CN1283639C - 治疗近视眼的哌仑西平有机酸盐及其滴眼剂 - Google Patents
治疗近视眼的哌仑西平有机酸盐及其滴眼剂 Download PDFInfo
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- CN1283639C CN1283639C CN 200410046270 CN200410046270A CN1283639C CN 1283639 C CN1283639 C CN 1283639C CN 200410046270 CN200410046270 CN 200410046270 CN 200410046270 A CN200410046270 A CN 200410046270A CN 1283639 C CN1283639 C CN 1283639C
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- pirenzepine
- acid
- eye
- sorbate
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Abstract
本发明涉及治疗近视眼的哌仑西平有机酸盐及其滴眼剂，本发明的哌仑西平有机酸盐与哌仑西平无机酸盐，如盐酸哌仑西平相比，具有较大的亲脂性，可以增加哌仑西平对角膜的通透性，提高疗效。
Description
技术领域：
本发明涉及适合眼内给药的哌仑西平有机酸盐及其药物组合物，与哌仑西平无机酸盐，如盐酸哌仑西平相比，这类盐具有较大的亲脂性，可以增加哌仑西平对角膜的通透性，提高疗效。
背景技术：
近视(Myopia)是一类极常见的疾病，往往起始于儿童时代。随着城市化以及电视、电脑的普及，近视的人群在向高发的方向发展。目前，全球范围内近视眼患者为人群的25％，在我国及周边国家中有较高的比例，尤其是青少年中比例更高，近年来更呈上升的趋势，据统计，在高考适龄人群中近视率高达80％以上。近视不仅将影响到患者的正常生活，并且易产生其他并发症。
近视多因眼球前后轴长过长，在无调节的情况下，平行光线聚焦于视网膜前的玻璃体内，结果在视网膜形成扩散光环，视物模糊。只有将物体移近，才能在视网膜上成像，看清物体。近视的发生常常与长期近距离视物和精细操作工作有关。由于长时间看近物或细小物体，睫状肌必须持续地收缩以增加晶状体的曲度，长此下去，导致睫状肌萎缩，调节力降低。
近年来，有人采用抗胆碱药通过阻断胆碱能神经对瞳状肌和瞳孔扩约肌的支配作用，用于治疗近视眼。McBrien于单眼进行形觉剥夺的小鸡玻璃体内注射阿托品，发现近视度数与眼球轴长明显小于对照组，并见阿托品不能减弱卡巴可(拟胆碱药)的调节作用及光照下的瞳孔收缩，从而得出结论，阿托品可以通过非调节机制阻止眼轴延长、降低实验性近视眼的屈光度。Stone通过对鸡实验发现非选择性M受体阻断剂阿托品能阻止形觉剥夺性近视眼的眼轴延长，进一步的实验证明阿托品的治疗近视的机制主要是直接作用于巩膜的。然而，阿托品为非选择性M受体阻断剂，同时可阻断M1、M2、M3受体。因为M1受体位于神经组织，而M3受体主要位于眼内肌，治疗近视只需要阻断虹膜中只有M1受体即可。
