Albert H. L. Chow

Particle Engineering for Pulmonary Drug Delivery

With the rapidly growing popularity and sophistication of inhalation therapy, there is an increasing demand for tailor-made inhalable drug particles capable of affording the most efficient delivery to the lungs and the most optimal therapeutic outcomes. To cope with this formulation demand, a wide variety of novel particle technologies have emerged over the past decade. The present review is intended to provide a critical account of the current goals and technologies of particle engineering for the development of pulmonary drug delivery systems. These technologies cover traditional micronization and powder blending, controlled solvent crystallization, spray drying, spray freeze drying, particle formation from liquid dispersion systems, supercritical fluid processing and particle coating. The merits and limitations of these technologies are discussed with reference to their applications to specific drug and/or excipient materials. The regulatory requirements applicable to particulate inhalation products are also reviewed briefly.

Particle Size Analysis in Pharmaceutics: Principles, Methods and Applications

AbstractPhysicochemical and biopharmaceutical properties of drug substances and dosage forms can be highly affected by the particle size, a critical process parameter in pharmaceutical production. The fundamental issue with particle size analysis is the variety of equivalent particle diameters generated by different methods, which is largely ascribable to the particle shape and particle dispersion mechanism involved. Thus, to enable selection of the most appropriate or optimal sizing technique, cross-correlation between different techniques may be required. This review offers an in-depth discussion on particle size analysis pertaining to specific pharmaceutical applications and regulatory aspects, fundamental principles and terminology, instrumentation types, data presentation and interpretation, in-line and process analytical technology. For illustration purposes, special consideration is given to the analysis of aerosols using time-of-flight and cascade impactor measurements, which is supported by a computational analysis conducted for this review.

Pharmacogenetics and herb-drug interactions: experience with Ginkgo biloba and omeprazole

OBJECTIVE Ginkgo biloba was found to exert a significant inductive effect on CYP2C19 activity. This study was designed to investigate the potential herb-drug interaction between G. biloba and omeprazole, a widely used CYP2C19 substrate, in subjects with different CYP2C19 genotypes. METHODS Eighteen healthy Chinese subjects previously genotyped for CYP2C19 were selected. All subjects received a single omeprazole 40 mg at baseline and then at the end of a 12-day treatment period with G. biloba (140 mg, bid). Multiple blood samples were collected over 12 h, and 24 h urine was collected post omeprazole dosing. Plasma and urine concentrations of omeprazole and its metabolites, 5-hydroxyomeprazole and omeprazole sulfone, were determined, and their pharmacokinetics calculated non-compartmentally. RESULTS Plasma concentrations of omeprazole and omeprazole sulfone were significantly decreased, and 5-hydroxyomeprazole significantly increased following G. biloba administration in comparison to baseline. A significant decrease in the ratio of area under the plasma concentration-time curve (AUC) of omeprazole to 5-hydroxyomeprazole was observed in the homozygous extensive metabolizers, heterozygous extensive metabolizers, and poor metabolizers, respectively. The decrease was greater in PMs than EMs. No significant changes in the AUC ratios of omeprazole to omeprazole sulfone were observed. Renal clearance of 5-hydroxyomeprazole was significantly decreased after G. biloba, but the change was not significantly different among the three genotype groups. CONCLUSION Our results show that G biloba can induce omeprazole hydroxylation in a CYP2C19 genotype-dependent manner and concurrently reduce the renal clearance of 5-hydroxyomeprazole. Co-administration of G. biloba with omeprazole or other CYP2C19 substrates may significantly reduce their effect, but further studies are warranted.

Self-nanoemulsifying drug delivery system (SNEDDS) for oral delivery of Zedoary essential oil: Formulation and bioavailability studies

