Transdermal alniditan delivery by skin electroporation.

The aim of this study was to evaluate the transdermal permeation of alniditan by electroporation and to compare with iontophoretic delivery. The influence of the electrical parameters of electroporation was investigated in vitro using a factorial design study. The transdermal flux of alniditan was enhanced by two orders of magnitude by application of high voltage electrical pulses. The electrical parameters of electroporation-i.e. the voltage, the duration and the number of pulses-allowed a control of drug permeation. Both transport during and after pulsing were shown to be important for alniditan transdermal delivery by electroporation. Electroporation was found more efficient in promoting alniditan permeation than an iontophoresis transferring the same amount of charges.

Transdermal permeation of alniditan by iontophoresis: in vitro optimization and human pharmacokinetic data.

PURPOSE: The aim of this paper was to assess the feasibility of electrically enhanced transdermal delivery of alniditan, a novel 5 HT1D agonist for the treatment of migraine. METHODS: An in vitro study was first performed to optimize the different parameters affecting iontophoresis efficiency. The mechanism of alniditan permeation by iontophoresis was investigated. Finally, a phase I clinical trial was performed to assess systemic delivery of alniditan by iontophoresis. RESULTS: i) In vitro: The optimal conditions were found with a buffer like ethanolamine at a pH of 9.5, with Ag/AgCl electrodes and a direct current application. Alniditan permeation was enhanced when increasing the current density, the duration of current application and the drug concentration. Iontophoresis slightly increased drug quantities in stratum corneum compared to passive diffusion but it strongly increased alniditan quantities in viable skin. ii) The objective to deliver in vivo 0.5 mg of alniditan within less than 1 h was reached but an erythema was detected at the anode. CONCLUSIONS: This study demonstrates the feasibility of iontophoretic delivery system for antimigraine compounds.

A study of the percutaneous absorption-enhancing effects of cyclodextrin derivatives in rats.

2-Hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) and 2,6-dimethyl-beta-cyclodextrin (D-beta-CyD) were studied for transdermal penetration enhancement of the cytochrome P450 inhibitor liarozole by an in vivo transdermal absorption rat model. The mode of action of penetration enhancement was investigated by differential scanning calorimetry (DSC). In-vivo, HP-beta-CyD, as a 20% aqueous solution, increased the absorption of liarozole approximately threefold and a 20% aqueous solution of D-beta-CyD decreased the percutaneous absorption of liarozole in blood by a factor of 0.6. However, pretreatment with D-beta-CyD (20%, 4 h) enhanced the transdermal absorption 9.4-fold. In the DSC experiments the thermal profile of human stratum corneum was practically unchanged after treatment with HP-beta-CyD, but treatment with D-beta-CyD revealed an interaction of D-beta-CyD with the protein and lipid fraction. Thus the results from DSC and those from the permeability experiments revealed that D-beta-CyD acts as a transdermal absorption enhancer by changing the stratum corneum barrier whereas HP-beta-CyD influences the partitioning behaviour of the drug in the skin.

Hydroxypropyl-beta-cyclodextrin can modulate the activity of spinally administered sufentanil.

Hydroxypropyl-beta-cyclodextrin increased the effectiveness of sufentanil after epidural and intrathecal administration in rats, both in terms of a longer duration of analgesia after a fixed dose of sufentanil, and in a reduction of the lowest ED50s to produce analgesia. There was also an increase in specificity, as indicated by the greater dissociation between the ED50s for analgesia and for supra-spinal side-effects. Maximal activity was measured after inclusion complexation of sufentanil in 10% hydroxypropyl-beta-cyclodextrin. At higher concentrations of hydroxypropyl-beta-cyclodextrin, both the activity and the specificity were attenuated. The increased safety of sufentanil in 10% hydroxypropyl-beta-cyclodextrin after spinal administration was also confirmed in terms of opioid-induced deviations in arterial PO2, PCO2 and oxygen saturation. At a dose of twice the ED50 for deep surgical analgesia, the sufentanil/hydroxypropyl-beta-cyclodextrin complex produced no changes in these parameters. With sufentanil alone at comparable analgesic doses, significant shifts in all three parameters were present immediately after drug administration. At higher concentrations of sufentanil in hydroxypropyl-beta-cyclodextrin changes in the three blood gases were present but the deviations were always smaller than those observed with comparable doses of plain sufentanil. These results support the notion that after complexation sufentanil is present longer at the spinal level after spinal administration. As a consequence, there is less free sufentanil available for redistribution into lipid tissue and into the circulatory system, producing less systemic side-effects.

Erbulozole (P.I.N.N.) (R 55 104) encapsulated into cyclodextrins: has it a combined antitumoral and radioprotective potential?

The clinically applicable formulation of the microtubule inhibitor erbulozole (R 55 104), dissolved into an aqueous hydroxypropyl-beta-cyclodextrin solution (designated as R 55 104-CYCLO), exerts a similar effect on growth delay of subcutaneous MO4 fibrosarcomas in mice, with or without 10 Gy gamma-irradiation given locally to the tumors 2 h later, compared to R 55 104 in water. The drug concentration can be reduced from 80 mg/kg to 5 mg/kg without affecting the activity of this particular drug-radiation combination. Furthermore, 80 mg/kg R 55 104-CYCLO show a radioprotective effect when given 2 h before total body irradiation of non-tumor bearing mice. A radiation dose of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 Gy respectively was given resulting in a LD50(30) of 5.97 Gy for the irradiated mice and 7.65 Gy for the drug-radiation treated animals (Dose Effect Factor = 0.78). Therapeutic implications of both observations are discussed.

Beta-cyclodextrins as vehicles in eye-drop formulations: an evaluation of their effects on rabbit corneal epithelium.

Beta-cyclodextrins are cyclic molecules with a hydrophilic outer side and a central hydrophobic cavity. Through the inclusion of drug molecules into their cavities, i.e. the formation of inclusion complexes, cyclodextrins are able to modify the physical and chemical properties of these molecules. When used in pharmaceutical formulations, they can improve the aqueous solubility, stability, dissolution rate, bioavailability and/or local tolerance of certain drugs. To make an initial evaluation of the potential use of beta-cyclodextrins as vehicles in ophthalmic eye-drop formulations, we studied the effect of a single and of multiple applications of hydroxypropyl-beta-cyclodextrin (HP-beta-CD) 12.5% and of dimethyl-beta-cyclodextrin (DM-beta-CD) 5 and 12.5% solutions on the corneal epithelium of albino and pigmented rabbits with slit lamp biomicroscopy (SLB) and scanning electron microscopy (SEM). We can conclude from this study that DM-beta-CD at concentrations of 5 and 12.5% is not a suitable vehicle for ophthalmic formulations since it is toxic to the corneal epithelium and that HP-beta-CD at a concentration of 12.5% is well tolerated by the rabbit eye and is not toxic to the corneal epithelium when evaluated by SLB and SEM.