James Alan Schriver Nightingale

Utility of Hydroxypropylmethylcellulose Acetate Succinate (HPMCAS) for Initiation and Maintenance of Drug Supersaturation in the GI Milieu

PurposeTo identify materials and processes which effect supersaturation of the GI milieu for low solubility drugs in order to increase oral bioavailability.MethodsA variety of small and polymeric molecules were screened for their ability to inhibit drug precipitation in supersaturated solutions. The best polymeric materials were utilized to create spray-dried dispersions (SDDs) of drug and polymer, and these were tested for drug form and homogeneity. Dispersions were tested in vitro for their ability to achieve and maintain drug supersaturation, for a variety of drug structures.ResultsOf the 41 materials tested, HPMCAS was the most effective at maintaining drug supersaturation. Drug/HPMCAS SDDs were consistently more effective at achieving and maintaining drug supersaturation in vitro than were SDDs prepared with other polymers. Drug/HPMCAS SDDs were effective in vitro for eight low solubility drugs of widely varying structure. Drug/HPMCAS SDDs were more effective at achieving and maintaining supersaturation than were rotoevaporated Drug/HPMCAS dispersions or physical mixtures of Drug and HPMCAS. The degree of achievable drug supersaturation increased with increasing polymer content in the SDD. The drug in Drug /HPMCAS SDDs was amorphous, and the dispersions were demonstrated to have a single glass transition and were thus homogeneous.ConclusionHPMCAS has been identified as a uniquely effective polymer for use in SDDs of low solubility drugs, with broad applicability across a variety of drug structures and properties.

Enhanced transdermal delivery of estradiol in vitro using binary vehicles of isopropyl myristate and short-chain alkanols

Abstract The effect of binary vehicles of isopropyl myristate (IPM) and short-chain alkanols on the enhancement of skin permeation of estradiol (E 2 ) was studied in vitro using human epidermal membrane. The steady-state fluxes of E 2 and solvents across the skin were determined from saturated solutions of neat and binary solvents of IPM and ethanol (EtOH), n -propanol ( n -PrOH), n -octanol ( n -OcOH), or isopropanol (i-PrOH). While the neat solvents modestly increased the E 2 flux, addition of IPM to the alkanols resulted in a synergistic enhancement of the E 2 flux. Among the (1:1) binary cosolvents evaluated, i-PrOH produced the highest E 2 flux (1.1 μg/cm 2 per h), which was 35-fold greater than from water and over 15-fold greater than from the neat solvents. This combination was also the best in terms of relative compositions of the IPM/i-PrOH cosolvents. A strong correlation between E 2 and i-PrOH fluxes suggested the enhancement for both permeants. While i-PrOH traversed the skin, IPM was retained in the stratum corneum. The uptake of both IPM and E 2 in the stratum corneum was largely increased by adding i-PrOH (up to 50%) to IPM.

Variation of human skin permeation in vitro: Ionic vs neutral compounds

Abstract The variation of skin permeation data has been investigated for ionic vs neutral permeants through human cadaver skin. In contrast to neutral ones, ionic permeants produced highly variable flux data with a positively skewed asymmetrical distribution. This permeant-dependent flux variation may suggest that different mechanisms are involved in the in vitro skin transport for ionic and neutral compounds.

Flow-Through System Effects on in Vitro Analysis of Transdermal Systems

The development of transdermal therapeutic systems (TTS) often involves in vitro evaluation of formulations and prototypes using flow-through diffusion cells. The apparent flux obtained from such methodologies does not accurately represent the actual (intrinsic) permeation of the compound through the skin. Flow-through system parameters, i.e., fraction collector tube volume, receiver cell volume, flow rate, and sampling interval, modify the flux yielding an apparent flux. Both finite-dose flux profiles and infinite-dose diffusional lag times are modified by these parameters. In this study, a transfer function is derived which describes the effect of these parameters. The intrinsic flux is calculated from apparent flux data using the transfer function and experimental flow-through system parameters. This allows the calculation of permeant flux profiles devoid of modification by the experimental methodology.

Pharmacokinetic evaluation of transdermal buprenorphine in man

Abstract Transdermal delivery of the synthetic opiate analgesic, buprenorphine, was studied in healthy volunteers. Pharmacokinetic, safety and tolerability data were obtained in a group of 12 healthy subjects following administration of a short intravenous infusion and the application of both aqueous- and ethanol-based fillable transdermal therapeutic systems (FTTS), containing 8 and 37.5 mg of drug, respectively. The total amount delivered by the 10 cm 2 aqueous reservoir system ranged from 0.11 to 0.67 mg over the 24 h application period and the steady state in vivo flux rates were 0.56–1.91 μg/cm 2 /h. The total amount delivered by the 5 cm 2 ethanol-based FTTS ranged from 0.33 to 0.96 mg and the steady state in vivo flux values were 2.14–5.62 μg/cm 2 /h. The results of the feasibility investigation demonstrated that transdermal delivery of buprenorphine produced sustained plasma levels of drug within the range observed after intravenous dosing and that an ethanolic formulation produced approximately a four-fold increase in transdermal flux. The in vivo investigation suggests that transdermal delivery could provide appropriate plasma levels of buprenorphine for sustained analgesic effect.