Ayhan Savaser

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.

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.

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.

Development and validation of an RP-HPLC method for the determination of valacyclovir in tablets and human serum and its application to drug dissolution studies

Abstract A specific, sensitive, simple, and rapid HPLC method has been developed for the determination of valacyclovir (VACL) in raw material, pharmaceutical dosage forms, and human serum, in order to carry out drug dissolution studies from tablets. The chromatographic separation was achieved with acetonitrile:methanol:0.067 M KH2PO4 (27:20:53, v/v/v) adjusted to pH 6.5 with 3 M NaOH as mobile phase, a Waters Spherisorb C18 column, and UV detection at 244 nm. Etodolac was used as an internal standard. Linearity range was 5–20,000 ng mL−1. Limit of detection obtained was 0.38 and 0.14 ng mL−1 in mobile phase and spiked human serum samples, respectively. The described method can be readily applied, without any interferences from the excipients, for the determination of the drug in tablets, human serum samples, and drug dissolution studies. #Presented at 11th International Pharmaceutical Technology Symposium, September 9–11, 2002, Istanbul, Turkey.

Nasal administration of metoclopramide from different dosage forms: in vitro, ex vivo, and in vivo evaluation

Nasal drug delivery is an interesting route of administration for metoclopramide hydrochloride (MTC) in preventing different kind of emesis. Currently, the routes of administration of antiemetics are oral or intravenous, although patient compliance is often impaired by the difficulties associated with acute emesis or invasiveness of parenteral administration. In this perspective, nasal dosage forms (solution, gel, and lyophilized powder) of MTC were prepared by using a mucoadhesive polymer sodium carboxymethylcellulose (NaCMC). In vitro and ex vivo drug release studies were performed in a modified horizontal diffusion chamber with cellulose membrane and excised cattle nasal mucosa as diffusion barriers. The tolerance of nasal mucosa to the formulation and its components were investigated using light microscopy. In vivo studies were carried out for the optimized formulations in sheep and the pharmacokinetics parameters were compared with oral solution and IV dosage form. The release of MTC from solution and powder formulations was found to be higher than gel formulation (p < 0.05). Histopathological examination did not detect any severe damage. Hydroxypropyl-β-cyclodextrin (HPβCD) used in powder formulations was found to be effective for enhancing the release and absorption of MTC. In contrast to in vitro and ex vivo experiments nasal bioavailability of gel is higher than those of solution and powder (p < 0.05). In conclusion, the NaCMC gel formulation of MTC with mucoadhesive properties with increased permeation rate is promising for prolonging nasal residence time and thereby nasal absorption.

Drug Dissolution Studies and Determination of Deflazacort in Pharmaceutical Formulations and Human Serum Samples by RP‐HPLC

Abstract A simple, sensitive, reproducible, and validated RP‐HPLC method with UV detection is described for the determination of deflazacort in raw material, pharmaceuticals, human serum samples, and in‐vitro drug dissolution studies. The separation was achieved using a C18 (250 × 4.6 mm; 5 µm) column and a mobile phase comprising acetonitrile, methanol, and 0.067 M KH2PO4 in the ratio (27:20:53, v/v/v), adjusted to pH 6.5 with 3 M NaOH. The results of analysis were treated statistically and it has been validated and proven to be rugged. The limit of detection and limit of quantification were found as 2.05 ng mL−1 and 6.83 ng mL−1 in mobile phase and 4.06 ng mL−1 and 13.55 ng mL−1 in human serum samples, respectively. The method produced linear response in the concentration ranges 10–30,000 ng mL−1 in mobile phase and 25–30,000 ng mL−1 in serum samples. The intra‐ and inter‐day assay precision of the method was within 0.92% relative standard deviations in mobile phase and 1.48% relative standard deviations in human serum samples. This method was successfully applied for the determination of the drug in tablet dosage form, human serum, and drug dissolution studies. The results were found to be accurate, reproducible, and free from interference from the excipients or endogenous substance. #Presented at 3rd Agean Analytical Chemistry Days, September 29–October 3, 2002, Levos, Greece.

Effect of different polymers and their combinations on the release of metoclopramide HCl from sustained-release hydrophilic matrix tablets

Metoclopramide HCl (MTC) is commonly used for the management of gastrointestinal disorders. It has a short biological half-life and is usually administered four times daily to maintain effective concentrations throughout the day. The aim of this study is to develop sustained-release hydrophilic matrix tablet formulations of drug to achieve reproducible and predictable release rates, extended duration of activity, decreased toxicity, reduction of required dose, optimized therapy, and improved patient compliance. Hydroxypropylmethyl cellulose (HPMC), carboxymethylcellulose sodium (NaCMC), chitosan and Carbopol 981 were incorporated in the matrix system separately or in combinations as release controlling factor by direct compression technique. Compatibility among the formulation components was assessed by DSC and FTIR analysis. MTC release from matrix was evaluated by using the US Pharmacopeia dissolution apparatus II. All formulations met the criteria of pharmacopeial requirements. Dissolution studies show that polymer type and concentration are important parameters on drug release. Chitosan, carbopol and NaCMC formulations exhibited pH-dependent drug release profile whereas HPMC did not. All the formulations containing 1:1 ratio of HPMC and chitosan exhibited desired drug release showing that all active substance releases progressively in a period of whole dissolution time and therefore it can be regarded as worthy of consideration for the manufacture of sustained-release MTC product.

