Pharmaceutical development of an amorphous solid dispersion formulation of elacridar hydrochloride for proof-of-concept clinical studies.

OBJECTIVE: A novel tablet formulation containing an amorphous solid dispersion (ASD) of elacridar hydrochloride was developed with the purpose to resolve the drug's low solubility in water and to conduct proof-of-concept clinical studies. SIGNIFICANCE: Elacridar is highly demanded for proof-of-concept clinical trials that study the drug's suitability to boost brain penetration and bioavailability of numerous anticancer agents. Previously, clinical trials with elacridar were performed with a tablet containing elacridar hydrochloride. However, this tablet formulation resulted in poor and unpredictable absorption which was caused by the low aqueous solubility of elacridar hydrochloride. METHODS: Twenty four different ASDs were produced and dissolution was compared to crystalline elacridar hydrochloride and a crystalline physical mixture. The formulation with highest dissolution was characterized for amorphicity. Subsequently, a tablet was developed and monitored for chemical/physical stability for 12 months at +15-25 °C, +2-8 °C and -20 °C. RESULTS: The ASD powder was composed of freeze dried elacridar hydrochloride-povidone K30-sodium dodecyl sulfate (1:6:1, w/w/w), appeared fully amorphous and resulted in complete dissolution whereas crystalline elacridar hydrochloride resulted in only 1% dissolution. The ASD tablets contained 25 mg elacridar hydrochloride and were stable for at least 12 months at -20 °C. CONCLUSIONS: The ASD tablet was considered feasible for proof-of-concept clinical studies and is now used as such.

Inventory of oral anticancer agents: Pharmaceutical formulation aspects with focus on the solid dispersion technique.

Dissolution from the pharmaceutical formulation is a prerequisite for complete and consistent absorption of any orally administered drug, including anticancer agents (oncolytics). Poor dissolution of an oncolytic can result in low oral bioavailability, high variability in blood concentrations and with that suboptimal or even failing therapy. This review discusses pharmaceutical formulation aspects and absorption pharmacokinetics of currently licensed orally administered oncolytics. In nearly half of orally dosed oncolytics poor dissolution is likely to play a major role in low and unpredictable absorption. Dissolution-limited drug absorption can be improved with a solid dispersion which is a formulation method that induces super-saturated drug dissolution and with that it enhances in vivo absorption. This review discusses formulation principles with focus on the solid dispersion technology and how it works to enhance drug absorption. There are currently three licensed orally dosed oncolytics formulated as a solid dispersion (everolimus, vemurafenib and regorafenib) and these formulations result in remarkably improved dissolution and absorption compared to what can be achieved with conventional formulations of the respective oncolytics. Because of the successful implementation of these three solid dispersion formulations, we encourage the application of this formulation method for poorly soluble oral oncolytics.

Fluorescence analysis in air pollution research.

Luminescence phenomena are of value in the analysis of air pollutants. The problems arising in the use of excitation and emission spectra under various conditions are discussed. Phenomena such as solvent, pH, and photochemical effects are shown to play an important role in the fluorimetric analysis of air pollutants. Many of the fluorimetric methods used in the trace analysis of organic airborne particulates involve factors such as direct measurement of the separated pollutant on a chromatogram or pherogram, quenching phenomena, scanning, excimer formation, charge-transfer fluorescence, sensitized fluorescence, and photo-oxidation on adsorbent or in solution. In addition, fluorescence assay methods are discussed in terms of selectivity, sensitivity, speed, simplicity, accuracy, precision, interferences, and the relation between concentration and fluorescence intensity.

Spectral characterisation of nitroarenes and polycyclic aldehydes, ketones, quinones and amines.

Three methods are introduced for the post-chromatographic spectral characterisation of carbonyl and nitro compounds. Most often, elution from the chromatogram is necessary, but sometimes fluorescence spectra can be obtained directly from the chromatograra. The usefulness and sensitivity of the methods have been demonstrated for a variety of nitroarenes and polycyclic aldehydes, ketones, quinones and amines.

Assay for 9-acridanone in urban atmosphere by thin-layer chromatography fluorimetric procedures.

9-Acridanone has been found in urban atmospheres. Four two-dimensional thin-layer Chromatographic methods have been described for the assay of this compound in urban atmospheres and in air pollution source effluents. Fluorimetric assay was done either directly on the plate or after elution. The best method involved two-dimensional separation on alumina-cellulose followed by elution and fluorimetric analysis of the acidic methanol solution. Urban atmospheres contain approximately 0.4 ng of 9-acridanone/m(3) of air.

