Shery Jacob

A simple practice guide for dose conversion between animals and human.

Understanding the concept of extrapolation of dose between species is important for pharmaceutical researchers when initiating new animal or human experiments. Interspecies allometric scaling for dose conversion from animal to human studies is one of the most controversial areas in clinical pharmacology. Allometric approach considers the differences in body surface area, which is associated with animal weight while extrapolating the doses of therapeutic agents among the species. This review provides basic information about translation of doses between species and estimation of starting dose for clinical trials using allometric scaling. The method of calculation of injection volume for parenteral formulation based on human equivalent dose is also briefed.

An Updated Overview on Therapeutic Drug Monitoring of Recent Antiepileptic Drugs

Given the distinctive characteristics of both epilepsy and antiepileptic drugs (AEDs), therapeutic drug monitoring (TDM) can make a significant contribution to the field of epilepsy. The measurement and interpretation of serum drug concentrations can be of benefit in the treatment of uncontrollable seizures and in cases of clinical toxicity; it can aid in the individualization of therapy and in adjusting for variable or nonlinear pharmacokinetics; and can be useful in special populations such as pregnancy. This review examines the potential for TDM of newer AEDs such as eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, perampanel, pregabalin, rufinamide, retigabine, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide. We describe the relationships between serum drug concentration, clinical effect, and adverse drug reactions for each AED as well as the different analytical methods used for serum drug quantification. We discuss retrospective studies and prospective data on the serum drug concentration–efficacy of these drugs and present the pharmacokinetic parameters, oral bioavailability, reference concentration range, and active metabolites of newer AEDs. Limited data are available for recent AEDs, and we discuss the connection between drug concentrations in terms of clinical efficacy and nonresponse. Although we do not propose routine TDM, serum drug measurement can play a beneficial role in patient management and treatment individualization. Standardized studies designed to assess, in particular, concentration–efficacy–toxicity relationships for recent AEDs are urgently required.

Delivery of a classical antihypertensive agent through the skin by chemical enhancers and iontophoresis.

Background/purpose: Oral therapy with antihypertensive agents is generally associated with severe GI side effects and low patient compliance. Therefore, development of a method of drug delivery that maintains the proper drug level for a prolonged period without adverse effects is required. Thus, transdermal delivery has all the necessities that are required for delivery of classical antihypertensive agents. However, the different approaches to enhance the transport of atenolol through intact skin have not resulted in a remarkable improvement.

Preparation and evaluation of fast-disintegrating effervescent tablets of glibenclamide.

Fast-dissolving effervescent tablets (FETs) were prepared by the modification of nonreactive liquid-based wet granulation technique. Effervescent systems are not stable in the presence of trace amount of moisture, and elimination or inactivation of free water is the key to stability apart from manufacturing in controlled humidity environment. Our main objective of the project was to develop FETs of glibenclamide based on highly plastic granules that can be compressed at low pressure to form fast-melting pharmaceutical tablets. In this study, we have screened various acid and carbonate sources for the effervescent system. Citric acid was coated with plastic materials such as polyethylene glycol (PEG), which provide a physical barrier to the reaction. The inherent hygroscopic nature of PEG could decrease the affinity for moisture of effervescent mixtures and can provide a stabilizing effect. Sodium bicarbonate was blended with sugar alcohol like mannitol, which would give a protective coating. PEG 1000 melts at body temperature (∼37°C) and thereby does not delay the reaction between the acid source and base. The present formulation using citric acid–sodium bicarbonate and citric acid–sodium glycine carbonate tablet with PEG and mannitol was found to have better reaction properties and reaction stability than does the standard citric acid–sodium bicarbonate tablet. FETs of glibenclamide might aid in dissolution due to increase in microenvironmental pH around the granules and saliva. Sensory study on disintegration time and mouth feel attributes ranked the present formulation based on grittiness, chalkiness, and overall preference as best.

Basic considerations in the dermatokinetics of topical formulations

Assessing the bioavailability of drug molecules at the site of action provides better insight into the efficiency of a dosage form. However, determining drug concentration in the skin layers following topical application of dermatological formulations is a great challenge. The protocols followed in oral formulations could not be applied for topical dosage forms. The regulatory agencies are considering several possible approaches such as tape stripping, microdialysis etc. On the other hand, the skin bioavailability assessment of xenobiotics is equally important for topical formulations in order to evaluate the toxicity. It is always possible that drug molecules applied on the skin surface may transport thorough the skin and reaches systemic circulation. Thus the real time measurement of molecules in the skin layer has become obligatory. In the last two decades, quite a few investigations have been carried out to assess the skin bioavailability and toxicity of topical/dermatological products. This review provides current understanding on the basics of dermatokinetics, drug depot formation, skin metabolism and clearance of drug molecules from the skin layers following application of topical formulations.