Simple and Reliable HPLC Method of Abacavir Determination in Pharmaceuticals, Human Serum and Drug Dissolution Studies from Tablets

Abstract This work describes a new, fully validated, simple, rapid, selective, and sensitive HPLC method with UV detection for the direct determination of abacavir in pharmaceutical dosage forms, raw materials, spiked human serum, and drug dissolution studies without any time‐consuming extraction or evaporation steps prior to drug assay. The mobile phase employed was methanol∶acetonitrile: 0.015 M KH2PO4 (36∶2.6∶61.4 v/v/v) adjusted to pH 6.9 with 5 N NaOH. The samples of 20 µL were injected onto a Waters Spherisorb ODSI (250 × 4.6 mm, 5 µm particle size) column. Ketoprofen was used as internal standard. The flow rate was 1.0 mL min−1. The retention times were 5.49 min for abacavir and 9.15 min for ketoprofen in mobile phase, 5.46 min for abacavir and 9.24 min for ketoprofen in serum samples. The samples were detected at 284 nm. The assay was linear in the concentration range 0.010–20 µgmL−1 (r = 0.999) with a slope of 1.35 × 10−3; intercept of 0.0841 and the limit of detection was 0.00093 µg mL−1 in mobile phase and 0.025–20 µg mL−1 (r = 0.999) with a slope of 1.44 × 10−3; intercept of 0.0733 and the limit of detection was 0.00418 µg mL−1 in human serum. The linearity of the detector response for abacavir was determined by plotting peak area ratios vs. concentration. It was successfully applied to the analysis of abacavir pharmaceutical preparations, and human serum samples without any interference by the excipients and endogenous substances. Moreover, the method can be used for the determination of abacavir for monitoring its concentration for in vitro dissolution studies.

The Development and In Vitro Evaluation of Sustained Release Tablet Formulations of Benzydamine Hydrochloride and its Determination

A novel oral controlled delivery system for benzydamine hydrochloride (BN) was developed and optimized. Hydrophilic matrix tablets of BN were prepared by using hydroxypropylmethylcellulose (HPMC) and chitosan as polymer substance to achieve required sustained release profile. The matrix tablets were prepared both direct compression and wet granulation method. The influence of matrix forming agents and binary mixtures of them on BN release was investigated. The formulated tablets were characterized by hardness, friability, thickness, weight variation and in vitro drug release. The formulated tablets had acceptable physicochemical characters. The quantity of BN present in the tablets and the release medium were estimated by a simple, sensitive, rapid and validated HPLC method. The dissolution results show that increased amount of polymer resulted in reduced and extended drug release. F7 formulation containing 12.5% HPMC and 12.5 % chitosan with direct compression method is the optimum formulation due to its better targeting profile in terms of release. Higuchi (diffusion) and Hixon-Crowell (erosion) kinetic profiles were achieved and this codependent mechanism of drug release was established. This formulation may provide an alternative for oral controlled delivery of BN and be helpful in the future treatment of primary normoreactive types of inflammation.

RP‐HPLC Assay of Rofecoxib from Pharmaceutical Dosage Forms and Human Plasma and Its Drug Dissolution Studies

ABSTRACT A high performance liquid chromatographic (HPLC) method is described for the determination of rofecoxib (RFC) in bulk drug, tablets, and human plasma samples. The methods are linear over the concentration ranges 0.005–30.0 and 0.010–10 µg mL−1 in mobile phase and human plasma, respectively. Chromatography was carried out on a reversed phase Spherisorb ODSI column using a mixture of acetonitrile:methanol: 0.067 M KH2PO4 (27:20:53, v/v/v) adjusted to pH 6.95 with 3 M NaOH. Detection was realized at 244 nm using a DAD detector. The retention time observed for RFC and etodolac (internal standard) at about 7.5 and 10.7 min, respectively. The proposed RP‐HPLC method was validated for precision, accuracy, ruggedness, and recovery. The limit of detection was found to be 0.00143 and 0.00301 µg mL−1 in mobile phase and human plasma samples, respectively. The proposed method allows a number of cost and time saving benefits. The described method can be readily applied for the analysis of tablets, drug dissolution studies, and human plasma samples. This method could be used without any interference from tablet matrix and endogenous substance from the plasma samples.