甘油单肉豆蔻酸酯 C14.0 0.8
甘油单棕榈酸酯 C16.0 22.3
甘油单硬脂酸酯 C18.0 2.5
甘油单油酸酯 C18.1 17.6
甘油单亚油酸酯 C18.2 54.8
甘油单花生酸酯 C20.0 0.3
甘油单山嵛酸酯 C22.0 0.3
C18.0代表化合物:
C18.1代表化合物:
C18.2代表化合物:
实施例2:含有地塞米松的植入组合物
通过将所示成分在闪烁管中合并、在水浴中加热熔化式(I)的亲脂化合物、涡流混合、然后在圆柱形模子中冷却所混合、熔化的配制物,由此制备以下表1中所示的1×3mm圆柱形小丸剂。
表1:制剂
制剂# | 式(I)化合物 | 地塞米松wt.% | 聚山梨酯80wt.% | 图# |
1 | Myvaplex 600P | 3.5 | 无 | 1 |
2 | Myverol 18-85 | 3.5 | 无 | 1 |
3 | Myvacel 5-07 | 3.5 | 1.5 | 1 |
4 | Myvacel 7-07 | 3.5 | 1.5 | 1 |
5 | 甘油单硬脂酸酯 | 3.5 | 无 | 2 |
6 | 甘油单肉豆蔻酸酯 | 3.5 | 无 | 2 |
7 | 甘油单山嵛酸酯 | 3.5 | 无 | 2 |
8 | 甘油单硬脂酸酯 | 3.5 | 无 | 3 |
9 | 甘油单硬脂酸酯 | 3.5 | 1.5 | 3 |
10 | 甘油单硬脂酸酯 | 3.5 | 2.5 | 3 |
11 | 甘油单硬脂酸酯 | 3.5 | 5 | 3 |
通过将一粒小丸剂置于含有1.5ml磷酸缓冲盐水的2ml管形瓶中来测量表1所示每种制剂中地塞米松的释放。磷酸缓冲盐水(“PBS”)含有0.8%NaCl、0.12%Na2HPO4和0.06%NaH2PO4:H2O。然后将瓶置于37℃烘箱中。在每个时间点,将瓶轻轻倒转两次,从瓶中移取60μl PBS用于地塞米松的HPLC分析,将60μl新鲜PBS加入小瓶,并将小瓶放回到烘箱中直至下一时间点。每种制剂一式三份进行实验。结果示于图1-3。
实施例3:配制成微粒悬浮于液体载体中的植入组合物
将醋酸阿奈可他(anecortave)粉末、甘油单硬脂酸酯和聚山梨酯80的75∶20∶5混合物加热以熔化甘油单硬脂酸酯并进行混合。然后将该混合物喷雾干燥以制备微粒。然后将微粒悬浮于包含氯化钠、磷酸氢二钠、磷酸二氢纳、羧甲基纤维素和泰洛沙泊的水性赋形剂中,以制备适于注射的组合物。
实施例4:使用前加温并通过插管注射的植入组合物
将醋酸阿奈可他粉末、Gelucire 39/01(饱和C12-C18饱和脂肪酸甘油酯的50∶45∶5混合物加热以熔化Gelucire 39/01并进行混合。注射前,将该组合物加热至约41℃并吸入注射器中。然后经过眼球筋膜下腔插管注射。冷却到37℃时,其形成固体蜡状物质。
实施例5:含有80μg前列腺素的植入组合物
通过将前列腺素类似物(5Z)-(9R,11R,15R)-9-氯-15-环己基-11,15-二羟基-3-氧杂-16,17,18,19,20-五降-5-前列腺烯酸异丙酯和必需量的产品PrecirolATO 5(Gattefossa)在闪烁管中合并、在水浴中加热熔化亲脂化合物、涡流混合、然后在圆柱形模子中冷却所混合、熔化的配制物,以制备两粒各含80μg所述前列腺素类似物的1μl大小的圆柱形小丸。根据生产商,PrecirolATO 5由棕榈硬脂酸(palmitostearic acid)的甘油单酯、二酯和三酯组成,其中主要是二酯成分。PrecirolATO 5通过用棕榈硬脂酸酯化甘油而合成。
如下测量前列腺素类似物从小丸中的释放:称重后,将小丸置于含有20ml PBS的闪烁管中。将各管保存在37℃烘箱中。在每个时间点,将管轻轻倒转几次(约5次)。然后从管中移取300μl溶解样品并将管放回烘箱。样品中所含前列腺素类似物的量通过HPLC分析确定。结果示于表2。
表2
时间(天) | 累积药物释放(μg) | 累积药物释放(最初80μg的%) | ||
1 | 1.70 | 1.84 | 2.18 | 2.17 |
3 | 28.6 | 32 | 36.67 | 37.65 |
8 | 73 | 76.6 | 93.59 | 90.12 |
11* | 65 | 69.4 | 83.33 | 81.65 |
*药物可能在溶解介质中降解。
实施例6:含有200μg前列腺素的植入组合物
