CN1129400A - 维生素e生育酚衍生物在眼科组合物中的应用 - Google Patents

维生素e生育酚衍生物在眼科组合物中的应用 Download PDF

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CN1129400A
CN1129400A CN95190533A CN95190533A CN1129400A CN 1129400 A CN1129400 A CN 1129400A CN 95190533 A CN95190533 A CN 95190533A CN 95190533 A CN95190533 A CN 95190533A CN 1129400 A CN1129400 A CN 1129400A
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M·L·马尼阿
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Abstract

公开了含维生素E生育酚衍生物的眼科组合物，这种组合物舒适并无刺激性。这些维生素E生育酚衍生物明显地增加难溶眼药的水溶解度。

Description

维生素E生育酚衍生物在眼科组合物中的应用
本发明总体上涉及眼科组合物；具体地说，本发明涉及使用某些维生素E生育酚衍生物以提供舒适、无刺激的眼科组合物。另外，本发明涉及使用这些维生素E生育酚衍生物以增加水液组合物中的难溶眼科药物的液解度。在本说明书中用于本发明的维生素E生育酚衍生物将被称为“维生素E生育酚衍生物”或“维生素E衍生物”或“TPGS”。
刺激和灼烧的感觉，以及一般的不舒适常与某种类型眼药的局部应用有关。相信这种眼的不舒适是由于这些眼药的某些功能团的存在引起的。这种产生眼不舒适的药剂的例子包括(但不限于)阻滞剂诸如β-受体阻滞药，前列腺素和前列腺素衍生物；蕈毒碱类，诸如毛果云香碱；a一肾上腺素能药，诸如肾上腺素、氯压定和安普尼丁；胆碱类，诸如卡巴胆碱，以及非甾体抗炎药(“NSAID”)，诸如双氯灭痛和苏洛芬。
配制眼科组合物以减少与这些眼药有关的固有不适已经做过许多试尝。这些试尝叙述于下列专利文献：US 4 559 343(Han等)，US4 911 920(Jani等)，US5 093 126(Jani等)，US 5 212 162(Missel等)。Hans等人叙述了加入黄嘌呤衍生物(诸如咖啡因)以降低NSAID的局部眼内应用引起的刺激；Jani等人的两篇文献指示在阻滞剂组合物中加入某种离子交换树脂以增加舒适感并提供持续的释放；Missel等教导将胶凝多糖和细的药物载体基质(“DCS”)结合，提供舒适和持续释放的眼科组合物。
另外，US4,960,799(Nagy)公开了含双氯灭痛和/或其药物学上可接受的盐的贮存稳定水基眼科组合物。Nagy的组合物包括EDTA和一诸如乙氧化蓖麻油之类的加溶剂。
现意外地发现，在眼科组合物中加入某种维生素E生育酚衍生物能使此组合物有舒适和无刺激感。也已发现，这些维生素E生育酚衍生物极大地提高了仅微溶于水液组合物中的许多化合物的水溶解度。
维生素E生育酚衍生物是水溶性的、有生物活性的维生素E同类物。这些维生素E衍生物已用作维生素E的代用品，特别是要求有水溶性时。此外，US 3 102 078叙述了使用这些衍生物溶解天然的水不溶性维生素，诸如维生素A、D和E。用维生素E衍生物提高维生素A和环孢菌素A的吸收也已有报道。参见例如Sokol，R.J.等人，″Improvement of Cyclosporin Absorption inChildren after Liver Transplatation by Means of Water—SolubleVitamin E，″The Jancet，338，212—215(1991)和Argao，E.A.等人，″d-α-Tocopheryl Polyethylene Glycol—1000 SuccinateEnhances the Apsorption of Vitamin D in Chronic CholestaticLiver Disease of Infancy and Childhood，″Pediatric Res.，31(2)：146—150(1992).