Chromatographic location and colorimetric determination of mercaptans, prolines and free radical precursors.

A new reagent, 7,7,8,8-tetracyanoquinodimethan (TCNQ), is introduced for the colorimetric determination of free radical precursors, such as cysteine, proline, hydroxyproline, the phenoxazine family and mercaptans. TCNQ is also useful in the location and characterization on paper or thin-layer chromatograms of proline, hydroxyproline, cysteine, polynuclear compounds, mercaptans, thiocarbonyl amides and thiosemicarbazones. In addition, aminoacid derivatives, such as the N-(phenylthiocarbamyl) amino-acids and the 3-phenylthiodantoins, can be located and characterized on chromatograms. TCNQ has been applied to the location and characterization of atmospheric proline, carbazole and 11H-benzo[a]carbazole. For characterization purposes absorption spectra were obtained directly from glass-fibre, paper, or thin-layer chromatograms from about 300 to 900 mmu.

Use of gas-liquid and thin-layer chromatography in characterising air pollutants by fluorometry.

Relatively large amounts of alkylated derivatives of the polynuclear aromatic hydrocarbons are present in some urban atmospheres. These compounds are believed to be derived from industrial sources. Because alkylation of the tetracyclic aromatic hydrocarbons can confer carcinogenic activity on the derivatives, the presence of substantial amounts of these alkylated compounds in the air needs thorough study. The R(F) value and the retention time, by themselves, are inadequate for characterisation of the polynuclear compounds. Gasliquid chromatography followed by fluorometric examination of the eluent bands, and mixed-adsorbent two-dimensional thin-layer chromatography followed by direct fluorometric examination are very useful in characterising all types of organic compound in the organic fractions of airborne particulates and effluents from air pollution sources.

Location and analysis of 2-deoxy sugars on chromatograms and pherograms by fluorescence.

A group of new reagents for the location of 2-deoxy sugars is introduced. A representative reagent is 4'-aminoacetophenone, which gives a green trimethine fluorogen with at least 0.5 microg of 2-deoxyribose, 2-deoxygalactose, or 2-deoxyglucose under neutral or slightly acidic conditions and the orange fluorescent anion under alkaline conditions at a lower limit of approximately 5 microg. Reagents such as 2-thiobarbituric acid, aniline-diphenylamine, and 2,4-pentanedione give vivid fluorescent colours with these sugars. Aniline-diphenylamine reagent was a useful fluorescent agent for locating the purine nucleosides and nucleotides and DNA. A new attachment for the spectropho-tofluorimeter has been evaluated. With this attachment fluorescence excitation and emission spectra are obtained directly from paper, glass fibre, or thin-layer chromatograms and pherograms in sizes up to 20 x 20 cm. Glass plates are handled as readily as paper chromatograms. The fluorescence spectra of the various fluorogens produced after separation were readily obtained directly from the chromatogram or pherogram. 2-Thiobarbituric acid and 4'-aminoacetophenone offered the greatest potential for future application to characterization and assay of 2-deoxy sugars. The aniline-diphenylamine procedure was the most useful for analysis of purine nucleosides and nucleotides and DNA. These various reagents show potential for application to air pollution studies in terms of location, characterization and assay of 2-deoxy sugars and their derivatives.

The effect of temperature on the fatty acid and phospholipid composition of Cephalosporium falciforme and Cephalosporium kiliense.

The effect of temperature on the lipid composition of Cephalosporium falciforme and Cephalosporium kiliense, causative agents of maduromycosis, was investigated. The fungi were grown at 28.5 C and 37 C in a chemically defined medium. The lipids were solvent extracted, purified on Sephadex, and separated into their component classes by silicic acid column chromatography. Five lipid classes were found: (a) sterol esters, (b) triacylglycerides, (c) free fatty acids, (d) sterols, and (e) phospholipids. Fatty acids were analyzed by gas liquid chromatography. Temperature induced changes of varying degrees occurred in both the fatty acid and phospholipid fractions of each organism.

Clinical application of percutaneous cardiopulmonary bypass for high risk coronary angioplasty.

