Ranjeet Prasad Dash

Role of mucoadhesive polymers in enhancing delivery of nimodipine microemulsion to brain via intranasal route

Intranasal drug administration is receiving increased attention as a delivery method for bypassing the blood–brain barrier and rapidly targeting therapeutics to the CNS. However, rapid mucociliary clearance in the nasal cavity is a major hurdle. The purpose of this study was to evaluate the effect of mucoadhesive polymers in enhancing the delivery of nimodipine microemulsion to the brain via the intranasal route. The optimized mucoadhesive microemulsion was characterized, and the in vitro drug release and in vivo nasal absorption of drug from the new formulation were evaluated in rats. The optimized formulation consisted of Capmul MCM as oil, Labrasol as surfactant, and Transcutol P as co-surfactant, with a particle size of 250 nm and zeta potential value of −15 mV. In vitro and ex vivo permeation studies showed an initial burst of drug release at 30 min and sustained release up to 6 h, attributable to the presence of free drug entrapped in the mucoadhesive layer. In vivo pharmacokinetic studies in rats showed that the use of the mucoadhesive microemulsion enhanced brain and plasma concentrations of nimodipine. These results suggest that incorporation of a mucoadhesive agent in a microemulsion intranasal delivery system can increase the retention time of the formulation and enhance brain delivery of drugs.

Simultaneous Quantification of Aliskiren, Valsartan and Sitagliptin by LC with Fluorescence Detection: Evidence of Pharmacokinetic Interaction in Rats

A sensitive, precise and simple LC method for the simultaneous quantification of aliskiren, valsartan and sitagliptin in rat plasma has been developed and validated. The chromatographic separation was achieved on a C18 column (250xa0mmxa0×xa04.6xa0mm, 5xa0μm) maintained at room temperature, using isocratic elution with acetonitrile/20xa0mM ammonium acetate buffer (35:65, v/v), pH adjusted to 4.85 with glacial acetic acid, and detected using a fluorescence detector. Liquid–liquid extraction of the aliskiren, valsartan and sitagliptin from the rat plasma with t-butyl methyl ether resulted in their high recoveries. LC calibration curves based on the extracts from the rat plasma were linear in the range of 25–2,000xa0ngxa0mL−1 for aliskiren and sitagliptin and 50–4,000xa0ngxa0mL−1 for valsartan. The limits of quantification were 25xa0ngxa0mL−1 for aliskiren and sitagliptin and 50xa0ngxa0mL−1 for valsartan. The precision and accuracy of the method were well within the generally accepted criteria for biomedical analysis. The described method was successfully applied to study the pharmacokinetics of aliskiren, valsartan and sitagliptin following oral administration, individually as well as in combination in Sprague–Dawley rats. The results of the study implied the occurrence of pharmacokinetic interaction upon the co-administration of these three drugs.

Therapeutic Potential and Utility of Elacridar with Respect to P-glycoprotein Inhibition: An Insight from the Published In Vitro, Preclinical and Clinical Studies

The occurrence of efflux mechanisms via Permeability-glycoprotein (P-gp) recognized as an important physiological process impedes drug entry or transport across membranes into tissues. In some instances, either low oral bioavailability or lack of brain penetration has been attributed to P-gp mediated efflux activity. Therefore, the objective of development of P-gp inhibitors was to facilitate the attainment of higher drug exposures in tissues. Many third-generation P-gp inhibitors such as elacridar, tariquidar, zosuquidar, etc. have entered clinical development to fulfil the promise. The body of evidence from in vitro and in vivo preclinical and clinical data reviewed in this paper provides the basis for an effective blockade of P-gp efflux mechanism by elacridar. However, clinical translation of the promise has been elusive not just for elacridar but also for other P-gp inhibitors in this class. The review provides introspection and perspectives on the lack of clinical translation of this class of drugs and a broad framework of strategies and considerations in the potential application of elacridar and other P-gp inhibitors in oncology therapeutics.

Formulation and pharmacokinetic evaluation of hard gelatin capsule encapsulating lyophilized Vasa Swaras for improved stability and oral bioavailability of vasicine

The oral bioavailability of vasicine (1) was investigated in hard gelatin capsules of lyophilized Vasa Swaras (aqueous extract of Adhatoda vasica Nees.,Fam.: Acanthaceae) The rat pharmacokinetic profile of lyophilized Vasa Swaras, Vasa Swaras, vasicine (1) (chief marker compounds of A. vasica) and a marketed capsule formulation of A. vasica were compared. Vasicine (1) was found to be more orally bioavailable from lyophilized Vasa Swaras, with an overall minor conversion to vasicinone (2).

