Topical corticosteroid delivery into human skin using hydrofluoroalkane metered dose aerosol sprays.

Drug loaded hydrofluoroalkane (HFA) sprays can generate effective pharmaceutical formulations, but a deeper understanding of the manner in which these dynamic systems drive the process of in situ semi-solid dosage form assembly is required. The aim of this study was to investigate the effect of the matrix assembly and composition on drug localisation in human skin. Comparing the characteristics of sprays constituting HFA 134a, ethanol (EtOH), poly(vinyl pyrrolidone) K90, isopropyl myristate (IPM), and poly(ethylene glycol) (PEG) demonstrated that the addition of non-volatile solvents acted to delay EtOH evaporation, control the degree of drug saturation (DS) and enhance the corticosteroid delivery from HFA spray formulations. In a dose matched skin penetration study the HFA sprays containing only EtOH as a co-solvent delivered 2.1 µg BMV (DS 13.5) into the tissue, adding IPM to the EtOH HFA delivered 4.03 µg BMV (DS 11.2), whist adding PEG to the EtOH HFA delivered 6.1 µg BMV (DS 0.3). Compared to commercial cream (delivering 0.91 µg BMV) the EtOH/PEG HFA spray deposited over 6 times (p<0.05) more drug into the skin. Post spray deposition characterisation of the semi-solid suggested that the superior performance of the EtOH/PEG HFA spray was a consequence of retarding EtOH evaporation and presenting the drug in an EtOH rich PEG residual phase, which promoted BMV passage through the SC and into epidermis.

Transient drug supersaturation kinetics of beclomethasone dipropionate in rapidly drying films.

Supersaturation is an effective method to enhance the delivery of active compounds into the skin, however the long-term instability of the drug in these formulations that exceed thermodynamic unity prevents clinical use. The creation of supersaturation in situ by volatile solvent evaporation after application may overcome this. The aim of this study was to determine how altering the kinetics of transient supersaturation and recrystallisation would effect the rate of beclomethasone dipropionate (BDP) release from metered dose aerosols (MDA) that also consisted of hydrofluoroalkane 134a, ethanol (EtOH), and poly(vinyl pyrrolidone) (PVP) K90. An MDA containing 10% EtOH generated a sub-saturated concentration of BDP immediately after dose actuation and did not become supersaturated until 30 min post-actuation. Increasing the EtOH to 20% (w/w) and thus the BDP to 1.76% created supersaturation upon dose actuation but the drug recyrstallised within minutes of application. It was shown that the formulations with higher DS had accelerated rates of release despite rapid recrystallisation (444.9+/-79.3 microg/(cm2 h) for the fastest compared to 206.5+/-23.0 microg/(cm2 h) for the slowest). In highly volatile sprays maintaining BDP supersaturation for extended periods of time was less important than generating instantaneous, high levels of supersaturation to enhance drug release.

Determining degree of saturation after application of transiently supersaturated metered dose aerosols for topical delivery of corticosteroids.

A transiently supersaturated drug delivery system has the potential to enhance topical drug delivery via heightened thermodynamic activity. The aim of this work was to quantify the degree of saturation (DS) for transiently supersaturated formulations using three traditional and one novel in vitro assessment methods. Metered dose aerosols (MDA) were formulated containing saturated levels of beclomethasone dipropionate monohydrate (BDP) or betamethasone 17-valerate (BMV) within a pressurised canister, and included ethanol (EtOH), hydrofluoroalkane 134a propellant and poly(vinyl pyrrolidone). Attempts to determine the DS via the measurement of drug flux through synthetic membranes did not correlate and was shown to be dependent on the EtOH concentration. The inability of these methods to accurately assess the drug DS may be due to the transient nature of the formulation and the volatile solvents dehydrating the membrane. A mathematical equation that used the evaporation rate of the formulation was derived to determine the theoretical DS at various time points after MDA actuation. It was shown that the MDAs became supersaturated with a high DS, this enhanced drug release from the formulation and therefore these preparations have the potential to increase the amount of drug delivered into the skin.

An investigation into solvent-membrane interactions when assessing drug release from organic vehicles using regenerated cellulose membranes.

The influence of organic solvents on artificial membranes when assessing drug release from topical formulations is, generally, poorly characterised yet current guidelines require no characterisation of the membrane before, during or after an experiment. Therefore, the aim of this study was to determine the effect of solvent-membrane interactions when using in-vitro Franz cell methods for the assessment of corticosteroid release and to assess compliance or otherwise with Higuchi's equation. The rate of beclometasone dipropionate monohydrate (BDP) and betamethasone 17-valerate (BMV) release across a regenerated cellulose membrane (RCM), from both saturated solutions and commercial formulations, was determined. Increasing the ratio of organic solvent, compared with aqueous phase, in the donor fluid (DF) resulted in up to a 416-fold increase in steady-state flux. Further, alterations in the receiver fluid (RF) composition caused, in some cases, 337-fold increases in flux. Analysis indicated that the RCM remained chemically unchanged, that its pore size remained constant and that no drug partitioned into the membrane, regardless of the DF or RF employed. However, it was observed that the organic solvents had a thinning effect on the RCM, resulting in enhanced flux, which was potentially due to the variation in the diffusional path length. Such findings raise issues of the veracity of data produced from any membrane release study involving a comparison of formulations with differing solvent content.

Manipulation of corticosteroid release from a transiently supersaturated topical metered dose aerosol using a residual miscible co-solvent.

PURPOSE: The creation of supersaturation transiently after application overcomes the issue of drug instability. However, if the solvents used to drive supersaturation evaporate too quickly, drug recrystallisation or rapid film drying can occur which will inhibit drug release. As such the effects of a residual solvent, poly(ethylene glycol) 400 (PEG), on the release, mobility and supersaturation kinetics of a transiently supersaturated formulation were studied. MATERIALS AND METHODS: Metered dose aerosol (MDA) formulations consisting of hydrofluoroalkane 134a, ethanol, poly(vinyl pyrrolidone) K90, beclomethasone dipropionate (BDP), and 0%, 5% or 10% w/w PEG were prepared in canisters sealed with metered dose valves and tested for release and adhesion over time. RESULTS: The addition of 10% PEG to the MDA formulation resulted in a significant reduction (p < 0.05) in steady state drug release rate (230.4 +/- 17.3 microg/cm(2)/h for 0% PEG MDA, 83.6 +/- 4.9 microg/cm(2)/h for 10% PEG MDA). The presence of PEG caused a delay in dose depletion (2 h for 0% PEG MDA versus 4 h for 10% PEG), retarded supersaturation kinetics and increased film drying time. CONCLUSION: Whilst equivalent amounts of BDP were released, the residual solvent altered the drug release profile to achieve more constant delivery.