Pharmacokinetic control of orally dosed cyclosporine A with mucosal drug delivery system.

Publisher: Wiley Country of Publication: England NLM ID: 7911226 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1099-081X (Electronic) Linking ISSN: 01422782 NLM ISO Abbreviation: Biopharm Drug Dispos Subsets: MEDLINE

Publication: Chichester : Wiley
Original Publication: Chichester [Eng.] Wiley.

Cyclosporine*/pharmacokinetics ; Cyclosporine*/administration & dosage ; Drug Delivery Systems* ; Rats, Sprague-Dawley*; Animals ; Male ; Administration, Oral ; Rats ; Immunosuppressive Agents/pharmacokinetics ; Immunosuppressive Agents/administration & dosage ; Immunosuppressive Agents/blood ; Drug Carriers/chemistry ; Intestinal Mucosa/metabolism ; Nanoparticles/chemistry ; Biological Availability ; Particle Size

This study aimed to control the oral absorption of cyclosporine A (CsA) with the use of a mucosal drug delivery system (mDDS). Mucopenetrating nanocarriers (MP/NCs) and mucoadhesive nanocarriers (MA/NCs) were prepared by flash nanoprecipitation employing polystyrene-block-poly(ethylene glycol) and polystyrene-block-poly(N,N-dimethyl aminoethyl methacrylate), respectively. Their particle distribution in the rat gastrointestinal tract were visualized by fluorescent imaging. Plasma concentrations were monitored after oral administration of CsA-loaded MP/NCs (MP/CsA) and MA/NCs (MA/CsA) to rats. MP/NCs and MA/NCs had a particle size below 200 nm and ζ-potentials of 4 and 40 mV, respectively. The results from in vitro experiments demonstrated mucopenetration of MP/NCs and mucoadhesion of MA/NCs. Confocal laser scanning microscopic images showed diffusion of MP/NCs in the gastrointestinal mucus towards epithelial cells and localization of MA/NCs on the surface of the gastrointestinal mucus layer. In a pH 6.8 solution, rapid and sustained release of CsA were observed for MP/CsA and MA/CsA, respectively. After oral dosing (10 mg-CsA/kg) to rats, amorphous CsA powder exhibited a time to maximum plasma concentration (T max ) of 3.4 h, maximum plasma concentration (C max ) of 0.12 μg/mL, and bioavailability of 0.7%. Compared with amorphous CsA powder, MP/CsA shortened T max by 1.1 to 2.3 h and increased the bioavailability by 43-fold to 30.1%, while MA/CsA prolonged T max by 3.4 to 6.8 h with C max and bioavailability of 0.65 μg/mL and 11.7%, respectively. These pharmacokinetic behaviors would be explained by their diffusion and release properties modulated by polymeric surface modification. The mDDS approach is a promising strategy for the pharmacokinetic control of orally administered CsA.
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20K07158 Japan Society for the Promotion of Science; 20K07180 Japan Society for the Promotion of Science; 20J22872 Japan Society for the Promotion of Science

Keywords: absorption; cyclosporine A; flash nanoprecipitation; mucosal drug delivery system; pharmacokinetic control

83HN0GTJ6D (Cyclosporine)
0 (Immunosuppressive Agents)
0 (Drug Carriers)

Date Created: 20240422 Date Completed: 20240626 Latest Revision: 20240626

20240627

10.1002/bdd.2388

38646776