A phase I pharmacokinetic and bioavailability study of a sublingual fentanyl wafer in healthy volunteers.

BACKGROUND: The sublingual administration of opioids is a simple and noninvasive method that provides rapid analgesia. In this phase I study we investigated the pharmacokinetics and bioavailability of a fentanyl wafer in healthy volunteers. The principal study objective was to investigate the pharmacokinetic profile of a new sublingual fentanyl wafer and to establish its absolute bioavailability. METHODS: Twenty-four healthy volunteers, mean age 23 years, were randomly assigned to receive the equivalent of fentanyl 100 µg by both the sublingual and IV routes. Blood samples were collected in sterile polypropylene tubes for 24 hours after each fentanyl administration. The pharmacokinetic parameters were determined by model-independent pharmacokinetic analyses of the plasma fentanyl concentration-time profiles. RESULTS: The mean absolute bioavailability of the sublingual fentanyl wafer was 78.9% (90% confidence interval [CI] 51.1% to 121.7%). The first detectable plasma fentanyl concentration time ranged from 2 to 10 minutes in all volunteers, and the mean (±SD) time to peak plasma concentration at 0.91 (±0.73) hours after administration. CONCLUSION: Sublingual administration of fentanyl as a wafer product resulted in rapidly detectable plasma fentanyl concentrations. The absolute bioavailability of 78.9% indicated a high systemic availability of fentanyl and suggests that further development of this wafer is justified.

Dihydroartemisinin-cyclodextrin complexation: solubility and stability.

Dihydroartemisinin (DHA) is a major metabolite of artemisinin and its derivatives, including arteether, artemether, and artesunate. To improve the solubility and stability of poorly soluble DHA, we prepared inclusion complexes with hydroxypropyl-beta-cyclodextrin (HPbetaCD) and recrystalized DHA to study its thermal stability. The complexes were characterized by differential scanning calorimetery (DSC), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction patterns (XRD), thermal stability, phase, and equilibrium solubility studies. Pure DHA was crystalline and remained crystalline after recrystallization, but its unit cell dimensions changed as exhibited by XRD. DHA-HPbetaCD complexes showed a phase transitions towards amorphous in DSC thermograms, FTIR spectra, and XRD patterns. The phase solubility profiles of complexes prepared in water, acetate buffer, and phosphate buffers were classified as A(L)-type, indicating the formation of a 1:1 stoichiometric inclusion complex. The equilibrium solubility of DHA was enhanced as a function of HPbetaCD concentration. DHA-HPbetaCD complexes showed an 89-fold increase in solubility compared to DHA. Solubilities of complexes containing 275.1 mM HPbetaCD in water, acetate buffer (pH 3.0), and phosphate buffer (pH 3.0 and 7.4) were 10.04, 7.96, 6.30, and 11.61 mg/ml, respectively. Hydrogen bonding was found between DHA and HPbetaCD, and it was stronger in complexes prepared in water than in buffers. However, the AH values were higher in buffer than water. DHA-HPbetaCD complexes prepared using commercial (untreated) or recrystallized DHA (no detectable impurity) showed a 40% increase in thermal stability (50 degrees C) and a 29-fold decrease in hydrolysis rates compared with DHA. The rank order of stability constants (K(s)) was: water, acetate buffer (pH 3.0), phosphate buffer (pH 3.0), and phosphate buffer (pH 7.4). Thus, HPbetaCD complexation with recrystalized DHA increases DHA solubility and stability.

Solid dispersions of dihydroartemisinin in polyvinylpyrrolidone.

In the present study the physicochemical characteristics of dihydroartemisinin, polyvinylpyrrolidone and their solid dispersions were evaluated at various proportions of drug and polyvinylpyrrolidone. These properties were investigated with X-ray diffraction, fourier transform infrared spectrophotometry, differential scanning calorimetry, equilibrium solubility at twenty five and thirty seven degree centigrade. X-ray diffraction analysis detected that dihydroartemisinin became more amorphous as drug carrier ratio was enhanced in solid dispersions. Fourier transform infrared spectra suggested that there was a hydrogen bonding interaction between dihydroartemisinin and polyvinylpyrrolidone in all solid dispersions. These interactions reflected the changes in crystalline structures of dihydroartemisinin. The thermal behavior of dihydroartemisinin was unusual as it exhibited melting exotherm instead of endotherm. In solid dispersions containing varying contents of polyvinylpyrrolidone, enthalpy change and peak area were enhanced while melting onset temperature decreased with increase in polyvinylpyrrolidone proportion. This was attributed to a solid-state interaction. Equilibrium solubility of dihydroartemisinin increased sixty-fold due to induction of polyvinylpyrrolidone. When this solubility was compared among thirty-seven and twenty five degree centigrade in solid dispersions, it was up to seven times more at higher temperature. Physicochemical characteristics of solid dispersions containing drug carrier ratio of one: nine prepared in acetonitrile, ethanol, methanol and tetrahydrofuran showed differences which indicated that properties of medium i.e. dielectric constant, dipole moment and structure, influenced the amount of amorphousness and related properties of dihydroartemisinin.

Effectiveness of a topical local anaesthetic spray as analgesia for dressing changes: a double-blinded randomised pilot trial comparing an emulsion with an aqueous lidocaine formulation.

