Comparative evaluation of porous versus nonporous mucoadhesive films as buccal delivery system of glibenclamide.

The present research work focused on the comparative assessment of porous versus nonporous films in order to develop a suitable buccoadhesive device for the delivery of glibenclamide. Both films were prepared by solvent casting technique using the 3(2) full factorial design, developing nine formulations (F1-F9). The films were evaluated for ex vivo mucoadhesive force, ex vivo mucoadhesion time, in vitro drug release (using a modified flow-through drug release apparatus), and ex vivo drug permeation. The mucoadhesive force, mucoadhesion time, swelling index, and tensile strength were observed to be directly proportional to the content of HPMC K4M. The optimized porous film (F4) showed an in vitro drug release of 84.47 ± 0.98%, ex vivo mucoadhesive force of 0.24 ± 0.04 N, and ex vivo mucoadhesion time of 539.11 ± 3.05 min, while the nonporous film (NF4) with the same polymer composition showed a release of 62.66 ± 0.87%, mucoadhesive force of 0.20 ± 0.05 N, and mucoadhesive time of 510 ± 2.00 min. The porous film showed significant differences for drug release and mucoadhesion time (p < 0.05) versus the nonporous film. The mechanism of drug release was observed to follow non-Fickian diffusion (0.1 < n < 0.5) for both porous and nonporous films. Ex vivo permeation studies through chicken buccal mucosa indicated improved drug permeation in porous films versus nonporous films. The present investigation established porous films to be a cost-effective buccoadhesive delivery system of glibenclamide.

Product development studies on surface-adsorbed nanoemulsion of olmesartan medoxomil as a capsular dosage form.

The present study aimed at development of capsular dosage form of surface-adsorbed nanoemulsion (NE) of olmesartan medoxomil (OLM) so as to overcome the limitations associated with handling of liquid NEs without affecting their pharmaceutical efficacy. Selection of oil, surfactant, and cosurfactant for construction of pseudoternary phase diagrams was made on the basis of solubility of drug in these excipients. Rationally selected NE formulations were evaluated for percentage transmittance, viscosity, refractive index, globule size, zeta potential, and polydispersity index (PDI). Formulation (F3) comprising of Capmul MCM® (10% v/v), Tween 80® (11.25% v/v), polyethylene glycol 400 (3.75% v/v), and double-distilled water (75% v/v) displayed highest percentage cumulative drug release (%CDR; 96.69 ± 1.841), least globule size (17.51 ± 5.87 nm), low PDI (0.203 ± 0.032), high zeta potential (-58.93 ± 0.98 mV), and hence was selected as the optimized formulation. F3 was adsorbed over colloidal silicon dioxide (2 ml/400 mg) to produce free-flowing solid surface-adsorbed NE that presented a ready-to-fill capsule composition. Conversion of NE to surface-adsorbed NE and its reconstitution to NE did not affect the in vitro release profile of OLM as the similarity factor with respect to NE was found to be 66% and 73% respectively. The %CDR after 12 h for optimized NE, surface-adsorbed NE, and reconstituted NE was found to be 96.69 ± 0.54, 96.07 ± 1.76, and 94.78 ± 1.57, respectively (p > 0.05). The present study established capsulated surface-adsorbed NE as a viable delivery system with the potential to overcome the handling limitations of NE.

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.

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.

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 C(max) (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 (C(max) 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.

Novel microbially triggered colon specific delivery system of 5-Fluorouracil: statistical optimization, in vitro, in vivo, cytotoxic and stability assessment.

The present study aimed to statistically optimize a colon specific formulation of 5-Fluorouracil for the treatment of colon cancer. A 3(2) full factorial design was used for optimization. The independent variables employed were amount of pectin and amount of starch paste, each at three levels. The evaluated responses were hardness, percent cumulative drug release (% CDR) at 5th h and t(90%) (time required for 90% of drug release). Drug release studies were carried out using change over media [pH 1.2, 7.4 and 6.5 in presence of 4% (w/v) rat caecal contents]. The optimized formulation was subjected to in vivo roentgenographic studies in New Zealand white rabbits to analyze the in vivo behaviour of the developed tablets. This formulation was also evaluated for cytotoxic potential using HT-29 human colon cancer cell lines. Pharmacokinetic studies in New Zealand white rabbits were conducted to determine the extent of systemic exposure provided by the developed formulation in comparison to an immediate release tablet. The optimized formulation consisting of pectin (66.67%, w/w) and starch paste (15%, w/w) released negligible amount of drug at pH 1.2 and pH 7.4 whereas significant (p < 0.05) drug release was observed at pH 6.5 in presence of 4% (w/v) rat caecal contents. Roentgenographic studies corroborated the in vitro observations, thus providing the "proof of concept". Pharmacokinetic studies revealed significant reduction in systemic exposure and cytotoxicity studies demonstrated enhanced cellular uptake of drug by the developed formulation. Shelf life of the formulation was found to be 2.83 years. The results of the study established pectin-based coated matrix tablet to be a promising system for the colon specific delivery of 5-FU so as to treat colon carcinoma.

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.

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.

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.

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.

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.

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.

Potential of microemulsions in drug delivery and therapeutics: a patent review.

The recent success of cyclosporin marketed formulation--Sandimmune Neoral by Sandoz in Europe has invigorated the gaining interest in microemulsions as potential drug delivery systems. These thermodynamically stable, transparent (or translucent) dispersions of oil and water stabilized by an interfacial film of surfactant molecules have potential applications whenever it is necessary to mix oil and water and where a large oil-water interface is required. Thus, microemulsions have drawn considerable interest. Until now excellent reviews covering aspects of bioavailability, theories, physical properties, formulation design, physical characterization, drug release and delivery potential have been cited in literature but there is no review that discusses the intellectual (patent) aspect of these delivery systems. In order to appreciate the intellectual potential of these delivery systems, this review summarizes the patents governing various applications of these delivery systems.

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.