Yalcin Ozkan

Enhanced bioavailability of piroxicam using Gelucire 44/14 and labrasol: in vitro and in vivo evaluation.

Piroxicam is a non-steroidal anti-inflammatory drug that is characterized by low solubility and high permeability. The purpose of the study was to investigate the in vitro and in vivo performance of the semi-solid dispersion prepared with Gelucire 44/14 and Labrasol into hard gelatin capsules (GL) for enhancing the dissolution rate of the drug. The results were evaluated by comparing with pure piroxicam filled into hard gelatin capsules (PP) and a commercially available tablet dosage form containing a piroxicam:beta-cyclodextrin complex (CD). The in vitro dissolution testing of the dosage forms was performed in different media (simulated gastric fluid, pH 1.2; phosphate buffers, pH 4.5 and 6.8; and water). Amongst the dosage forms, GL provided at least 85% piroxicam dissolution within 30 min in each of the media, behaving like a fast-dissolving immediate release drug product. Oral bioavailability of 20 mg piroxicam in GL, CD, and PP was compared after administration of a single dose to eight healthy volunteers. Three treatments were administered in crossover fashion, separated by a washout period of 2 weeks. Piroxicam was monitored in plasma by high-performance liquid chromatography. The apparent rate of absorption of piroxicam from GL (Cmax=2.64 micrograms/ml, tmax=82.5 min) was significantly higher than that of the PP (Cmax=0.999 micrograms/ml, tmax=144 min) (P<0.05) and similar to that of CD (Cmax=2.44 micrograms/ml, tmax=120 min) (P>0.05). The relative bioavailability values as the ratios of mean total AUC for GL relative to PP and CD, were 221 and 98.6%. Piroxicam is characterized by a slow and gradual absorption via the oral route and this causes a delayed onset of therapeutic effect. Thus, plain piroxicam preparations are not indicated for analgesia. The results of the in vivo study revealed that the GL dosage form would be advantageous with regards to rapid onset of action, especially in various painful conditions where an acute analgesic effect is desired.

Studies of Floating Dosage Forms of Furosemide: In Vitro and In Vivo Evaluations of Bilayer Tablet Formulations

For the purpose of enhancement the bioavailability of furosemide (FR), a floating dosage form with controlled release of FR was designed in this study. Because of the lower solubility of active material in the gastric medium, it was first enhanced by preparing an inclusion complex of FR with beta-cyclodextrin (β-CD) in a 1:1 proportion using the kneading method. Following the design of dosage form, bilayer floating tablets were prepared. After dissolution rate studies were performed using the continuous flow-through cell method, the formulation that provided delivery of active material near the target profile was given to six healthy male volunteer subjects, and in vivo tests were performed. It was determined by radiographs that floating tablets prepared by adding BaSO4 stayed in the stomach for 6 hr. Further, values of the area under the plasma concentration-time curve (AUC) obtained with the floating dosage form were about 1.8 times those of the conventional FR tablet in blood analyses; maximum and minimum plasma concentrations were also found to be between the desired limits. In urine analyses, the peak diuretic effect seen in classical preparations was decreased and prolonged in floating dosage forms. Also, a considerably significant correlation was detected between in vivo results and in vitro data of the dissolution rate, and it was concluded that the modified continuous flow-through cell method is usable for in vitro dissolution rate tests of floating dosage forms.

