Development of self-micellizing solid dispersion system employing amphipathic copolymer for the improvement of dissolution and oral bioavailability of cyclosporine A

,Hideyuki Sto,Tkhiro Mizumoto, Kyo Yuminoki,Nohumi Hshimoto, Stomi Onoue,

aUniversity of Shizuoka,52-1 Yada,Suruga-ku,Shizuoka 422-8526,Japan

bILS Inc.,1-2-1 Kubogaoka,Moriya,Ibaraki 302-0104,Japan

cSetsunan University,45-1 Nagaotoge-cho,Hirakata,Osaka 573-0101,Japan

Development of self-micellizing solid dispersion system employing amphipathic copolymer for the improvement of dissolution and oral bioavailability of cyclosporine A

Hiroki Suzukia,Hideyuki Satoa,Yoshiki Kojoa,Takahiro Mizumotob, Kayo Yuminokic,Naohumi Hashimotoc,Yoshiki Setoa, Satomi Onouea,*

aUniversity of Shizuoka,52-1 Yada,Suruga-ku,Shizuoka 422-8526,Japan

bILS Inc.,1-2-1 Kubogaoka,Moriya,Ibaraki 302-0104,Japan

cSetsunan University,45-1 Nagaotoge-cho,Hirakata,Osaka 573-0101,Japan

A R T I C L E I N F O

Article history:

Available online 23 November 2015

Cyclosporine A

Amphipathic copolymer

Self-micellizing solid dispersion

Oral bioavailability

The main objective of the present study is to develop a selfmicellizing solid dispersion(SMSD)system of cyclosporine A (CsA)using an amphiphilic copolymer,poly[MPC-co-BMA](pMB) to improve the biopharmaceutical properties of CsA(Fig.1A). Unlike conventional carrier compounds,pMB would perform the bifunctional ability as both polymeric carrier of solid dispersion system and solubilizer derived from a high micellizing property,which could be considered benefcial for the production of highly water soluble formulation of poorly water soluble compound[1].Improvement in the aqueous solubility has been believed to be a key consideration for acquiring potent pharmacological effects of BCS class II drug like CsA.However,far less is known about its feasibility and applicability of pMB to solid dispersion systems and CsA with its high molecular weight.

pMB-based solid dispersion of CsA with drug loading 15% (w/w)was prepared using a wet-milling system,and its physicochemical properties were characterized with respect to the morphology,particle size distribution,dissolution behavior,crystallinity and stability.Pharmacokinetic studies of orally dosed CsA formulations were also performed to assess the improvement of oral absorption in rats.The cytotoxicity of pMB was assessed in rat intestinal IEC-6 cells,and the pMB was less cytotoxic than polysorbate 80,a non-ionicsurfactant with a wide safety margin.The SMSD/CsA exhibited immediate formation of fne micelles with a mean diameter of ca.180 nm when introduced into aqueous media. There was marked improvement in the dissolution behavior of the SMSD/CsA compared with amorphous CsA.Even after storage at 40°C/75%relative humidity,the dissolution behavior of aged SMSD/CsA seemed to be almost identical to that of its freshly prepared equivalent,and CsA in aged SMSD/ CsA was still in amorphous form.After oral administration of SMSD/CsA(10 mg CsA/kg)in rats,enhanced CsA exposure was observed with increases of Cmaxand bioavailability by ca. 11-and 42-fold,respectively,compared with those of amorphous CsA(Fig.1B).From these fndings,the pMB-based SMSD system might be an effcacious approach for improvements in oral bioavailability of CsA.

Fig.1–The schematic image(A)and pharmacokinetic study after oral administration(B)of SMSD/CsA.

Acknowledgements

This work was supported in part by a Grant-in-Aid for Scientifc Research(C)(No.24590200;S.Onoue)from the Ministry of Education,Culture,Sports,Science,and Technology;and a grant from the Takeda Science Foundation.

R E F E R E N C E

[1]Onoue S,Kojo Y,Suzuki H,et al.Development of novel solid dispersion of tranilast using amphiphilic block copolymer for improved oral bioavailability.Int J Pharm 2013;452(1–2):220–226.

*E-mail address:onoue@u-shizuoka-ken.ac.jp.

Peer review under responsibility of Shenyang Pharmaceutical University.

http://dx.doi.org/10.1016/j.ajps.2015.10.038

1818-0876/©2016 The Authors.Production and hosting by Elsevier B.V.on behalf of Shenyang Pharmaceutical University.This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).