Transdermal delivery of alprazolam from a monolithic patch: formulation based on in vitro characterization.

Alprazolam, a benzodiazepine widely used for the treatment of psychiatric disorders, has been aimed to be formulated in a transdermal delivery system (TDS) prototype. A series of TDS prototypes dosed in all cases at 0.35 mg·cm(-2) of alprazolam were prepared as a monolithic drug in adhesive matrix using acrylic pressure-sensitive adhesives (PSA) of acrylate vinyl acetate (Duro-tack(®)). The effects of several permeation enhancers as azone, transcutol, propylene glycol, dodecyl alcohol, decyl alcohol, diethanolamine, N-methyl pyrrolidone and lauric acid were studied. Prototypes have been characterized based on adhesion parameters (peel adhesion and shear adhesion), in vitro human skin permeation and in vitro drug release according to European Pharmacopoeia for the selected prototype. Best results show that a combination of permeation enhancers from different chemical groups is able to provide almost a 33 fold increase in the transdermal alprazolam flux of an aqueous saturated dispersion (from 0.054 ± 0.019 to 1.76 ± 0.21 µg h.cm(-2)). Based on these in vitro flux data, a predictive simulation of the achievable plasmatic levels was performed assuming a constant systemic infusion of drug. In summary, it is possible to obtain a prototype of a TDS of alprazolam with adequate adhesive properties (peel adhesion and shear adhesion) and able to predict sustained therapeutic plasmatic levels.

Influence of the formulation on the in vitro transdermal penetration of sodium diclofenac. Evaluation of the topical and systemic anti-inflammatory activity in the rat.

A study on the transdermal permeation through human skin was performed with a series of 6 semisolid formulations (A-F) containing 1% sodium diclofenac (CAS 15307-79-6) (w/w). A commercially available drug preparation was tested as a reference. Based on permeation characteristics, a study on the topical and systemic anti-inflammatory activities of three formulations (A, F and the reference formulation) was conducted using the model of erythema induced by UV radiation in hairless rats. This is expected, together with the index of topical anti-inflammatory activity to allow the selection of the most suitable formulation for dermal application. The following representative parameters were measured in the permeation study: amount of diclofenac permeated at 24 h, flow, lag time and amount of drug retained in skin at 24 h. Of the formulations tested, diclofenac formulated in the reference formulation showed the highest values of amount of diclofenac permeated at 24 h, amount of drug retained in skin at 24 and flow. As regards the skin inflammation test, no significant differences (p < 0.05) are seen between the topical and systemic anti-inflammatory activities of the three formulations tested. However, in absolute value, formulation F shows a lower systemic activity, which would prevent potential side effects of diclofenac. Since the topical anti-inflammatory index obtained for this formulation was > 1, it is concluded that a good therapeutic performance could be obtained in the treatment of local inflammation with diclofenac by using formulation F.

Influence of formulation on the in vitro transdermal penetration of flutrimazole.

Flutrimazole (1-[(2-fluorophenyl)(4-fluorophenyl)phenylmethyl]-1 H-imidazole, CAS 119006-77-8, UR-4056) is a new wide spectrum local imidazolic antifungal agent that has already been formulated as a dermal cream (FDC). A comparative study was carried out of the release of flutrimazole from two emulsions in which the drug has been incorporated differently: one dissolved in the oily phase (E24) and the other dispersed in the aqueous formulation phase (E25). Based on the E25 formulation, two more dermal creams were prepared, E27 with benzyl alcohol and E28 with diazolidinyl urea as preservative agents. A comparative study of transdermal penetration including E27, E28, FDC (reference 1% flutrimazole dermal cream) and 1% flutrimazole hydroalcoholic solution was also performed. An amount of the sample dosage form containing 10 mg of flutrimazole was applied to a Franz type cell. The penetration membrane used was cellulose acetate in the release studies and human skin provided by a plastic surgery clinic in the transdermal penetration study. The amount released after 7 h was 36.3 +/- 4.9 micrograms when flutrimazole was dissolved (E24) and 35.9 +/- 5.3 micrograms when flutrimazole was dispersed (E25). Although the differences were not significant, the cream with dispersed flutrimazole was selected for further penetration studies due to its better stability observed in previous studies. The amounts of drug penetrated after 44 h were 31.3, 41.5, 38.3 and 186.5 micrograms for E27, E28, FDC dermal creams and topical hydroalcoholic solution, respectively. The solution showed a statistically significant difference (p < 0.05) from the other formulations, however, no differences were observed between the dermal cream formulations. No differences were neither obtained between the different dermal creams when the amount of drug retained in the skin was compared. This allows to assert that the excipients used do not have different influences on transdermal penetration. In all cases, the mean quantity penetrated in relation to the dose applied was at most 0.5%. These results allow to infer that flutrimazole shows scarce transdermal penetration. Further, the amount of flutrimazole retained per gram of skin is more than 100 times the MIC per gram obtained in previous in vitro studies. It may be assumed that the topical application of the new formulations assayed would allow to obtain a good therapeutic response.

