Development of novel formulations to enhance in vivo transdermal permeation of tocopherol.

Tocopherol represents a big challenge for transdermal permeation owing to its extreme hydrophobicity and large molecular mass. The aim of the present study was to develop alpha-tocopherol (T) topical formulations and evaluate their ex vivo and in vivo permeation. Franz diffusion cells were used for ex vivo permeation, and neonatal rats were used for in vivo permeation. Seven gel formulations and 21 liquid formulations were investigated for physical stability, viscosity and permeation of T. Analysis of T was performed by a validated HPLC method using a UV detector. The ex vivo permeation from gel and emulsion formulations was very poor (0.001-0.015%). Highest permeation was observed from monophasic liquid formulations containing dimethyl sulfoxide (DMSO), tocopheryl polyethylene glycols (TPGs), propylene glycol, ethanol and 9.5% T. The in vivo results demonstrated higher retention in the epidermis compared to subcutaneous tissues, 1377 and 1.13 µg g⁻¹, respectively. Increasing T concentration from 4.8 to 9.5% did not increase the amount permeated or % of T retained. It was concluded that simple solutions of T in the presence of DMSO and TPGs were more promising systems for effective transdermal permeation compared to gel, emulsion or oleaginous systems.

Formulation and in vitro evaluation of salbutamol sulphate in situ gelling nasal inserts.

The aim of this study was to formulate salbutamol sulfate (SS), a model drug, as mucoadhesive in situ gelling inserts having a high potential as nasal drug delivery system bypassing the first-pass metabolism. In situ gelling inserts, each containing 1.4% SS and 2% gel-forming polymer, hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose sodium (CMC Na), sodium alginate (AL), and chitosan (CH) were prepared. The inserts were investigated for their different physicochemical properties. The weight of inserts was 16-27 mg, drug content was 3.9-4.2 mg, thickness ranged between 15 and 28 µm and surface pH was 5-7. Cumulative drug released from the inserts exhibited extended release for more than 10 h following the decreasing order: CH>AL>CMC Na>HPMC. The drug release from CMC Na and AL inserts followed zero-order kinetics while HPMC and CH inserts exhibited non-Fickian diffusion mechanism. The inserts exhibited different water uptake (7-23%) with the smallest values for CH. Differential scanning calorimetry study pointed out possible interaction of SS and oppositely charged anionic polymers (CMC Na and AL). The mucoadhesive in situ gelling inserts exhibited satisfactory mucoadhesive and extended drug release characteristics. The inserts could be used for nasal delivery of SS over about 12 h; bypassing the hepatic first-pass metabolism without potential irritation.

In vitro/in vivo correlation of fast release mephenamic acid microspheres in humans.

OBJECTIVES: The objectives of this study were to assess the bioavailability of an optimized mephenamic acid (MFA) microspheres (test) against a Ponstan® capsule (reference) in healthy volunteers, and to establish a correlation with in vitro parameters. SUBJECTS AND METHODS: Four subjects received the test and reference (250 mg MFA each) in a randomized crossover design, separated by a 1-week washout period. The drug was analyzed in plasma by a specific high-performance liquid chromatographic method. The relevant pharmacokinetic parameters [maximum plasma concentration (C(max)), time of peak concentration (T(max)), area under plasma concentration-time curves from 0 to 12 h (AUC(0-12)) and area under plasma concentration-time curves from zero to ∞ (AUC(0-)∞)] were calculated from the plasma drug concentration-time data. RESULTS: The test product exhibited faster absorption (T(max) of 1.87 ± 0.482 vs. 2.14 ± 0.20 h; C(max) of 5.91 ± 0.604 vs. 3.58 ± 0.671 µg/ml) when compared to the reference. The relative bioavailability of the test compared to the reference capsule was 172%. Good correlations were established between the in vitro 90% dissolution (T90) and each of the AUC(0-12) and T(max), as well as between the percentage of drug released and plasma concentrations. CONCLUSION: The formulation of MFA microsphere with polyethylene glycol improved the dissolution rate and bioavailability of MFA, as evidenced by a higher C(max), AUC(0-12) and AUC(0-)∞, and shorter T(max) values. Good correlations between T90 and both AUC(0-12) and T(max) as well as between the percentage of drug released and plasma concentrations were achieved.

Comparative bioavailability of norfloxacin tablets based on blood and urine data.

OBJECTIVE: To assess the bioavailability of norfloxacin from urinary excretion relative to plasma concentration. MATERIALS AND METHODS: Twelve healthy volunteers (22-33 years) participated in the study. Each received a previously developed (M), a local (L) and a multinational (Noroxin) tablet (Ref), 400 mg each, according to a random balanced three-way crossover design on 3 different days. Blood samples were collected over a 12-hour period and urine over a 24-hour period. Norfloxacin concentrations were analyzed by a validated HPLC method. RESULTS: An initial estimate of bioequivalence of the three products was obtained using analysis of variance on transformed data and based on confidence interval calculation. Elimination pharmacokinetic parameters (half-life and renal clearance) calculated from plasma concentration and urinary excretion data (mean values, n = 36) were comparable to reported values for norfloxacin. Interproduct differences in elimination parameters (mean values, n = 12) were statistically insignificant (F values, ANOVA). Strong association was found between the mean of plasma concentration and urinary excretion rates for many volunteers (F values, regression analysis). Relative bioavailability values calculated for the local and previously developed products relative to Noroxin were higher than 85% based on area under the curve and urinary excretion. Bioequivalence could not be established among the three tested products based on calculated 90% confidence intervals. CONCLUSION: Urinary excretion of norfloxacin may be a useful noninvasive tool for bioavailability assessment of norfloxacin oral formulations.