Vikas Bali

Study of surfactant combinations and development of a novel nanoemulsion for minimising variations in bioavailability of ezetimibe

The present study aimed at developing an optimal nanoemulsion of ezetimibe and evaluating its stability, pharmacodynamic and pharmacokinetic potential. Solubility of ezetimibe was determined in various vehicles. Surfactants and cosurfactants were grouped in two different combinations to construct pseudoternary phase diagrams. Formulations were selected from the o/w nanoemulsion region and were subjected to various thermodynamic stability and dispersibility tests. Optimized formulations were characterized for their percentage transmittance, refractive index, viscosity, droplet size and zeta potential. Release rate of optimized formulations was determined using an in vitro dissolution test. The formulation used for assessment of lipid lowering potential and bioavailability contained Capryol 90 (10%, v/v), Tween 20 (33.33%, v/v), PEG 400 (16.67%, v/v), double distilled water (40%, v/v). The release of drug from the nanoemulsion formulations was extremely significant (p<0.001) in comparison to the drug suspension. More than 60% of the drug was released in the initial 1h of the dissolution study in comparison to the drug suspension. The value of total cholesterol in the group administered with the formulation PF1 was highly significant (p<0.001) with respect to the group administered with the suspension of the drug. The plasma concentration time profile of ezetimibe from nanoemulsion represented greater improvement of drug absorption than the marketed formulation and simple drug suspension. The shelf life of the nanoemulsion was found to be 5.94 years at room temperature. The present study established nanoemulsion formulation to be one of the possible alternatives to traditional oral formulations of ezetimibe to improve its bioavailability.

Iontophoresis - An Approach for Controlled Drug Delivery: A Review

The recent approval of lidocaine hydrochloride and epinephrine combined iontophoretic patch (Lidosite Vysteris Inc.) for localized pain treatment by FDA has invigorated the gaining interest in iontophoretic drug delivery systems for the transdermal delivery of drugs. This technique of facilitated movement of ions across a membrane under the influence of an externally applied electric potential difference, is one of the most promising physical skin penetration enhancing method. The rationale behind using this technique is the capability of this method to increase the systemic delivery of high molecular weight compounds with controlled input kinetics and minimum inter-subject variability, which is otherwise achieved only when parentral route of administration is used. Recently, good permeation of larger peptides like insulin has been achieved through this technique in combination with chemical enhancers. This review briefly describes the factors which affect iontophoretic drug delivery and summarizes the studies conducted recently using this technique in order to achieve higher systemic absorption of the drugs having low passive diffusion otherwise. The effect of permeation enhancers (chemical enhancers) on iontophoretic flux of drugs has also been described. Present review also provides an insight into reverse iontophoresis. Various parameters which affect the transdermal absorption of drugs through iontophoresis like drug concentration, polarity of drugs, pH of donor solution, presence of co-ions, ionic strength, electrode polarity etc. have also been reviewed in detail.

Nanocarrier for the enhanced bioavailability of a cardiovascular agent: in vitro, pharmacodynamic, pharmacokinetic and stability assessment.

The goals of the current study were to develop and characterize a nanoemulsion of ezetimibe, evaluate its stability, lipid lowering and pharmacokinetic profile. Solubility of the drug was estimated in various oils and surfactants. Existence of nanoemulsion region was confirmed by plotting phase diagrams. Various thermodynamic stability and dispersibility tests were performed on the formulations chosen from phase diagram. Percentage transmittance, refractive index, viscosity, droplet size and zeta potential of the optimized formulations were determined. Dialysis bag method was employed to study the release rate. The formulation selected for bioavailability estimation contained Capryol 90 (10%, v/v), Crempophor EL (11.25%, v/v), Transcutol(®) P (33.75%, v/v), and double distilled water (45%, v/v). The release rate from the nanoemulsion was highly significant (p<0.001) in contrast to the drug suspension. The level of total cholesterol in the group receiving nanoemulsion CF1 was found to be highly significant (p<0.001) in comparison to the group receiving drug suspension. Bioavailability studies in rats revealed superior absorption of ezetimibe from nanoemulsion as compared to the marketed formulation and drug suspension. The shelf life of the nanoemulsion was estimated to be 18.53 months. The present study corroborated nanoemulsion to be a promising choice to improve the bioavailability of ezetimibe.

