Amita Joshi

Gastroretentive delivery of rifampicin: In vitro mucoadhesion and in vivo gamma scintigraphy

Rifampicin, a first line anti-tubercular drug, has maximum solubility and permeability in the stomach. An oral multi-particulate formulation with site specific sustained delivery of rifampicin was developed. This oral gastroretentive rifampicin formulation consisted of rifampicin pellets for immediate release as the loading dose and a bio/mucoadhesive rifampicin tablet for extended release. Immediate release pellets of rifampicin were prepared by extrusion-spheronization process and were evaluated for physico-mechanical properties: usable yield, size, shape, abrasion resistance, mechanical crushing force, residual moisture and drug release. For the mucoadhesive rifampicin formulation, statistical experimental strategy was utilized to simultaneously optimize the effect of two independent variables namely amount of Carbopol and MCC. The two dependent responses selected were, work of adhesion; estimated using Texture Analyzer and T(50%); determined from dissolution studies. Graphical and mathematical analysis of the results allowed the identification and quantification of the formulation variables influencing the selected responses. To study the gastrointestinal transit of the optimized gastroretentive formulation, the in vivo gamma scintigraphy was carried out in six healthy human volunteers, after radiolabeling the formulation with (99m)Tc. The transit profiles demonstrated that the dosage form was retained in the stomach for more than 320 min. The human data validates the design concept and signifies the potential of the developed system for stomach targeted delivery of rifampicin for improved bioavailability.

Dissolution test for site-specific release isoniazid pellets in USP apparatus 3 (reciprocating cylinder): Optimization using response surface methodology

The present work aims to predict drug release from novel site-specific release isoniazid pellets, in USP dissolution test apparatus 3, using the response surface methodology (RSM). Site-specific release isoniazid pellets were prepared by extrusion-spheronization followed by aqueous coating of Acryl-EZE. RSM was employed for designing of the experiment, generation of mathematical models and optimization study. A 3(2) full factorial design was used to study the effect of two factors (at three levels), namely volume of dissolution medium (150, 200, 250 ml) and reciprocation rate (5, 15, 25 dips per min). Amount of drug released in 0.1N hydrochloric acid at 2h and in pH 6.8 phosphate buffer at 45 min were selected as responses. Results revealed that both, the volume of medium and reciprocation rate, are significant factors affecting isoniazid release. A second order polynomial equation fitted to the data was used to predict the responses in the optimal region. The optimized conditions resulted in dissolution data that were close to the predicted values. The proposed mathematical model is found to be robust and accurate for optimization of dissolution test conditions for site-specific release isoniazid pellets.

Solid lipid nanoparticles (SLN) of Efavirenz as lymph targeting drug delivery system: Elucidation of mechanism of uptake using chylomicron flow blocking approach.

The aim of the present work was to develop a lymph targeted SLN formulation of antiretroviral (ARV) drug and to have an understanding of its underlying mechanism of uptake by the lymphatics. The lymphatics are the inaccessible reservoirs of HIV in human body. Efavirenz (EFV) is a BCS class II, ARV drug that undergoes extensive first pass metabolism. The EFV SLN formulation was prepared using Gelucire 44/14, Compritol 888 ATO, Lipoid S 75 and Poloxamer 188 by hot homogenization technique followed by ultrasonication method, with mean particle size of 168 nm, polydispersity index (PDI) <0.220, and mean zeta potential of -35.55 mV. DSC and XRPD studies revealed change in crystallinity index of drug when incorporated into SLN. In vitro drug release was found to be prolonged and biphasic in PBS pH 6.8. There was no significant change in the mean particle size, PDI, zeta potential and entrapment efficiency of EFV SLN after storage at 30 ± 2°C/60 ± 5%RH for two months. The results from lymphatic transport and tissue distribution study indicate that a significant part of the EFV had by-passed portal system and was recovered in the lymph via chylomicron uptake mechanism. Reduction in the amount (44.70%) of the EFV reaching to liver indicates that major amount of EFV bypasses the liver and thereby, enhances the oral bioavailability of the EFV. A significant amount of EFV was found in spleen, a major lymphatic organ. EFV SLN seems to have potential to target the ARV to lymphatics for the better management of HIV.

