Fundamental understanding of drug absorption from a parenteral oil depot.

Oil depots are parenteral drug formulations meant for sustained release of lipophilic compounds. Until now, a comprehensive understanding of the mechanism of drug absorption from oil depots is lacking. The aim of this paper was to fill this gap. A clinical study with healthy volunteers was conducted. An oil depot with nandrolone decanoate and benzyl alcohol was subcutaneously administered in the upper arm of female volunteers. Pharmacokinetic profiles of both substances were related to each other and to literature data. Benzyl alcohol absorbs much more rapidly than nandrolone. In detail, it appears that benzyl alcohol enters the central compartment directly, while nandrolone decanoate is recovered in serum after a lag time. This lag time is also seen in literature data, although not reported explicitly. The absorption of nandrolone is enhanced by the presence of benzyl alcohol. This is most likely an effect of altered oil viscosity and partition coefficient between the oil and aqueous phase. The absorption rate constant of compounds is found to be related to the logP of the solubilized prodrug. The absorption rate is however not only determined by the physico-chemical properties of the formulation but also by the tissue properties. Here, it is argued that lymphatic flow must be considered as a relevant parameter.

Acetónido de triamcinolona sin conservantes / Triamcinolone acetonide without solvents

Objetivo: La purificación del preparado comercial de triamcinolona acetónido disponible es importante para evitar el efecto potencialmente tóxico del disolvente alcohol bencílico. Presentamos una nueva técnica de preparación de triamcinolona en polvo, a partir de su forma pura, sin disolventes y diluida con agua destilada estéril. Dada su escasa solubilidad en aguase describe cómo preparar y controlar dicha suspensión. Material y método: El acetónido de triamcinolona es preparado por el Servicio de Farmacia del Hospital, en condiciones de máxima esterilidad, bajo campana de flujo laminar. La suspensión de triamcinolona es envasada en un vial primario, capsulado y posteriormente esterilizado en autoclave a 121 ◦C. Del vial primario se obtienen dosis individualizadas de 4 mg/0,1 ml. Resultados: Se obtiene la dosis real administrada (3,77 mg/0,1 ml) mediante cuantificación de triamcinolona por cromatografía líquida de alta resolución (HPLC). La estabilidad física, química y microbiológica conservando el vial entre 2-8◦ se mantiene a los 6 meses. Conclusión: Se presenta un método de preparación de triamcinolona en estado puro, obteniendo una concentración muy próxima a la dosis óptima, evitando el uso de disolventes y con máxima garantía de esterilidad(AU)

Objective: The purification of commercially prepared triamcinolone acetonide is important in order to avoid the potential toxic side-effects of the solvent benzyl alcohol. We present a new technique for preparation of pure triamcinolone acetonide by dissolving the powder in sterile distilled water with no additional solvents. As the triamcinolone powder is relatively insoluble in water, we describe the sterile method used for the preparation and control of this suspension. Materials and methods: The triamcinolone acetonide is prepared in our hospital pharmacy, under optimum sterile conditions, and then packaged in a primary vial, sealed and sterilized in an autoclave at 121 ºC. This vial contains an individual dose of 4 mg/0.1 ml. Results: A final dose for an intravitreal administration of 3.77 mg/0.1 ml triamcinolone acetonide was obtained using high pressure liquid chromatography (HPLC). The chemical,physical and microbiological stability allows the solution to be kept at a temperature of 2-8 ◦C for 6 months. Conclusions: A rapid method is presented for preparing triamcinolone acetonide in pure state without preservatives in a concentration near the standard dose and under optimum sterile conditions(AU)

Fragrance material review on benzyl alcohol.

