Esmail M. Niazy

Differences in penetration-enhancing effect of Azone through excised rabbit, rat, hairless mouse, guinea pig and human skins

The transdermal delivery of dihydroergotamine (DHE), from propylene glycol formulations with and without 6.0% laurocapram (Azone), and the penetration enhancing effect of Azone were evaluated in vitro on excised rabbit, rat, hairless mouse, guinea pig and human skins utilizing improved Franz diffusion cells. The steady-state flux of DHE from the propylene glycol formulation without Azone were 0.045, 0.270, 0.395, 0.128 and 10.035 μg/cm2 per h across excised human, rat, guinea pig, rabbit and hairless mouse, respectively. Under the influence of the enhancer, Azone increased DHE penetration through excised skin of the various species used in this study in the following order: rabbit skin > human skin > rat skin > guinea pig skin > hairless mouse skin. The maximum enhancement factor of Azone (251.47) was obtained across rabbit skin and the minimum enhancing effect (14.44) was observed in the case of hairless mouse skin. The enhancement factor of Azone across human skin was 54.56. These results show that animal skins are poor models for human skin under the conditions used. The lag time of DHE, from the propylene glycol formulation containing 6.0% Azone, through human skin was longer than the lag times across all other skin species tested in this investigation.

Influence of oleic acid and other permeation promoters on transdermal delivery of dihydroergotamine through rabbit skin

Abstract Dihydroergotamine (DHE) has recently been suggested as a potential candidate for transdermal administration. In an attempt to increase transdermal delivery of the drug, different enhancers including oleic acid, lauric acid, procaine hydrochloride and urea, were evaluated in vitro, utilizing improved Franz diffusion cells. Oleic acid was found to be the most effective enhancer tested, increasing the percutaneous absorption of DHE by 208-fold. It was found that procaine hydrochloride and lauric acid enhanced transdermal delivery of DHE by 2- and 3-fold, respectively. On the other hand, the formulation containing 6.0% urea did not show any significant difference from the control. The sizable enhancement observed with oleic acid in this study warrants in vivo experimentation with DHE/oleic acid formulations in the future.

In vivo evaluation of sustained-release microspheres of metoclopramide hydrochloride in beagle dogs

The in vivo absorption characteristics of metoclopramide hydrochloride microspheres prepared from cellulose propionate polymer by an emulsion-solvent evaporation method were evaluated using six male beagle dogs. Metoclopramide was administered intravenously at a dose of 4 mg and orally as a single dose (10 mg) of microspheres and conventional tablets (Plasil®) on three separate occasions. Statistically significant differences were found between the two oral treatments in both the time and magnitude of the peak generated (p < 0.05). The absorption rate (Cmax/AUC) was significantly slower following the administration of microspheres. No significant difference was found between the two treatments in the area under the plasma concentration-time curve (AUC), indicating a comparable extent of absorption. The mean residence time (MRT) and mean absorption time (MAT) were dramatically increased following microsphere administration compared to the conventional tablets. The absolute bioavailability of metoclopramide from the microspheres and the conventional tablets was 72 and 65%, respectively. The in vivo results were found to be consistent with the in vitro availability of the drug.

Improved Liquid Chromatographic Method for Acyclovir Determination in Plasma

Abstract A simple and reproducible method for determining acyclovir (ACV) in plasma is presented. The method involved the use of acetaminophen as internal standard. A single extraction step was performed using trichloroacetic acid for protein separation. After pH adjustment, samples from the supernatent layer were directly injected into a high pressure liquid chromatograph. Components separation was perfected through manipulation of solvent combinations and pH. The acyclovir and the internal standard retention times were 8.5 and 11 min. respectively. High correlation was obtained between AUC and the drug concentration (r>0.99). Statistical analysis showed that the method is highly reproducible for ACV determination in aqueous solutions or in plasma. The mean drug recovery was better than 88%. The sensitivity obtained should enable the use of the method in future bioavailability and/or pharmacokinetic studies.

Analysis of Prazosin in Plasma by High-Performance Liquid Chromatography Using Fluorescence Detection

Abstract A high-performance liquid chromatographic procedure using fluorescence detection has been developed for the determination of prazosin in plasma. Propyl-hydroxybenzoate was used as the internal standard. The chromatography was performed using adsorbsphere phenyl column; the mobile phase consisted of 30:70% acetonitrile to 0.05 M phosphate buffer and was adjusted to pH 3.3–3.4 using phosphoric acid; a flow rate of 1.5 ml/min; and the effluent was monitored at excitation and emission wavelengths of 247 and 394 nm, respectively. The retention times for prazosin and the internal standard were 4.0 and 6.0 min., respectively. The intraday coefficients of variation (CV) ranged from 1.15 to 4.96% at three different concentrations and the interday CVs varied from 0.05 to 8.99%. The mean (± SD) absolute and relative recovery of prazosin were found to be 97.4±3.14 and 100.68±2.19, respectively. Stability tests showed that prazosin is stable for at least 2 weeks in plasma after freezing. The minimum detectabl...