Topical cannabinoid enhances topical morphine antinociception

Opioids and cannabinoids produce antinociception through both spinal and supraspinal action. Both opioids and cannabinoids also have important peripheral action. Many previous studies indicate that systemically administered cannabinoids enhance antinociceptive properties of opioids. Experiments were conducted to test the hypothesis that topical cannabinoids would enhance the topical antinociceptive effects of morphine. Antinociception was measured in the radiant tail‐flick test after immersion of the tail of mice into a solution of dimethyl sulfoxide (DMSO) containing WIN 55, 212‐2, a cannabinoid agonist and morphine, an opioid agonist. Morphine and WIN 55, 212‐2 produce time dependent topical analgesic effects limited to the portion of the tail exposed to drugs. WIN 55, 212‐2 had a potency lower than that of morphine. The topical antinociceptive effects of WIN 55, 212‐2 were blocked by systemic pretreatment of cannabinoid CB1 receptor selective antagonist, AM 251. This suggests that topical antinociceptive effects of WIN 55, 212‐2 involve CB1 receptors. Combination of topical WIN 55, 212‐2 with topical morphine yielded significantly greater analgesic effects than that of topical morphine alone. The ability of the CB1 receptor antagonist AM 251 to antagonize the enhancement of antinociception of morphine by WIN 55, 212‐2 indicates that WIN 55, 212‐2 acts through a CB1 receptor to enhance the potency of topical morphine. Additionally, spinally administered ineffective doses of WIN 55, 212‐2 potentiated the antinociceptive effects of topical morphine. These results demonstrate an antinociceptive interaction between topical opioids with topical, and spinal cannabinoids. These observations are significant in using of topical combination of cannabinoid and morphine in the management of pain.

In vitro release studies of chlorpheniramine maleate from gels prepared by different cellulose derivatives

The objective of this study was to evaluate the in vitro and ex vivo percutaneous absorption of chlorpheniramine maleate (CPM) from different hydrogel formulations. Various concentrations of polymers, including hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (NaCMC) and methyl cellulose (MC) were used in the hydrogel formulations. All experiments were conducted using cellulose dialysis membrane. The passive permeation of CPM was affected by the polymer concentrations. The effect of each polymer on the release rate of CPM was found to be statistically different (P<0.05). The formulation which exhibited maximum drug release through cellulose membrane was then used with other membranes namely polyurethane membrane, rat skin and human skin. The release rate of CPM from different membranes was found to be statistically different (P<0.05). Within the different diffusional barriers rat skin was found to be best alternative to human skin. It seems suitable the use of cellulose derivatives for topical application of CPM to obtain high therapeutic concentration at the application site. The synthetic membranes can be used to assess product performance in quality assurance but give little indication of its performance ex vivo.

SIMULTANEOUS DETERMINATION OF PARACETAMOL AND METHOCARBAMOL IN TABLETS BY RATIO SPECTRA DERIVATIVE SPECTROPHOTOMETRY AND LC

The application of the ratio spectra derivative spectrophotometry and high-performance liquid chromatography (HPLC) to the simultaneous determination of paracetamol (PAR) and methocarbamol (MET) in combined pharmaceutical tablets is presented. The spectrophotometric procedure is based on the use of the first derivative of the ratio spectra obtained by dividing the absorbtion spectrum of the binary mixtures by a standard spectrum of one of the compounds. The first derivative amplitudes were measured at 243.0 and 230.3 nm for the assay of PAR and MET, respectively. Calibration graphs were established for 2-30 microg ml for PAR and 2-36 microg/ml for MET in binary mixture. The detection limits for PAR and MET were found 0.097 and 0.079 microg/ml, respectively; while the quantification limits were 0.573 microg/ml for PAR and 1.717 microg/ml for MET. For the HPLC procedure, a reversed-phase column with a mobile phase of methanol-water (60:40, v/v), was used to separate both compounds with a detection of 274.0 nm. Linearity was obtained in the concentration range of 2 300 and 1.5-375 microg/ml for PAR and MET, respectively. The detection and quantification limits were found to be 0.42 and 1.4 microg/ml for PAR and 0.36 and 1.2 microg/ml for MET, respectively. The relative standard deviations were found to be less than 0.52%, indicating reasonable repeatibility of both methods. The proposed methods were successfully applied to the determination of these drugs in commercial tablets.

Electrochemical reduction of metronidazole at activated glassy carbon electrode and its determination in pharmaceutical dosage forms.

A voltammetric method has been developed for the determination of metronidazole in dosage forms. The method is based on the electrochemical reduction of the drug at a glassy carbon electrode activated by applying a new pretreatment. The influence of pH, concentration, scan rate and presence of organic solvent and surfactant has been studied. The current is proportional to the concentration and permits the drug to be determined in the concentration range 2 x 10(-6)-6 x 10(-4) M in Britton-Robinson buffer (pH 10). Furthermore, results obtained by the proposed method have been compared with USP XXIII procedure which involves a HPLC method.

