Birgitte Møllgaard

Vehicle effect on topical drug delivery. III. Effect of Azone on the cutaneous permeation of metronidazole and propylene glycol

Abstract The ability of Azone (1-dodecylazacycloheptan-2-one), a novel penetration enhancer, to increase the percutaneous delivery of metronidazole has been investigated, across full thickness human skin in vitro. A finite dose technique was used employing several vehicles. Azone at a concentration of 1% was found to be as effective as 5% and 10% concentrations in achieving enhanced transport of metronidazole. The presence of propylene glycol was found to be necessary for maximal enhancement, and the penetration of this compound was also found to be markedly enhanced by Azone. The delivery of metronidazole within the first 20 h of the experiments was increased about 25 times in the presence of 1% Azone. Repeated doses of the drug after a single dose of Azone indicated that the effect of Azone on the skin remains after several days.

Permeation of estradiol through the skin — effect of vehicles

Abstract The cutaneous permeation characteristics of estradiol were examined to evaluate the effect of 21 different organic solvents, some of which are commonly used in topical formulations. The steady-state permeation rate (Fss) through excised human abdominal skin mounted in open diffusion cells was compared to a reference consisting of estradiol applied in volatile solvent. Fss varied in the range of 0.001–0.215 μg cm-2 h-1 where dimethyl sulphoxide and glycols most effectively increased the permeation. Estradiol solubility was determined in all the vehicles and the magnitude of the vehicle effect on the skin was quantified in terms of relative apparent diffusion coefficient. Mainly the facilitating effect could be ascribed to a change in the nature of the skin barrier. It appeared that the estradiol flux from propylene glycol vehicles was unaffected by occlusion and smaller changes in the applied propylene glycol amount.

Pro-drugs as drug delivery systems XXIII. Improved dermal delivery of 5-fluorouracil through human skin via N-acyloxymethyl pro-drug derivatives

Abstract The percutaneous permeation characteristics of two N-1-acyloxymethyl derivatives of 5-fluorouracil were determined and compared with that of 5-fluorouracil using excised human skin mounted in open diffusion cells. The derivatives, particularly 1-butyryloxymethyl-5-fluorouracil, permeated more readily through the human skin than 5-fluorouracil and at the same time were delivered in the form of parent drug due to cutaneous metabolism as mediated by hydrolytic enzymes. The better permeabilities of the derivatives were ascribed to their higher lipophilicities as expressed in terms of the octanol-water partition coefficients. It appeared that N-acyloxymethyl derivatives of 5-fluorouracil may be promising pro-drug candidates with enhanced topical bioavailability compared to the parent drug. Leaching of hydrolytic enzymes from the skin preparations into the receptor phase was found to take place during the permeation study and its significance is discussed in relation to the question of extent of cutaneous and bulk phase metabolism.

Dermal drug delivery — Improvement by choice of vehicle or drug derivative☆

Abstract Propylene glycol was found to easily permeate human skin in vitro, and its accelerating effect on metronidazole permeation could be ascribed to a possible “carrier-solvent” effect. Incorporation of Azone® in propylene glycol vehicles enhanced the permeation rate by decreasing the lag time of permeation of the drug as well as propylene glycol from the vehicle. This effect of azone lasted for the subsequent application of the drug where ozone was omitted from the vehicle, indicating that the accelerant might modify the cutaneous barrier in vitro. Pro-drug derivatives of metronidazole and of 5-fluorouracil have been developed which permit increased cutaneous drug permeation and simultaneously undergo conversion to the parent drug by the cutaneous hydrolytic enzymes. Enzyme-mediated hydrolysis by a human skin homogenate of aliphatic esters of metronidazole is presented.

Rotating dialysis cell as in vitro release method for oily parenteral depot solutions.

The purpose of the study was to investigate an in vitro release method based on a rotating dialysis cell for parenteral oil depot formulations using different model conditions and test formulations. The total amount of drug released from the rotating dialysis cell was in accordance with the theoretical values calculated from the partition coefficients. The release rates were shown to depend on the total amount of drug available for the release process and to follow first order kinetics. The rotating dialysis cell has a potential as in vitro release method for characterization of oily depot formulations for parenteral administration.

