Montenegro Lucia, Carbone Claudia, Condorelli Gabriele, Drago Rossella, Puglisi Giovanni
Department of Pharmaceutical Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
Drug Dev Ind Pharm. 2006 Jun;32(5):539-48. doi: 10.1080/03639040600599806.
In this work we investigated the effects of oil phase lipophilicity on in vitro drug release from topical o/w microemulsions (MEs) containing low percentages of emulsifiers. Three different lipids, isopropyl myristate (IPM), isopropyl palmitate (IPP), and isopropyl stearate (IPS), whose lipophilicity increased in the order IPM < IPP <IPS, were used as oil phase to prepare o/w MEs containing low amounts (7.7% w/w) of two surfactant/cosurfactant mixtures, isoceteth-20/glyceryl oleate (5:2) (MEs 1-3) and oleth-20/glyceryl oleate (5:2) (MEs 4-6). All the MEs were prepared using the phase inversion temperature (PIT) method. Three active compounds (0.5% w/w), Naproxen (NAP), Idebenone (IDE), and Butylmethoxydibenzoylmethane (BMBM), were selected as model drugs and their release rates from PIT MEs were evaluated using Franz-type diffusion cells. All the MEs gave a mean droplet diameter ranging from 28 to 44 nm and showed a single peak in size distribution. The addition of IDE to MEs 1-6 did not significantly change ME droplet size. On the contrary, an increase of the droplet size beyond the ME limit (150 nm) was observed when isoceteth-20 was used as surfactant to prepare MEs containing NAP or MEs containing BMBM and IPS as oil phase. Pseudo-first order release rates were observed only for NAP from MEs 1-3, while MEs containing IDE showed an initial slow release followed by an increased release of the test compound. The release rate constants were found to be dependent on the ME composition and on the active compound incorporated. The highest release rate was observed from ME 1 containing IPM as oil phase and NAP as drug. As regards BMBM, its release rate was not calculated since no release was observed until 6 h from the beginning of the experiment. The cumulative amount of active compound released after 22 h was inversely related to drug lipophilicity (NAP Log P = 2,9; IDE Log P 3,5; BMBM Log P 4,8). These findings could be attributable to a reduced thermodynamic activity of the drugs in the vehicles containing the most lipophilic oil phase due to an increase of drug solubility which could lead to an unfavorable drug partition from the oil phase. The results of this study suggest that the choice of proper combinations of oil phase lipids and emulsifiers may allow achieving drug controlled delivery from topical o/w MEs with low emulsifier content.
在本研究中，我们考察了油相亲脂性对含低百分比乳化剂的外用o/w型微乳剂（MEs）体外药物释放的影响。选用三种不同的脂质，肉豆蔻酸异丙酯（IPM）、棕榈酸异丙酯（IPP）和硬脂酸异丙酯（IPS），其亲脂性按IPM < IPP < IPS的顺序递增，作为油相来制备含少量（7.7% w/w）两种表面活性剂/助表面活性剂混合物（异鲸蜡醇聚醚-20/油酸甘油酯（5:2）（MEs 1 - 3）和油醇聚醚-20/油酸甘油酯（5:2）（MEs 4 - 6））的o/w型MEs。所有MEs均采用相转变温度（PIT）法制备。选择三种活性化合物（0.5% w/w），萘普生（NAP）、艾地苯醌（IDE）和丁基甲氧基二苯甲酰甲烷（BMBM）作为模型药物，并使用Franz型扩散池评估它们从PIT MEs中的释放速率。所有MEs的平均液滴直径在28至44 nm范围内，且粒径分布呈单峰。向MEs 1 - 6中添加IDE并未显著改变ME液滴大小。相反，当使用异鲸蜡醇聚醚-20作为表面活性剂制备含NAP的MEs或含BMBM且以IPS为油相的MEs时，观察到液滴大小增加超过了ME的限度（150 nm）。仅在MEs 1 - 3中观察到NAP的伪一级释放速率，而含IDE的MEs显示出初始缓慢释放，随后测试化合物的释放增加。发现释放速率常数取决于ME的组成以及所掺入的活性化合物。从以IPM为油相且以NAP为药物的ME 1中观察到最高释放速率。至于BMBM，由于从实验开始直至6 h均未观察到释放，因此未计算其释放速率。22 h后释放的活性化合物累积量与药物亲脂性呈负相关（NAP Log P = 2.9；IDE Log P 3.5；BMBM Log P 4.8）。这些发现可能归因于在含有最亲脂性油相的载体中药物的热力学活性降低，这是由于药物溶解度增加，可能导致药物从油相的分配不利。本研究结果表明，选择合适的油相脂质和乳化剂组合可能有助于实现从低乳化剂含量的外用o/w型MEs中进行药物控释。
