Effect of lecithin coating on the pulmonary absorption of furosemide in rats.

The effect of lecithin coating on the pulmonary absorption of furosemide after application by metered dose inhalers (MDI) containing HFA 227 was evaluated in rats. The plasma concentration of furosemide after application of lecithin-coated furosemide was higher than that after application of the un-coated form. Since the disposition in the lung 2 min after application of un-coated furosemide was significantly lower than that after application of the coated form and the adsorption to a polyethylene tube used for the application of the un-coated form was significantly higher than that of the coated form, the higher plasma concentration after application of lecithin-coated furosemide could be partly related to the efficient delivery of the furosemide particles to the lung. The permeation-enhancing effect of the lecithin coating was investigated using Calu-3 cell monolayers. The cumulative amount of furosemide permeated over 2 h from a suspension containing lecithin-coated furosemide through the monolayers was significantly higher than that from a conventional furosemide suspension. This enhancing effect could also contribute to the high plasma concentration of furosemide in rats. The lecithin-coated furosemide will be useful for the formulation of MDI offering high bioavailability.

Excised porcine skin experimental systems to validate quantitative microdialysis methods for determination of drugs in skin after topical application.

Microdialysis is useful as a method to evaluate the disposition of drugs in the skin to design improved transdermal delivery systems (TDDSs). In this study, quantitative microdialysis methods were validated in excised porcine skin experimental systems in vitro. Flurbiprofen (FP), used as a model drug, showed high affinity for the skin tissues in equilibrium states between the medium and skin. The membrane clearances of FP for permeation through the membrane of a dialysis fiber placed in the skin (CL(m in S)) were lower than that in the medium. The adsorption of components in the skin to the membrane surface of the dialysis fiber and accumulation of FP near the dialysis fiber are the most likely reasons for this. When CL(m in S) was used to predict the extracellular FP concentration in skin (C(T)), the value obtained was lower than that expected from the FP concentration in the medium on the dermis side, which should be equal to C(T) at equilibrium. In the zero net flux (ZNF) method, in which the concentration difference of perfusate (DeltaC) between the inflow and outflow were used to obtain C(T), the predicted C(T) was similar to the expected value. In an in vitro skin permeation experiment, the ZNF method was used for the prediction of C(T) near the dialysis fiber. The predicted C(T) was over 10 times higher than the FP concentration in the medium on the dermis side, suggesting a concentration gradient in the dermis. Although the ZNF method is good for predicting the C(T) in skin, the mass balance has to be considered for the quantitative evaluation of the skin permeation of drugs. In this study, the effect of the mass transfer of FP from the perfusate to the skin on the cumulative amount of FP passing through the skin was relatively low because of the use of suitable solutions as perfusate. The perfusion conditions and schedules should be designed carefully for quantitative evaluations using the ZNF method. These results provide useful information for the in vivo application of quantitative microdialysis to evaluate TDDS.

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.

Effect of camellia oil on the permeation of flurbiprofen and diclofenac sodium through rat and pig skin.

The effect of camellia oil on the permeation of flurbiprofen (FP) and diclofenac sodium (DFS), used as model drugs, through rat and pig skin was examined. Two different types of camellia oil were used: one of them was purified by distillation and the other was purified by filtration without heating. The distilled camellia oil (DCO) and the filtered camellia oil (FCO) were applied to the skin as a pretreatment. Permeation of FP through the skins pretreated with FCO and DCO was enhanced, while that of DFS was suppressed. The effects of FCO were greater than those of DCO as far as enhancement and suppression were concerned. The effect of FCO on FP permeation could be due to oleic acid, one of the major components of FCO. On the other hand, FCO and oleic acid had opposite effects on the penetration of DFS. This result suggests that other active components which suppress the permeation of DFS may be present in FCO. Since the penetration-suppressing agents will be useful for skin care products, studies of such agents will be important in the future.

A rabbit ear flap perfusion experiment to evaluate the percutaneous absorption of drugs.

A rabbit ear flap single-pass perfusion system was examined as an experimental method for studying the relationship between the physiological conditions of tissues and drug disposition after topical applications. Tyrode solutions containing bovine serum albumin (BSA) and sucrose or flurbiprofen (FP), used as a model drug, were perfused through the vessel in the ear flap to evaluate the physiological conditions prior to the application of FP to the skin surface. The extracellular volume and distribution properties of FP in the perfused ear were similar to those in an in vivo experimental system. In addition, the perfused ear flap exhibited a pharmacological response to bradykinin (BK). The amount of FP in the outflow Tyrode solution containing BSA after application to the skin surface of the perfused ear decreased with the addition of BK, while that in the tissues under the application site increased. FP binds to BSA, which leaked from the intravascular space, and could be retained in the tissues under the application site. The protein binding also affected the redistribution of FP to other tissues in the ear flap after application to the skin. The rabbit ear perfusion system is a useful method for studying the percutaneous absorption of drugs especially variations in the disposition of drugs in oedematous tissues.