哌仑西平(pirenzepine)是选择性M1受体阻滞剂，具有选择性抗胆碱作用。近年的研究发现，哌仑西平对防治近视的发生、发展有明显效果，单次在玻璃体腔内注射哌仑西平能够降低视网膜乙酰胆碱和胆碱水平达9h(Cottriall CL，Annies R，BrewJ，et al.Pirenzepine reduces retinal acetylcholine and dopamine levels.Proc AustNeurosci Soc，1999，10：55)。在恒河猴、小鸡及其他哺乳动物实验模型中的研究表明，哌仑西平可阻止实验性近视的发生，其作用与阿托品相当，且没有阿托品因选择性较差而带来的副作用(Cottriall CL，McBrien NA，Annies R，et al.Prevention of formdeprivation myopia with pirenzepine：a study of drug delivery and distribution.OphthalPhysiol Opt，1999，4：327-335)。研究表明：哌仑西平被认为治疗近视的作用更直接、有效。与阿托品不同，哌仑西平的瞳孔散大副作用小，安全性高，易被患者接受。
WO 90/15604和US5637604申请了一个治疗动物后天发展的眼前后轴长延长所致近视的滴眼剂。该专利采用选择性胆碱受体阻滞剂，它们作用于脑、神经组织或神经元，阻滞其胆碱能受体，而对眼睫状肌无作用。其中包括哌仑西平、特仑西平等。该专利未涉及给药系统的设计。
WO 02/096418申请了一个哌仑西平的凝胶剂的专利。该专利中的哌仑西平凝胶剂的粘度范围在20℃、切应速度为1s-1的条件下为10000-300000cps，其中含哌仑西平的浓度为0.001-3％，粘度为15000-200000的纤维素衍生物0.5-5％、以及其他组分如氯化钠、溴化十六烷基三甲胺、苯扎氯胺、硼酸、碳酸钠、氯化钾、丙二醇、聚氧乙烯、聚氧丙烯、聚乙烯醇、泊洛沙姆188、枸橼酸钠、依地酸二钠等。考虑到哌仑西平的稳定性问题，滴眼凝胶剂的制备分两部分，HPMC凝胶液采用热压灭菌，而含药的溶液采用过滤灭菌，且滴眼剂的pH为5.0。
然而，上述专利均未涉及哌仑西平的吸收利用的问题。哌仑西平亲水性很高，而亲脂性较低，因而采用简单的滴眼剂给药，其透过角膜进入巩膜的吸收率较低。戴怡康、褚仁远指出：由于亲脂性较低，哌仑西平难以透过角膜到达眼内(戴怡康，褚仁远，哌仑西平滴眼剂在兔房水中的药代动力学研究，眼视光学杂志，2002，4(4)：228-229)。尽管眼用制剂的适宜pH范围是5-9，但是，WO 02/096418中的pH为5.0，已经为下限，生产、贮存中容易产生低于5.0的情况，导致对眼睛刺激性的产生。
已经报道的的哌仑西平制剂中，哌仑西平是以无机盐形式存在的，本发明为克服上述缺陷，提供了哌仑西平的有机酸盐，提高了其脂溶性、稳定性，以确保哌仑西平在治疗近视的应用中无刺激性，制剂稳定，同时哌仑西平可以较好地透过角膜层，确保其有效性。
发明内容：
本发明提供哌仑西平有机酸盐和含有哌仑西平有机酸盐的复盐，本发明的哌仑西平有机酸盐是指哌仑西平与有机酸形成的盐，所述有机酸包括但不限于以下有机酸，山梨酸(sorbic acid)、马来酸(maleic acid)、富马酸(fumaric acid)、枸橼酸(citric acid)、苯磺酸、甲基苯磺酸、龙胆酸、乳糖酸、葡萄糖醛酸、酒石酸、乳酸、琥珀酸、草酸、丁酸、异丁酸、2-乙基丁酸(二乙基乙酸)、戊酸、异戊酸、三甲基乙酸、苯甲酸、苯乙酸、肉豆蔻酸(十四烷酸)、棕榈酸(十六烷酸)、硬脂酸(十八酸)、油酸、亚油酸、a-亚麻酸、香草酸、丁香酸、绿原酸、阿魏酸、缬草酸、甘草酸、齐墩果酸、熊果酸、辛酸、莽草酸、月桂酸、肉桂酸、牛磺酸、烟酸、异烟酸、十二烷基苯磺酸等。
本发明的含有哌仑西平有机酸盐的复盐是指两种或两种以上的酸与哌仑西平形成的复盐，其中至少一种是有机酸，如盐酸哌仑西平与上述有机酸形成的盐酸哌仑西平有机酸盐。
