J. Domenech

Assessment of diclofenac permeation with different formulations: anti-inflammatory study of a selected formula.

The aim of this study was to improve the transdermal permeation of sodium diclofenac. Permeation studies were carried out in vitro using human skin (0.4 mm thick) from plastic surgery as a membrane. Four liquid formulations of 1% (w/w) sodium diclofenac were assayed: three ternary solvent systems (M4, M5, M6) and one microemulsion (M3). A 1% (w/w) solution of sodium diclofenac and a commercially available semisolid preparation were tested as reference formulations. The following permeation parameters for diclofenac were assessed: permeability coefficient, flux and drug permeated and retained in the skin at 24 h. The highest values of these parameters were obtained with formula M4, which contains transcutol 59.2%, oleic acid 14.9% and d-limonene 5% (w/w) as permeation enhancers. The anti-inflammatory activity of this formula was compared with that of the semisolid preparation on carrageenan-induced paw edema in rats. As expected from in vitro results, the M4 diclofenac delivery system showed higher activity than the semisolid preparation, both when applied locally (to the inflammation area) and when applied systemically (to the back). Neither treatment irritated the skin when tested on rabbits in a 72-h trial. These results suggest that topical delivery of sodium diclofenac with an absorption enhancer such as a mixture of oleic acid and d-limonene (M4) may be an effective medication for both dermal and subdermal injuries.

In vitro based index of topical anti-inflammatory activity to compare a series of NSAIDs

The aim of the present work was to generate an index to predict topical efficiency of a series of nonsteroidal anti-inflammatory drugs (NSAIDs): indomethacin, diclofenac, ketoprofen, piroxicam, tenoxicam and ketorolac. This index took into account both biopharmaceutic and pharmacodynamic aspects. The biopharmaceutic aspect, based on the maximal flux (J(m)), was determined experimentally from transdermal studies carried out with human skin in previous work. The pharmacodynamic aspect, based on the ability to inhibit cyclooxygenase-2 (COX-2) in vitro, was determined by incubating human dermal fibroblasts in culture, pre-treated with phobol-12-myristate-13-acetate (PMA) for 6 h, with 25 microM [(14)C]-arachidonic acid (AA) in the presence of several drug concentrations. The most potent inhibitor of COX-2 activity in induced fibroblasts was diclofenac while indomethacin, ketoprofen and ketorolac were approximately equipotent. Piroxicam and tenoxicam were inhibitors at higher concentrations. Based on the proposed index of the topical anti-inflammatory activity (ITAA) diclofenac, ketorolac, ketoprofen and indomethacin exhibited acceptable efficiency for external use. However, piroxicam and tenoxicam showed the lowest topical anti-inflammatory activity of the series assayed. In conclusion, indomethacin ketorolac, ketoprofen and diclofenac have shown good intrinsic feasibility for formulation into topical pharmaceutical forms. However, for dermatological formulations of oxicams, use of penetration enhancers may be unavoidable.

Effect of d-limonene on the transdermal permeation of nifedipine and domperidone

The aim of this research is to study the profile of transdermal permeation of nifedipine and domperidone. Permeation studies were carried out using the skin of hairless rat and human skin as a membrane mounted in a permeation system in vitro. The influence of the type of skin used and the presence of d-limonene on the transdermal penetration of these drugs were studied. The drugs studied permeate approx. 3 times faster through rat skin than through human skin. The type of skin has no influence on the lag time. d-Limonene increases the values of the permeability constant (Kp), flux (J) and lag time (t1) for both drugs, but not the lag time for domperidone when human skin is used. The effect of the enhancer on the enhancement index (EI) of domperidone varies with the type of skin used (EI = 15.7 (rat skin) and EI = 7.7 (human skin). When human skin is used, although penetration is increased by d-limonene, the concentration values predicted at steady state are below therapeutic levels for both studied drugs.

An improved cryopreservation method for porcine buccal mucosa in ex vivo drug permeation studies using Franz diffusion cells

The use of isolated animal models to assess percutaneous absorption of molecules is frequently reported. The porcine buccal mucosa has been proposed as a substitute for the buccal mucosa barrier on ex vivo permeability studies avoiding unnecessary sacrifice of animals. But it is not always easy to obtain fresh buccal mucosa. Consequently, human and porcine buccal mucosa is sometimes frozen and stored in liquid nitrogen, but this procedure is not always feasible. One cheaper and simpler alternative is to freeze the buccal mucosa of freshly slaughtered pigs in a mechanical freezer, using DMSO and albumin as cryoprotective agents. This study compared the ex vivo permeability parameters of propranolol hydrochloride through porcine buccal mucosa using a Franz diffusion cell system and HPLC as detection method. The freezing effects on drug permeability parameters were evaluated. Equally histological studies were performed. Furthermore, the use of the parameter transmucosal water loss (TMWL) as an indicator of the buccal mucosa integrity was evaluated just as transepidermal water loss (TEWL) is utilized for skin integrity. The results showed no difference between fresh and frozen mucosal flux, permeability coefficient or lag time of propranolol. However, statistical significant difference in TMWL between fresh and frozen mucosa was observed.