A toxicologic and dermatologic review of benzyl alcohol when used as a fragrance ingredient is presented. Benzyl alcohol is a member of the fragrance structural group Aryl Alkyl Alcohols and is a primary alcohol. The AAAs are a structurally diverse class of fragrance ingredients that includes primary, secondary, and tertiary alkyl alcohols covalently bonded to an aryl (Ar) group, which may be either a substituted or unsubstituted benzene ring. The common structural element for the AAA fragrance ingredients is an alcohol group -C-(R1)(R2)OH and generically the AAA fragrances can be represented as an Ar-C-(R1)(R2)OH or Ar-Alkyl-C-(R1)(R2)OH group. This review contains a detailed summary of all available toxicology and dermatology papers related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for benzyl alcohol were evaluated then summarized and includes physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, skin sensitization, elicitation, phototoxicity, photoallergy, toxicokinetics, repeated dose, reproductive toxicity, genotoxicity, and carcinogenicity data. A safety assessment of the entire Aryl Alkyl Alcohols will be published simultaneously with this document; please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all Aryl Alkyl Alcohols in fragrances.

Inhibitors of the tyrosine kinase EphB4. Part 4: Discovery and optimization of a benzylic alcohol series.

Optimization of our bis-anilino-pyrimidine series of EphB4 kinase inhibitors led to the discovery of compound 12 which incorporates a key m-hydroxymethylene group on the C4 aniline. 12 displays a good kinase selectivity profile, good physical properties and pharmacokinetic parameters, suggesting it is a suitable candidate to investigate the therapeutic potential of EphB4 kinase inhibitors.

Dose and airflow dependence of benzyl alcohol disposition on skin.

The penetration of benzyl alcohol (BA) through split-thickness cadaver skin was measured in nonoccluded Franz cells placed in a fume hood. BA, dissolved in a small volume of ethanol and spiked with (14)C radiolabel, was applied to skin at nine doses ranging from 0.9 to 10600 microg/cm(2). The percentage of radioactivity penetrated after 24 h increased gradually with dose, ranging from 19.8 +/- 2.9% at the lowest dose to 29.2 +/- 3.0% at the highest. Less than 4% of the radioactivity was retained in the tissue at 24 h; the remainder was considered to be evaporated. These data and those from a previous study were analyzed in terms of a finite dose diffusion/evaporation model. The analysis showed that the increase in BA absorption with dose was consistent with a threefold increase in BA diffusivity in the stratum corneum, as its concentration increased from tracer levels to saturation. The variable diffusivity model was able to describe the combined observations from the two studies to within an rms error of 4.2% of dose. A method of estimating the diffusion model parameters independently of the experiment was found to yield good agreement with the experimentally-derived values at low and moderate doses.

The FEMA GRAS assessment of benzyl derivatives used as flavor ingredients.

This publication is the eighth in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA). In 1993, the panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavoring substances under conditions of intended use. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, pharmacokinetics and toxicology. Flavor ingredients are evaluated individually and in the context of the available scientific information on the group of structurally related substances. Scientific data relevant to the safety evaluation of the use of benzyl derivatives as flavoring ingredients is evaluated. The group of benzyl derivatives was reaffirmed as GRAS (GRASr) based, in part, on their self-limiting properties as flavoring substances in food; their rapid absorption, metabolic detoxication, and excretion in humans and other animals, their low level of flavor use, the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels determined from subchronic and chronic studies and the lack of significant genotoxic and mutagenic potential. This evidence of safety is supported by the fact that the intake of benzyl derivatives as natural components of traditional foods is greater than their intake as intentionally added flavoring substances.

Absorption and evaporation of N,N-diethyl-m-toluamide from human skin in vitro.