Percutaneous cardiopulmonary bypass support was electively instituted prior to coronary angioplasty in 16 patients at high risk for hemodynamic collapse. In all cases the dilated artery supplied greater than 2/3 of the functioning myocardium. Eight patients had moderate LV dysfunction with ejection fraction 25-40%. Eight patients had an ejection fraction less than 20%. A 21 French cannula and a 17 French cannula were percutaneously inserted into the femoral vein and artery. Cardiopulmonary bypass support was instituted using a Bio-Medicus centrifugal pump just prior to coronary angioplasty at flow rates of 3.5-5 liters/minute. Thirteen patients had single vessel angioplasty and three patients had multivessel angioplasty. Complete loss of systolic function was observed in 9 (56%) patients. This finding when present confirms the absolute requirement for cardiopulmonary support. Technical success was achieved in all 16 patients (100%), clinical success was achieved in 14 patients (88%). Patient followup (mean 10 months) revealed 3 patients with class I-II angina and 10 patients were asymptomatic. There was one late death. In conclusion, percutaneous cardiopulmonary bypass support for carefully selected high risk patients may allow coronary angioplasty to be performed safely and effectively despite complete loss of systolic function during balloon inflation.

Analysis of atomospheric carcinogens and their cofactors.

Problems in the sampling and analysis of a variety of key air pollutants have been considered. The pollutants of primary interest were those with carcinogenic, mutagenic or cofactor activity. These include benzo[a]pyrene, polynuclear aromatic hydrocarbons, aldehydes, alkylating agents, amines, chloromethyl ethers, epoxides nitrosamines, nitrogen dioxide, nitrates, sulfate and sulfite. Screening tests of the analytical and bioassay types were also discussed; a large variety of these tests were summarized in tables. Concentrations of benzo[a]pyrene in urban atmospheres, in highly polluted atmospheres and effluents, and in a large variety of environment mixtures were reported.

Chemical composition and potential 'genotoxic' aspects of polluted atmospheres.

The chemical composition of the gaseous, vapour and particulate phases of the atmosphere has been reported in terms of background, urban and highly polluted levels. Too little is known about the chemical composition of polluted atmospheres and other environments, and the situation will worsen as a result of the steadily increasing production of a wide variety of chemicals. This and other evidence presented in this paper indicates that the human race has not yet felt the full impact of the burgeoning chemical environment in terms of genotoxic effects. Some highly suggestive data from the literature have been presented to indicate that carcinogenesis and mutagenesis in human beings involve not only the attack of a primary genotoxicant, but that genetic factors, cofactors, antifactors and sometimes precursors can play important roles in the process of genotoxicity. Evidence has been presented to indicate that genotoxic effects are much more prevalent among human beings than is commonly believed. Since inherited effects arise from mutation of a germ cell, cancer probably from mutation of a somatic cell, atherosclerosis possibly from some mutagenic effect and the debilitating effects of some aspects of ageing possibly from a somatic mutation of the metabolic type, then mutagenesis in these four postulated types could be the overwhelmingly major cause of death in modern society.

Ultrasonic extraction of total particulate aromatic hydrocarbons (TpAH) from airborne particles at room temperature.

A superior enrichment procedure for the extraction of TpAH from airborne particles collected on glass fiber filter paper is described. The sample is suspended in a solvent and subjected to ultrasonic waves at room temperature with glass powder to adsorb polar coextractives. The TpAH in the filtered extracts are separated from other compounds by high speed liquid chromatography. Sensitivity is in the nanogram range, and the procedure is highly reproducible. Significantly larger amounts of TpAH are recovered than with Soxhlet extraction for 6 to 8 hours, and the percentage of pAH in the extracts is much higher. The entire procedure requires approximately 40 minutes, most of which is waiting time.

Synergistic effects in sonochemical sterilization.

The synergistic effects observed during the sterilization of Bacillus subtilis var. niger ATCC 9372 by the combined action of ethylene or propylene oxide with high-intensity airborne sound waves (34.8 kc/sec) were investigated. It has been shown that the number of surviving spores deposited on paper strips decreases exponentially with the sound intensity at sample level. Reductions of the order of one-third of the time required for standard propylene oxide sterilization have been observed by using the combined action of sound waves with gaseous sterilization. At the present time, maximal synergistic effects seem to be achieved for the following experimental conditions: propylene oxide concentration, 500 to 1,000 mg/liter; acoustic intensity, 161 to 162 db; contact time, 80 min; temperature, 60 C; and relative humidity, 40%. The basic mechanism involved in sonochemical sterilization seems to be more of a physical (accelerated gas diffusion) than a chemical nature.