David J. Cutler

What is a Suitable Dissolution Method for Drug Nanoparticles

PurposeMany existing and new drugs fail to be fully utilized because of their limited bioavailability due to poor solubility in aqueous media. Given the emerging importance of using nanoparticles as a promising way to enhance the dissolution rate of these drugs, a method must be developed to adequately reflect the rate-change due to size reduction. At present, there is little published work examining the suitability of different dissolution apparatus for nanoparticles.MethodsFour commonly-used methods (the paddle, rotating basket and flow-through cell from the US Pharmacopia, and a dialysis method) were employed to measure the dissolution rates of cefuroxime axetil as a model for nanodrug particles.ResultsExperimental rate ratios between the nanoparticles and their unprocessed form were 6.95, 1.57 and 1.00 for the flow-through, basket and paddle apparatus respectively. In comparison, the model-predicted value was 7.97. Dissolution via dialysis was rate-limited by the membrane.ConclusionsThe data showed the flow-through cell to be unequivocally the most robust dissolution method for the nanoparticulate system. Furthermore, the dissolution profiles conform closely to the classic Noyes–Whitney model, indicating that the increase in dissolution rate as particles become smaller results from the increase in surface area and solubility of the nanoparticles.

Pharmacokinetics of dexamethasone and its relationship to dexamethasone suppression test outcome in depressed patients and healthy control subjects

The pharmacokinetics of dexamethasone (DEX) were studied in 9 drug-free melancholically depressed patients and 10 healthy control subjects matched by sex and age. Each subject received 1 mg of DEX administered orally and by the (i.v.) route at 11:00 PM and serial blood samples were collected over the next 17 hours until 4:00 PM. There were no significant differences between the diagnostic groups and DEX bioavailability, peak plasma level, time to maximum concentration, or in elimination half-life after oral administration. Bioavailability estimates indicated that DEX absorption was incomplete and variable mean = 61%, SD = 14) in controls as well as depressed patients. In both groups there was a wide interindividual variability in plasma DEX levels following both oral and i.v. routes of administration. This variability could not be reliably predicted by differences in age, sex, or weight between subjects. The factors that accounted for most the variability in 4:00 PM plasma DEX levels after oral administration were clearance, bioavailability, and time to reach maximum concentration. Plasma DEX levels were lower in 3 depressed nonsuppressors compared to 3 matched controls who suppressed. No single pharmacokinetic factor was shown to be responsible for the lower DEX levels in the depressed nonsuppressors. These results indicate that plasma DEX levels need to be measured in each individual during the DST procedure so that this information may be taken into consideration when interpreting DST results.

High-Performance Liquid-Chromatographic Assay for Hydroxychloroquine and Metabolites in Blood and Plasma, Using a Stationary Phase of Poly(styrene Divinylbenzene) and a Mobile Phase At Ph 11, with Fluorimetric Detection

A sensitive rapid high-performance liquid chromatographic assay for hydroxychloroquine and three major metabolites, desethylhydroxychloroquine, desethylchloroquine and bisdesethylchloroquine, has been developed. An ion-suppression separation technique is used with a macroporous polymer, poly(styrene divinylbenzene), stationary phase and a mobile phase of methanol--water with triethylamine, pH 11. A single ether extraction from alkalinized plasma or whole blood, with chloroquine added as an internal standard, is used. Using fluorescence detection, with excitation at 337 nm, the limit of sensitivity is 1 ng/ml. Some anti-inflammatory drugs which may be used concurrently for rheumatoid disorders are shown not to interfere with the assay. Samples of whole blood and plasma obtained from rheumatoid patients contained hydroxychloroquine and all three metabolites.

Simulation of kinetic data on the influx and efflux of chloroquine by erythrocytes infected with plasmodium falciparum: Evidence for a drug-importer in chloroquine-sensitive strains

Literature data on influx and efflux kinetics of chloroquine (CQ) with erythrocytes infected with the malaria parasite Plasmodium falciparum were simulated using a four-compartment model with first-order exchange between the compartments. The four compartments represent (1) the buffer surrounding the infected erythrocyte; (2) the cytosol of the host erythrocyte; (3) the parasite cytosol; and (4) the food vacuole. Simulations showed that basal membrane transport of CQ, estimated from data on influx of CQ into uninfected red cells, largely accounts for uptake and release of CQ by erythrocytes infected with two different CQ-resistant (CQ-R) parasite strains. In contrast, the rate of uptake of CQ by erythrocytes infected with a CQ-sensitive (CQ-S) strain is substantially higher than predicted by uptake with membrane transfer by basal diffusion of CQ. Simulations also indicate that the difference in kinetics of CQ uptake by erythrocytes infected with the CQ-S and CQ-R strains can be explained by a net increase in the inward permeability coefficient at the host erythrocyte membrane, the composite membrane surrounding the parasite or the food vacuole membrane. The results are consistent with the presence of a drug-importer for CQ in erythrocytes infected with sensitive strains, which is absent in those infected with resistant strains. They are not consistent with the hypothesis that CQ resistance is attributable to a drug-exporter in resistant cells which is lacking in sensitive cells.

