Intestinal absorption of penclomedine from lipid vehicles in the conscious rat: contribution of emulsification versus digestibility.

While the inclusion of highly lipophilic compounds in self-emulsifying drug delivery systems (SEDDS) is often reported to result in strongly enhanced oral absorption, it is still controversial whether further lipolysis of the dispersed lipidic material is required for final transfer to the enterocyte membranes. In order to assess the relative roles of lipid vehicle dispersion and vehicle digestibility in the oral absorption of penclomedine (Pcm), a series of formulations of Pcm in medium chain triglyceride (MCT)/tocophersolan (TPGS) was developed having three sizes (160 nm, 720 nm, and mm-sized ('crude' oil)); with or without the inclusion of tetrahydrolipstatin (THL), a known lipase-inhibitor. Oral absorption of Pcm was studied after administration of small volumes of these formulations in the conscious rat. Kinetic evaluation was performed using population analysis. Formulations with particle size 160 nm had the highest relative bioavailability (set at F=1), whereas administration in particle size 720 nm had slightly lower bioavailability (F=0.79). Co-inclusion of THL yielded similar bioavailability for these two SEDDS. 'Crude' oil formulations had F=0.62 (without THL) and 0.25 (with THL). The data in the current investigation emphasize the prominent role of increased vehicle dispersion relative to digestibility in the absorption of Pcm from MCT-TPGS in submicron emulsions. Only with Pcm administered as undispersed MCT, absorption was more dependent on the action of lipase as bioavailability was inhibited two-fold by the co-incorporation of THL.

Evaluation of bioadhesive capacity and immunoadjuvant properties of vitamin B(12)-Gantrez nanoparticles.

PURPOSE: To design bioadhesive Gantrez AN (poly[methyl vinyl ether-co-maleic anhydride], PVM/MA) nanoparticles (NP) coated with vitamin B(12) (Vit B(12)), and investigate their application in oral antigen delivery. METHODS: The association of Vit B(12) to Gantrez AN nanoparticles was performed by the direct attachment of reactive Vit B(12) to the surface of the nanoparticles (NPB), or linking to the copolymer chains in dimethylformamide prior to NP formation (NPB-DMF). Nanoparticles were characterized by measuring the size, zeta potential, Vit B(12) association efficacy, and stability of Vit B(12) on the surface of the nanoparticles. In vivo bioadhesion study was performed by the oral administration of fluorescently-labeled nanoparticle formulations to rats. Both systemic and mucosal immune responses were evaluated after oral and subcutaneous immunization with ovalbumin (OVA) containing Vit B(12)-coated nanoparticles. RESULTS: The Vit B(12) nanoparticles displayed homogenous size distribution with a mean diameter of about 200 nm and a negative surface charge. The association efficiency of Vit B(12) to NPB-DMF formulation was about two times higher than to the NPB, showing also a higher surface stability of Vit B(12). The bioadhesion study demonstrated that NPB-DMF had an important tropism to the distal portions of the gut, which was about two and 3.5 times higher than the tropism observed for NPB and control NP, respectively (p < 0.05). Oral administration of OVA-NPB-DMF induced also stronger and more balanced serum anti-OVA titers of IgG2a (Th1) and IgG1 (Th2) compared to control OVA-NP. In addition, oral immunization with OVA-NPB-DMF induced a higher mucosal IgA response than subcutaneous administration. CONCLUSIONS: These results indicate the benefits of bioadhesive Vit B(12)-coated nanoparticles in oral antigen delivery eliciting systemic and mucosal immune response.