可载药W/O/W多重乳液稳定性研究及多重乳液担载胰岛素初探
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摘要
蛋白类药物经口服后易被胃肠道内的酶降解而失去活性，所以该类药物几乎都采用注射给药，这给患者带来了极大的痛苦。由于水包油包水型(W／O／W)多重乳液可以保护被包埋的蛋白类药物，并具有一定的缓释功能，因此它可以作为蛋白类药物的载体，实现蛋白类药物的口服给药。然而W／O／W多重乳液担载药物体系至今没有实现商业化，主要问题是难以制备出稳定的多重乳液。因此研究W／O／W多重乳液的稳定性非常有意义。
本文制备了石蜡-span80(山梨糖醇酐单油酸酯)-tween80(聚氧乙烯山梨醇酐单油酸酯)W／O／W多重乳液，研究了界面性质、粘度性质以及通过油膜的水传递性质对其稳定性的影响，确定了这些性质对W／O／W多重乳液稳定性的影响，并调控这些性质以制备出相对稳定的多重乳液，并采用此多重乳液担载胰岛素。
首先，本文考察了与W／O／W多重乳液稳定性密切相关的油水界面性质。确定了tween-80在水中的临界胶束浓度为1.34×10~(-3)mol／l，span-80在石蜡中的临界反胶团浓度为4.15×10~(-5)mol／l，计算出tween-80和span-80在溶液中的最小用量。研究了吸附有表面活性剂的界面的扩张粘弹性，发现可以通过调节表面活性剂的配比来调节界面粘弹性。当界面受到高频扩张和压缩时，界面弹性为恢复界面形变的主要动力，而当发生低频扩张和压缩时，界面粘度为阻滞界面形变的主要动力。
其次，本文考察了W／O／W多重乳液体系的粘度性质对其稳定性的影响。表明多重乳液粘度的增加有利于保持其稳定，但起始W／O乳液粘度的增加对W／O／W多重乳液粘度影响不大，而在外水相加入高聚物是W／O／W多重乳液增粘的主要手段：本部分还利用已有粘度模型和改善的粘度模型计算一个衡量多重乳液不稳定性程度的参数——溶胀率，从另一方面来量化乳液粘度与乳液稳定性的关系，证明了使用粘度模型计算溶胀率是可行的，从而为定量多重乳液的水传递量提供了一种方法。
本文还考察了W／O／W多重乳液体系中一个重要的传质现象——水传递对W／O／W多重乳液稳定性的影响。研究表明内外水相间的渗透压差会引起水在两相间的扩散，并且同时促进了聚并的发生，显著地影响多重乳液的形貌和稳定性，所以有必要对渗透压下的水扩散进行控制。为了对渗透压差下的水扩散进行控制，论文建立了两个简化的多重乳液乳珠模型。通过单滴模型得到了多重乳液中水传递方向的判据，通过统计平均半径模型预测了在内外水相中，使多重乳液体系中的水传递达到平衡时的盐浓度，从而确立了一种简单易行的维持多重乳液稳定性的方法。并首次采用差分扫描量热仪(DSC)检测不同稳定态下的多重乳液中的水传递过程，当W／O／W多重乳液经过一个冷冻循环时，通过两个放热峰的位置和大小变化，跟踪水的传递过程，并判断乳液的稳定程度，检测结果表明统计平均半径模型预测的多重乳液稳定程度与实验测定吻合较好。
随后，本文采用正交实验，通过极差分析、方差分析、单因素变量分析优化了多重乳液的制备条件，优化条件为：span-80浓度12wt％，tween-80浓度4wt％，起始乳液制备温度50℃，油水比5:3，乳水比1:2。所得乳液的平均粒径为14.6μm，一致率为0.24。在此基础上，在内外水相中分别加入0.0205mol／l和0.0184mol／l的氯化钾，保证内水相水滴间及内外水相间达到水传递平衡，进一步增强了乳液的稳定性。为延长药剂的货架期，提出用外相凝胶化来增加多重乳液药剂体系的稳定性，采用魔芋胶和黄原胶复配，使W／O／W多重乳液外水相发生凝胶化，制备出了新型的外相凝胶化W／O／W多重乳液体系，通过对载药凝胶化W／O／W多重乳液稳定性以及该体系在人工胃肠液中流变性的考察，表明该体系不仅在贮存期非常稳定，而且能在人工胃肠液中恢复流动性，有利于药物的分散、释放和吸收。
最后，本文以胰岛素为模型药物，用W／O／W多重乳液担载胰岛素，考察了该药剂体系对药物的包埋和释放，以及对药物的保护作用。实验表明该体系对胰岛素的包埋率可达90％以上，可以很好地保护胰岛素使其免受胃肠蛋白酶的降解。
Water-in-oil-in-water(W/O/W) multiple emulsions have great potentials for application in many fields, especially in pharmacy because of their special character of encapsulating water-soluble substances. W/O/W multiple emulsions loading protein drugs in the internal phase have three functions: protecting protein drugs from being degraded by enzymes in stomach and intestine; releasing drug slowly through oil phase to achieve the aim of sustained release; realizing oral administer so as to relieve the pain of patients. However, multiple emulsions have not been commercially available due to one main reason of their instability. Therefore, it is significant to study the stability of multiple emulsions.