The aim of the present study was to develop a self-nanoemulsifying drug delivery system (SNEDDS) for the oral delivery of Zedoary turmeric oil (ZTO), an essential oil extracted from the dry rhizome of Curcuma zedoaria. Pseudo-ternary phase diagrams were constructed to identify the efficient self-emulsification regions. ZTO could serve as a partial oil phase with the aid of the second oil phase to enhance drug loading. Increasing the surfactant concentration reduced the droplet size but increased the emulsification time, while the reverse effect was observed by increasing the co-surfactant concentration. Based on the emulsification time, droplet size and zeta potential after dispersion into aqueous phase, an optimized formulation consisting of ZTO, ethyl oleate, Tween 80, transcutol P (30.8:7.7:40.5:21, w/w) and loaded with 30% drug was prepared. Upon mixing with water, the formulation was rapidly dispersed into fine droplets with a mean size of 68.3+/-1.6 nm and xi-potential of -41.2+/-1.3 mV. The active components remained stable in the optimized SNEDDS stored at 25 degrees C for at least 12 months. Following oral administration of ZTO-SNEDDS in rats, both AUC and C(max) of germacrone (GM), a representative bioactive marker of ZTO, increased by 1.7-fold and 2.5-fold respectively compared with the unformulated ZTO.

Coriolus versicolor: A Medicinal Mushroom with Promising Immunotherapeutic Values

Coriolus versicolor(CV) is a medicinal mushroom widely prescribed for the prophylaxis and treatment of cancer and infection in China. In recent years, it has been extensively demonstrated both preclinically and clinically that aqueous extracts obtained from CV display a wide array of biological activities, including stimulatory effects on different immune cells and inhibition of cancer growth. The growing popularity of aqueous CV extracts as an adjunct medical modality to conventional cancer therapies has generated substantial commercial interest in developing these extracts into consistent and efficacious oral proprietary products. While very limited information is available on the physical chemical, and pharmacodynamic properties of the active principles present in these extracts, there has been sufficient scientific evidence to support the feasibility of developing at least some of these constituents into an evidence‐based immunodulatory agent. In this article, the background, traditional usage, pharmacological activities, clinical effects, adverse reactions, active constituents, and regulatory aspects of CV are reviewed. Presented also in this review are the current uses and administration, potential drug interactions, and contraindication of aqueous extracts prepared from CV.

Aerosolisation behaviour of micronised and supercritically-processed powders

Comparative analysis of salmeterol xinafoate (SX) powders was carried out to define the aerodynamic properties and mechanism of particle dispersion relevant to the use of these materials in dry powder inhalation drug delivery. Particle sizing methodology was evaluated using laser diffraction, time-of-flight and Andersen cascade impactor measurements combined with electron microscopy and surface area determination. Particle interactions, assessed on the basis of powder bulk density and inverse gas chromatography surface energy measurements, were compared with the aerodynamic forces generated by a dry-powder dispersion device. The supercritically produced material showed by a factor of seven reduced tensile strength of the aggregates and indicated a two-fold increase of fine particle fraction deposited in a cascade impactor when blended with lactose. This effect was explained by the reduced particle aggregation at low differential air pressures and flow rates. A relatively small value of aerodynamic stress required to disperse supercritically produced particles in comparison to micronized material comes from: (a) lower bulk density (loose aggregate structure), (b) larger volume mean diameter, (c) larger aerodynamic shape factor and (d) smaller specific free energy of S-SX particles, in this order of priority. It is shown that aggregation between primary drug particles is important for SX/lactose formulations because such aggregates survive the pre-separation impactor stage.

Neuroprotective effect of honokiol and magnolol, compounds from Magnolia officinalis, on beta-amyloid-induced toxicity in PC12 cells

Amyloid β peptide (Aβ) induced toxicity is a well‐established pathway of neuronal cell death which might play a role in Alzheimers disease. In this regard, the toxic effect of Aβ on a cultured Aβ‐sensitive neuronal cell line was used as a primary screening tool for potential anti‐Alzheimers therapeutic agents. The effects of nine pure compounds (vitamin E, α‐asarone, salidroside, baicolin, magnolol, gastrodin, bilobalide, honokiol and β‐asarone) from selected Chinese herbs on neuronal cell death induced by Aβ in NGF‐differentiated PC12 cells were examined. Only two of the studied compounds, honokiol and magnolol, significantly decreased Aβ‐induced cell death. Further experiments indicated that their neuroprotective effects are possibly mediated through reduced ROS production as well as suppression of intracellular calcium elevation and inhibition of caspase‐3 activity. The results provide for the first time a scientific rationale for the clinical use of honokiol and magnolol in the treatment of Alzheimers disease. Copyright

Curcumin-conjugated magnetic nanoparticles for detecting amyloid plaques in Alzheimer's disease mice using magnetic resonance imaging (MRI).

