A novel in situ-forming ophthalmic drug delivery system from alginates undergoing gelation in the eye
A novel in situ-forming ophthalmic drug delivery system from alginates undergoing gelation in the eye
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DOI：
10.1016/s0168-3659(96)01523-4
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发表时间：
1997-02-17
影响因子：
10.8
通讯作者：
Peled, Y
中科院分区：
文献类型：
--
作者：
Cohen, S;Lobel, E;Peled, Y
通过使用由表现出可逆的液体-凝胶相转变的聚合物制备的原位形成的眼用药物递送系统，可以克服由稀释和从眼睛排出引起的眼用溶液的差的生物利用度。在本论文中，我们证明了海藻酸钠的水溶液可以在眼睛中凝胶化，而无需添加外部钙离子或其他二价/多价阳离子。藻酸盐凝胶化的程度以及因此毛果芸香碱的释放取决于聚合物主链中古洛糖醛酸（G）残基的百分比。G含量大于65%的藻酸盐，如Manugel DMB，在加入模拟泪液后立即形成凝胶，而G含量低的藻酸盐，如凯尔顿LV，以相对较慢的速率形成弱凝胶。体外研究表明，毛果芸香碱从藻酸盐凝胶中缓慢释放，超过24小时的时间，并且释放主要通过从凝胶中扩散而发生。在37 ℃下孵育的前12小时，水凝胶在释放介质中的溶解可忽略不计。用2%（w/v）硝酸毛果芸香碱溶液或由高G含量DMB藻酸盐组成的原位凝胶形成制剂处理的兔眼的眼内压（IOP）测量表明，与硝酸毛果芸香碱作为溶液递送时的3小时相比，DMB显著延长了毛果芸香碱的降压作用的持续时间至10小时。相比之下，在用溶液中的毛果芸香碱或凯尔顿LV藻酸盐滴眼液制剂处理的兔之间，IOP降低的持续时间和程度没有明显差异。本研究的总体结果表明，在原位凝胶海藻酸盐系统，高G含量的聚合物的基础上，是一个很好的药物载体的延长交付毛果芸香碱。
Poor bioavailability of ophthalmic solutions caused by dilution and drainage from the eye can be overcome by using in-situ-forming ophthalmic drug delivery systems prepared from polymers that exhibit reversible liquid-gel phase transition. In the present paper, we demonstrate that an aqueous solution of sodium alginate can gel in the eye, without the addition of external calcium ions or other bivalent/polyvalent cations. The extent of alginate gelation and consequently the release of pilocarpine, depended on the percent guluronic acid (G) residues in the polymer backbone. Alginates with G contents of more than 65%, such as Manugel DMB, instantaneously formed gels upon their addition to simulated lacrimal fluid, while those having low G contents, such as Kelton LV, formed weak gels at a relatively slow rate. In vitro studies indicated that pilocarpine is released slowly from alginate gels, over a period of 24 h, and the release occurs mostly via diffusion from the gels. Dissolution of the hydrogels in the releasing media was negligible for the first 12 h of incubation at 37 degrees C. Intraocular pressure (IOP) measurements of rabbit eyes treated with 2% (w/v) pilocarpine nitrate in solution, or in the in-situ gel forming formulation composed of the high G content DMB alginate, indicated that DMB significantly extended the duration of the pressure reducing effect of pilocarpine, to 10 h, as compared to the 3 h when pilocarpine nitrate was delivered as a solution. In contrast, there was no apparent difference in the duration and extent of IOP decrease between rabbits treated with pilocarpine in solution or in the Kelton LV alginate eye drop formulations. The overall results of this study indicate that the in situ-gelling alginate system, based on polymers with high G contents, is an excellent drug carrier for the prolonged delivery of pilocarpine.