Rapid Human Skin Permeation and Topical Anaesthetic Activity of a New Amethocaine Microemulsion

We developed a fast-acting, topical, 4% (w/w) amethocaine microemulsion and tested its in vitro permeation in isolated human skin. Comparison with a commercial amethocaine gel (Ametop® ) was performed using Franz diffusion cells. Permeability coefficient (kp), flux (J) and percentage permeation after 10 h of microemulsion application were, in all cases, 1.5 times higher than those of the gel. The values obtained for the P1 parameter [1], 1.06·10–2 cm (microemulsion) and 0.724·10–2 cm (gel) indicate that the microemulsion excipients favour amethocaine deposition in the skin, increasing the permeability coefficient, amount of drug retained in the skin, and the flux achieved. Analgesic activity was also examined in rats made hyperalgesic or allodynic after carrageenan-induced inflammation. The rats were distributed into four groups (n = 5–9 per group), each group receiving topically either amethocaine microemulsion, amethocaine gel (Ametop), amethocaine subcutaneous infiltration or nothing (controls). In edematous paws, anti-hyperalgesic activity appeared at 4.2 and 13.8 min after application of amethocaine microemulsion and gel, respectively. These effects are lower than after 0.5% w/w amethocaine infiltration. Amethocaine microemulsion was the only topical formulation with an anti-allodynic effect, although this effect was less than with amethocaine infiltration. These results suggest that microemulsion could be a valuable formula for improving amethocaine permeation and thus bringing rapid pain relief.

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.

A comparative ex vivo drug permeation study of beta-blockers through porcine buccal mucosa.

Apparent permeability coefficients (kp) of a series of beta-blockers: acebutolol, atenolol, labetalol, metoprolol, oxprenolol and propranolol, through porcine buccal mucosa were determined. The aim of the study was to determine the permeation parameters (apparent permeability coefficient, kp; flux, J; and lag time, TL) as a measure of the intrinsic permeability of porcine buccal mucosa to these drugs, in order to predict the efficacy of their possible administration through human buccal mucosa. A positive linear correlation was observed between the apparent permeability coefficient, kpand the partition coefficient, P. Oxprenolol and propranolol are the drugs that presented the highest values of kp: 0.3231×10(2) cm/h and 0.5666×10(2) cm/h, respectively. Multiple linear regression (MLR) using least square estimation was performed on the data set with logkpas dependent variable and the descriptors as predictor variables. The potential systemic capacity after a buccal administration was predicted by estimating the plasma concentrations at steady-stated (Css). Considering the entire process of permeation ex vivo, propranolol and oxprenolol would seem to be the best candidates for administration through the buccal mucosa.

Influence of d-limonene on the transdermal penetration of felodipine

SummaryFelodipine is a calcium antagonist, one of the dihydropyridines, with potential application in transdermal therapeutic systems (TTS). Earlier studies reported that the high lag time of this drug limited its potential development in a TTS. The present study analyzes the effect of d-limonene at concentrations of 0.5, 1, 5 and 10% on the transdermal penetration of this drug. The study was performed using a diffusion technique in vitro, with the skin of the hairless rat. d-Limonene significantly reduced the lag time (T1) to 1.4 h at a concentration of 1% (compared with 9.8 h in its absence). Higher concentrations did not produce a significant decrease in the value of this parameter. The presence of d-limonene in the formulae produces an increase in the permeability constant (Kp) and the flux (J). The relation between this increase and the percentage of d-limonene was non-linear. An asymptotic value was obtained at a concentration of 5%, with increases of 993% and 1570% for Kp and J, respectively.

Estimation of Transdermal Permeation Parameters in Non-stationary Diffusion Experiments. Application to Pre-treatment Studies with Terpenes

No HeadingPurpose.To estimate the applicability of transdermal drug permeation parameters in a finite-dose model for skin pre-treated with terpenes and to evaluate the enhancing effect of some terpene formulations on alprazolam permeation.Methods.In vitro enhancement of alprazolam human skin permeation was investigated using a pre-treatment with different terpene solutions. Vertical diffusion, Franz-type cells were used. Intrinsic drug permeation was also investigated. Transdermal permeation parameters were estimated from the per-meation tabulates using different theoretical approaches for their calculation. Two groups of permeation parameters were calculated: modelistic (diffusion of a finite-dose of drug model) and parameters non-dependent of a diffusional model.Results.In control experiments, all approaches of data treatment satisfactorily described the experimental permeation profiles. When skin pre-treatment was investigated, the fitting of a mathematical sigmoid function was much better than the diffusional approach. Pre-treatment of the skin with Limonene dissolved in ethanol / propylene glycol and Menthol dissolved in propylene glycol increased 15 and 10 times respectively the permeation parameters of alprazolam.Conclusions.Using enhancers that are rapidly cleared from the skin, skin permeability does not remain constant during the permeation experiment and therefore it is not possible to calculate parameters that are usually true coefficients or definite values. In this case, non-modelistic parameters can be used to estimate an enhancing effect.

Absolute Bioavailability and Absorption Profile of Cyanamide in Man

AbstractA pharmacokinetic study of cyanamide, an inhibitor of aldehyde dehydrogenase (EC1.2.1.3) used as an adjuvant in the aversive therapy of chronic alcoholism, has been carried out in healthy male volunteers following intravenous and oral administration. Cyanamide plasma levels were determined by a sensitive HPLC assay, specific for cyanamide. After intravenous administration cyanamide displayed a disposition profile according to a two-compartmental open model. Elimination half-life and total plasma clearance values ranged from 42.2 to 61.3 min and from 0.0123 to 0.0190 L · kg−1· min−1, respectively. After oral administration of 0.3, 1.0, and 1.5 mg/kg