A Rapid and Sensitive High-Performance Liquid Chromatographic Method for the Determination of Metoclopramide in Plasma and Its Use In Pharmacokinetic Studies

Abstract A rapid and sensitive high-performance liquid chromatographic (HPLC) assay has been developed for the determination of metoclopramide in plasma. The assay is performed after single extraction of metoclopramide and diazepam (internal standard) from alkalinized plasma into ether and eluted from a Nova Pak C18-column with a mobile phase composed of acetonitrile:water (55:45%, v/v) adjusted to pH 3. The column eluent was monitored at 273 nm. Measurement was achieved by taking the peak-height ratios of the drug to the internal standard. The detection limit for metoclopramide in plasma is 5 ng/ml. Within-day coefficients of variation (CVs) ranged from 3.05 to 4.43% and between-day (CVs) from 4.1 to 5.7% at three different concentrations. Preliminary stability tests showed that metoclopramide is stable for at least 3 weeks in plasma after freezing. The method is applied for the determination of the pharmacokinetic parameters of metoclopramide after administration of two tablet formulations, to 4 healthy...

Transdermal delivery enhancement of haloperidol from gel formulations by 1,8-cineole

The feasibility of using 10% 1,8‐cineole as an enhancer for transdermal delivery of haloperidol has been examined. In‐vitro transdermal delivery across full‐thickness human, rabbit and hairless mouse skins was measured from three polymer gel systems, hypromellose (hydroxypropylmethylcellulose), Carbomer (Carbopol) 940 and macrogol (polyethylene glycol) using Franz cells. Values for the permeability coefficient kp, calculated as the product (Kh)×(D/h2) where these two factors were obtained from curve fitting of the non‐steady‐state equation over 24 h, were similar from the three formulations. The value of kp from hypromellose was significantly enhanced by cineole by factors of 6.2 (4.6–8.1), 5.6 (5.0–6.2) and 3.0 (2.6–3.4) for human, rabbit and mouse, respectively (mean and 95% confidence intervals). Enhancement ratios for K: 13.3 (8.3–20), 3.1 (2.5–3.9) and 2.0 (1.5–2.6), were higher than those for D: 0.47 (0.41–0.55), 1.8 (1.6–2.1) and 1.5 (1.3–1.8). This suggested that the barrier function of the skin lipids was marginally affected and the main effect was to increase the thermodynamic activity of the drug in the barrier. The enhancement achieved in human skin suggested that delivery could be safely enhanced by terpenoids.

Development and in-vitro evaluation of sustained-release meclofenamic acid microspheres

Meclofenamic acid (MFA) sustained-release microspheres were prepared by the solvent evaporation method using cellulose propionate (CP) polymer and acetone as the polymer solvent. Polyethylene glycol (PEG) was used as a channelling agent to improve the release properties of MFA at 1:2:1 drug to polymer to PEG ratio. The microspheres prepared at three different speeds (600, 800 and 1000 rpm) were characterized with regard to their surface morphology, average drug content, particle size distribution and release profiles in phosphate buffer, pH 8.0 at 37 degrees C. The microspheres were stored under accelerated conditions for 3 months and the effect of storage on the different characteristics was studied. Spherical particles with essentially smooth surface and few residual drug crystals on the surface were formed. Smaller particles were formed at higher agitation speeds. The release rate of MFA from these microspheres was not affected by the molecular weight of CP polymer. PEG 2000 was found to have a more enhancing effect on the rate of the release than PEG 4000. The physical properties of the microspheres and their release characteristics were not altered by storing the product at 40 degrees C/80% relative humidity (R.H.) for 3 months.

Effect of Vehicle and Drug Concentration on transdermal delivery of Dihydroergotamine using excised Animal Skin

AbstractDihydroergotamine (DHE) is widely used in the treatment, of migraine as I.M. injection of 1.0 mg/ml. Absorption of DHE averaged 23% when taken orally and the drug is subjected to extensive first-pass effect. The physicochemical and pharmacokinetic characteristics of DHE such as small dose, low M.W. and extensive hepatic metabolism, suggests that this drug is a possible candidate for trans-dermal delivery.The purpose of this study was to investigate the effect of vehicle and dose variation on the percutaneous absorption of DHE. In-vitro diffusion studies were conducted utilizing improved Franz diffusion cells. The rabbit skin obtained from the dorsal area was employed as a barrier membrane.

Effect of azone and other penetration enhancers on the percutaneous absorption of dihydroergotamine

Abstract In vitro drug diffusion studies were conducted, utilizing improved Franz diffusion cells, to estimate the effects of Azone and other additives (deoxycholic acid, dimethyl formamide, lecithin and 2-pyrrolidone) on the percutaneous absorption of dihydroergotamine (DHE). Rabbit skin obtained from the dorsal area was used as a barrier membrane. Among various absorption promoters tested, Azone was the most effective agent for enhancing the percutaneous absorption of DHE; the extent of enhancement ranged from 11-fold with 1.0% Azone coapplied with DHE, to 334-fold when skin was pretreated with 6.0% Azone. It was found that lecithin increased the transdermal delivery of DHE by 13.5-fold over the control. On the other hand the formulation containing 6.0% dimethyl formamide (DMF) did not show any significant difference from the control. In contrast, other additives tested including deoxycholic acid and 2-pyrrolidone showed a decrease in the amount of drug transported across the skin as compared to the control.