The W/O/W multiple emulsions are composed of liquid paraffin, span-80(sorbitan monooleate) and tween-80(polyoxyethylene sorbitan monooleate). The two-step preparation method is applied to prepare multiple emulsions. Several properties influencing the stability of multiple emulsions are investigated, such interfacial property, viscous property, and water transport and so on. In this study, some methods controlling the stability of multiple emulsions are given and some mechanisms about the stability of emulsion are explained.
Firstly, properties of the oil and water interface are studied. The CMC of tween-80 in water and that of span-80 in oil measured through interfacial tension are 1.34×10~(-3)mol/l and 4.15×10~(-5)mol/l, respectively. And the minimum concentrations of tween-80 in water and span-80 in oil are calculated. The dilational viscoelasticity of interface with different surfactants are tested, which encompasses interfacial viscosity is a main means to resist the deformation under low deformation rate and at the same time interfacial elasticity is a main means to recover the deformation under fast deformation rate. Furthermore, modulating the proportion of surfactants can adjust the dilational viscoelasticity of interface.
Secondly, the effects of viscosity on stability of W/O/W multiple emulsions are investigated from two aspects: viscosity of primary emulsion, viscosity of polymer. Meanwhile, the feasibility of viscosity model calculating the swelling ratio of multiple emulsions is evaluated. The studies indicate that the viscosity of primary emulsion has little effect on that of multiple emulsions, polymers increase the viscosity of multiple emulsions obviously and that the viscosity model can be used to calculate the swelling ratio of multiple emulsions.
Thirdly, an important mass transfer, water transport, related to the stability of multiple emulsion system is investigated. For the W/O/W multiple emulsion system in this study, several factors evoking water transport are researched one by one, such as micelle water carrying, osmotic pressure facilitating, and coalescence. Experimental studies indicate that the coalescence under osmotic pressure is obvious and the control of water transport is needed so as to keep the stability of multiple emulsions. In order to control water transport, two simple models are established,(ⅰ) one droplet model, giving the criterion to judge the water transport direction, and(ⅱ) statistic mean droplet radius, helping to control water transport when the second-composite is added into the internal phase. Models are proved by experimental phenomena.
Fourthly, technical conditions preparing multiple emulsions are optimized. Orthogonal experiments are used to fix on the optimized operation condition, such as the concentration of surfactants, the ratio of oil to water, the temperature of preparation. Based on the orthogonal experiments, range analysis, variance analysis and single factor analysis, the best experiment conditions preparing stable emulsion are determined as follows: 12wt% of span-80, 4wt% of tween-80, preparation at 50℃, the volume ratio of oil to water 5:3, and the volume ratio of emulsion to water 1:2. The mean droplet size of multiple emulsions prepared is 14.6μm, and the coherence is 0.24. The water transport is controlled when 0.0205 mol/l potassium chloride is added into the internal phase and 0.0184 mol/l potassium chloride is in the external phase. An intensity synergistic effect of konjac gum and xanthan gum has been found to prepare the gel system. The optimal proportion is that the complex gelatin consisted of 20wt% konjac gum and 80wt% xanthan gum while the complex gelatin is lwt% in the external phase. A gelatin multiple emulsions system is prepared making the multiple emulsions much more stable.