Focused-ion-beam Milling: A Novel Approach to Probing the Interior of Particles Used for Inhalation Aerosols

PurposeThe current study aimed to examine the pharmaceutical applications of the focused-ion-beam (FIB) in the inhalation aerosol field, particularly to particle porosity determination (i.e. percentage of particles having a porous interior).Materials and MethodsThe interior of various spray dried particles (bovine serum albumin (BSA) with different degrees of surface corrugation, mannitol, disodium cromoglycate and sodium chloride) was investigated via FIB milling at customized conditions, followed by viewing under a high resolution field-emission scanning electron microscope. Two sets of ten particles for each sample were examined.ResultsFor the spray-dried BSA particles, a decrease in particle porosity (from 50 to 0%) was observed with increasing particle surface corrugation. Spray-dried mannitol, disodium cromoglycate and sodium chloride particles were determined to be 90–100%, 0–10% and 0% porous, respectively. The porosity in the BSA and mannitol particles thus should be considered for the aerodynamic behaviour of these particles.ConclusionsThe FIB technology represents a novel approach useful for probing the interior of particles linking to the aerosol properties of the powder. Suitable milling protocols have been developed which can be adapted to study other similar particles.

Antimalarials in rheumatic diseases

The antimalarials hydroxychloroquine and chloroquine remain established and effective agents for the treatment of rheumatoid arthritis and systemic lupus erythematosus. Although the mechanisms of action remain uncertain, evidence is accumulating that the antirheumatic and immunological effects of the antimalarials are related to their massive distribution into the cellular acid-vesicle system. These drugs are attracting new interest because their relative safety recommends their use in early rheumatoid arthritis and as a component of second-line antirheumatic drug combinations. The absence of data examining the effect of antimalarials upon radiological progression of rheumatoid arthritis needs to be rectified. Recent understanding of the pharmacokinetics of these drugs reveals that steady-state concentrations are not achieved for at least 3-4 months. Preliminary information also suggests a relationship between blood concentrations and effect. Taken together, these data suggest that more effective dosage regimens will be possible when therapeutic concentration ranges are properly established.

Apparent Dose-Dependence of Chloroquine Pharmacokinetics Due to Limited Assay Sensitivity and Short Sampling Times

SummaryWe have shown that apparent nonlinearities in the pharmacokinetics of chloroquine and wide variability in reported kinetic values are possibly artefacts of experimental design. We have used simulated data based on linear equations to demonstrate that chloroquine kinetics may appear to be dose-dependent if samples are collected over a short period or if they are assayed with a method of low sensitivity.

Kinetics and thermodynamics of chloroquine and hydroxychloroquine transport across the human erythrocyte membrane

Chloroquine (CQ) and hydroxychloroquine (HCQ) have almost identical molecular volumes but showed very different permeability characteristics. The permeability coefficient for the unionised species of CQ (2.0 cm/sec at 25 degrees) was about fifty times that of HCQ (0.039 cm/sec at 25 degrees), but the apparent activation energy for transport (85 kJ/mol for CQ, 81 kJ/mol for HCQ) was almost identical for the two drugs. The partition coefficient of CQ into various organic solvents was much higher than for HCQ, but the different permeability behaviour cannot be quantitatively explained by partitioning behaviour into hexane or octanol, two solvents commonly used to mimic the membrane interior. A comparison of permeability and partitioning characteristics suggests that the barrier phase for these drugs within the membrane can be modelled by a mixed solvent of 5% octanol in hexane. The results suggest that interactions with hydrogen bonding groups within the membrane are important in the membrane transport of these drugs, and that the membrane does not behave functionally as a simple hydrocarbon barrier.

High-performance liquid chromatographic separation of the enantiomers of hydroxychloroquine and its major metabolites in biological fluids using an α1-acid glycoprotein stationary phase

An enantioselective two-stage off-line assay has been developed for the analysis of hydroxychloroquine and its three major metabolites in biological fluids. The first non-stereoselective stage of the assay (PRP-1 column) separates and quantitates parent drug and metabolites. Fractions containing hydroxychloroquine and each of the metabolites are collected manually, evaporated, reconstituted in mobile phase and re-injected onto an alpha 1-acid glycoprotein column to separate and determine proportions of individual enantiomers. Preliminary results from patients samples indicate that the disposition of hydroxychloroquine and its major metabolites is enantioselective. p6

High-performance liquid chromatographic analysis of mometasone furoate and its degradation products: application to in vitro degradation studies.

A method of analysis of mometasone furoate in pharmaceutical formulations and biological fluids is necessary to study the degradation kinetics and determine its stability. A simple high-performance liquid chromatographic method was developed for simultaneous determination of mometasone furoate and its degradation products in human plasma. Plasma (0.5 ml) was extracted with dichloromethane after addition of the internal standard, dexamethasone 21-acetate. Separation was achieved on a Beckman C(8) column with UV detection at 248 nm. The calibration curve was linear ranging from 0.2 to 100 microg/ml. The mean extraction efficiency was >86%. Precision of the assay was <10% (CV), and was within 10% at the limit of quantitation (0.2 microg/ml). Bias of the assay was lower than 7%. The limit of detection was 50 ng/ml for a 0.5-ml sample. The assay was applied successfully to the in vitro kinetic study of degradation of mometasone furoate in human plasma and simulated biological fluids.