Song Keon-Hyoung, Chung Suk-Jae, Shim Chang-Koo
Department of Pharmaceutics, College of Pharmacy, Seoul National University, 599 Kwanak-Ro, Kwanak-Gu, Seoul 151-742, Korea.
J Control Release. 2005 Sep 2;106(3):298-308. doi: 10.1016/j.jconrel.2005.05.016.
The feasibility of using proliposomes containing salmon calcitonin (sCT) and absorption enhancing agents, as an oral delivery system, to improve the intestinal absorption of sCT was explored using rats and Caco-2 cell systems.
Seventeen surfactants were examined for their effects with reference to accelerating the permeability of sCT (300 microg/ml) across Caco-2 cell monolayers, and damage to the intestinal epithelial cells, as measured by the change in transepithelial electrical resistance (TEER) across the cell monolayer. Proliposomes containing sCT (0.75%, w/w) and sodium taurodeoxycholate (NaTDC, 2.5%, w/w) (TDC proliposomes) were prepared according to the standard method using sorbitol and phosphatidylcholine as core and wall-forming materials, respectively, administered intra-duodenally to rats, and plasma concentrations of sCT were subsequently determined by LC-MS.
Among the surfactants examined, some bile salts including NaTDC appeared to be the most advantageous when estimated based on the balance between the permeation enhancement (e.g., a 10.8-fold increase in the permeability of sCT for 0.1% NaTDC) and damage to the cells (e.g., a 3.55-fold decrease in the TEER value for 0.1% NaTDC). The administration of TDC proliposomes resulted in a 7.1-fold increase in the bioavailability (i.e., 0.49%) of sCT, when administered duodenally to rats. The size of the reconstituted liposomes in water was significantly smaller (e.g., 23.2 nm, number weighted diameter), and the entrapment efficiency (EE) of sCT in the reconstituted liposomes was 2.8-fold larger (54.9%), for TDC proliposomes, compared to proliposomes prepared without NaTDC (sCT proliposomes).
A 7.1-fold increase in the bioavailability of sCT could be achieved from the TDC proliposomes. In addition to the intrinsic activity of the bile salt to fluidize the membrane, the simultaneous delivery of sCT and NaTDC to the site of absorption in the intestine via proliposomes and the subsequent formation of lipophilic ion-pair complexes between sCT and NaTDC at the site might have been contributing factors in this outstanding absorption enhancement.
利用大鼠和Caco - 2细胞系统，探索使用含有鲑鱼降钙素（sCT）和吸收增强剂的前体脂质体作为口服给药系统来提高sCT肠道吸收的可行性。
检测了17种表面活性剂对sCT（300微克/毫升）跨Caco - 2细胞单层通透性的促进作用，以及对肠道上皮细胞的损伤情况，通过跨细胞单层的跨上皮电阻（TEER）变化来衡量。按照标准方法，分别以山梨醇和磷脂酰胆碱作为核心和成膜材料，制备含有sCT（0.75%，w/w）和牛磺脱氧胆酸钠（NaTDC，2.5%，w/w）的前体脂质体（TDC前体脂质体），经十二指肠给予大鼠，随后通过液相色谱 - 质谱法测定血浆中sCT的浓度。
在所检测的表面活性剂中，基于渗透增强（例如，0.1% NaTDC使sCT的通透性增加10.8倍）和细胞损伤（例如，0.1% NaTDC使TEER值降低3.55倍）之间的平衡来评估，一些胆盐包括NaTDC似乎是最具优势的。当经十二指肠给予大鼠时，TDC前体脂质体使sCT的生物利用度提高了7.1倍（即0.49%）。与未添加NaTDC制备的前体脂质体（sCT前体脂质体）相比，TDC前体脂质体在水中重构脂质体的尺寸明显更小（例如，数量加权直径为23.2纳米），并且sCT在重构脂质体中的包封率提高了2.8倍（54.9%）。
TDC前体脂质体可使sCT的生物利用度提高7.1倍。除了胆盐使膜流化的固有活性外，通过前体脂质体将sCT和NaTDC同时递送至肠道吸收部位，以及随后在该部位sCT与NaTDC之间形成亲脂性离子对复合物，可能是这种显著吸收增强的促成因素。
