The hydrochloride, sulphate and ethylcarbonate salts of quinine were given in single oral doses (600 mg base equivalent) to nine healthy male subjects according to a cross-over design. No statistically significant differences were noted in the plasma drug concentration-time profiles although inter- and intra-subject variation in AUC, Cmax and tmax values was appreciable. The ethylcarbonate salt may be preferred for use in paediatric patients because of its neutral taste.
A novel multiparticulate sustained-release theophylline formulation, which consisted of spherical drug pellets coated with a rate-controlling membrane, was evaluated in vivo. Two preparations that differ solely in the coat thickness, and hence rate of in vitro drug release, were studied in comparison with a solution of the drug. Both preparations produced serum concentration profiles that are reflective of a slow and sustained rate of absorption. The in vivo release versus time profiles calculated using a deconvolution procedure showed that the two preparations differed in the rate but not the extent of drug release. Satisfactory correlation was also obtained between the in vivo and the in vitro results. When the two preparations were further compared using the parameters, time to reach peak concentration (Tp), peak concentration (Cp), and total area under the serum concentration versus time curves (AUC), a statistically significant difference was observed in the Tp and Cp values but not the AUC values, suggesting that the preparations differed in the rate but not the extent of absorption. In addition, the extent of absorption from both preparations was comparable to that obtained with the drug solution.
A high-performance liquid chromatography assay equipped with a glassy carbon electrode for electrochemical detection (HPLC-ECD) was developed at reductive mode for the analysis of artemisinin, the antimalarial drug from Artemisia annua (Asteraceae) in human plasma. This method was selective, sensitive, and produced satisfactory recovery, precision, and accuracy. Analysis of plasma samples from 8 male volunteers given 10 mg kg-1 of artemisinin orally as an aqueous suspension showed a mean peak plasma concentration (Cmax) of 580.89 ng ml-1 +/- 88.64 SD at 2.5 h +/- 0.5 SD after dosing, and the mean area under the plasma concentration-time curve (AUC0-infinity) was 2227.57 ng h ml-1 +/- 677.22 SD. In addition, the elimination rate constant (Ke), elimination half-life (t1/2), and apparent volume of distribution (Vd) were calculated to be 0.2971 h-1 +/- 0.0644 SD, 2.42 h +/- 0.46 SD, and 16.26 l kg-1 +/- 3.44 SD, respectively.
A simple high-performance liquid chromatographic method using fluorescence detection was developed for the determination of acyclovir in human plasma. The method entailed direct injection of the plasma sample after deproteination. It is both specific and sensitive with a detection limit of 30 ng/ml at a signal-to-noise ratio of 3:1, and is thus suitable for use in pharmacokinetic studies of acyclovir. The method had a mean absolute recovery of 96%, while the within-day and between-day coefficients of variation and percentages error were all less than 8%. The calibration curve was linear over a concentration range of 62.5-4000 ng/ml.
A simple liquid chromatographic method using amperometric detection was developed for the determination of naltrexone in human plasma. Prior to analysis, naltrexone and the internal standard (naloxone) were extracted from plasma samples using a 9:1 mixture of chloroform and isopropyl alcohol. The mobile phase comprised 0.1 M disodium hydrogen orthophosphate (pH 3.5) and acetonitrile (85.5:14.5, v/v). Analysis was run at a flow-rate of 0.8 ml/min with the detector operating under oxidative mode at an applied potential of +0.95 V. The method is specific and sensitive with a detection limit of approximately 1 ng/ml at a signal-to-noise ratio of 3:1. Mean recovery value of the extraction procedure was about 93%, while the within day and between day coefficient of variation and percent error values of the assay method were all less than 10%. The calibration curve was linear over a concentration range of 1.5-100 ng/ml.
Ethyl acrylate-methyl methacrylate copolymer (Eudragit NE40D) was evaluated as matrix material for preparing controlled-release tablets of diclofenac sodium. Drug release could be modified in a predictable manner by varying the Eudragit NE40D content, but was pH dependent, being markedly reduced at lower pH. This could be attributed to the low solubility of the drug at these pH values. Thermal treatment of the tablets at 60 degrees C was also found to affect the rate of drug release, which was found to decrease with an increase in the treatment duration, but could be stabilized after 96 hr of treatment. This was also associated with a corresponding increase in the tablet tensile strength. However, treatment of the granules for 5 hr prior to compaction into tablets could shorten the stabilizing time of the drug release to 48 hr and that of the tensile strength to 24 hr. The effect of thermal treatment may be ascribed to better coalescence of the Eudragit particles to form a fine network, resulting in matrix of higher tortuosity and lower porosity.