Preparation and evaluation of niosome gel containing acyclovir for enhanced dermal deposition

Abstract Niosomes suggest a versatile vesicle delivery system with possible transport of drugs via topical route for skin delivery. The aim of the present research was to optimize niosome gel formulation of acyclovir and to evaluate in both in vitro and in vivo rabbit model. Niosome formulations were formulated by coacervation phase separation technique with different ratios of nonionic surfactants, phospholipids and cholesterol using 32 factorial design. Altering the surfactant concentration has influenced the drug entrapment, but not vesicle size. At high surfactant combinations, the acyclovir release from niosomes was strongly influenced by cholesterol:lecithin ratio. Ex vivo drug permeation data indicate substantial difference in flux values and was influenced by the niosome composition. Ex vivo studies using formulation (B8) for drug deposition indicate greater amount of niosome being diffused into the skin layers and formed a depot, compared to commercial acyclovir cream (control). Two distinct dermatopharmacokinetic profiles were observed, in vivo, for niosome gel formulation (B8) and control, which were analog to the profiles observed with ex vivo deposition studies. In vivo plasma drug level suggests low systemic exposure of acyclovir (Cmax: 9.44 ± 2.27 ng/mL and 14.54 ± 3.11 ng/mL for niosome formulation and control, respectively). Comparison of kinetic data of acyclovir in the stratum corneum and plasma signifies that the niosome formulation forms a depot in the epidermis or dermis region. This study concludes that the niosome gel formulation (B8) could be a viable vesicular system for an impressive transdermal delivery of acyclovir by topical application.

Dose translation between laboratory animals and human in preclinical and clinical phases of drug development

Preclinical Research & Development

An updated overview with simple and practical approach for developing in vitro-in vivo correlation

Preclinical Research & Development

Cyclodextrin complexes: Perspective from drug delivery and formulation

Cyclodextrins (CDs) have been widely investigated as a unique pharmaceutical excipient for past few decades and is still explored for new applications. They are highly versatile oligosaccharides which possess multifunctional characteristics, and are mainly used to improve the physicochemical stability, solubility, dissolution rate, and bioavailability of drugs. Stability constant, factors affecting complexation, techniques to enhance complexation efficiency, the preparation methods for molecular inclusion complexes and release of guest molecules are discussed in brief. In addition, different CD derivatives and their pharmacokinetics are elaborated. Further, the significance of CD complex in aqueous solubility, dissolution and bioavailability, stability, and taste masking is explained. The recent advancement of CDs in developing various drug delivery systems is enlightened. Indeed, the potential of CDs by means of inclusion complex formation have widen the applicability of these materials in various drug delivery systems including ocular, osmotic, mucoadhesive, transdermal, nasal, and targeted delivery systems. Feasibility studies have been performed on the benefit of these cyclic oligomers as nanocarriers, a strategy that can modify the drugs with improved physicochemical properties. Studies also demonstrated the feasibility of CDs to self‐assemble in the form of stable nanoaggregates, which may extend the scope of CDs in drug delivery to the continually expanding list of new drug entities.

Acid neutralization capacity and cost-effectiveness of antacids sold in various retail pharmacies in the United Arab Emirates

The objective of this research was to determine the acid neutralization capacity (ANC) at 37°C ± 2°C (as per United States Pharmacopeia 30 and the National Formulary 25) of antacid preparations sold in various retail pharmacies in the United Arab Emirates. Another important objective was to quantify the sodium and calorific content of antacids, as well as overall monthly consumption, and cost of therapy of different antacids from different manufacturers. The tablet and liquid antacids fall into four statistically different ANC groups. Three of the tablet antacids have an ANC similar to that of liquid antacid medications described as being in the high-ANC class. Of the five liquid antacids tested, only two were found to have a high ANC between four production lots at 5% level of significance. The ANC of the most effective liquid antacid was twice that of the lowest. However, this variation in capacity for neutralization is not observed in the product description of antacid brands. A standard dose is one to two teaspoons: one teaspoon will neutralize 20.2–35.92 mEq and two teaspoons will neutralize 40.44–71.84 mEq depending on the antacid selected. It is apparent from the results of quantification that maximum ANC combined with a minimum dosage volume–weight ratio is achieved by antacids from the high- or intermediate/high-ANC group. Consumption of these categories of antacids is beneficial as they contain less sodium and fewer calories and they are less expensive for pharmacists and/or the public. The monthly cost of daily high-dose therapy is much lower for high-ANC tablet antacids than for low-ANC tablet antacids. In conclusion, if antacids are to be used optimally, it is imperative that the ANC is specified on the product label.