Ultra-adaptable nanovesicular systems: a carrier for systemic delivery of therapeutic agents.

The skin acts as a barrier and prevents transcutaneous delivery of therapeutic agents. Transferosomes are novel vesicular systems that are several times more elastic than other vesicular systems. These are composed of phospholipids, edge activator and ethanol and are applied in a non-occlusive manner. Owing to their ultradeformability, they have the potential to deliver therapeutic agents across the intact skin in a non-invasive and non-allergenic manner. The present review attempts to provide an in-depth account of ultra-adaptable nanovesicular systems. The current investigation, besides compiling existing knowledge in a systematic manner, also includes information like regulatory aspects of excipients used in preparation, summary of clinical investigations performed, marketed preparations available, research reports and patent reports related to transfersomes.

Therapeutic Potential of Mucoadhesive Drug Delivery Systems - An Updated Patent Review

There has been a burgeoning interest among the research scientists to associate the drugs to polymeric particulate systems due to the propensity of these systems to interact with the mucosal surface. Transmucosal delivery of drugs through mucosal lining of nasal, rectal, vaginal, ocular and oral cavity entails advantages like prolongation of residence time at the absorption site, enhanced contact with underlying mucosa eventually leading to enhanced absorption of the active ingredient. Such systems not only provide local targeting of drugs but also offer a better control over their systemic delivery. Hence, the objective of the present review is to provide an overview of the mucoadhesive drug delivery systems with special emphasis on the intellectual aspects of these systems. This paper also attempts to extend the information present on mucoadhesive drug delivery systems in the existing literature by focussing on the update on the patents granted as well as applications published for these systems. Some newer mucoadhesive formulations like mucoadhesive microparticles and nanoparticles have also been discussed.

Novel nanoemulsion for minimizing variations in bioavailability of ezetimibe

The objectives of the present study were to develop an optimal nanoemulsion of ezetimibe and evaluate its stability, lipid lowering and pharmacokinetic potential. Solubility of ezetimibe was determined in various vehicles. Pseudoternary phase diagrams were constructed to determine the existence of nanoemulsion region. Formulations were selected from the oil/water nanoemulsion region and subjected to various thermodynamic stability and dispersibility tests. Release rate of optimized formulations was determined using in vitro dissolution test. The formulation used for evaluation contained Capryol 90 (10% v/v), Tween 80 (15% v/v), Transcutol® P (30% v/v), double distilled water (45% v/v). The release of drug from the nanoemulsion was highly significant (P <0.001) when compared to the drug suspension. The value of total cholesterol in the group administered with the formulation TF1 was highly significant (P <0.001) with respect to the group administered with the suspension of the drug. The plasma concentration time profile of ezetimibe from nanoemulsion represented greater improvement of drug absorption than the marketed formulation and drug suspension. The shelf life of the nanoemulsion was found to be 5.94 years at room temperature. The present study established nanoemulsion to be a possible alternative for minimizing variation in bioavailability of ezetimibe.

Therapeutic Applications of Nanoemulsion Based Drug Delivery Systems: A Review of Patents in Last Two Decades

Nanoemulsions have garnered considerable attention in research as well as in therapeutics due to their advantages like thermodynamic stability, optical clarity, ease of preparation, and unique property of behaving as super-solvent for solubilizing both hydrophobic and hydrophilic solutes. Due to above mentioned attributes, nanoemulsions find numerous applications in diagnosis as well as therapy of diseases. Hence, the aim of the current review is to recapitulate these applications of this novel drug delivery system by discussing the patents governing various applications of this system.

Anticancer efficacy, tissue distribution and blood pharmacokinetics of surface modified nanocarrier containing melphalan.

