Enhanced Dissolution and Oral Bioavailability of Cyclosporine A: Microspheres Based on αβ-Cyclodextrins Polymers

Abstract

Cyclosporine (CsA) has a selective property of suppressing various T-lymphocyte functions. This is of utmost importance in preventing allograft rejection by several organ transplantations, as well as in the treatment of systemic and local autoimmune disorders. However, the poor water solubility of CsA can be a major hurdle for its absorption into the blood stream, which leads to low bioavailability and thus less efficacy. The aim of this study was to prepare, characterize, and evaluate in vitro as well as in vivo, the potential of the innovative CsA drug delivery system. The latter contains CsA in spherical amorphous solid dispersion (SASD) which is embedded in an original α-cyclodextrin and β-cyclodextrin polymer mixture (Poly-αβ-CD) as a multifunctional amorphous carrier. The new developed SASD formulation showed that CsA was molecularly dispersed in αβ-cyclodextrins in an amorphous form, as was confirmed by physicochemical characterization studies. Interestingly, the peptide secondary structure, and thus, the drug activity was not impacted by the preparation of SASD as was shown by circular dichroism. Furthermore, the in vitro CsA release profile kinetics was almost identical to the commercially available product Neoral®. This study presents the first in vivo proof-of-concept for a novel drug delivery system based on Poly-αβ-CD containing CsA, with SASD allowing for increased bioavailibility. The pharmacokinetic parameters of cyclosporine A from the spherical spray-dried dispersion formulation was demonstrated in a “rat” animal model. For comparison, the commercially available Neoral® was studied. Importantly, the pharmacokinetic parameters were improved by extending Tmax from 2 to 3 h after the oral administration in rats, and eventually preventing the enterohepatic circulation. All these results clearly demonstrate the improved pharmacokinetic parameters and enhanced bioavailability of CsA in the new developed drug delivery system. These data demonstrated the superiority of the newly developed Poly-αβ-CD formulation for oral administration of the poorly soluble CsA in vivo without altering its secondary structure. Poly-αβ-CD can be a very useful tool for the oral administration of poorly water-soluble drugs.

New Nanoparticle Formulation for Cyclosporin A: In Vitro Assessment

“…To circumvent the above-mentioned limitations, a nanoparticle (NP) formulation could be a promising approach to increase the bioavailability, solubility, and circulation time as well as deliver this peptide into targeted tissues and organs. To this end, several CsA-loaded nanoparticles have been developed, including lipid-based nanoparticles [ 22 , 23 ], microspheres [ 24 , 25 ], or polymeric nanoparticles [ 26 , 27 ]. However, these formulations are mainly developed for oral or local administration (i.e., ocular, cutaneous) and possess some limitations such as low entrapment efficacy, inconsistent drug release, and sometimes toxicity [ 28 , 29 , 30 ].…”

Implementation of Water‐Soluble Cyclodextrin‐Based Polymers in Biomedical Applications: How Far Are We?

“…The same group also synthesized a mixed CTR‐p αβ CyD using the same polycondensation procedure. [ 70 ]…”

“…Skiba et al proposed the encapsulation in pCyDs of Cyclosporine A (CsA, Table 5), a drug able to suppress various T‐lymphocyte functions. [ 70 ] The poor water solubility of CsA is a major hurdle for its absorption into the blood stream, which leads to low bioavailability and thus lower efficacy. The innovative CsA drug delivery system contains CsA in spherical amorphous solid dispersion (SASD) which is embedded in a mixed α CyD and β CyD polymer obtained using citric acid (CTR‐ αβ pCyD), as a multifunctional amorphous carrier.…”

Immunosuppressive Drugs

“…Pharmacokinetics: Its oral bioavailability ranges from 30% to 90% ( Lahiani-Skiba et al, 2018 ). Due to the lipophilic nature, it exhibit more than 95% affinity for binding with blood proteins ( Sasano et al, 2017 ).…”