Laura Matilainen

Improved dissolution and bioavailability of phenytoin by sulfobutylether-β-cyclodextrin ((SBE)7m-β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) complexation

Abstract The inclusion complexation of phenytoin with charged and neutral water-soluble cyclodextrins (CDs), (SBE)7m-β-CD and HP-β-CD, was studied in order to improve the low aqueous solubility and incomplete oral bioavailability of phenytoin. Effects of CDs on the aqueous solubility of phenytoin were determined by phase-solubility method at pH 7.4 and 11.0. Solubility of phenytoin increased as a function of CD concentration, showing AL type diagrams for both (SBE)7m-β-CD and HP-β-CD which indicate a formation of 1:1-complexes. Solid inclusion complexes of phenytoin with (SBE)7m-β-CD and HP-β-CD were prepared by freeze-drying. Dissolution rate of phenytoin was increased with inclusion complexes as well as with phenytoin/HP-β-CD physical mixture in vitro. Also the freeze-drying of phenytoin tended to enhance the dissolution of phenytoin in vitro. However, plain phenytoin (300.0 mg) pharmacokinetics after oral administration as a crystal form and as a freeze-dried form were comparable in dogs. CD-based formulations of phenytoin increased peak plasma concentration of phenytoin about 1.6-fold and bioavailability (AUC0–24 h) of phenytoin about 2-fold compared to plain phenytoin. Oral pharmacokinetics were not statistically different among various CD formulations. This study indicates that increased bioavailability of phenytoin in the presence of CDs was due to an increased extent of drug dissolution.

Cyclodextrins and chitosan derivatives in sublingual delivery of low solubility peptides: A study using cyclosporin A, α-cyclodextrin and quaternary chitosan N-betainate

Systemic drug delivery through intraoral membranes may offer a promising administration route for lipophilic peptide drugs. The aim of the present study was to investigate the effect of alpha-cyclodextrin (alpha-CD) and a novel chitosan derivative, chitosan N-betainate (CH), on sublingual absorption of a hydrophobic model peptide cyclosporin A (CsA), and the effect of temperature on the complexation of CsA with alpha-CD. Complexation of CsA with alpha-CD was studied using the phase-solubility method. Sublingual absorption of CsA was studied by administration of solid CsA/alpha-CD complex (with and without CH solution), solid CsA/alpha-CD/CH formulation and solid plain CsA to rabbits. The solubility of CsA in aqueous alpha-CD solution (14%) increased with decreasing temperature; the solubility of CsA at room temperature, +5 and +1 degrees C was 1.2, 12 and 19mg/ml, respectively. The bioavailability of CsA after administration of plain CsA, solid CsA/alpha-CD and solid CsA/alpha-CD/CH (0.6+/-0.5, 1.4+/-0.7 and 1.7+/-0.8%, respectively; mean+/-S.D.) was further increased when solid CsA/alpha-CD was administered together with CH solution (3.2+/-2.2%). The present study shows that decreased temperature can be effectively utilized to produce CsA/alpha-CD complexes. It was also shown that alpha-CD and CH may be advantageous in sublingual delivery of lipophilic peptides, although the absolute bioavailability remains low.

The stability and dissolution properties of solid glucagon/γ-cyclodextrin powder

In the present study, the solid-state stability and the dissolution of glucagon/gamma-cyclodextrin and glucagon/lactose powders were evaluated. Freeze-dried powders were stored at an increased temperature and/or humidity for up to 39 weeks. Pre-weighed samples were withdrawn at pre-determined intervals and analyzed with HPLC-UV (HPLC=high performance liquid chromatography, UV=ultraviolet), HPLC-ESI-MS (ESI-MS=electrospray ionization mass spectrometry), SEC (size-exclusion chromatography), turbidity measurements and solid-state FTIR (Fourier Transform Infrared Spectroscopy). Dissolution of glucagon was evaluated at pH 2.5, 5.0 and 7.0. In addition, before storage, proton rotating-frame relaxation experiments of solid glucagon/gamma-cyclodextrin powder were conducted with CPMAS ((13)C cross-polarization magic-angle spinning) NMR (nuclear magnetic resonance) spectroscopy. In the solid state, glucagon was degraded via oxidation and aggregation and in the presence of lactose via the Maillard reaction. The solid-state stability of glucagon/gamma-cyclodextrin powder was better than that of glucagon/lactose powder. In addition, gamma-cyclodextrin improved the dissolution of glucagon at pH 5.0 and 7.0 and delayed the aggregation of glucagon after its dissolution at pH 2.5, 5.0 and 7.0. There was no marked difference between the proton rotating-frame relaxation times of pure glucagon and gamma-cyclodextrin, and thus, the presence of inclusion complexes in the solid state could not be ascertained by CPMAS NMR. In conclusion, when compared to glucagon/lactose powder, glucagon/gamma-cyclodextrin powder exhibited better solid-state stability and more favorable dissolution properties.