Review of the pharmacokinetics of dalbavancin, a recently approved lipoglycopeptide antibiotic

Abstract Dalbavancin, a recently approved glycopeptide antibiotic, whose disposition is not affected by renal function as compared to vancomycin is used to treat serious infections caused by Staphylococci and Streptococci including multiple drug-resistant strains. Although reviews of the pharmacodynamic and clinical efficacy of dalbavancin have been published, a comprehensive overview of the pharmacokinetic properties including distribution and disposition in animals and humans has not been published. The aim of this review is to summarize the pharmacokinetics of dalbavancin, which justifies the intravenous dosing regimens and to provide considerations and perspectives with regard to dosing strategies. It is concluded that dalbavancin, despite high protein binding offers pharmacokinetic benefits such as good tissue penetration and long half-life. Dalbavancin may be a drug of choice and replace more resource demanding intravenous drugs to treat serious infections in a hospital setting.

Comparative pharmacokinetics of three SGLT-2 inhibitors sergliflozin, remogliflozin and ertugliflozin: an overview

Abstract 1.u2002Several sodium-glucose cotransporter-2 (SGLT-2) inhibitors are in clinical use for the management of type 2 diabetes. The objectives of the current review were: (a) to provide a comparative pharmacokinetics including absorption, distribution, metabolism and excretory (ADME) profiles of three SGLT-2 inhibitors namely: sergliflozin, remogliflozin and ertugliflozin; (b) to provide some perspectives on possible developmental issues. 2.u2002Based on the half-life (t1/2) values observed in humans, the rank order of the three SGLT-2 inhibitors was ertugliflozin (16u2009h) > remogliflozin (2–4u2009h) > sergliflozin (1–1.5u2009h). Therefore, while once a day dosing of ertugliflozin is possible, the other two drugs need to be dosed more frequently. Perhaps, the short t1/2 of sergliflozin may have contributed for its discontinuation. 3.u2002Although there was paucity of published data on the metabolism, transporter related and excretory aspects for sergliflozin, the other two drugs provided a differentiating profile. However, the compiled data suggested that there may be a minimal or no risk of pharmacokinetic drug interaction issues associated with any of the reviewed drugs. 4.u2002Because of the crowded development pipeline and approved SGLT-2 inhibitors, the safety and efficacy of sergliflozin, remogliflozin and ertugliflozin appear to be a key from differentiation perspective.

Pharmacokinetics of Phytopharmaceuticals: A Peek into Contingencies and Impediments in Herbal Drug Development

Plant secondary metabolites have been extensively used in the treatment of many diseases and have served as compounds of interest, both in their natural form and as templates for synthetic modification. With the help of the traditional knowledge, indigenous people try to derive therapeutic materials from thousands of plants; however, their safety and efficacy remain a vital concern. Natural product-based drug discovery involves the identification of new chemical entities (NCEs) of potential therapeutic interest through chemical synthesis or isolation from natural sources. Although some of these drugs have entered the international pharmacopeia through the study of ethnopharmacology and traditional medicine, they are very small in number. It is because of limitations with the availability of proper guidelines for standardization, manufacture, and quality control, which are required for herbal medicinal products. Data regarding the safety and efficacy needs to be generated from preclinical and clinical pharmacokinetic and pharmacodynamic studies. A better understanding of pharmacokinetics and bioavailability of phytopharmaceuticals can be of immense help in designing the rational dosage regimens. Based on the preclinical pharmacokinetic data, suitable formulations may be developed to ensure optimum efficacy and safety. In this article, the authors would like to share their research experiences about various aspects of pharmacokinetics, which need to be addressed to generate reliable data on safety and efficacy of herbal drugs. This information would be helpful in designing rationalized preclinical pharmacokinetic studies.