通过将前列腺素类似物(5Z)-(9R,11R,15R)-9-氯-15-环己基-11,15-二羟基-3-氧杂-16,17,18,19,20-五降-5-前列腺烯酸异丙酯和必需量的产品Compritol888 ATO(Gattefossa)在闪烁管中合并、在水浴中加热熔化亲脂化合物、涡流混合、然后在圆柱形模子中冷却所混合、熔化的配制物,以制备两粒各含有200μg所述前列腺素类似物的3μl大小的圆柱形小丸。根据生产商,Compritol888 ATO由山嵛酸的甘油单酯、二酯和三酯组成,其中主要是二酯成分。Compritol888 ATO通过用山嵛酸酯化甘油而合成。
如下测量前列腺素类似物从小丸中的释放:称重后,将小丸剂置于含有20ml PBS的闪烁管中。将各管保存在37℃烘箱中。在每个时间点,将管轻微倒转几次(约5次),然后从管中移取300μl溶解样品并将管放回烘箱。样品中所含前列腺素类似物的量通过HPLC分析确定。结果示于表3。
表3
时间(天) | 累积药物释放(μg) | 累积药物释放(最初80μg的%) | ||
1 | 12.18 | 11.38 | 5.37 | 4.78 |
3 | 3.32 | 3.02 | 1.46 | 1.27 |
8 | 12.1 | 14.04 | 5.33 | 5.90 |
11 | 25.6 | 31 | 11.28 | 13.03 |
15 | 52.6 | 66.4 | 23.17 | 27.90 |
22 | 54.6 | 102.4 | 24.05 | 43.03 |
30 | 88.8 | 107.4 | 39.12 | 45.13 |
本发明已参考一些优选的实施方案进行了描述;然而,应该理解其也可以以其他特定形式或者其变体实施,只要不背离其精神或基本特征即可。因此,此处描述的实施方案在所有方面应认为是阐明性的而非限制性的,本发明的范围由所附权利要求书而不是前述说明书指出。
Claims (19)
1.适于植入选自泪点、泪小管、眼前节、眼后节、眼球筋膜下腔、脉络膜上腔和结膜下腔的位点的眼内植入组合物,包含分子量为150-4000的亲脂化合物和药学有效量的药物,但是不含表面活性剂或防腐剂之外的聚合物成分和与水混溶或可分散于水中的有机溶剂,其中该组合物在≤37℃的温度下是固体或半固体且该亲脂化合物选自二甘醇单硬脂酸酯、丙二醇单硬脂酸酯、甘油单月桂酸酯、甘油二月桂酸酯、甘油单肉豆蔻酸酯、甘油二肉豆蔻酸酯、甘油单棕榈酸酯、甘油二棕榈酸酯、甘油单硬脂酸酯、甘油二硬脂酸酯、甘油单油酸酯、甘油二油酸酯、甘油单亚油酸酯、甘油二亚油酸酯、甘油单花生酸酯、甘油二花生酸酯、甘油单山嵛酸酯和甘油二山嵛酸酯,其中该组合物包含至少30%重量的亲脂化合物。
2.权利要求1的眼内植入组合物,其中亲脂化合物的分子量≤2000。
3.权利要求2的眼内植入组合物,其中亲脂化合物的分子量≤1000。
4.权利要求1的眼内植入组合物,其中该组合物包含两种或多种亲脂化合物的混合物。
5.权利要求1的眼内植入组合物,其中亲脂化合物的熔点≥34℃。
6.权利要求4的眼内植入组合物,其中至少一种亲脂化合物的熔点<34℃但是混合物的熔点≥34℃。
7.权利要求1的眼内植入组合物,其中亲脂化合物选自二甘醇单硬脂酸酯、丙二醇单硬脂酸酯、甘油单硬脂酸酯、甘油单亚油酸酯、甘油单油酸酯、甘油单棕榈酸酯和它们的混合物。
8.权利要求1的眼内植入组合物,其中亲脂化合物选自甘油单月桂酸酯、甘油二月桂酸酯、甘油单肉豆蔻酸酯、甘油二肉豆蔻酸酯、甘油单棕榈酸酯、甘油二棕榈酸酯、甘油单硬脂酸酯、甘油二硬脂酸酯、甘油单油酸酯、甘油二油酸酯、甘油单亚油酸酯、甘油二亚油酸酯、甘油单花生酸酯、甘油二花生酸酯、甘油单山嵛酸酯和甘油二山嵛酸酯。
9.权利要求1的眼内植入组合物,其中该组合物包含至少50%重量的亲脂化合物。
10.权利要求1的眼内植入组合物,其中的药物选自抗青光眼剂、抗感染剂、非甾族和甾族抗炎剂、生长因子、免疫抑制剂、神经保护剂、血管生成抑制剂和抗过敏剂。
11.权利要求1的眼内植入组合物,其中该组合物还包含一种或多种选自表面活性剂、防腐剂和稳定剂的赋形剂。
12.权利要求11的眼内植入组合物,其中该组合物包含选自泰洛沙泊、聚山梨酯20、聚山梨酯60和聚山梨酯80的表面活性剂。
13.权利要求11的眼内植入组合物,其中该组合物包含选自季铵防腐剂的防腐剂。
14.权利要求11的眼内植入组合物,其中该组合物包含选自螯合剂和抗氧化剂的稳定剂。
15.权利要求1的眼内植入组合物,其中该组合物被制成圆柱形、圆锥形和球形。