The penetration of DEET through split-thickness cadaver skin was measured in non-occluded Franz cells placed either in a fume hood or on a laboratory workbench. DEET, dissolved in a small volume of ethanol and spiked with (14)C radiolabel was applied to skin at doses from 0.02 to 11000 microg/cm(2). DEET penetration was greater for cells placed on the workbench, and the percentage of radioactivity penetrated after 72 h increased gradually with dose, for doses up to 680 microg/cm(2). At higher doses, it declined. Percent penetration ranged from 11.5 +/- 3.2% for a dose of 0.021 microg/cm(2) in the fume hood to 71.9 +/- 5.5% for a dose of 260 microg/cm(2) on the workbench. Results were interpreted in terms of a diffusion/evaporation model having three parameters-a solubility value for the chemical in the upper stratum corneum, M(sat); a mass transfer coefficient for evaporation, k(evap); and a characteristic time for diffusion, h(2)/D. The parameters obtained from fitting the model to the data (normalized to the fume hood environment) were M(sat) = 18 microg/cm(2) and k(evap) = 2.6 x 10(-5) cm/h. The value of h(2)/D decreased from 16 h at a DEET dose of 25 microg/cm(2) to 10 h at 1480 microg/cm(2), consistent with an increase in skin permeability of about 1.5-fold over this dose range. This effect was confirmed by means of an additional study in which skin samples pretreated with increasing amounts of unlabeled DEET were washed and redosed with (14)C-benzyl alcohol. A small (1.7-fold), but significant, increase in benzyl alcohol penetration with increasing amount of DEET was obtained. Thus, DEET enhanced its own skin permeation rate as well as that of another compound, but the effect was modest and not likely to be a major concern for compounds coadministered with DEET.

Disposition of benzyl alcohol after topical application to human skin in vitro.

Dissipation of a volatile compound or mixture from the skin surface after topical application involves both diffusion and evaporation. This report presents a detailed test of a previously described first-order kinetic approach to modeling this problem. Modified Franz diffusion cells fitted with a vapor trap were used to obtain absorption and evaporation data for benzyl alcohol (1% solution in ethanol) after application to human skin in vitro. Airflow over the skin surface (upsilon) was controlled in the experiment and accounted for in the model by allowing the evaporation rate constant(s) to vary as a function of upsilon. A linear dependence was found over the working range of the system, 10-100 mL/min. Three kinetic models were developed, all of which satisfactorily correlated cumulative absorption and evaporation results over the full range of upsilon (n = 120, s = 4-5%, r2 = 0.98-0.99). One of these was the model presented previously, in which all dissipation occurs from a single skin compartment. However, more details of the evaporation and absorption profiles could be accounted for by means of two-compartment models that explicitly consider the surface film present in the early stages post-application. The latter models seem to be better candidates for describing the time evolution of the volatile mixture evolving from the skin surface after topical application of, e.g., a complex fragrance or perfume.

Single-photon emission tomography imaging of serotonin transporters in the nonhuman primate brain with [(123)I]ODAM.

We have described previously a selective serotonin transporter (SERT) radioligand, [(123)I]IDAM. We now report a similarly potent, but more stable IDAM derivative, 5-iodo-2-[2-[(dimethylamino)methyl]phenoxy]benzyl alcohol ([(123)I]ODAM). The imaging characteristics of this radioligand were studied and compared against [(123)I]IDAM. Dynamic sequences of single-photon emission tomography (SPET) scans were obtained on three female baboons after injection of 375 MBq of [(123)I]ODAM. Displacing doses (1 mg/kg) of the selective SERT ligand (+)McN5652 were administered 120 min after injection of [(123)I]ODAM. Total integrated brain uptake of [(123)I]ODAM was about 30% higher than [(123)I]IDAM. After 60-120 min, the regional distribution of tracer within the brain reflected the characteristic distribution of SERT. Peak specific binding in the midbrain occurred 120 min after injection, with an equilibrium midbrain to cerebellar ratio of 1. 50+/-0.08, which was slightly lower than the value for [(123)I]IDAM (1.80+/- 0.13). Both the binding kinetics and the metabolism of [(123)I]ODAM were slower than those of [(123)I]IDAM. Following injection of a competing SERT ligand, (+)McN5652, the tracer exhibited washout from areas with high concentrations of SERT, with a dissociation kinetic rate constant k(off)=0.0085+/-0.0028 min(-1) in the midbrain. Similar studies using nisoxetine and methylphenidate showed no displacement, consistent with its low binding affinity to norepinephrine and dopamine transporters, respectively. These results suggest that [(123)I]ODAM is suitable for selective SPET imaging of SERT in the primate brain, with higher uptake and slower kinetics and metabolism than [(123)I]IDAM, but also a slightly lower selectivity for SERT.