Toshinobu Seki

Determination of diffusion coefficients of peptides and prediction of permeability through a porous membrane

The diffusion coefficient (D) of peptide and protein drugs needs to be determined to examine the permeability through biological barriers and to optimize delivery systems. In this study, the D values of fluorescein isothiocyanate (FITC)‐labelled dextrans (FDs) and peptides were determined and the permeability through a porous membrane was discussed. The observed D values of FDs and peptides, except in the case of insulin, were similar to those calculated based on a relationship previously reported between the molecular weight and D of lower‐molecular‐weight compounds, although the molecular weight range was completely different. The observed D value of insulin was between the calculated values for the insulin monomer and hexamer. The permeability of poly‐lysine and insulin through the membrane was determined and the observed values were compared with predicted values by using the relationship between molecular weight and D and an equation based on the Renkin function. The observed permeability of insulin through the membrane was between that of the predicted permeability for the insulin monomer and hexamer. For the permeation of insulin, the determination of D was useful for estimating the permeability because of the irregular relationship between molecular weight and D. The methodology used in this study will be useful for a more quantitative evaluation of the absorption of peptide and protein drugs applied to mucous membranes.

Formulation design and pharmaceutical evaluation of an HFA 227-based furosemide metered dose inhaler

A new hydrofluoroalkane (HFA 227) propellant was evaluated for the replacement of traditional chlorofluorocarbons (CFCs) in metered dose inhaler (MDI) formulations containing furosemide as a model drug for the treatment of asthma. The effect of ethanol as a cosolvent on the solubility of solvents and surfactants in HFA 227 was examined first. All solvents and surfactants used were miscible at 1% with HFA 227 containing 1% ethanol. The effects of ethanol and surfactants on the properties of the furosemide suspension in HFA 227 were examined. In the ethanol-HFA 227 system, the sedimentation time of primary drug particles in HFA 227 was increased by the addition of 10% ethanol, while the particle size of furosemide was larger than the size limit (5 μm) at ethanol concentrations over 10%. The content of ethanol in an HFA 227-based MDI should be lower than 10%. In the ethanol-surfactant-HFA 227 system containing 5% ethanol, the longest sedimentation time was 53 s/cm for 0.1% oleic acid, but the sedimentation time was 25 s/cm for 1.0% oleic acid. HFA 227-based furosemide MDIs were prepared using metered valves and aluminium canisters. The dose variation of HFA 227-based MDI with oleic acid using ethanol as a cosolvent remained within 10% over the expected actuation counts without any tail-off phenomenon. The in vitro deposition analysis using a glass twin impinger apparatus suggested that the HFA 227-based furosemide MDI with oleic acid and ethanol was equivalent to the corresponding CFC-based MDI, in regard to the delivery of furosemide to the lungs.

An HFA 227-based metered dose inhaler containing furosemide coated with lecithin

Furosemide was coated with lecithin and the resulting material was used for the formulation of an MDI consisting of HFA 227 without cosolvents. The lecithin coating did not affect the SEM observation. The furosemide content of the lecithin-coated furosemide was in agreement with that calculated from the amounts of furosemide and lecithin used. In the case of MDI containing uncoated furosemide, the amount released depended both on the sequential actuations and daily use. On the other hand, the amounts released from the MDI containing the lecithin-coated furosemide were stable under all circumstances. Continuous leakage was observed for the MDI containing uncoated furosemide when five actuations were carried out before storage. In the case of the MDI containing lecithin-coated furosemide, no leakage of propellant after actuation was observed. These results suggest that the lecithin coating is useful for stable release and avoidance of leakage of propellant after actuation. HFAs-based MDIs without cosolvents could be developed using this technology.

Enhancing effects of medium chain aliphatic alcohols and esters on the permeation of 6-carboxyfluorescein and indomethacin through rat skin.

Medium chain aliphatic alcohols (C8-C12) and methyl or propyl esters of medium chain fatty acids (C8-C12) enhanced the permeation of 6-carboxyfluorescein (6-CF) and indomethacin (IND) through excised rat skin. The enhancing effects of the aliphatic alcohols for 6-CF and IND decreased with the increase in carbon chain length. The dependence on the carbon chain length was different from that exhibited by medium-chain fatty acids previously reported. In the case of fatty acid esters, the enhancing effects were lower than those of aliphatic alcohols and fatty acids. The relationship between the enhancing effects and the total number of carbon atoms in the esters was different for 6-CF and IND. The dependence on the total number of carbon atoms was similar to that in the aliphatic alcohols for 6-CF, and greater effects were observed in the shorter esters. On the other hand, no definite trends were observed for IND. Although the relationships between the structure and skin permeation-enhancing effect of the aliphatic alcohols and fatty acid esters used in this study are not yet fully understood, they are possible candidates as permeation enhancers for hydrophilic and lipophilic drugs. Further experiments, including examination of the location and environment of the lipophilic carbon chain and hydrophilic groups of such enhancers in the stratum corneum, are needed to optimize transdermal delivery systems containing them.