Single-dose study to compare the pharmacokinetics of HFA flunisolide and CFC flunisolide.

The hydrofluoroalkane (HFA) formulation of the inhaled corticosteroid flunisolide is a modification of the original chlorofluorocarbon (CFC) formulation. HFA flunisolide replaces CFC with an HFA propellant and uses a built-in spacer in its pressurized metered-dose inhaler. The average HFA flunisolide particle size is 1.2 microm compared with 3.8 microm for the CFC formulation. The smaller particle size improves lung targeting, allowing a reduction in the HFA flunisolide dose relative to CFC flunisolide while maintaining comparable efficacy. In a study of 12 healthy men, pharmacokinetic parameters were determined after single doses of 1000 microg CFC flunisolide delivered without a spacer, 340 microg HFA flunisolide delivered through a spacer, and 516 microg HFA flunisolide delivered without a spacer. A standard noncompartmental analysis of the concentration data was performed and mean (+/- S.D.) pharmacokinetic values were reported. Peak plasma concentrations (observed C(max)) were similar for the three treatments. Area under the curve up to the time corresponding to the last measurable concentration (AUC(0)(-)(tlast)) was similar for the CFC and HFA flunisolide, plus spacer groups (4.4 +/- 1.6 ng x h/mL and 5.0+/- 4.2 ng x h/mL, respectively); however, AUC(0)(-)(tlast) for the HFA flunisolide without spacer group was comparatively lower than for the CFC group (3.5 +/- 1.6 ng x h/mL). Observed C(max) and AUC(0)(-)(tlast) for 6 beta-OH flunisolide, the first-pass metabolite of flunisolide and an indicator of oropharyngeal deposition, were significantly higher in the CFC flunisolide group than in either HFA flunisolide group.

Deposition and pharmacokinetics of flunisolide delivered from pressurized inhalers containing non-CFC and CFC propellants.

Our objective was to assess the deposition and pharmacokinetics of a novel formulation of flunisolide (Aerobid, Forest Laboratories) in hydrofluoroalkane (HFA) 134a delivered by pressurized metered dose inhaler (pMDI). The design was a two-way crossover investigation in 12 healthy male subjects comparing HFA-134a flunisolide by pMDI versus pMDI plus 50 mL spacer device. Four of these subjects also took part in a two-way crossover investigation comparing chlorofluorocarbon (CFC) flunisolide pMDI versus pMDI plus Aerochamber holding chamber. The imaging technique of gamma scintigraphy was used to quantify total and regional lung deposition of flunisolide. Plasma levels of flunisolide and its major metabolite (6beta-OH flunisolide) were also determined. The spacer and Aerochamber reduced oropharyngeal deposition dramatically for both the HFA and CFC products (mean 59.8 to 14.9% (p < 0.01) of ex-valve (metered) dose for HFA product; 66.3 to 12.3% (p < 0.01) of ex-valve dose for CFC product) owing to deposition of part of the dose on the walls of the add-on devices themselves. Lung deposition averaged 22.6 and 40.4% (p < 0.01) of the ex-valve dose for the HFA formulation used with pMDI alone and with pMDI plus spacer. Mean lung deposition of the CFC formulation delivered via the Aerochamber (mean 23.4%) was higher than that for the CFC pMDI alone (mean 17.0%), but this difference was not statistically significant. Lung deposition expressed as percentage ex-device (delivered) dose averaged 68.3% for HFA pMDI plus spacer and 19.7% for CFC pMDI. Plasma levels of flunisolide were higher for the pMDI plus spacer than for pMDI alone, reflecting higher lung deposition via the spacer, but plasma levels of the 6beta-OH flunisolide metabolite were higher for the pMDI alone as a consequence of higher oropharyngeal deposition. When delivered via the spacer, pulmonary targeting of the flunisolide HFA formulation was improved compared with the CFC formulation, which should benefit patients by providing satisfactory asthma therapy from a much-reduced delivered dose of flunisolide.

Flunisolide HFA vs flunisolide CFC: pharmacokinetic comparison in healthy volunteers.

Two preparations of flunisolide, an inhaled corticosteroid, were compared in a parallel, multiple-dose study of 31 healthy volunteers. The new flunisolide preparation substitutes hydrofluoroalkane (HFA) for chlorofluorocarbon (CFC) as a propellant and incorporates a spacer into its pressurized metered-dose inhaler (pMDI). In this study, subjects were randomly assigned to receive flunisolide CFC 1000 microg bid; flunisolide HFA 170 microg bid; or flunisolide HFA 340 microg bid. Dosing was continued for 13.5 days. Plasma samples were analyzed after the first dose on day 1 and again after 13.5 days of treatment. No significant differences in day 1 dose-adjusted peak plasma concentrations (C(max)) were observed. Dose proportionality in C(max) and area under the concentration--time curves (AUC) was observed for the flunisolide HFA 170 and 340 microg bid groups on days 1 and 14. Day 1 mean dose-adjusted AUC was significantly greater in the flunisolide CFC 1000 microg bid group than in either flunisolide HFA group, indicating greater systemic availability of flunisolide CFC. Oral clearance and volume of distribution were significantly higher for flunisolide CFC than for flunisolide HFA. This may be due to greater oropharyngeal deposition by the flunisolide CFC formulation. Another indicator of greater flunisolide CFC oropharyngeal deposition was observed in C(max) and AUC(0--tlast) values for 6beta-OH flunisolide, the first-pass metabolite of flunisolide. The values of these pharmacokinetic parameters were significantly higher in the flunisolide CFC group than in the 340 microg bid flunisolide HFA group on days 1 and 14. However, this was not the case for cortisol values where flunisolide HFA accounted for less oropharyngeal deposition and more targeted delivery without adverse events. The study demonstrated that flunisolide HFA administered through a pMDI with built-in spacer was safe and well tolerated in healthy volunteers.

Surface characterization and platelet adhesion studies on fluorocarbons prepared by plasma-induced graft polymerization.

It is believed that the interactions between the biological environment and biomaterial surface are the key factors influencing its biocompatibility. Therefore, plasma processing, which can vary the surface properties without altering the bulk properties, has been considered as one of the important techniques for improving a materials' biocompatibility. In this investigation, plasma-induced grafting polymerization of vinylidene fluoride (VDF) and chlorotrifluoroethylene (CTFE), instead of direct plasma polymerization, was attempted with an aim to improve the substrate blood compatibility. Contact angle measurement indicated both fluorocarbon-grafted Pdyethylenes (PEs) are hydrophobic. Due to the additional fluorine and chlorine atoms on the CTFE chain, the PCTFE-grafted PE exhibited a higher hydrophobicity than the PVDF-grafted one. ESCA analysis has revealed that these two plasma-induced fluorocarbon deposits contain almost no CFx (x > 2) binding on the surface layer, indicating the grafting polymerization mainly follows the free radical mechanism instead of the molecule-highly-fragmented reaction steps commonly seen in the direct plasma polymerization treatment. In addition, ATR-FTIR has shown the surface chemical configuration of these PVDF- and PCTFE-grafted PEs to be very similar to those of the bulk samples of PVDF and PCTFE. The surface roughness decreased after oxygen plasma treatment and was further reduced by VDF and CTFE grafting polymerization. In vitro platelet adhesion testing indicated these two fluorocarbon grafted PEs are less platelet-activating than the nontreated PE control and oxygen plasma activated one.