Volume 45, Issue 3 pp. 117-126
ORIGINAL ARTICLE

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

Kohei Yamada

Kohei Yamada

Laboratory of Biopharmacy, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan

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Kurt D. Ristroph

Kurt D. Ristroph

Department of Chemical & Biological Engineering, A301 EQUAD, Princeton University, Princeton, New Jersey, USA

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Yuuki Kaneko

Yuuki Kaneko

Laboratory of Biopharmacy, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan

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Hoang D. Lu

Hoang D. Lu

Department of Chemical & Biological Engineering, A301 EQUAD, Princeton University, Princeton, New Jersey, USA

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Robert K. Prud’homme

Robert K. Prud’homme

Department of Chemical & Biological Engineering, A301 EQUAD, Princeton University, Princeton, New Jersey, USA

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Hideyuki Sato

Hideyuki Sato

Laboratory of Biopharmacy, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan

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Satomi Onoue

Corresponding Author

Satomi Onoue

Laboratory of Biopharmacy, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan

Correspondence

Satomi Onoue, Laboratory of Biopharmacy, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.

Email: [email protected]

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First published: 22 April 2024

Abstract

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 (Tmax) of 3.4 h, maximum plasma concentration (Cmax) of 0.12 μg/mL, and bioavailability of 0.7%. Compared with amorphous CsA powder, MP/CsA shortened Tmax by 1.1 to 2.3 h and increased the bioavailability by 43-fold to 30.1%, while MA/CsA prolonged Tmax by 3.4 to 6.8 h with Cmax 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.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interests.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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