Microemulsion-based media as novel drug delivery systems

Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.

Strategies to Address Low Drug Solubility in Discovery and Development

Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs.

Lipid formulations for oral administration of drugs: non-emulsifying, self-emulsifying and 'self-microemulsifying' drug delivery systems.

Purpose This review highlights the state-of-the-art in pharmaceutical microemulsions with emphasis on self-emulsifying systems, from both a physical and biopharmaceutical perspective Although these systems have several pharmaceutical applications, this review is primarily focused on their potential for oral drug delivery and intestinal absorption improvement

Lipid microemulsions for improving drug dissolution and oral absorption: physical and biopharmaceutical aspects

Self-emulsifying drug delivery systems (SEDDSs) represent a possible alternative to traditional oral formulations of lipophilic compounds. In the present study, a lipophilic compound, WIN 54954, was formulated in a medium chain triglyceride oil/nonionic surfactant mixture which exhibited self-emulsification under conditions of gentle agitation in an aqueous medium. The efficiency of emulsification was studied using a laser diffraction sizer to determine particle size distributions of the resultant emulsions. An optimized formulation which consisted of 25% (w/w) surfactant, 40% (w/w) oil, and 35% (w/w) WIN 54954 emulsified rapidly with gentle agitation in 0.1 N HCl (37 degrees C), producing dispersions with mean droplet diameters of less than 3 microns. The self-emulsifying preparation was compared to a polyethylene glycol 600 (PEG 600) solution formulation by administering each as prefilled soft gelatin capsules to fasted beagle dogs in a parallel crossover study. Pharmacokinetic parameters were determined and the absolute bioavailability of the drug was calculated by comparison to an i.v. injection. The SEDDS improved the reproducibility of the plasma profile in terms of the maximum plasma concentration (Cmax) and the time to reach the maximum concentration (tmax). There was no significant difference in the absolute bioavailability of WIN 54954 from either the SEDDS or the PEG formulations.

Self-emulsifying drug delivery systems: formulation and biopharmaceutic evaluation of an investigational lipophilic compound.

A study has been conducted on the HPLC analysis of barbiturate mixtures in which coeluting components with similar UV spectra could be distinguished by diode array detection. Mixtures containing phenobarbital and barbital in combination from about 0.25 to 0.00025 mg/mL each were measured using the spectral overlay, absorbance ratio, peak maximum absorbance and purity parameter techniques. The most sensitive of the standard methods available was absorbance ratio plotting in which the presence of 0.0125 mg/mL barbital could be distinguished from phenobarbital at 0.2375 mg/mL.

Analysis of Barbiturate Mixtures Using HPLC with Diode Array Detection

Recent developments in HPLC analysis of analgesics have been rapid, paralleling the growth of chromatographic sciences as a whole. Although analgesics have been used for hundreds of years and chromatgraphic separations have been carried out on them for decades, liquid chromatographic analysis of analgesics has advanced most rapidly in the past 5–7 years . The present review will focus on applications of HPLC to the analysis of commercial analgesics in this time period with emphasis on novel developments and applications associated with the improved accuracy, sensitivity and specificity in herent in current LC systems.

Terry D. Wilson

Papers

Self-emulsifying drug delivery systems: formulation and biopharmaceutic evaluation of an investigational lipophilic compound.

Analysis of Barbiturate Mixtures Using HPLC with Diode Array Detection

Recent Advances in HPLC Analysis of Analgesics

Structural influences on the amperometric detection of opiates in high-performance liquid chromatography.

High-performance liquid chromatographic determination of fentanyl citrate in a parenteral dosage form.