Wang Gen-Ming, Chen Chien-Ho, Ho Hsiu-O, Wang Sheng-Shi, Sheu Ming-Thau
Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, 95 Wenchang Road, Taipei, Taiwan, ROC.
Int J Pharm. 2006 Aug 17;319(1-2):71-81. doi: 10.1016/j.ijpharm.2006.03.041. Epub 2006 Apr 7.
In this study, chitosan capsules with asymmetric membrane to induce osmotic effects and in situ formation of the delivery orifice were optimally prepared and characterized. Chitosan capsules were formed on stainless steel mold pins by dipping the pins into a chitosan solution followed by forming asymmetric structure by dipping into a quenching solution containing tripolyphosphate (TPP) to cause an ionic cross-linking reaction between the outer layer of chitosan and TPP. Factors influencing the properties of the capsule membrane, such as the molecular weight of chitosan, the dipping solution and dipping time, and the quenching solution and time, were optimized to successfully produce osmotic chitosan capsules with asymmetric membrane using chitosans that possessed different viscosities. In situ formation of a delivery orifice on the asymmetric membrane of the chitosan capsule was proven by the observation of a jet stream of chlorophyll being released from the capsule. Drugs with different solubility were selected, and a linear correlation between drug solubility and the initial drug release rate calculated from the slope of the drug release profile was used to verify that the delivery orifices that were in situ formed on the asymmetric membrane of the chitosan capsules induced by osmotic effect was responsible for the drug release. Water permeability across the optimally produced asymmetric membrane of the capsule from chitosan of 500 cps (300-700 cps) quenched with TPP for 30 min (C500/TPP30) was determined to be 1.40 x 10(-6)cm(2)h(-1)atm(-1) at 37.0+/-0.5 degrees C. The encapsulation of poorly water-soluble drugs, felodipine (FE) and nifedipine (NF), in such an asymmetric chitosan capsule was capable of creating a sufficient osmotic effect to activate the release of the drug with the addition of SLS and HPMC. The multiple regression equations of maximal release percent at 24h for FE and NF confirmed that both sodium lauryl sulfate (SLS) and hydroxypropyl methylcellulose (HPMC) positively influenced this response factor, and the effect of SLS was greater than that of HPMC.
在本研究中，对具有不对称膜以诱导渗透效应并原位形成给药孔的壳聚糖胶囊进行了优化制备和表征。通过将不锈钢模具销浸入壳聚糖溶液中，然后再浸入含有三聚磷酸钠（TPP）的骤冷溶液中以在壳聚糖外层与TPP之间引发离子交联反应，从而在不锈钢模具销上形成壳聚糖胶囊。对影响胶囊膜性能的因素进行了优化，如壳聚糖的分子量、浸渍溶液和浸渍时间以及骤冷溶液和时间，以使用具有不同粘度的壳聚糖成功制备出具有不对称膜的渗透型壳聚糖胶囊。通过观察从胶囊中释放出的叶绿素喷射流，证实了壳聚糖胶囊不对称膜上给药孔的原位形成。选择了不同溶解度的药物，并利用药物溶解度与根据药物释放曲线斜率计算出的初始药物释放速率之间的线性相关性，来验证由渗透效应在壳聚糖胶囊不对称膜上原位形成的给药孔是药物释放的原因。在37.0±0.5℃下，用TPP骤冷30分钟（C500/TPP30）的500 cps（300 - 700 cps）壳聚糖制成的最佳不对称膜胶囊的水渗透率为1.40×10⁻⁶cm²h⁻¹atm⁻¹。在这种不对称壳聚糖胶囊中包封难溶性药物非洛地平（FE）和硝苯地平（NF），通过添加十二烷基硫酸钠（SLS）和羟丙基甲基纤维素（HPMC）能够产生足够的渗透效应以激活药物释放。FE和NF在24小时时最大释放百分比的多元回归方程证实，十二烷基硫酸钠（SLS）和羟丙基甲基纤维素（HPMC）均对该响应因子有正向影响，且SLS的影响大于HPMC。