Intestinal absorption of a series of 6-fluoquinolone derivatives: a comparative study.

The intestinal absorption rate constants of the five 6-fluoquinolones (norfloxacin, ciprofloxacin, pefloxacin, CNV 8802 and CNV 8804), have been estimated in the rat (n = 5) by means of an "in situ" intestinal perfusion method. Remaining 6-fluoquinol one concentrations in the perfusion liquid at fixed time (15, 30, 45, 60, 75, 90 and 120 minutes) were determined using a HPLC procedure with UV detection. Absorptions rate constants were estimated according to first order kinetics. A simple non-linear correlation between Ka and log K' on the one hand and a multiple linear correlation between Ka and the structural theoretical parameters: molar volume, dipolar moment and the charge associated to nitrogen 18 on the other, were performed. Only a correlation between Ka values as dependent variable versus dipolar moment and molecular volume values has been obtained, but this correlation is not statistically significant (p = 0.1808) and not accurate enough to have predictive value.

Study of the release process of drugs: suppositories of paracetamol.

The release process of paracetamol, formulated in suppositories, prepared with four different Suppocire masses (AM, AML, AS2X and AP), having different hydrophilia, supplied by Gattefossé, was investigated. The release study of paracetamol was carried out "in vitro" by means of the Dissotest apparatus (Sotax), built on the base of the flow-through method. The assay conditions were: pH 7.4 and flow rate of 20 ml/min. The release process was evaluated using the following amodelistic parameters: the mean dissolution time (MDT), the variance of dissolution time (VDT), the dissolution efficiency (DE) and the maximum amount dissolved determined experimentally (Qmax). The amodelistic parameters, after their statistical analysis by the Kruskal-Wallis test, followed by the comparison between data pairs by the Mann-Whitney "U" test, proved that there are significant differences (p less than 0.05), with the exception of Qmax, between the four masses tested. This study shows that the masses which have a surfactant in their composition (AS2X and AP) offer a better release of paracetamol than those which have no surfactant (AM and AML).

UV-induced erythema model: a tool in dermatopharmacology for testing the topical activity of non-steroidal anti-inflammatory agents in man.

UV-induced erythema is a well known inflammatory model applied both in animal and human skin to test the activity of topical non-steroidal anti-inflammatory compounds in a great variety of pharmaceutical formulations. The aim of this study was to evaluate the inhibitory efficacy of piroxicam in two different topical formulations (cream 0.5, 1 and 1.5% and gel 1%) as compared to three non-steroidal compounds, benzydamine, etofenamate and indomethacin (cream 5%), on erythema induced after UV-injury on the back of 5 healthy subjects. The results showed that piroxicam in cream formulation, indomethacin cream and etofenamate gel have a similar effect, decreasing the erythema size 7 h after irradiation. However, benzydamine cream and piroxicam gel showed no effect with this method. We may conclude that this model is adequate and precise for selecting the most appropriate galenic dosage form for an active compound in terms of its clinical efficacy when topically administered.

Relationships between biophasic disposition and pharmacokinetic behavior in nonsteroid antiinflammatory drugs.

The time course of biophasic amounts of two nonsteroid antiinflammatory drugs (naproxen and oxyphenbutazone) after an intravenous dose of both drugs in rats (5 and 20 mg/kg, respectively) and their relationships with the drug amounts in central and peripheral compartments as defined through blood level data obtained after the same intravenous dose of the drug, are described. To assess the first point, the carrageenin-induced rat paw edema method is employed. Through previously established dose-response curves obtained after administration of different i.v. doses, the conversion of responses to biophasic amounts is achieved by means of the corresponding model equations. To calculate kinetic parameters through the fitting of the concentration-time data, a least-squares method based on the Marquardt algorithm is used on a computer. It can be concluded that the biophasic compartment cannot be identified as the "central" or the "peripheral" kinetic ones, being, however, the output biophasic rate constant not significantly different from the terminal disposition rate constant, beta or lambda 2.