Leaching of hydrolytic enzymes from human skin in cutaneous permeation studies as determined with metronidazole and 5-fluorouracil pro-drugs

Abstract The leaching of hydrolytic enzymes out of the dermal side of excised human skin into the receptor phase of a permeation cell was studied using the esters metronidazole benzoate and l-butyryloxymethyl-5-fluorouracil as test compounds. The enzyme activity in the receptor phase increased rapidly and was essentially complete after an exposure time of 20 h. The half-life for the hydrolysis of metronidazole benzoate in the phosphate buffer, pH 7.4, receptor phase exposed to the skin for 20 h was 3.1 h, whereas that in non-exposed receptor phase was 1000 h. It is emphasized that receptor phase metabolism due to leached enzymes may be of significance when assessing concurrent transport and metabolism of drugs or prodrugs in permeation studies using human skin. Metronidazole benzoate permeated more readily through the skin than metronidazole which was ascribed to its higher skin-vehicle partition coefficient. Only hydrolyzed metronidazole was detected in the receptor phase.

In vitro evaluation of dermal prodrug delivery — transport and bioconversion of a series of aliphatic esters of metronidazole

Abstract The ability of a series of aliphatic ester prodrugs to improve cutaneous delivery of metronidazole has been investigated. In permeation studies using full thickness human skin in vitro the derivatives lead only to a 1.5-fold enhancement of permeation compared to the parent drug. The influence of non-specific cutaneous hydrolytic enzymes on the rate of hydrolysis of the ester derivatives was determined in homogenates prepared from human skin. It was observed that the susceptibility of the esters to undergo enzyme-catalyzed cleavage was strongly affected by the length of the acyi side chain making the valerate and caproate esters the best substrates. The experimental data demonstrate that no single ester derivative can be selected with optimal properties regarding both skin permeation and enzymatic regeneration to metronidazole. Due to the relatively small variation in permeation rate of the compounds, however, the butyrate ester seems to fulfill the requirements of good permeation characteristics as well as a quick conversion to metronidazole (t 1 2 in skin homogenate is 1.0 h at 37°C).

Vehicle effect on topical drug delivery. IV. Effect of N-methylpyrrolidone and polar lipids on percutaneous drug transport

The ability of N-methylpyrrolidone and polar lipids to increase the percutaneous delivery of metronidazole was investigated across full thickness human non-occluded skin in vitro. A finite dose technique was used employing several vehicles. Fatty acids and alcohol were effective in presence of propylene glycol, whereas N-methylpyrrolidone increased metronidazole penetration in presence of isopropyl myristate. Moreover, N-methylpyrrolidone was found to permeate the skin readily when applied in the neat state or in a mixture with isopropyl myristate. The combined results indicate that the variation in barrier permeability to metronidazole is associated with the rate of N-methylpyrrolidone permeating the skin.

Permeation of linoleic acid through skin in vitro

The syndrome of essential fatty-acid (EFA) deficiency is being recognized in persons suffering from fat malabsorption and in patients maintained on fat-free parenteral nutrition. Thus, Press et a1 (1974) reported that repeated cutaneous application of EFA rich oil reverses the plasma biochemical manifestation of EFA deficiency in man. However, Hunt et al(l978) failed to reverse deficiency in neonates by topical application of even higher doses of EFA-rich oil. Although EFA deficiency can be reversed or prevented using intravenous fat emulsions, the efficiency of topical essential fatty-acids is a relevant question because of the risks and inconveniences of infusion therapy. A scaly condition of the skin and abnormally high rate of transepidermal water loss are characteristic symptoms of EFA-deficiency. Recently, Elias et al (1980) and Houtsmuller & Beek (1981) found that topical application of free linoleic acid is capable of improving the barrier function locally on EFA-deficient animals without prior correction of the systemic deficiency state. The mode of action was suggested to be by a specific effect of linoleic acid rather than a secondary response to normalized prostaglandin levels. Based on the stated effect of topical linoleic acid on EFA deficiency abnormalities, the present experiments were undertaken to determine the permeability of rat skin and human skin to free linoleic acid.

Intramuscular rate of disappearance of oily vehicles in rabbits investigated by gamma-scintigraphy

The fate of oily vehicles administered intramuscularly was followed with whole body gamma-scintigraphy. Groups of six rabbits received injections administered into the upper hind leg. No differences were observed in disappearance rates of various volumes (50–400 μl) of either fractionated coconut oil or sesame oil. Addition of two different concentrations of a drug substance, zuclopenthixol decanoate, to fractionated coconut oil did not influence the disappearance rate of the vehicle. Half-lives of the two oils at the injection site were in the order of 1 week for fractionated coconut oil and 1 month for sesame oil. Both oils spread approximately 25% along the muscle fibres during the first 24 h after administration. Radioactivity was mainly excreted with the urine. Insignificant amounts of radioactivity were found in blood, liver and carcass after 10 days.