本发明优选的哌仑西平有机酸盐是哌仑西平的山梨酸盐、马来酸盐、富马酸盐、枸橼酸盐、苯磺酸盐、甲基苯磺酸盐、龙胆酸盐、乳糖酸盐、葡萄糖醛酸盐、酒石酸盐、乳酸盐、琥珀酸盐、草酸盐、丁酸盐、异丁酸盐、2-乙基丁酸盐、戊酸盐、异戊酸盐、辛酸盐、三甲基乙酸盐、苯甲酸盐、苯乙酸盐、肉豆蔻酸盐、棕榈酸盐、硬脂酸盐、油酸盐、亚油酸盐、a-亚麻酸盐、香草酸盐、丁香酸盐、绿原酸盐、阿魏酸盐、缬草酸盐、甘草酸盐、齐墩果酸盐、熊果酸盐、莽草酸盐、月桂酸盐、肉桂酸盐、牛磺酸盐、烟酸盐、异烟酸盐、十二烷基苯磺酸盐。
优选的复盐是盐酸哌仑西平的山梨酸盐、马来酸盐、富马酸盐、枸橼酸盐、苯磺酸盐、甲基苯磺酸盐、龙胆酸盐、乳糖酸盐、葡萄糖醛酸盐、酒石酸盐、乳酸盐、琥珀酸盐、草酸盐、丁酸盐、异丁酸盐、2-乙基丁酸盐、戊酸盐、异戊酸盐、辛酸盐、三甲基乙酸盐、苯甲酸盐、苯乙酸盐、肉豆蔻酸盐、棕榈酸盐、硬脂酸盐、油酸盐、亚油酸盐、a-亚麻酸盐、香草酸盐、丁香酸盐、绿原酸盐、阿魏酸盐、缬草酸盐、甘草酸盐、齐墩果酸盐、熊果酸盐、莽草酸盐、月桂酸盐、肉桂酸盐、牛磺酸盐、烟酸盐、异烟酸盐、十二烷基苯磺酸盐。
本发明更优选的是盐酸哌仑西平的山梨酸盐、马来酸盐、枸橼酸盐、龙胆酸盐复盐。
本发明还提供含有本发明的哌仑西平有机酸盐或复盐的药物组合物。本发明的药物组合物，必要时可加入药物可接受的载体，在本发明的组合物中，可含有哌仑西平有机酸盐的重量百分比为0.001-10％，其余为药物可接受的载体。
本发明的药物组合物采用眼内给药系统，包括普通滴眼剂、眼膏剂、眼用凝胶剂(包括生物粘附性凝胶、即位凝胶)、胶体系统(脂质体、毫微球)、环糊精包合物等。
普通滴眼剂包括眼用溶液剂、混悬剂。眼膏剂是指以凡士林为赋形剂制成的眼用半固体制剂。
生物粘附凝胶剂是指以含有多个亲水基团的聚合物为材料制成的与角膜具有粘附力的凝胶剂。这类聚合物包括玻璃酸、羟丙甲基纤维素(HPMC)、聚乙烯醇(PVA)、羧甲基纤维素钠(CMC-Na)、聚丙烯酸(PAA)。这类凝胶剂通常呈非牛顿流体的流变学特性，即随着切应速度的提高，液体的粘度增加，这有利于制剂在眼内的停留，防止药物被泪液冲洗掉，从而提高药物透过角膜的比例。
即位凝胶是指滴眼剂本身为可以自由流动的液体，受pH、温度变化，制剂在滴入眼睑后形成凝胶，从而增加制剂在眼中的驻留，提高角膜透过率。pH触变的即位凝胶主要由纤维素醋酸酞酸酯(CAP)、卡波沫等组成，当制剂在pH 7.4的条件下能迅速变为凝胶剂。温度触变的即位凝胶主要由在32-36℃可变为凝胶的聚合物组成，这类聚合物包括结冷胶等组成。
胶体系统包括脂质体和毫微球，其中药物包于脂质体或毫微球中，滴入眼内后，药物慢慢释放。
环糊精包合物是指药物包于环糊精中形成的制剂，药物的溶解度和稳定性可以大大提高。
在上述哌仑西平有机酸盐的眼用制剂中，加入了适量其它辅料，包括等渗调节剂、角膜吸收促进剂、防腐剂等。
等渗调节剂主要用于调节制剂的渗透压，使之与泪液的渗透压相当，以降低刺激性。等渗调节剂包括氯化钠、氯化钾等。
哌仑西平的角膜促进剂包括依地酸二钠、阳离子型表面活性剂(如苯扎氯铵、苯扎溴铵等)、聚山梨酯(如聚山梨酯20、80等)、胆酸盐(如胆酸钠、脱氧胆酸钠等)。
制剂中哌仑西平有机酸盐或复盐可以直接和其它物料溶于水中；也可以制成冻干粉或压制成片剂，用前溶于适宜的溶剂中。
本发明还提供哌仑西平有机酸盐或复盐的制备方法，该方法包括经过哌仑西平游离碱与有机酸混合的步骤，或经过哌仑西平盐酸盐和有机酸混合的步骤。
本发明的药物组合物，可以按照制剂学的常规技术，制成本发明的眼用药物制剂。
本发明还提供哌仑西平有机酸盐或复盐在制备治疗或预防近视眼药物中的应用。所述近视眼是人或动物后天发展的眼前后轴长延长所致近视。包括成年和未成年人的近视眼，优选的是未成年人所患近视。
本发明的目的在于提供治疗近视的哌仑西平有机酸盐或复盐及其眼内给药系统，使哌仑西平易于透过角膜，防止刺激性的产生，提高哌仑西平的稳定性，使制剂达到安全、有效的治疗近视的目的。