Finally, insulin is taken as model drug encapsulated into the internal phase of W/O/W multiple emulsions. The encapsulated efficiency is up to 90% and sustained release is attained to some extent. W/O/W multiple emulsion can protect insulin against proteolytic enzymes in the gastrointestinal tract and it can release insulin in artificial intestinal juice. At the same time, external phase is dealt with by gel making the multiple emulsions keep the stability on shelf life. The experiments show that the gelled multiple emulsions can renew its fluidity when taking orally, which is advantageous to release and absorption of drugs.
本文制备了石蜡-span80(山梨糖醇酐单油酸酯)-tween80(聚氧乙烯山梨醇酐单油酸酯)W／O／W多重乳液，研究了界面性质、粘度性质以及通过油膜的水传递性质对其稳定性的影响，确定了这些性质对W／O／W多重乳液稳定性的影响，并调控这些性质以制备出相对稳定的多重乳液，并采用此多重乳液担载胰岛素。
首先，本文考察了与W／O／W多重乳液稳定性密切相关的油水界面性质。确定了tween-80在水中的临界胶束浓度为1.34×10~(-3)mol／l，span-80在石蜡中的临界反胶团浓度为4.15×10~(-5)mol／l，计算出tween-80和span-80在溶液中的最小用量。研究了吸附有表面活性剂的界面的扩张粘弹性，发现可以通过调节表面活性剂的配比来调节界面粘弹性。当界面受到高频扩张和压缩时，界面弹性为恢复界面形变的主要动力，而当发生低频扩张和压缩时，界面粘度为阻滞界面形变的主要动力。
其次，本文考察了W／O／W多重乳液体系的粘度性质对其稳定性的影响。表明多重乳液粘度的增加有利于保持其稳定，但起始W／O乳液粘度的增加对W／O／W多重乳液粘度影响不大，而在外水相加入高聚物是W／O／W多重乳液增粘的主要手段：本部分还利用已有粘度模型和改善的粘度模型计算一个衡量多重乳液不稳定性程度的参数——溶胀率，从另一方面来量化乳液粘度与乳液稳定性的关系，证明了使用粘度模型计算溶胀率是可行的，从而为定量多重乳液的水传递量提供了一种方法。
本文还考察了W／O／W多重乳液体系中一个重要的传质现象——水传递对W／O／W多重乳液稳定性的影响。研究表明内外水相间的渗透压差会引起水在两相间的扩散，并且同时促进了聚并的发生，显著地影响多重乳液的形貌和稳定性，所以有必要对渗透压下的水扩散进行控制。为了对渗透压差下的水扩散进行控制，论文建立了两个简化的多重乳液乳珠模型。通过单滴模型得到了多重乳液中水传递方向的判据，通过统计平均半径模型预测了在内外水相中，使多重乳液体系中的水传递达到平衡时的盐浓度，从而确立了一种简单易行的维持多重乳液稳定性的方法。并首次采用差分扫描量热仪(DSC)检测不同稳定态下的多重乳液中的水传递过程，当W／O／W多重乳液经过一个冷冻循环时，通过两个放热峰的位置和大小变化，跟踪水的传递过程，并判断乳液的稳定程度，检测结果表明统计平均半径模型预测的多重乳液稳定程度与实验测定吻合较好。
随后，本文采用正交实验，通过极差分析、方差分析、单因素变量分析优化了多重乳液的制备条件，优化条件为：span-80浓度12wt％，tween-80浓度4wt％，起始乳液制备温度50℃，油水比5:3，乳水比1:2。所得乳液的平均粒径为14.6μm，一致率为0.24。在此基础上，在内外水相中分别加入0.0205mol／l和0.0184mol／l的氯化钾，保证内水相水滴间及内外水相间达到水传递平衡，进一步增强了乳液的稳定性。为延长药剂的货架期，提出用外相凝胶化来增加多重乳液药剂体系的稳定性，采用魔芋胶和黄原胶复配，使W／O／W多重乳液外水相发生凝胶化，制备出了新型的外相凝胶化W／O／W多重乳液体系，通过对载药凝胶化W／O／W多重乳液稳定性以及该体系在人工胃肠液中流变性的考察，表明该体系不仅在贮存期非常稳定，而且能在人工胃肠液中恢复流动性，有利于药物的分散、释放和吸收。
最后，本文以胰岛素为模型药物，用W／O／W多重乳液担载胰岛素，考察了该药剂体系对药物的包埋和释放，以及对药物的保护作用。实验表明该体系对胰岛素的包埋率可达90％以上，可以很好地保护胰岛素使其免受胃肠蛋白酶的降解。
Water-in-oil-in-water(W/O/W) multiple emulsions have great potentials for application in many fields, especially in pharmacy because of their special character of encapsulating water-soluble substances. W/O/W multiple emulsions loading protein drugs in the internal phase have three functions: protecting protein drugs from being degraded by enzymes in stomach and intestine; releasing drug slowly through oil phase to achieve the aim of sustained release; realizing oral administer so as to relieve the pain of patients. However, multiple emulsions have not been commercially available due to one main reason of their instability. Therefore, it is significant to study the stability of multiple emulsions.