The bioavailability of a generic preparation of acyclovir (Avorax) was compared with the innovator product, Zovirax. Twelve healthy volunteers participated in the study, conducted according to a randomized, two-way crossover design. The preparations were compared using the parameters area under the plasma concentration time curve (AUC(0-infinity), peak plasma concentration (Cmax), and time to reach peak plasma concentration (Tmax). No statistically significant difference was observed between the Tmax or the logarithmic transformed AUC(0-infinity) and C(max) values of the two preparations. In addition, the 90% confidence interval for the ratio of the logarithmic transformed AUC(0-infinity) values of Avorax over those of Zovirax was found to lie between 0.85 and 1.06, while that of the logarithmic transformed Cmax values was between 0.95 and 1.25, being within the bioequivalence limit of 0.80-1.25. Moreover, the elimination rate constant (k(e)), elimination half-life (t(1/2)), and apparent volume of distribution (Vd) values obtained with the two preparations were comparable and not significantly different statistically.
A simple high-performance liquid chromatographic method using fluorescence detection was developed for the determination of ketoconazole in human plasma. The method entailed direct injection of the plasma sample after deproteinization using acetonitrile. The mobile phase comprised 0.05 M disodium hydrogen orthophosphate and acetonitrile (50:50, v/v) adjusted to pH 6. Analysis was run at a flow-rate of 1.5 ml/min with the detector operating at an excitation wavelength of 260 nm and an emission wavelength of 375 nm. The method is specific and sensitive with a quantification limit of approximately 60 ng/ml and a detection limit of 40 ng/ml at a signal-to-noise ratio of 3:1. Mean absolute recovery value was about 105%, while the within-day and between-day coefficient of variation and percent error values of the assay method were all less than 14%. The calibration curve was linear over a concentration range of 62.5-8000 ng/ml.
A study was conducted to compare the in vivo bioavailability of a generic metoprolol tablet preparation (Metoprolol) with that of the innovator product, Betaloc. Both preparations have a labeled dose of 100 mg metoprolol tartrate. Twelve healthy adult male volunteers participated in the study, which was conducted according to a standard two-way crossover design with a washout period of 1 week. The bioavailability was compared using the total area under the plasma level versus time curve (AUC0-infinity), peak plasma concentration (Cmax), and time to reach peak plasma concentration (Tmax). No statistically significant difference was observed between the logarithmically transformed AUC0-infinity values or the logarithmically transformed Cmax values of the two preparations. However, a statistically significant difference was observed between the Tmax values, but may not be therapeutically significant or important. Moreover, the 90% confidence interval (CI) for the ratio of the logarithmically transformed AUC0-infinity values of Metoprolol over those of Betaloc was calculated to be between 0.94 and 1.02, while that of Cmax was between 0.98 and 1.01, both of which are within the acceptable limit of 0.80-1.25. From the data obtained, it was also observed that a high proportion of our volunteers of Asian origin appeared to be poor metabolizers of metoprolol, which was consistent with what had been observed in our previous study of another preparation of metoprolol.
A simple high-performance liquid chromatographic method was developed for the determination of ranitidine in human plasma. Prior to analysis, ranitidine and the internal standard (metoprolol) were extracted from alkalinized plasma samples using dichloromethane. The mobile phase was 0.05 M potassium dihydrogenphosphate-acetonitrile (88:12, v/v) adjusted to pH 6.5. Analysis was run at a flow-rate of 1.3 ml/min and at a detection wavelength of 229 nm. The method is sensitive with a detection limit of 1 ng/ml at a signal-to-noise ratio of 3:1, while the quantification limit was set at 15 ng/ml. The calibration curve was linear over a concentration range of 15-2000 ng/ml. Mean recovery value of the extraction procedure was about 90%, while the within-day and between-day coefficients of variation and percent error values of the assay method were all less than 15%.