Multivariate optimization of formulation and process variables influencing physico-mechanical characteristics of site-specific release isoniazid pellets

In the present study, isoniazid was formulated as site-specific release pellets with high drug loading (65%, w/w) using extrusion-spheronization followed by aqueous coating of Sureteric (35% weight gain). A statistical experimental strategy was developed to optimize simultaneously the effect of the two formulation variables and one process variable on the critical physico-mechanical properties of the core pellets of isoniazid. Amount of granulating fluid and amount of binder were selected as formulation variables and spheronization speed as a process variable. A 2(3) full factorial experimental design was employed for the present study. Pellets were characterized for physico-mechanical properties viz. usable yield, pellet size, pellips, porosity, abrasion resistance, mechanical crushing force, residual moisture and dissolution efficiency. Graphical and mathematical analysis of the results allowed the identification and quantification of the formulation and process variables active on the selected responses. A polynomial equation fitted to the data was used to predict the responses in the optimal region. The optimum formulation and process parameters were found to be 44.24% (w/w) of granulating fluid, 2.13% (w/w) of binder and spheronization speed of 1000rpm. Optimized formulation showed usable yield 84.95%, particle size 1021.32microm, pellips 0.945, porosity 46.11%, and abrasion resistance 0.485%. However, mechanical crushing force, residual moisture and dissolution efficiency were not significantly affected by the selected independent variables. These results demonstrate the importance of, amount of water, binder and spheronization speed, on physico-mechanical characteristics of the isoniazid core pellets with high drug loading.

Lipid based nanoemulsifying resveratrol for improved physicochemical characteristics, in vitro cytotoxicity and in vivo antiangiogenic efficacy.

Resveratrol, a dietary non-flavonoid polyphenolic phytoalexin, has gained attention in cancer chemoprevention. However, poor aqueous solubility and cellular bioavailability has limited its therapeutic application. We formulated a lipid based delivery system of resveratrol with self nanoemulsifying ability. Several edible and safe lipids, surfactants and cosolvents were screened for solubilization of resevratrol. Developed formulation comprised of Acrysol K 150 as a lipid and mixture of Labrasol and Transcutol HP as the surfactant system, as these components showed higher solubility. Pseudoternary phase diagram was constructed to identify the region of nanoemulsification. The formulations showed rapid emulsification with an average globule diameter; 85nm to 120nm and slight negative zeta potential. The nanocompositions exhibited cloud point above 55°C and were stable toward the gastrointestinal pH and thermodynamic stress testing. As compared to pristine resveratrol, the developed delivery system showed significant increase in vitro cytotoxicity in MCF-7 breast cancer cells. In vivo chick chorioallantoic membrane assay revealed enhanced antiangiogenic activity of composition with high lipid level. Briefly, lipid based nanoemulsifying resveratrol dramatically enhanced the anticancer and antiangiogenic activities, thus increasing its potential application in cancer chemotherapy.

Chronomodulated press-coated pulsatile therapeutic system for aceclofenac: optimization of factors influencing drug release and lag time

DOI: 10.2147/CPT.S16504 Background: The objective of this study was to develop and evaluate a press-coated pulsatile drug delivery system intended for treatment of early morning stiffness and symptomatic relief from pain in patients with rheumatoid arthritis. Methods: The formulation involved press coating of a rupturable coat around a rapidly d isintegrating core tablet of aceclofenac. A three-factor, two-level, full factorial design was used to i nvestigate the influence of amount of glyceryl behenate, amount of sodium chloride in the coating c omposition, and the coating level on the responses, ie, lag time to release and amount of aceclofenac released in 450 minutes. Results: Glyceryl behenate and the coating level had a significant influence on lag time, while sodium chloride helped in the rupture of the coat by acting as a channeling agent. After the coat was ruptured, the core tablet showed a rapid release of aceclofenac due to the presence of Ac-Di-Sol. Graphical analysis of effects by Lenth’s method and Bayesian analysis of coefficients enabled identification of variables active on the selected responses. The optimized formulation comprised 20% w/w glyceryl behenate and 2.2% w/w sodium chloride with a 650 mg coating level, and showed a desired lag time of 358.23 minutes, which mimics the fluctuating symptoms of rheumatoid arthritis, followed by rapid release of aceclofenac.

Effect of Various Formulation Parameters on the Properties of Hydrogel Wound Dressings