The W/O/W multiple emulsions are composed of liquid paraffin, span-80(sorbitan monooleate) and tween-80(polyoxyethylene sorbitan monooleate). The two-step preparation method is applied to prepare multiple emulsions. Several properties influencing the stability of multiple emulsions are investigated, such interfacial property, viscous property, and water transport and so on. In this study, some methods controlling the stability of multiple emulsions are given and some mechanisms about the stability of emulsion are explained.
Firstly, properties of the oil and water interface are studied. The CMC of tween-80 in water and that of span-80 in oil measured through interfacial tension are 1.34×10~(-3)mol/l and 4.15×10~(-5)mol/l, respectively. And the minimum concentrations of tween-80 in water and span-80 in oil are calculated. The dilational viscoelasticity of interface with different surfactants are tested, which encompasses interfacial viscosity is a main means to resist the deformation under low deformation rate and at the same time interfacial elasticity is a main means to recover the deformation under fast deformation rate. Furthermore, modulating the proportion of surfactants can adjust the dilational viscoelasticity of interface.
Secondly, the effects of viscosity on stability of W/O/W multiple emulsions are investigated from two aspects: viscosity of primary emulsion, viscosity of polymer. Meanwhile, the feasibility of viscosity model calculating the swelling ratio of multiple emulsions is evaluated. The studies indicate that the viscosity of primary emulsion has little effect on that of multiple emulsions, polymers increase the viscosity of multiple emulsions obviously and that the viscosity model can be used to calculate the swelling ratio of multiple emulsions.
Thirdly, an important mass transfer, water transport, related to the stability of multiple emulsion system is investigated. For the W/O/W multiple emulsion system in this study, several factors evoking water transport are researched one by one, such as micelle water carrying, osmotic pressure facilitating, and coalescence. Experimental studies indicate that the coalescence under osmotic pressure is obvious and the control of water transport is needed so as to keep the stability of multiple emulsions. In order to control water transport, two simple models are established,(ⅰ) one droplet model, giving the criterion to judge the water transport direction, and(ⅱ) statistic mean droplet radius, helping to control water transport when the second-composite is added into the internal phase. Models are proved by experimental phenomena.
Fourthly, technical conditions preparing multiple emulsions are optimized. Orthogonal experiments are used to fix on the optimized operation condition, such as the concentration of surfactants, the ratio of oil to water, the temperature of preparation. Based on the orthogonal experiments, range analysis, variance analysis and single factor analysis, the best experiment conditions preparing stable emulsion are determined as follows: 12wt% of span-80, 4wt% of tween-80, preparation at 50℃, the volume ratio of oil to water 5:3, and the volume ratio of emulsion to water 1:2. The mean droplet size of multiple emulsions prepared is 14.6μm, and the coherence is 0.24. The water transport is controlled when 0.0205 mol/l potassium chloride is added into the internal phase and 0.0184 mol/l potassium chloride is in the external phase. An intensity synergistic effect of konjac gum and xanthan gum has been found to prepare the gel system. The optimal proportion is that the complex gelatin consisted of 20wt% konjac gum and 80wt% xanthan gum while the complex gelatin is lwt% in the external phase. A gelatin multiple emulsions system is prepared making the multiple emulsions much more stable.
Finally, insulin is taken as model drug encapsulated into the internal phase of W/O/W multiple emulsions. The encapsulated efficiency is up to 90% and sustained release is attained to some extent. W/O/W multiple emulsion can protect insulin against proteolytic enzymes in the gastrointestinal tract and it can release insulin in artificial intestinal juice. At the same time, external phase is dealt with by gel making the multiple emulsions keep the stability on shelf life. The experiments show that the gelled multiple emulsions can renew its fluidity when taking orally, which is advantageous to release and absorption of drugs.
引文
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