Pharmacokinetics

This study aimed to develop hydrophilic matrix based controlled release  gastroretentive drug delivery system of Lamivudine floating matrix tablets, which after oral administration are designed to prolong the gastric residence time, increase the drug bioavailability and diminish the side effects of irritating drugs. FTIR studies revealed that there is no interaction between the drug and polymers used for the formulation. Among all the formulations F21 containing HPMC K100M, Carbopol 934P, Polyox WSR 303 and sodium bicarbonate, as gas generating agent was selected as optimized formulation based on physico chemical properties, floating lag time (34 sec) and total floating time (>24 h). From in vitro dissolution studies, the optimized formulation F21 showed drug release of 99.36±5.36%, whereas 92.36±5.02% of the drug was released from the marketed product within 24h. From in vivo bioavailability studies, after oral administration of floating tablet containing 100 mg Lamivudine, the Cmax, Tmax, and AUC0–∞ of optimized gastroretentive formulation were found to be 32.11±3.16 µg/mL, 8.00±1.26 h and 225±28.14 µg*h/ml, respectively. Cmax and AUC values of optimized formulation were found to be significantly higher than of marketed product, where longer gastric residence time is an important condition for prolonged or controlled drug release and also for improved bioavailability. Hence, gastro retention can be a promising approach to enhance bioavaiilability of Lamivudine with narrow absorption window in upper GIT.

The objective of present study was to prepare and evaluate orally fast dissolving film of Esomeprazole magnesium trihydrate for the effective management of peptic ulcers to prevent excess amount of acid secretion in the stomach. Drug Esomeprazole was identified using DSC, FTIR and XRD. To improve the water solubility beta cyclodextrin complex of drug in 1:1 milimolar ratio was prepared. Solubility of drug in complex was found to be 7.67±0.52 mg/ml, represents the complex formation between drug and beta cyclodextrin. 21 batches of fast dissolving film of beta cyclodextrin complex were prepared by using different type of film forming agent, different concentration of film forming agent, different type of plasticizers, and different concentration of plasticizer agent. On evaluation, HPMC E15 and propylene glycol was optimized. Most of the films were homogeneous, transparent, colorless, flexible and easily peel out. The prepared films were subjected to characterization for weight variations, thickness, disintegration time, dissolving time, drug release pattern, % moisture loss etc.  On drug release kinetic mode study, optimized fast dissolving film following Higuchi model.  The scanning electron photomicrograph of the film showed smooth surface with some little pores and without any scratches or transverse striations which is an indication of uniform distribution of drug particles and fast disintegration. Films were stored at different temperature did not show any changes in the physical appearance. Clear, transparent and homogeneous films remained throughout the 90 days but at accelerated temperature conditions, some part of film was breakdown during Peeling out.

The authors proposed a simple, rapid and sensitive liquid chromatography / tandem mass spectrometry assay method for the determination of nateglinide in human plasma using carbamazepine as internal standard (IS). Analyte and the IS were extracted from the human plasma via liquid-liquid extraction using ethyl acetate. The chromatographic separation was achieved on a C18 column by using a mixture of 0.1% formic acid buffer –acetonitrile buffer (20:80, v/v) as the mobile phase at a flow rate of 0.8 mL/min. The calibration curve obtained was linear (r2 ³ 0.99) over the concentration range of 10.0–10005 ng/mL. Method validation was performed as per FDA guidelines and the results met the acceptance criteria. The proposed method was found to be applicable to pharmacokinetic studies.

In this paper the authors proposed a simple, sensitive and selective liquid chromatography–tandem mass spectrometry (LC–MS/MS) assay method for the determination of mosapride in human plasma. This method employed mosapride–d5 as an internal standard (IS). Analyte and the IS were extracted form 100 µL of human plasma using solid–phase extraction with no drying, evaporation and reconstitution steps. The chromatographic separation was achieved on a C18 column by using a mixture of methanol and 5mM ammonium acetate (80:20, v/v) as the mobile phase at a flow rate of 1.0 mL/min. The linearity of the method was established in the concentration range 0.18–60.0 ng/mL with r2 ³ 0.99. The intra–day and inter–day precision (%CV) and accuracy results in five validation batches across five concentration levels were well within the acceptance limits. The validated method was found to be applicable to clinical studies.

In this paper the authors proposed a simple, sensitive and selective liquid chromatography–tandem mass spectrometry (LC–MS/MS) assay method for the determination of darifenacin in human plasma. This method employed solifenacin as an internal standard (IS). Analyte and the IS were extracted form 200 µL of human plasma using protein precipitation technique. The chromatographic separation was achieved on a C18 column by using a mixture of acetonitrile and 5mM ammonium formate in 0.01% formic acid (90:10, v/v) as the mobile phase at a flow rate of 1.0 mL/min. The linearity of the method was established in the concentration range 0.05–20.5 ng/mL with r2 ³ 0.99. The intra–day and inter–day precision (%CV) and accuracy results in three validation batches across five concentration levels were well within the acceptance limits. The validated method was successfully applied to a pharmacokinetic study in humans under fasting condition with 15 mg darifenacin extended release tablet.