Controlled release buccal patches were fabricated using Eudragit NE40D and studied. Various bioadhesive polymers, namely hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose and Carbopol of different grades, were incorporated into the patches, to modify their bioadhesive properties as well as the rate of drug release, using metoprolol tartrate as the model drug. The in-vitro drug release was determined using the USP 23 dissolution test apparatus 5 with slight modification, while the bioadhesive properties were evaluated using texture analyzer equipment with chicken pouch as the model tissue. The incorporation of hydrophilic polymers was found to affect the drug release as well as enhance the bioadhesiveness. Although high viscosity polymers can enhance the bioadhesiveness of the patches, they also tend to cause non-homogeneous distribution of the polymers and drug, resulting in non-predictable drug-release rates. Of the various bioadhesive polymers studied, Cekol 700 appeared to be most satisfactory in terms of modifying the drug release and enhancement of the bioadhesive properties.
A study was conducted to compare the bioavailability of a generic product of atenolol (Normaten FC) with the innovator product, Tenormin. Twelve healthy adult volunteers participated in the study conducted according to a randomized, two-way crossover design. The preparations were compared using area under the plasma concentration-time curve AUC0-infinity, peak plasma concentration Cmax, and time to reach peak plasma concentration Tmax. No statistically significant difference was obtained between the Tmax values and the logarithmic transformed AUC0-infinity and Cmax values of the two products. Moreover, the 90% confidence interval for the ratio of the logarithmically transformed AUC0-infinity values of Normaten FC over those of Tenormin was found to lie between 0.82 and 0.98, while that of the logarithmically transformed Cmax values was between 0.82 and 1.09, both being within the bioequivalence limit of 0.80-1.25. The values of elimination half-life t1/2 between the two products were also found comparable and not significantly different statistically. The t1/2 values obtained in our study were slightly longer than those reported in the literature for other population groups.
The bioavailability of a generic preparation of naltrexone (Narpan) was compared with the innovator product, Trexan. Twelve healthy volunteers participated in the study, conducted according to a completely randomized, two-way crossover design. The preparations were compared using the parameters area under the plasma concentration-time curve AUC0-infinity, peak plasma concentration Cmax, and time to reach peak plasma concentration Tmax. No statistically significant difference was observed between the logarithmic transformed AUC0-infinity and the logarithmically transformed Cmax values of the two preparations. Also, no statistically significant difference was observed between the untransformed Tmax values. In addition, the 90% confidence interval for the ratio of the logarithmic transformed AUC0-infinity values of Narpan over those of Trexan was found to lie between 0.87 and 1.01, while that of the logarithmic transformed Cmax values was between 0.94 and 1.23, both being within the bioequivalence limit of 0.80-1.25. The numerical values of the elimination half-life (t1/2) obtained with the two preparations were also not significantly different and were comparable to those reported in the literature.
A method using a texture analyzer equipment and chicken pouch as the biological tissue was investigated for measuring the bioadhesive properties of polymers under simulated buccal conditions. The method was evaluated using two polymers, namely Carbopol 974P and Methocel K4M while the instrument variables studied included the contact force, contact time and speed of withdrawal of the probe from the tissue. The parameters measured were the work of adhesion and peak detachment force. Longer contact time and faster probe speed not only gave better reproducibility of results, but also better sensitivities for both parameters measured. On the other hand, a certain level of contact force was found essential for achieving good bioadhesion, above which there was no further contribution to the bioadhesion process. When the method was applied to determine the bioadhesiveness of several polymers, the values obtained for the work of adhesion and peak detachment force were quite consistent in the ranking of the polymers. The Carbopols were found to have the highest values, followed by gelatin, sodium carboxymethyl celluloses and hydroxypropylmethyl celluloses. On the other hand, Alginic acid, Eudragit RLPO and RSPO, and Chitosan appeared to have low bioadhesive values.
This study was conducted to compare the bioavailability of two controlled-release metformin preparations (Diabetmin Retard and Glucophage Retard) and also to correlate the in vitro and in vivo data obtained with the two preparations. Twelve healthy volunteers participated in the study, conducted according to a completely randomized, two-way crossover design. The preparations were compared using area under the plasma concentration-time curve AUC0-infinity, time to reach peak plasma concentration Tmax, and peak plasma concentration Cmax, while correlation was determined between in vitro release and in vivo absorption. Diabetmin Retard demonstrated a slower rate of in vitro release, but a faster rate of in vivo absorption than Glucophage Retard. However, the in vivo absorption of both products was found to be slower than that of drug released in vitro. A satisfactory relationship could be established between the in vitro and in vivo results, but there was no rank order correlation. No statistically significant difference was observed between the two preparations in the parameters AUC0-infinity and Cmax. However, a slight but statistically significant difference was observed between the Tmax values, but it may not be therapeutically significant. Moreover, the 90% confidence interval for the ratio of the logarithmic transformed AUC0-infinity values, as well as the logarithmic transformed Cmax values, of Diabetmin Retard over those of Glucophage Retard was within the acceptance criteria of 0.80-1.25.