Diagnosis of Alzheimers disease (AD) can be performed with the assistance of amyloid imaging. The current method relies on positron emission tomography (PET), which is expensive and exposes people to radiation, undesirable features for a population screening method. Magnetic resonance imaging (MRI) is cheaper and is not radioactive. Our approach uses magnetic nanoparticles (MNPs) made of superparamagnetic iron oxide (SPIO) conjugated with curcumin, a natural compound that specifically binds to amyloid plaques. Coating of curcumin-conjugated MNPs with polyethylene glycol-polylactic acid block copolymer and polyvinylpyrrolidone by antisolvent precipitation in a multi-inlet vortex mixer produces stable and biocompatible curcumin magnetic nanoparticles (Cur-MNPs) with mean diameter <100 nm. These nanoparticles were visualized by transmission electron microscopy and atomic force microscopy, and their structure and chemistry were further characterized by X-ray diffraction, thermogravimetric analysis, X-ray photoelectron spectroscopy, time-of-flight secondary ion mass spectrometry, and Fourier transform infrared spectroscopy. Cur-MNPs exhibited no cytotoxicity in either Madin-Darby canine kidney (MDCK) or differentiated human neuroblastoma cells (SH-SY5Y). The Papp of Cur-MNPs was 1.03 × 10(-6) cm/s in an in vitro blood-brain barrier (BBB) model. Amyloid plaques could be visualized in ex vivo T2*-weighted magnetic resonance imaging (MRI) of Tg2576 mouse brains after injection of Cur-MNPs, and no plaques could be found in non-transgenic mice. Immunohistochemical examination of the mouse brains revealed that Cur-MNPs were co-localized with amyloid plaques. Thus, Cur-MNPs have the potential for non-invasive diagnosis of AD using MRI.

Spray freeze drying with polyvinylpyrrolidone and sodium caprate for improved dissolution and oral bioavailability of oleanolic acid, a BCS Class IV compound

Spray-freeze-drying (SFD) of oleanolic acid (OA), a BCS Class IV compound, with polyvinylpyrrolidone-40 (PVP-40) as stabilizer and sodium caprate (SC) as wetting agent and penetration enhancer produced kinetically stable, amorphous solid dispersion systems with superior in vitro dissolution performance, and better and more uniform absorption in comparison with commercial OA tablet. Relative to the SC-free formulation, the presence of SC in the formulation resulted in a significant increase in the in vivo absorption rate of OA while exerting no apparent impact on the extent of OA absorption. The SFD-processed OA formulations and commercial OA tablet generally exhibited large inter-animal variability in oral bioavailability, consistent with the absorption characteristics of BCS Class IV compounds. Inclusion of SC coupled with the replacement of OA with its sodium salt (OA-Na) in the formulation was shown to substantially decrease the observed absorption variability. Above results suggested that increases in both dissolution rate and intestinal permeability of BCS Class IV compounds, as exemplified by the SFD-processed dispersion system containing both OA-Na and SC, are critical to reducing the large inter-individual absorption variability commonly observed with this class of drugs.

Hygroscopic Study of Glucose, Citric Acid, and Sorbitol Using an Electrodynamic Balance: Comparison with UNIFAC Predictions

balance (EDB). The mass fraction of solute (mfs), dee ned as the ratio of the dry solute mass to the solution mass, of the additives was measured as a function of relative humidity (RH) at equilibrium. Bulk measurements and literature data suggest that these three additives all crystallize at their respective saturation conditions. However, crystallization or deliquescence was not observed for the suspended particles of the three additives. They behave as nondeliquescentmaterialsandsorbanddesorbwaterreversibly.At RH = 5%,citricacidparticlesstillcontain » 8wt%residualwater, which corresponds to a stoichiometry of citric acid monohydrate. Glucose and sorbitol particles are essentially water-free. Universal FunctionalActivityCoefe cient (UNIFAC)modelpredictsthewater activities of glucose, citric acid, and sorbitol (expressed as mfs of the particles ) to within §16%, 24%, and 6% of those determined by the EDB, respectively.