Gastro esophageal reflux disease is a chronic, recurrent disease that affects millions of people worldwide. Proton pump inhibitors are a group of drugs whose main action is a pronounced and long-lasting reduction of gastric acid production. These drugs are utilized in the treatment of many conditions such as Dyspepsia, Peptic ulcer disease, Gastro esophageal reflux disease. Currently proton pump inhibitors are available in both oral and injectable formulation. Proton pump inhibitors are substituted benzimidazoles that inhibit gastric acid secretion via inhibition of the gastric H+/K+ ATPase pump. Although there are some differences in pharmacokinetics and binding affinity for the pump, these drugs are comparatively similar in their efficacy in treatment of gastric diseases. The delayed release proton pump inhibitors effectively suppress gastric acid secretion and successfully treat acid-related disorders. Each differs somewhat in its formulations. The difference in the formulations has not been translated  into clinical advantages over the delayed release proton pump inhibitors. Novel multiple formulations approaches are required for proton pump inhibitors to enhance acid suppression. Although the individual proton pump inhibitors have similar efficacy in many cases, differences between them should be considered when choosing a treatment regimen.

This paper describes a simple, rapid and sensitive bioanalytical method based on liquid chromatography / tandem mass spectrometry (LC–MS/MS) for the determination of integrase inhibitor raltegravir in human plasma samples. Carbamazepine was used as an internal standard (IS). Analyte and the internal standard were extracted from 200 µL of human plasma via solid phase extraction. The chromatographic separation was achieved on a C18 column by using a mixture of acetonitrile and 0.1% formic acid (90:10, v/v) as the mobile phase at a flow rate of 0.8 mL/min. The calibration curve obtained was linear (r2 ³ 0.99) over the concentration range of 20.1–4007 ng/mL. Method validation was performed as per FDA guidelines and the results met the acceptance criteria. A run time of 2.0 min for each sample made it possible to analyze more number of samples in short time, thus increasing the productivity. The proposed method was found to be applicable to pharmacokinetic studies in humans.

This study describes the development and characterization of Enteric coated pellets of duloxetine hydrochloride that results to improve gastric stability and enhance oral systemic exposure of novel serotonin and nor-epinephrine reuptake inhibitor (SNRI), duloxetine. Duloxetine Pellets were prepared by coating drug solution on sugar sphere followed by various layering in fluidized bed Coater (FBC) with different polymers like hydroxy propyl methylcellulose (HPMC E5), Crospovidone, Hypermellose Acetate Succinate and polysorbate 80 in suitable proportion. In vitro Dissolution studies were carried out in 0.1N HCl (pH: 2) for two hours followed by Phosphate buffer (pH: 6.8) for 1.5 hours with USP (Type-II) dissolution method. Absorption studies for Optimized pellets were carried out in Rats at 5 mg/kg dose; pellets were filled in Capsule size 9 administered orally with modified gavage needle. The optimized formulation has better correlation in both In vitro and In vivo system. The systemic exposure (AUC) and maximum concentration in plasma (Cmax) of entiric coated pellets of duloxetine was significantly higher than conventional suspension formulation. Finally it can be concluded that multiparticulate approach can be used to improve the stability and systemic exposure of pH sensitive and poorly water-soluble drugs such as duloxetine.

The aim of this study was to evaluate the bioequivalence of Diopolol (containing Bisoprolol fumarate 10 mg) tablet of SAVA Healthcare Ltd, India with Concore (Containing Bisoprolol hemifumarate 10 mg) tablet of Merck Serono, Germany in healthy adult volunteers. This open label, balanced, single-dose, randomized, two period, two sequences ,crossover oral bioequivalence study was conducted in 24 healthy human adult male subjects under fasting condition. Subjects received bisoprolol 10 mg of either test or reference formulation with a washout period of 7 days. After study drug administration, serial blood samples were collected over a period of 48 hours. The plasma concentrations of bisoprolol were determined by a validated method using LC/MS/MS. Pharmacokinetic parameters Cmax, Tmax, T1/2, AUC0-t, AUC0-∞, and kel, were determined for both the formulations. The formulations were to be considered bioequivalent if the geometric least square mean ratio of test and reference of Cmax, AUC0-t, and AUC0-∞, were within the predetermined bioequivalence range of 80% to 125%. A total of 24 subjects were enrolled. No significant differences were found based on analysis of variance. The 90% confidence intervals (CI) of Cmax, AUC0-t and AUC0-∞, of bisoprolol were 103.29 - 115.15, 103.73 - 116.62, and 94.78 - 116.64 respectively This study shows that the test formulation is bioequivalent to the reference formulation for bisoprolol.

The present study was aimed to study the requirements of bioequivalence for registration of pharmaceutical products in various countries. It is essential for pharmaceutical industry to study the guidelines of bioequivalence for respective country where industry would like to apply for ANDA and thus want to enter into generic market. This study gives insight about requirements of bioequivalence with study parameters such as study design, fasting or fed state studies, volunteers recruitment, study dose, sampling points, analytical method validation parameters, moieties to be measured in plasma, pharmacokinetic parameters, criteria for bioequivalence, GCP requirements etc. which are needed for pharmaceutical industry to carry out bioequivalence studies and to file ANDA. Test products for these bioequivalence studies are usually manufactured by a sponsor or manufacturer while reference is provided by the government laboratories of respective countries. Sampling points also varies with respect to the regulatory guidelines of these countries. India follows Indian GCP guidelines, South-Africa MCC GCP guidelines and Australia follows ICH GCP guidelines. Criteria of bioequivalence, for India and South-Africa is 90% CI 80-125% for Cmax, AUCt, AUCo-inf. for Australia 90% CI 80-125% for Cmax, hAUCt, AUCo-inf.