| dc.description.abstract | Optimum therapeutic outcomes require not only proper drug selection but also effective
drug delivery and monitoring. The aim of this thesis was to A) study drug delivery
through the skin with a liquid formulated to promote absorption, B) develop and validate
methods to analyze the drug in the samples obtained, C) assess appropriate methods to
measure the transdermal delivery of drug, and D) apply to pharmacodynamics.
The stability of a rectal formulation of diazepam, Diastat®, and a quality control of a
topical form, TDS® diazepam, were studied using high performance liquid
chromatography (HPLC) with ultraviolet absorption detection (UV). It was found that
diazepam at 10 mg/mL was stable in solution at various temperatures for at least 4 weeks.
A pharmacokinetic study of diazepam delivery from the TDS® delivery system was
compared with delivery of the drug following rectal administration of Diastat® in 12
healthy volunteers. The TDS® diazepam was evaluated for safety and no adverse effects
or events were observed. The preparation was found to be able to deliver diazepam
systemically in humans, the confidence interval (CI) of the ratios for Cmax and AUC of
diazepam from the two formulations A (TDS®): B (rectal) were not contained within the
bioequivalence limit 80–125%, Cmax (0–72h): 7.3–14% and AUC0-72h: 20–38%. In
addition, the 90% CI of desmethyldiazepam (A:B) ratio were not contained within the
bioequivalence limit, Cmax (0–72h): 38–54% and AUC0-72h: 33–58%. Although not
bioequivalent to Diastat® these finding suggest that skin may be an alternative method of
diazepam delivery but further developments and studies would be required.
The development and validation of fast, high throughput methods to evaluate tetracaine
from skin tape samples was another challenge. Sensitive and reliable capillary
electrophoresis with UV and HPLC-UV methods were developed and validated to
measure tetracaine in skin using tape samples from volunteers given 1 mL Ametop gel
(4% w/w of tetracaine) to support a pharmacokinetic drug delivery study of Ametop. The
results from these validation studies demonstrated an equal ability of the two methods to
measure tetracaine concentrations reproducibly and accurately. The Bland Altman test
was in a range of ± 1.96 SD from the mean (SD = ± 8.02, Mean = 2.23), and percentage
error (± 20%.), which show an acceptable difference. The assays were found to possess
both the sensitivity and specificity necessary to measure the analyte in the skin tape
stripping at the concentrations range in these tapes.
Finally, observation of appropriate methods to measure the transdermal drug in vivo
techniques, such as microdialysis (MD) and tape stripping (TS) have been employed by
plotting a concentration time profile to investigate the capability of measuring tetracaine
(pharmacokinetics) in local tissue, instead of measuring tetracaine by conventional
systemic measurements. The results showed that the tetracaine Cmax concentration was
higher in the stratum corneum compared with the major metabolites of tetracaine, 4-
butylaminobenzoic acid (BABA) by 3 and 10 times in MD and plasma, respectively. TS
samples reached the maximum concentration quicker than BABA in dialysate and plasma
samples (p = 0.002). The median tmax was higher in plasma (IQR -53minutes, 95% CI: -
30– -105) compared with tape samples. The AUC and Cmax for tetracaine were higher in
TS compared with BABA in MD and plasma (Mean AUC0-4h: 88582, 55594 and 13208
nM.min: Mean Cmax (0–4h), 850, 459, 110 nM, respectively).
In addition, the AUC and Cmax values demonstrated that data from the TS study showed
less variability compared with the data from plasma. The most variable data were for MD
(CV%; AUC0-4h, 24, 63, and 85%: Cmax (0–4h), 42, 60, 80%, respectively). AUC and
Cmax (Bartlett’s test, p = 0.004 for AUC; and Levene’s test, p = 0.042, and 0.028,
respectively)
This thesis has demonstrated that 1) diazepam was successfully delivered through the
skin into the systemic circulation by the TDS® system, 2) novel methods have been
developed for the measurement of tetracaine and its metabolite, and 3) the methods have
been successfully applied to three different sample types employed in pharmacokinetic
studies. | en_US |