哌仑西平目前为盐酸盐，其脂溶性较低，角膜透过性较差、稳定性不高。本发明的哌仑西平机酸盐或复盐，与盐酸盐相比，这类盐具有较大的脂溶性，油水分配系数较大，角膜透过率得到较大的提高。
本专利中所述的油水分配系数是指在pH 7.4的水溶液中测得的正辛醇/水中的分配系数。
本专利中所述的角膜透过率是指药物透过角膜的程度和速度。药物滴入眼睑后，通过测定药物在眼房水中的浓度而获得。
本专利的特点是药物更稳定、角膜透过率更高、刺激性更小，易于制造和使用。盐酸哌仑西平的稳定pH(pHm)为5.0，组成复盐后pHm将接近7.0。
具体实施方式：
下面为本专利的实施例，但下述实施例并不限置本专利的权利范围。哌仑西平有机酸盐的制备：
实施例1
哌仑西平游离碱的制备：
取100g盐酸哌仑西平溶于适量蒸馏水，经阳离子交换树脂交换、以甲醇洗脱，除去甲醇，在旋转蒸发仪上除去甲醇得哌仑西平游离碱。
实施例2
山梨酸哌仑西平的制备：
取哌仑西平游离碱10g，溶于甲醇10mL中；另取山梨酸6.39g，加热使溶解于甲醇中；将山梨酸溶液滴加于哌仑西平游离碱溶液中，在旋转蒸发仪上浓缩至2mL，置于冰箱中过夜，滤过，得山梨酸哌仑西平。
实施例3
马来酸哌仑西平的制备：
取哌仑西平游离碱10g，溶于甲醇10mL中；另取马来酸3.31g，加热使溶解于甲醇中；将马来酸溶液滴加于哌仑西平游离碱溶液中，在旋转蒸发仪上浓缩至2mL，置于冰箱中过夜，滤过，得马来酸哌仑西平。
实施例4
枸橼酸哌仑西平的制备：
取哌仑西平游离碱10g，溶于甲醇10mL中；另取枸橼酸5.99g，加热使溶解于甲醇中；将枸橼酸溶液滴加于哌仑西平游离碱溶液中，在旋转蒸发仪上浓缩至2mL，置于冰箱中过夜，滤过，得枸橼酸哌仑西平。
实施例5
龙胆酸哌仑西平的制备：
取哌仑西平游离碱10g，溶于甲醇10mL中；另取龙胆酸8.78g，加热使溶解于甲醇中；将龙胆酸溶液滴加于哌仑西平游离碱溶液中，在旋转蒸发仪上浓缩至2mL，置于冰箱中过夜，滤过，得龙胆酸哌仑西平。
哌仑西平复盐的制备：
实施例6
山梨酸盐酸哌仑西平复盐的制备：
取盐酸哌仑西平11g，溶于蒸馏水2mL中；另取山梨酸3.19g，加热使溶解于甲醇中；将山梨酸溶液滴加于盐酸哌仑西平溶液中，置于冰箱中过夜，滤过，得山梨酸盐酸哌仑西平复盐。
实施例7
马来酸盐酸哌仑西平复盐的制备：
取盐酸哌仑西平11g，溶于蒸馏水2mL中；另取马来酸1.16g，加热使溶解于甲醇中；将马来酸溶液滴加于盐酸哌仑西平溶液中，置于冰箱中过夜，滤过，得马来酸盐酸哌仑西平复盐。
实施例8
枸橼酸盐酸哌仑西平复盐的制备：
取盐酸哌仑西平11g，溶于蒸馏水2mL中；另取枸橼酸3g，加热使溶解于甲醇中；将枸橼酸溶液滴加于盐酸哌仑西平溶液中，置于冰箱中过夜，滤过，得枸橼酸盐酸哌仑西平复盐。
实施例9
龙胆酸盐酸哌仑西平复盐的制备：
取盐酸哌仑西平11g，溶于蒸馏水2mL中；另取龙胆酸4.4g，加热使溶解于甲醇中；将龙胆酸溶液滴加于盐酸哌仑西平溶液中，置于冰箱中过夜，滤过，得龙胆酸盐酸哌仑西平复盐。
实施例10
哌仑西平有机酸盐的鉴定：
分别对上述各哌仑西平的有机酸盐进行元素分析，结果表明(表1)：各有机酸盐的元素组成与理论值一致。证明已经制备成盐。
表1 哌仑西平有机盐元素分析数据
| 元素种类 | 游离碱 | 山梨酸盐 | 马来酸盐 | 枸橼酸盐 | 龙胆酸盐 | |
| 理论值 | C(％)H(％)O(％)N(％) | 64.946.0219.939.11 | 64.706.4316.7012.17 | 59.105.3520.5614.99 | 53.485.5328.5212.48 | 60.095.0124.2810.62 |