在本发明组合物中使用的维生素E生育酚衍生物是高度水溶性的二羧酸的维生素E生育酚酯的聚亚氧烷基二醇酯。这类的代表性酯包括二羧酸的维生素E生育酚酯的聚亚氧乙基二醇酯，其中酯的聚亚氧乙基二醇部分(有时仅指酯的聚亚氧乙基乙二醇部分)的分子量范围为约600—6000，优选约600—1500。这种酯及其制备方法公开于US2 680 749(Cawley等)中。最优先选择的酯是琥珀酸α-生育酚聚亚氧乙基二醇(1000)酯，是一种a-生育酚琥珀酸酯的聚亚氧乙基二醇酯，其中分子的聚亚氧乙基二醇部分的平均分子量约为1000。
一般，在本发明组合物中使用一种或多种维生素E衍生物，其量低于约30％(重量)。如维生素E衍生物是用作加溶剂的，其用量最好为约0.1—20％(重量)，优选约0.1—5％(重量)。当维生素E衍生物是用于提高舒适性时，其用量最好为约0.1—20％(重量)，优选约0.5—10％(重量)。
可用于本发明组合物中并通过本发明方法给药的适合的眼药包括，但不限于下列类型化合物的外消旋和对映体形式以及眼科学上可接受的盐和酯：
一青光眼药物，诸如阻滞剂(例如β-受体阻滞药、噻吗心安和卡替洛尔)；α-激动剂(例如安普尼丁和相关的2-取代氨基咪唑啉)；碳酸酐酶抑制剂；多巴胺激动剂和拮抗剂；缩瞳胆碱类(例如毛果云香碱和卡巴胆碱)；前列腺素和前列腺素衍生物；ACE抑制剂；甾体类(例如糖肾上腺皮质激素和不影响血管的(angiostatic)甾体类)以及钙离子通道阻滞剂；
—抗高血压药；
—非甾体抗炎药，包括(但不限于)被分类为芳基烷酸或杂芳基烷酸的那些类药，诸如双氯灭痛、氟尔洛芬、苏洛芬、酮咯酸、吲哚美辛和酮洛芬；
—甾体抗炎剂，诸如氟去氧强的松龙、地塞米松、泼尼松、四氢皮质甾醇和曲安西龙；
—抗菌药和抗感染药，诸如氨基糖甙类(例如托布霉素)；喹诺酮类(例如环丙氟哌酸和氧氟沙星)；β-内酰胺类(例如头孢孟多之类的头孢菌素)；
—抗真菌药，诸如游霉素；
—抗病毒药，诸如阿昔洛韦和更昔洛韦；
—抗白内障药和抗氧化剂；
—抗过敏药；-抗代谢药，诸如5-氟尿嘧啶(5-FU)和氨甲喋呤—抗代谢药，诸如5-氟尿嘧啶(5-FU)和氨甲喋呤；
—免疫抑制剂，诸如环孢菌素，FK—506和拉氟米物；
—生长因子，诸如EGF、FGF、PDGF；及
—上列药物的前药。
眼药的组合也可用于本发明的组合物。另外，在没有眼药的配方中，本发明在干眼的预防和处理中也可用于补充眼泪。
本发明的组合物还可包括其它眼科学上可接受的组分：例如缓冲液(例如磷酸缓冲液、硼酸缓冲液和柠檬酸缓冲液)，螯合剂(例如EDTA)，防腐剂(苯扎氯铵、Polyquad和Dymed)和渗透压调节剂(例如氯化钠和甘露醇糖)。本发明的组合物也可包括粘度改性剂，诸如纤维素醚如羟丙基甲基纤维素(HPMC)、羟乙基纤维素(HEC)、乙基羟乙基纤维素、羟丙基纤维素、甲基纤维素和羧甲基纤维素；聚羧乙烯(Carbopol)；聚乙烯醇；聚乙烯吡咯烷酮；藻酸盐；角叉菜胶和瓜耳、刺梧桐、琼脂糖、刺槐豆、黄蓍和呫吨胶。此类粘度改性剂的浓度可在约0.1—5％(重量)间变化，但这类配方一般粘度在约10—1000cps。
但有TPGS的眼科组合物可再含有聚合物，这种聚合物在物理或化学刺激下发生溶液至凝胶的过渡，如PH、离子浓度和/或温度的变化。
含于本发明组合物中之眼药可随意制成微胶囊。这些微胶囊可分散在含TPGS的水载体中以增进舒适度。另外，水溶或水不溶性眼药的配合物可以掺合在含TPGS的载体中。水溶性配合物的例子包括传统的在眼药和咖啡因、环糊精、水杨酸盐、苯甲酸盐之间形成的配合物、水不溶性配合物的例子包括眼药(药物)树脂配合物。
下面的实施例是为了进一步说明本发明的各个方面，无意在任何方面对本发明进行限制。实施例1
下面的配方是本发明优选组合物的代表性配方。
    组分                      配方(wt％)
 A      B       C       D       E       F      G