Formulation of zolmitriptan sublingual tablets prepared by direct compression with different polymers: In vitro and in vivo evaluation

First-pass metabolism can be overcome by sublingual drug delivery, and quick drug entry into the systemic circulation can be obtained. In certain diseases such as migraine therapy, taking fast pharmacological response is an important criteria. In this study, zolmitriptan sublingual tablets were prepared by direct compression method using different mucoadhesive polymers such as hydroxypropyl methyl cellulose, chitosan and sodium carboxy methyl cellulose at a concentration range of 0.5-5% to reduce flushing action of saliva and provide enough time for drug to be absorbed. Tablets were evaluated for the physical properties, and optimum formulations were chosen for in vivo studies to carry on sheep model. The tablets disintegrated rapidly, and dissolution tests revealed that zolmitriptan was dissolved from the formulation within the compendial limits. This especially showed us that the concentration range of polymers is in acceptable limit. It was also concluded that microcrystalline cellulose, spray-dried lactose and sodium starch glycolate are the appropriate excipient and formulated in good proportions. In vivo studies indicated that formulation containing 5% chitosan has the maximum C(max) and AUC and minimum t(max) values (p<0.05). As a result, sublingual tablet administration of zolmitriptan formulated with appropriate excipients and especially with chitosan seems promising alternative to traditional routes.

Enhanced release of solid dispersions of etodolac in polyethylene glycol

This work examines the release of etodolac from various molecular weight fractions of polyethylene glycol (PEG) solid dispersions. Solid dispersions of etodolac were prepared in different molar ratios of drug/carrier by using solvent and melting methods. The release rate of etodolac from the resulting complexes was determined from dissolution studies by use of USP dissolution apparatus 2 (paddle method). The physical state and drug:PEG interaction of solid dispersions and physical mixtures were characterized by X-ray diffraction (XRD), infrared spectroscopy (IR) and differential scanning calorimetry (DSC). The dissolution rate of etodolac is increased in all of the solid dispersion systems compared to that of the pure drug and physical mixtures. The solid dispersion compound prepared in the molar ratio of 1:5 by the solvent method was found to have the fastest dissolution profile. The physical properties did not change after 9 months storage in normal conditions.

Electroanalytical study of nifedipine using activated glassy carbon electrode

The electrochemical properties of nifedipine have been investigated in aqueous solution by linear sweep and cyclic voltammetry. The method is based both on the reduction and on the oxidation of the drug at a glassy carbon electrode activated by applying a new pre-treatment. The voltammograms of nifedipine on pH, concentration and scan rate have been carefully examined. Both the electroreduction and electrooxidation of nifedipine allow its determination at pH 1.5 in the concentration range of 2 x 10(-5)-6 x 10(-4) M and 8 x 10(-5)-1 x 10(-3) M, respectively. The method has been applied to commercial samples (tablets and capsules).

High-performance liquid chromatographic analysis of verapamil and its application to determination in tablet dosage forms and to drug dissolution studies

A high-performance liquid chromatographic procedure with two detectors is presented for the determination of verapamil in pharmaceutical dosage forms. The procedure is based on the use of reversed-phase high-performance liquid chromatography with UV and fluorimetric detectors. Each analysis required no longer than 6 min for both detection procedures. Quantification was achieved by measurement of the ratio of the peak area of the drug to the internal standard (fluoxetine) and the detection limit was 10 ng/ml for the UV detector and 750 pg/ml for the fluorimetric detector. There was no significant difference between inter- and intra-day studies for verapamil determined for two different concentrations (0.05 and 1.00 microgram/ml). This process could be used to determine verapamil concentrations in the range 0.025-50 and 0.0008-20 micrograms/ml for UV and fluorimetric detection, respectively. These methods were applied, without any interference from the excipients, for the determination of the drug in tablets and in drug dissolution studies. It is suggested that the proposed HPLC procedures could be used for routine quality control and dosage form assay of verapamil hydrochloride.