| 实际测定值 | C(％)H(％)O(％)N(％) | 64.655.9920.019.35 | 63.856.0217.2112.92 | 58.785.4421.0214.76 | 52.875.7728.5312.83 | 61.034.9924.229.76 |
哌仑西平有机酸盐眼用凝胶剂的制备：
实施例11
山梨酸哌仑西平眼用凝胶剂的制备：
A)取羟丙甲基纤维素K100M适量，按4％的比例使溶于注射用水中，滴加1N HCl或NaOH调节pH7.0，121℃下灭菌30分钟，放置过夜。
B)按哌仑西平游离碱的浓度为4％称取山梨酸哌仑西平，加入苯扎氯胺(万分之一)、依地酸二钠(万分之四)，加氯化钠适量(约1％)，滴加1N NaOH调节至pH 7.0，溶液经0.22μm微孔滤膜滤过。
C)将A、B两液等体积混合，灌装。
实施例12
眼用山梨酸哌仑西平的制备：
A)取羟丙甲基纤维素K100M适量，按2％的比例使溶于注射用水中，加入苯扎氯胺(十万分之五)、依地酸二钠(万分之二)，加氯化钠适量(约0.5％)，滴加1N HCl或NaOH调节pH7.0，121℃下灭菌30分钟，放置过夜。
B)山梨酸哌仑西平适量(相当于游离碱100mg)无菌分装于容器中，用前于A液即可。
实施例13
盐酸山梨酸哌仑西平眼用凝胶剂的制备：
A)取羟丙甲基纤维素K100M适量，按4％的比例使溶于注射用水中，滴加1N HCl或NaOH调节pH7.0，121℃下灭菌30分钟，放置过夜。
B)按哌仑西平游离碱的浓度为4％称取盐酸哌仑西平，加入适量山梨酸、苯扎氯胺(万分之一)、依地酸二钠(万分之四)，加氯化钠适量(约1％)，滴加1N NaOH调节至pH 7.0，溶液经0.22μm微孔滤膜滤过。
C)将A、B两液等体积混合，灌装。
实施例14
眼用马来酸哌仑西平脂质体的制备
取磷脂酰胆碱二棕榈酸酯(DPPC)、胆固醇按1.85∶1溶于乙醇中，在旋转蒸发器上除去乙醇，得到双层磷脂膜。加入马来酸哌仑西平水溶液，水化。挤出通过90-100nm的滤膜制备脂质体。
实施例15
眼用马来酸哌仑西平环糊精包合物的制备
按等摩尔比取β-环糊精和马来酸哌仑西平溶于水中，过0.22μm微孔滤膜滤过，经冷冻干燥的马来酸哌仑西平环糊精包合物。
实施例16
各种哌仑西平有机酸盐油水分配系数的测定
用正辛醇饱和的重蒸水制备含有含游离碱0.1％、pH为7的各种哌仑西平有机酸盐或盐酸哌仑西平的磷酸二氢钾-硼砂缓冲溶液，加入氯化钠调节离子强度至0.154mol/L。取上述溶液各5mL与等量水饱和的正辛醇混合，置于(34±0.5)℃恒温水浴中，电磁搅拌下平衡24hrs，离心分离两相。分别测定测定平衡前后溶液中的药物浓度和油相中药物的浓度，计算油水分配系数。
结果表明：形成有机酸盐后，哌仑西平的油水分配系数显著提高，以马来酸为例，其油水分配系数约为盐酸哌仑西平的近20倍。
表2 哌仑西平有机酸盐油水分配系数
| 盐酸盐 | 山梨酸复盐 | 马来酸复盐 | 枸橼酸复盐 | 龙胆酸复盐 | |
| 油水分配系数 | 0.169 | 0.458 | 2.940 | 2.746 | 0.367 |
实施例17
离体角膜透过实验
取家兔，麻醉致死。摘除眼球置于中。沿距角膜边缘2mm的巩膜处做横切，分离角膜。除去晶状体、玻璃体等眼球后部组织，剥离虹膜，得带有2mm巩膜环的角膜。处死动物后20min内开始角膜透过实验。采用渗透扩散装置，包括供给池和接受池，保持离体角膜的形状将其固定在两池之间，使上皮层面向供给池。供给池内加入哌仑西平各种有机酸盐或盐酸哌仑西平的凝胶剂2mL，接受池为林格溶液，整个装置放入(34±05)℃恒温水浴中开始实验。于试验开始后的第5，15，30，45，60，90，120min从接受池取样1mL并立即补充等体积的空白预先用95％∶5％ O2和CO2混合气体饱和的34℃林格溶液。样品用0.22μm的微孔滤膜过滤，取续滤液测定哌仑西平的浓度，按下式计算各种盐的角膜透过系数。