The work presented in this manuscript was undertaken to evaluate the effect of various formulation parameters on the essential properties of hydrogel wound dressings. PVA and PVP based hydrogel dressing systems were prepared by irradiation cross-linking and freeze thawing method. Prepared hydrogels were characterized for swelling index, water vapor transmission rate (WVTR), mechanical strength, gel fraction and in-vitro drug release. Hydrogel dressings prepared by irradiation method showed better physico-mechanical properties like swelling index, WVTR, and transparency as compared to hydrogels prepared by freeze thaw method, except the mechanical strength, which was less in case of hydrogels, prepared using irradiation method. An increase in concentration of PVP resulted in increase in tensile strength and swelling index, and decrease in gel fraction of hydrogel due to higher degree of cross linking. Overall, addition of PVP improves physico-mechanical properties of hydrogel as compared to Plain PVA containing hydrogels. An increase in irradiation dose increases tensile strength, but decreases equilibrium swelling of hydrogels. Gel fraction also increases with increase in irradiation dose up of 50 to 60 kGy, however further increase in irradiation dose decreases gel fraction of hydrogel, as polymer degradation process exceeds cross linking process. Finally, the drug release studies were performed using silver sulfadiazine (AgSD) as a model drug in hydrogel prepared by freeze-thaw method and drug release was found to be zero-order suggesting constant drug availability on the hydrogel applied wound, which is highly desirable.

Nanoarchitectures for Neglected Tropical Protozoal Diseases: Challenges and State of the Art

Abstract Leishmaniasis and trypanosomiasis (Chagas disease and African sleeping sickness) are potentially lethal, tropical neglected diseases. These vector-borne protozoal diseases represent a significant global burden and pose a great challenge to formulation scientists due to biological and biopharmaceutical issues associated with the long-term treatment. The rate of discovery of new antiparasitic drug is relatively slow due to the lack of economic incentives in this area. Therapeutic problems include toxicity due to high dose, teratogenicity, development of resistance, and low response in case of patients coinfected with HIV. Such several challenges necessitate modulation of delivery of existing drugs for safe and effective therapy. Nanocarriers like polymeric nanoparticles, lipid-based systems, nanosuspensions, and inorganic nanocarriers improve solubility, bioavailability, and stability. The nanosize allows efficient transport across biological membranes, amelioration in tissue tolerance, and improved cellular uptake, thus enabling drug delivery to the target sites. The chapter focuses on the biological and biopharmaceutical concerns in the design of nanodelivery systems of antiprotozoal drugs. The role of the various nanocarriers in overcoming the challenges for effective therapy of parasitic infections is emphasized with the help of state-of-the-art to date. Applications of phyto-nanocarriers for the treatment of neglected parasitic infections are also discussed.

Improving bioavailability of nutraceuticals by nanoemulsification

Increased life expectancy and awareness of the role of nutraceuticals in the treatment and prevention of disease has stimulated research, development, and marketing of novel nutraceuticals. Nutraceuticals are safe and exhibit a wide spectrum of biological and pharmacological actions like antioxidant, antimicrobial, antiinflammatory, cardioprotective, lipid lowering, hepatoprotective, chemopreventive, and anticancer activity. Despite the promising pharmacological effects and safety, poor aqueous solubility and impaired bioavailability of nutraceuticals has limited their clinical applications. It also makes their addition in food products difficult. Efforts are now directed to encapsulate and protect the nutraceuticals using cutting-edge formulation technologies. Nanoemulsion-based encapsulated delivery of nutraceuticals is an innovative, commercially viable approach for improving the functionality. Nanoemulsions are formulated using generally recognized as safe (GRAS) excipients, namely, oil, surfactant, and cosurfactant/cosolvent. Manufacturing of nanoemulsions involves relatively simple unit operations, such as mixing and homogenization. Nanoemulsions exhibit comparatively higher bioaccessibility, physical stability, and optical clarity. The chapter describes the concept of nutraceuticals, nanoemulsion fabrication, with special emphasis on nanoemulsification of curcumin, resveratrol, and lutein for enhancing the therapeutic efficacy.

Impact of Ternary Solvent System in Stability-Indicating Assay Method of Bambuterol: Design of Experiments Approach.

High-performance liquid chromatography method for anti-asthmatic β2-agonist drug bambuterol, its process-related impurities and its major degradation products was developed and validated using quality by design concept. A 3(3) full factorial design was employed to study the effect of three independent factors, namely, ratio of organic modifiers in mobile phase, pH of the buffer and flow rate of the mobile phase. The responses considered were retention time of the last peak and resolution of poorly separated peaks (drug and PR-4 and drug and DP-3). The optimum conditions for separation were determined with the aid of design of experiments. The optimized ternary solvent composition was a mixture of 10 mM ammonium acetate buffer (pH 6.0), methanol and acetonitrile in the ratio of 90:5: 5 (v/v/v) in solvent reservoir A and 10:45:45 (v/v/v) in solvent reservoir B. The separation of the analytes was achieved by using a gradient method. The predictability criteria of the optimized method demonstrated good correlation between observed and predicted response. The method was validated for specificity, linearity, accuracy, precision and robustness in compliance with the International Conference on Harmonization guidelines Q2R1.