Reappraisal and perspectives of clinical drug–drug interaction potential of α-glucosidase inhibitors such as acarbose, voglibose and miglitol in the treatment of type 2 diabetes mellitus

Abstract 1.u2003Amidst the new strategies being developed for the management of type 2 diabetes mellitus (T2DM) with both established and newer therapies, alpha glucosidase inhibitors (AGIs) have found a place in several treatment protocols. 2.u2003The objectives of the review were: (a) to compile and evaluate the various clinical pharmacokinetic drug interaction data for AGIs such as acarbose, miglitol and voglibose; (b) provide perspectives on the drug interaction data since it encompasses coadministered drugs in several key areas of comorbidity with T2DM. 3.u2003Critical evaluation of the interaction data suggested that the absorption and bioavailability of many coadministered drugs were not meaningfully affected from a clinical perspective. Therefore, on the basis of the current appraisal, none of the AGIs showed an alarming and/or overwhelming trend of interaction potential with several coadministered drugs. Hence, dosage adjustment is not warranted in the use of AGIs in T2DM patients in situations of comorbidity. 4.u2003The newly evolving fixed dose combination strategies with AGIs need to be carefully evaluated to ensure that the absorption and bioavailability of the added drug are not impaired due to concomitant food ingestion.

Two Decades-Long Journey from Riluzole to Edaravone: Revisiting the Clinical Pharmacokinetics of the Only Two Amyotrophic Lateral Sclerosis Therapeutics

The recent approval of edaravone has provided an intravenous option to treat amyotrophic lateral sclerosis (ALS) in addition to the existing oral agent, riluzole. The present work was primarily undertaken to provide a comprehensive clinical pharmacokinetic summary of the two approved ALS therapeutics. The key objectives of the review were to (i) tabulate the clinical pharmacokinetics of riluzole and edaravone with emphasis on absorption, distribution, metabolism and excretion (ADME) properties; (ii) provide a comparative scenario of the pharmacokinetics of the two drugs wherever possible; and (iii) provide perspectives and introspection on the gathered clinical pharmacokinetic data of the two drugs with appropriate conjectures to quench scientific curiosity. Based on this review, the following key highlights were deduced: (i) as a result of both presystemic metabolism and polymorphic hepatic cytochrome P450 (CYP) metabolism, the oral drug riluzole exhibited more inter-subject variability than that of intravenous edaravone; (ii) using various parameters for comparison, including the published intravenous data for riluzole, it was apparent that edaravone was achieving the desired systemic concentrations to possibly drive the local brain concentrations for its efficacy in ALS patients with lesser variability than riluzole; (iii) using scientific conjectures, it was deduced that the availability of intravenous riluzole may not be beneficial in therapy due to its fast systemic clearance; (iv) on the contrary, however, there appeared to be an opportunity for the development of an oral dosage form of edaravone, which may potentially benefit the therapy option for ALS patients by avoiding hospitalization costs; and (v) because of the existence of pharmaco-resistance for the brain entry in ALS patients, it appeared prudent to consider combination strategies of edaravone and/or riluzole with suitable P-glycoprotein efflux-blocking drugs to gain more favorable outcomes in ALS patients.

SIMULTANEOUS QUANTIFICATION OF ROSUVASTATIN AND FENOFIBRIC ACID BY HPLC-UV IN RAT PLASMA AND ITS APPLICATION TO PHARMACOKINETIC STUDY

A sensitive, precise, and simple HPLC method was developed for the simultaneous quantification of rosuvastatin and fenofibric acid in rat plasma. The chromatographic separation was achieved on a C18 (250 mm × 4.6 mm, 5 mm) column maintained at room temperature, using isocratic elution with acetonitrile:0.1%disodium hydrogen orthophosphate buffer (50:50%, v/v) and detected using UV-Visible detector at a UV wavelength of 248 nm. The liquid–liquid extraction of both the drugs from rat plasma with ethyl acetate resulted in their high recoveries (≥80%). HPLC calibration curves based on the extracts from the rat plasma were linear in the range of 50–3000 ng/mL for rosuvastatin and 100–6000 ng/mL for fenofibric acid. The lower limits of quantification were 50 and 100 ng/mL for rosuvastatin and fenofibric acid, respectively. The precision and accuracy of the method were well within the accepted criteria (±15%) for biomedical analysis. Stability studies showed that both the drugs were stable in rat plasma for short- and long-term period for sample preparation and analysis. The described method was successfully applied to study the pharmacokinetics of rosuvastatin and fenofibrate in Sprague–Dawley rats following a single dose, oral administration in combination. The application of the method confirmed its utility.