The objectives of the present study were to circumvent the moisture-associated instability, enhance bioavailability and achieve enhanced passive targeting of melphalan to the ovaries. Solubility of the drug was determined in various excipients to select the components of nanoemulsion. Pseudoternary phase diagrams were constructed using aqueous titration method. Formulations selected from the pseudoternary phase diagram were subjected to thermodynamic stability and dispersibility studies to select the final test formulations which were characterized for average globule size, polydispersity index (PDI), zeta potential, viscosity, refractive index, in-vitro drug release and percentage transmittance to optimize the final formulation. Pharmacokinetic and biodistribution studies of the optimized formulation in comparison to the pure drug suspension were done using γ-scintigraphy on female Balb/c mice. In-vitro cytotoxicity study on Hela cervical cancer cell lines was also done to compare the anticancer activity of the developed formulation with respect to the pure drug solution. In vitro-in vivo correlation was established for the amount of drug released and the amount of drug absorbed using suitable deconvolution. Stability studies on the final formulation were performed at 40 ± 2 °C and 75 ± 5% RH for 3 months and the shelf life was determined. Capmul MCM, Tween 80 and Transcutol P (S(mix)) were selected as the oil, surfactant and co-surfactant respectively on the basis of solubility studies. Out of 17 formulations prepared, six formulations were selected as the final test formulations on the basis of thermodynamic stress and dispersibility tests. The optimized formulation composed of oil (10%, v/v), S(mix) (35%, v/v), and double distilled water (55%, v/v). Bioavailability studies revealed 4.83 folds enhancement in bioavailability of the drug from nanoemulsion as compared to that from suspension. Biodistribution studies revealed more than 2 folds increase in uptake of the drug from nanoemulsion by ovaries as compared to that from the suspension. In vitro cytotoxicity studies demonstrated augmented anticancer potential of the drug in the form of nanoemulsion formulation in comparison to the drug solution. Level A correlation was established between the amount of drug released and the amount of drug absorbed. The shelf life of the formulation was found to be 1.30 years. The results demonstrate surface modified nanoemulsion to be a promising approach so as to increase stability, bioavailability and cellular uptake of the drug.

Recent Advances in Pelletization Technique for Oral Drug Delivery: A Review

Multiparticulate dosage forms are receiving a great deal of attention as alternative system for oral drug delivery. The present review outlines the recent findings on the manufacturing and evaluation of spherical pellets published over the past decade. The techniques namely extrusion-spheronization, hot melt extrusion, freeze pelletization, cryopelletization have been discussed along with parameters affecting pelletization. Evaluation of quality of the pellets is discussed with reference to the size distribution, shape, surface morphology, specific surface area, friability, tensile strength, density, porosity, disintegration time and in vitro dissolution studies of pellets. The use of multiparticulate dosage forms as a promising system for the oral delivery of many therapeutic agents has also been examined in the current review.

Bilayered transmucosal drug delivery system of pravastatin sodium: statistical optimization, in vitro, ex vivo, in vivo and stability assessment.

The objective of the present study was to develop a mucoadhesive sustained release bilayered buccal patch of pravastatin sodium using Eudragit S100 as the base matrix so as to surmount hepatic first pass metabolism and gastric instability of the drug. A 32 full factorial design was employed to study the effect of independent variables viz. levels of HPMC K4M and carbopol 934P on % cumulative drug release, mucoadhesion time and mucoadhesive force. Amount of carbopol 934P and HPMC K4M significantly influenced characteristics like swelling index, in vitro mucoadhesive force, drug release, and mucoadhesion time. In vitro evaluation revealed that formulations exhibited satisfactory technological parameters. The mechanism of drug release was found to be non-Fickian diffusion. Different permeation enhancers were investigated to improve the permeation of drug from the optimized patches (F9) across the buccal mucosa. Formulation [F9 (P3)] containing 4% (v/v) dimethyl sulfoxide exhibited desirable permeation of drug. Histopathological studies performed using goat buccal mucosa revealed no mucosal damage. Bioavailability studies in rabbits demonstrated that [F9 (P3)] significantly higher Cmax (67.34 ± 3.58 ng/ml) and AUC0-∞ (350.27 ± 9.59 ng/ml×h) (p < 0.05) of pravastatin sodium from optimized patch than IR tablet (Cmax 58.73 ± 4.63 ng/ml and AUC0-∞ 133.80 ± 8.25 ng/ml×h). Formulation [F9 (P3)] showed sustained drug plasma concentration over a period of 10 h which was significantly longer than oral tablet (p < 0.05). Stability studies as per ICH guidelines established physical stability of the patch and chemical stability drug. The present study established potential of the optimized mucoadhesive buccal patches to circumvent the hepatic first-pass metabolism, gastric instability and to improve bioavailability of pravastatin sodium.