双氯灭痛钠地塞咪松维生素E TPGS(1000)三甲醇氨基甲烷硼酸甘露醇苯扎氯铵NaClEDTA二钠 0.1    0.1     0.1     0.1     0.1     ---    0.1---    ---     ---     ---     ---     0.1    ---3.0    3.0     3.0     3.0     3.0     3.0    3.00.23   0.23    0.23    1.2     1.2     ---    0.231.0    0.1     0.1     1.5     1.5     ---    1.04.0    ---     ---     3.0     4.0     ---    4.00.01   0.01    0.01    0.01    0.01    0.01   ------    0.7     0.7     ---     ---     ---    ---0.1    0.1     0.1     0.1     0.1     ---    ---
HPMC精氨酸HCl和/或NaOH纯水 ---     0.1     0.3    0.1    0.3   ---    ------     ---     ---    0.5    ---   ---    ---
                   pH7.4
                     加足至100％
制备
配方D的制备方法如下，配方A—C和E—G按类似方法制备。
10％(W/V)维生素E TPGS母液的制备如下，将约150g维生素ETPGS置烧杯中于热板上加热熔融，同时搅拌以确保均匀。然后将100g熔融的TPGS加入800ml接近沸腾的双蒸蒸馏水。混合物经搅拌后让其冷却至室温以保证完全溶解。然后在所得溶液中加入足量的水使成为1升母液。
将双氯灭痛钠(0.3g)加入90ml的10％TPGS母液中。双氯灭痛完全溶解后，将下列组分顺序加入溶液，同时搅拌使每一组分完全溶解后再加入下一组分：1.5g精氨酸，9.0g甘露糖醇，4.5g硼酸，3.6g三甲醇氨基甲烷和0.3g乙二胺四乙酸钠。在上述溶液中加入6.0ml的0.5％苯扎氯铵溶液，接着加入15ml的2％HPMC溶液。再加150ml水，然后用HCl和/或NaOH将配方的PH调至7.4。在所得的溶液中加入足量的水使总的溶液体积为300ml。最终溶液的重量克分子渗透压浓度约为300mOsm/kg。
实施例2
下述配方是本发明另一代表性组合物，其中有按本发明配制的前列腺素与环糊精的配合物。
    组分     浓度(wt％)
前列腺素羟丙基-β-环糊精三甲醇氨基甲烷硼酸甘露糖醇苯扎氯铵EDTA二钠维生素E TPGS(1000)HCl/NaOH纯水     0.253.01.21.51.00.010.13.0pH至74.加足至100％
制备
将适量的三甲醇氨基甲烷、硼酸、甘露糖醇、BAC和EDTA加入90ml的10％TPGS母液中，在另一容器中将9g羟丙基-β-环糊精溶于150ml水，在其中加入0.75g前列腺素。然后将两溶液混合在一起，调节PH至7.4，并加水至300ml体积。
实施例3
下述配方是本发明另一代表性组合物，其中前列腺素与Duolite(胆甾胺树脂，由Rohm & Haas，Philadelphia，Pennsylvania提供)的结合物是按本发明方法配制的。
    组分     浓度(wt％)
前列腺素Duolite维生素E TPGS三甲醇氨基甲烷硼酸甘露糖醇苯扎氯铵EDTA二钠HCl/NaOH纯水     0.250.253.01.21.54.00.010.1pH至7.4加足至100％
制备
将前列腺素(0.75g)溶于200ml水中，加入极细的Duolite(0.75g)，使溶液平衡2小时。在平衡时期有约95％的药与树脂结合。在另一容器中，将适合量的三甲醇氨基甲烷、硼酸、BAC、乙二胺四乙酸钠和甘露糖醇加入90ml的10％TPGA母液。然后将两部分溶液混合，用HCl和/或NaOH调节PH至7.4。加入足量水使最后体积为300ml。
本发明以最佳具体实施方案进行了描述。但须知它可以其它特定形式或其变体具体体现而不脱离其精神或主要特征。上述具体实施方案因而被考虑是对各方面进行说明的，而不是给予限制。本发明的范围是在所附权利要求书中指出，而不是以上的叙述。