16.包含分子量为150-4000的亲脂化合物和药学有效量的药物、但是不含表面活性剂或防腐剂之外的聚合物成分和与水混溶或可分散于水中的有机溶剂的眼内植入组合物在制备眼科可接受药物中的用途,其中该组合物在≤37℃的温度下是固体或半固体且该亲脂化合物选自二甘醇单硬脂酸酯、丙二醇单硬脂酸酯、甘油单月桂酸酯、甘油二月桂酸酯、甘油单肉豆蔻酸酯、甘油二肉豆蔻酸酯、甘油单棕榈酸酯、甘油二棕榈酸酯、甘油单硬脂酸酯、甘油二硬脂酸酯、甘油单油酸酯、甘油二油酸酯、甘油单亚油酸酯、甘油二亚油酸酯、甘油单花生酸酯、甘油二花生酸酯、甘油单山嵛酸酯和甘油二山嵛酸酯,其中该组合物包含至少30%重量的式(I)亲脂化合物,且其中将所制备的药物植入眼中选自以下的位点:泪点、泪小管、眼前节、眼后节、眼球筋膜下腔、脉络膜上腔和结膜下腔。
17.权利要求16的用途,其中将该组合物加温至高于室温的温度并通过插管施用。
18.权利要求16的用途,其中该组合物作为固体或半固体施用。
19.权利要求16的用途,其中将眼内植入组合物悬浮于液体载体中并经插管施用而植入眼中。
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US10806566B2 (en) | 2017-06-13 | 2020-10-20 | Alcon Inc. | Intraocular lens compositions |
RU2675691C1 (ru) * | 2017-09-14 | 2018-12-21 | Федеральное Государственное бюджетное образовательное учреждение высшего образования Дагестанский государственный медицинский университет Министерства здравоохранения Российской Федерации | Способ длительной перфузии субтенонового пространства лекарственными средствами |
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CY1107166T1 (el) | 2012-10-24 |
US20080241224A1 (en) | 2008-10-02 |
PL206594B1 (pl) | 2010-08-31 |
AU2003248777A1 (en) | 2004-02-02 |
MXPA05000632A (es) | 2005-03-31 |
EP1521573B1 (en) | 2008-01-02 |
DE60318446T2 (de) | 2008-05-21 |
ATE382330T1 (de) | 2008-01-15 |
PT1521573E (pt) | 2008-02-08 |
DK1521573T3 (da) | 2008-03-25 |
US8178576B2 (en) | 2012-05-15 |
DE60318446D1 (de) | 2008-02-14 |
CA2491313C (en) | 2011-05-24 |
JP4463681B2 (ja) | 2010-05-19 |
CN1668277A (zh) | 2005-09-14 |
KR20050023409A (ko) | 2005-03-09 |
US20040013704A1 (en) | 2004-01-22 |
ZA200410096B (en) | 2006-07-26 |
ZA200410095B (en) | 2006-07-26 |
ES2295647T3 (es) | 2008-04-16 |
US7678827B2 (en) | 2010-03-16 |
KR101003518B1 (ko) | 2010-12-30 |
WO2004006890A1 (en) | 2004-01-22 |
JP2006500328A (ja) | 2006-01-05 |
PL374743A1 (en) | 2005-10-31 |
EP1521573A1 (en) | 2005-04-13 |
AU2003248777B2 (en) | 2008-02-14 |
CA2491313A1 (en) | 2004-01-22 |
BR0312635A (pt) | 2005-04-19 |
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