结果表明：哌仑西平有机酸盐的角膜透过系数显著提高。
表3 哌仑西平有机盐角膜透过系数测定数据(n＝6)
| 盐酸盐 | 山梨酸复盐 | 马来酸复盐 | 枸橼酸复盐 | 龙胆酸复盐 | |
| 角膜透过系数×105(ug/s·cm2) | 1.07±0.08 | 1.42±0.12 | 6.56±0.11 | 4.23±0.15 | 1.36±0.09 |
实施例18
哌仑西平滴眼剂家兔房水中的药物动力学
40只兔按取样时间随机分为8组，每组5只兔。每隔两周更换处方给药，共2次(分别盐酸哌仑西平眼用凝胶剂和山梨酸哌仑西平眼用凝胶)。给药时分别在一眼结膜囊内滴配制好的哌仑西平滴眼剂2滴(100μL)，左眼不用药。于滴眼后的0.5、1、2、4、8、12、24、48h时，共8个时间点，分别抽取右眼的房水0.2ml。取房水0.1mL，加入0.1mL甲醇，漩涡混合，以沉淀蛋白及杂质。以16000r/min速度离心10min，取上清液，注入高效液相色谱仪，记录峰面积，以外标法计算含量。每个时间点取5只眼，以其平均值作为该时间点哌仑西平在房水中的浓度。
结果表明：
表3 40只家兔滴各种哌仑西平有机盐滴眼液后药物在房水中的浓度(ng/ml)
| 时间 | ||||||||
| 0.5 | 1 | 2 | 4 | 8 | 12 | 24 | 48 | |
| 盐酸盐 | 21.6±13.08 | 49.1±21.23 | 60.4±15.37 | 77.5±12.14 | 80.2±16.5 | 34.6±10.76 | 25.6±11.34 | 12.3±9.26 |
| 山梨酸复盐 | 36.4±12.56 | 55.2±11.25 | 71.8±17.34 | 84.2±13.84 | 90.6±14.9 | 54.7±17.22 | 37.8±13.56 | 16.7±8.75 |
| 马来酸复盐 | 58.7±12.52 | 100.2±11.74 | 194.9±20.51 | 288.5±18.7 | 208.2±13.7 | 105.9±13.18 | 69.2±12.77 | 25.4±10.12 |
| 枸橼酸复盐 | 58.4±15.11 | 91.1±17.42 | 175.3±13.7 | 187.5±15.9 | 208.8±10.1 | 87.8±14.52 | 55.4±14.13 | 22.9±10.02 |
| 龙胆酸复盐 | 29.8±11.57 | 45.9±14.28 | 73.0±11.34 | 88.2±14.02 | 79.7±16.8 | 49.2±12.57 | 38.0±12.48 | 21.2±9.88 |
Claims (8)
1.用于治疗或/预防近视眼的哌仑西平山梨酸盐或盐酸哌仑西平山梨酸盐。
2.含有权利要求1的哌仑西平山梨酸盐或盐酸哌仑西平山梨酸盐的药物组合物。
3.权利要求2中的药物组合物，是经眼给药的组合物。
4.权利要求3的药物组合物，是滴眼剂、眼膏剂、眼用凝胶剂、眼用胶体系统制剂、眼用环糊精包合物制剂。
5.权利要求4的药物组合物，其中哌仑西平有机酸盐的重量百分比为0.001-10％。
6.权利要求1的哌仑西平山梨酸盐或盐酸哌仑西平山梨酸盐的制备方法，其特征在于，经过哌仑西平游离碱或哌仑西平盐酸盐与山梨酸混合的步骤。
7.权利要求1的哌仑西平山梨酸盐或盐酸哌仑西平山梨酸盐在制备治疗或预防近视眼药物中的应用。
8.权利要求7的应用，其中所述近视眼是人或动物后天发展的眼前后轴长延长所致近视。
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