Claims (20)

1.一种眼科组合物，该组合物包括：
选自抗青光眼药、抗高血压药、非甾体类抗炎药、甾体类抗炎药、抗细菌药、抗感染药、抗真菌药、抗病毒药、抗白内障药、抗氧化药、抗过敏药、抗代谢药、免疫抑制剂、生长因子和它们的前药的一种或多种治疗有效量的眼药；
明显降低与所说眼药局部眼科使用有关的不适和刺激有效的一定量维生素E生育酚衍生物；或
眼科可接受的载体。
2.权利要求1的组合物，其中的眼药是非甾体类抗炎药。
3.权利要求2的组合物，其中非甾体炎抗类药包括芳基烷酸或杂芳基烷酸或其眼科可接受的盐、酯或酰胺。
4.权利要求3的组合物，其中非甾族抗炎药选自双氯灭痛、氟尔洛芬、苏洛芬、酮咯酸、吲哚美辛、酮洛芬，以及它们的眼科学上可接受的盐、酯或酰胺。
5.权利要求4的组合物，其中非甾体抗炎药选自双氯灭痛和其眼科学上可接受的盐、酯和酰胺。
6.权利要求4的组合物，其中非甾体抗炎药选自苏洛芬和其眼科学上可接受的盐、酯和酰胺。
7.权利要求1的组合物，其中维生素E生育酚衍生物选自琥珀酸生育酚酯的一种或多种维生素E聚亚氧乙基二醇酯，其中酯的聚亚氧乙基二醇部分的分子量范围约为600一6000。
8.权利要求7的组合物，其中酯的聚亚氧乙基二醇部分的平均分子量约为1000。
9.权利要求1的组合物，其中维生素E生育酚衍生物的浓度低于约30％(重量)。
10.权利要求9的组合物，其中维生素E生育酚衍生物的浓度在约0.1—20％(重量)之间。
11.权利要求10的组合物，其中维生素E生育酚衍生物的浓度在约0.5—10％(重量)之间。
12.一种治疗或控制眼炎的方法，该方法包括眼内局部使用权利要求2的组合物。
13.权利要求12的方法，其中非甾体抗炎药包括芳基烷酸或杂芳基烷酸或其眼科学上可接受的盐、酯或酰胺。
14.权利要求13的方法，其中非甾体抗炎药选自双氯灭痛和其眼科学上可接受的盐、酯或酰胺。
15.一种改进含一种或多种眼刺激性眼药之眼科组合物的舒适性和减少其刺激性的方法，该方法包括在此眼科组合物中加入一定量维生素E生育酚衍生物的步骤，该维生素E生育酚衍生物能有效地明显降低与所说眼药局部眼科使用有关的不舒适和刺激性。
16.权利要求15的方法，其中维生素E生育酚衍生物选自一种或多种琥珀酸生育酚酯的维生素E聚亚氧乙基二醇酯，其中酯的聚亚氧乙基二醇部分的分子量范围在约600—6000之间。
17.权利要求16的方法，其中聚亚氧乙基二醇部分的平均分子量约为1000。
18.权利要求15的方法，其中维生素E生育酚衍生物的浓度低于约30％(重量)。
19.权利要求18的方法，其中维生素E生育酚衍生物的浓度在约0.1—20％(重量)之间。
20.权利要求19的方法，其中给生素E生育酚衍生物的浓度约为10％(重量)。
CN95190533A 1994-05-06 1995-05-08 维生素e生育酚衍生物在眼科组合物中的应用 Pending CN1129400A (zh)

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