The bioavailability of a generic preparation of metformin (Diabetmin from Hovid Sdn Bhd) was evaluated in comparison with a proprietary product (Glucophage from Lipha Pharma Ltd., UK).
A simple high-performance liquid chromatographic method using UV detection was developed for the determination of alpha-tocopherol in human plasma. The method entailed direct injection of the plasma sample after deproteinization using acetonitrile-tetrahydrofuran (3:2). The mobile phase comprised methanol-tetrahydrofuran (94:6) and analysis was run at a flow-rate of 1.5 ml/min with the detector operating at 292 nm. A Crestpak C18S (5 microm, 250 mm x 4.6 mm ID) was used for the chromatographic separation. The method had a mean recovery of 93%, while the within-day and between-day coefficients of variation and percentage errors were all less than 7%. The speed, specificity, sensitivity and reproducibility of this method make it particularly suitable for routine determination of alpha-tocopherol in human plasma. Moreover, only a small sample plasma volume (100 microl) is required for the analysis.
The bioavailability of a generic preparation of ketoconazole (Zorinax from Xepa-Soul Pattinson, Malaysia) was evaluated in comparison with the innovator product (Nizoral from Janssen Pharmaceutica, Switzerland). Eighteen healthy male volunteers participated in the study conducted according to a two-way crossover design. The bioavailability was compared using the parameters, total area under the plasma concentration-time curve (AUC0-infinity), peak plasma concentration (Cmax) and time to reach peak plasma concentration (Tmax). No statistically significant difference was observed between the values of the two products in all the three parameters. Moreover, the 90% confidence interval for the ratio of the logarithmic transformed AUC0-infinity and Cmax values of Zorinax over Nizoral was found to lie between 0.82-1.04 and 0.83-1.02, respectively, being within the acceptable equivalence limit of 0.80-1.25. These findings indicate that the two preparations are comparable in the extent and rate of absorption. In addition, the elimination rate constant (ke) and apparent volume of distribution (Vd) were calculated. For both parameters, there was no statistically significant difference between the values obtained from the data of the two preparations. Moreover, the values are comparable to those reported in the literature.
A simple high-performance liquid chromatographic method using fluorescence detection was developed for the determination of vitamin E especially delta-, gamma- and alpha-tocotrienols in human plasma. The method entailed direct injection of plasma sample after deproteinization using a 3:2 mixture of acetonitrile-tetrahydrofuran. The mobile phase comprised 0.5% (v/v) of distilled water in methanol. Analyses were run at a flow-rate of 1.5 ml/min with the detector operating at an excitation wavelength of 296 nm and emission wavelength of 330 nm. This method is specific and sensitive, with a quantification limit of approximately 40, 34 and 16 ng/ml for alpha-, gamma- and delta-tocotrienol, respectively. The mean absolute recovery values were about 98% while the within-day and between-day relative standard deviation and percent error values of the assay method were all less than 12.0% for alpha-, gamma- and delta-tocotrienol. The calibration curve was linear over a concentration range of 40-2500, 30-4000 and 16-1000 ng/ml for alpha-, gamma- and delta-tocotrienol, respectively. Application of the method in a bioavailability study for determination of the above compounds was also demonstrated.
Lipophilicity was evaluated as a possible mechanism for drug retardation from a glyceryl monostearate matrix system. Lipophilicity of the glyceryl monostearate matrix system was studied using contact angle measurement of water droplets on the surface of compressed disks, extrudate ascension of water, and movement of water through a powder mixture packed in a high-performance liquid chromatographic (HPLC) column. Increase in glyceryl monostearate content resulted in an increase in water droplet contact angle, decrease in the rate of water ascending the extrudate, and increase in the pressure values as a function of flow rate of water moving through the powder mixture. These could be due to the increase in lipophilicity of the matrix, rendering the matrix less wettable. As a result, the rate of water penetration into the matrix decreased, and the drug release could be sustained.