BACKGROUND: Partial thickness skin graft wounds are painful. Topically applied lidocaine has been used for analgesia in several clinical trials. This study compared the effectiveness of two different formulations of topical local anaesthetic for dressing changes of partial thickness skin graft donor sites. METHODS: A double-blind randomised controlled, pilot trial was conducted in 29 patients undergoing split thickness skin graft surgery. Subjects were randomised to either a 3% lidocaine emulsion formulation "Treatment E" (NOPAYNE™) or a 4% aqueous solution "Treatment A" (Xylocaine™). Subjects received one spray per 3 cm(2) of donor site area followed by up to two further spays as required. Endpoints included pain intensity measured by the numerical rating scale (NRS) up to 1h after dressing change commencement, sting sensation, overall satisfaction and lidocaine plasma concentration. RESULTS: The 60 min pain scores for E and A were 1.3 ± 0.3 (mean ± SEM) and 1.8 ± 0.4 (p=0.98) respectively. Nearly 90% of patients were very satisfied with their treatment. The mean plasma concentrations of lidocaine for A and E were 0.132 mg/l and 0.040 mg/l respectively (p=0.069). CONCLUSION: The topical local anaesthetic formulations achieved low pain scores during dressing changes. The safety profile was potentially improved with the emulsion formulation of lidocaine.

Improving the solubility and bioavailability of dihydroartemisinin by solid dispersions and inclusion complexes.

Dihydroartemisinin (DHA) is a poorly water-soluble drug that displays low bioavailability after oral administration. Attempts have been made to improve the solubility of DHA. Yet, no information is available concerning improved bioavailability. This study aimed to improve the water solubility of DHA by two systems: solid dispersions with polyvinylpyrrolidone (PVPK30, PVPK25, PVPK15) and inclusion complexes with hydroxypropyl-ß-cyclodextrin (HPßCD), as well as improving the bioavailability of both systems. The phase transition of DHA with hydrophilic polymers was evaluated by X-ray diffraction (XRD) and differential scanning calorimetery (DSC). DHA became amorphous in DHA-HPßCD complexes and showed more amorphous behavior in XRD analyses with rise in molecular weight of PVP. Melting onset temperature of DHA decreased, while DSC thermograms revealed the peak area and enhanced enthalpy change (DH) in solid dispersions as well as inclusion complexes. DHA solubility was enhanced 84-fold in DHA-HPßCD complexes and 50-times in DHA-PVPK30. The improved solubility using the four polymers was in the following order: HPßCD > PVPK30 > PVPK25 > PVPK15. Values of area under curve (AUC) and half life (t(1/2)) of DHA-PVPK30 were highest followed by DHA-HPßCD, DHA-PVPK15 and DHA-PVPK25. V(d)/f of DHA-PVPK30 was 7-fold. DHA-HPßCD, DHA-PVPK15 and DHA-PVPK25 showed significantly different pharmacokinetic parameters compared with DHA solutions. The 95% confidence interval was meaningful in AUC and t(1/2). Pharmacokinetic parameters revealed that all four-test preparations were significantly more bioavailable than DHA alone.

Linked electronic medication systems in community pharmacies for preventing pseudoephedrine diversion: a review of international practice and analysis of results in Australia.

INTRODUCTION AND AIMS: Pseudoephedrine is a precursor often diverted into the illegal manufacture of amphetamine type substances (ATS). The aim of this study was to evaluate the effectiveness of a linked electronic medication recording system (LEMS) established in Australian pharmacies in 2005 for preventing the diversion of pseudoephedrine. DESIGN AND METHODS: The number of illegal ATS laboratories detected in each jurisdiction of Australia from 1996-1997 to 2004-2005 were analysed by linear regression nationally and by each jurisdiction. The statistical significance of seizures in 2005-2006 was based on the comparison of the observed value to the 95% prediction confidence intervals calculated from the historical data for each jurisdiction and nationally. RESULTS: Pharmacies in Queensland commenced an LEMS in late 2005 to minimise retail pseudoephedrine diversion. The number of ATS laboratories seized in 2005-2006 in Queensland was significantly lower (P < 0.05) than predicted by historical data. For all other jurisdictions and nationally the totals of laboratories seized in 2005-2006 were not significantly different from predicted values. DISCUSSION AND CONCLUSIONS: The significant decline in ATS illegal laboratories seized in Queensland in 2005-2006 suggests the effective use of LEMS in pharmacies to minimise pseudoephedrine diversion. In order to evaluate a national LEMS, more frequent data on numbers of linked pharmacies, ATS laboratories seized and indicators of pseudoephedrine sales and misuse are required. Testing the use of LEMS by pharmacies for preventing the diversion of other medicines seems appropriate.

Purification of PEGylated nanoparticles using tangential flow filtration (TFF).

A tangential flow filtration system was evaluated to purify PEGylated nanoparticles. Two widely used surfactants, PVA and sodium cholate were efficiently removed from an empty nanoparticles suspension using the proposed system. During drug loading, surfactant (PVA) was observed to be entrapped within the core of the nanoparticle to a higher extent, hence was purified at a comparatively slower rate. The presence of dextran sulfate enhanced the drug loading but also resulted in reduced purification rate; this was described by the hypothesis of PVA inclusion within the core of the nanoparticles. Practically, it was possible to correlate the slow purification rate of PVA to its reduced filtration flow during the purification of the empty and loaded nanoparticles containing dextran sulfate. Indirectly, this system was capable of revealing the influence of an excipient and drug on the nanoparticle surface.