Mohini Chaurasia

Cross-linked guar gum microspheres: A viable approach for improved delivery of anticancer drugs for the treatment of colorectal cancer

In the present work, guar gum microspheres containing methotrexate (MTX) were prepared and characterized for local release of drug in the colon, which is a prerequisite for the effective treatment of colorectal cancer. Guar gum microspheres were prepared by the emulsification method using glutaraldehyde as a cross-linking agent. Surface morphological characteristics were investigated using scanning electron microscopy. Particle size, shape, and surface morphology were significantly affected by guar gum concentration, glutaral dehyde concentration, emulsifier concentration (Span 80), stirring rate, stirring time, and operating temperature. MTX-loaded microspheres demonstrated high entrapment efficiency (75.7%). The in vitro drug release was investigated using a US Pharmacopeia paddle type (type II) dissolution rate test apparatus in different media (phosphate-buffered saline [PBS], gastrointestinal fluid of different pH, and rat cecal content release medium), which was found to be affected by a change to the guar gum concentration and glutaraldehyde concentration. The drug release in PBS (pH 7.4) and simulated gastric fluids followed a similar pattern and had a similar release rate, while a significant increase in percent cumulative drug release (91.0%) was observed in the medium containing rat cecal content. In in vivo studies, guar gum microspheres delivered most of their drug load (79.0%) to the colon, whereas plain drug suspensions could deliver only 23% of their total dose to the target site. Guar gum microspheres showed adequate potential in achieving local release of drug in in vitro release studies, and this finding was further endorsed with in vivo studies.

Targeting of gastrointestinal tract for amended delivery of protein/peptide therapeutics: Strategies and industrial perspectives

Delivery of proteins/peptides to the gastrointestinal (GI) tract via peroral/oral route involves tremendous challenges due to unfavorable environmental conditions like harsh pH, presence of proteolytic enzymes and absorption barriers. Detailed research is being conducted at the academic and industrial levels to diminish these troubles and various products are under clinical trials. Several approaches have been established to optimize oral delivery of proteins and peptides and can be broadly categorized into chemical and physical strategies. Chemical strategies include site specific mutagenesis, proteinylation, glycosylation, PEGylation and prodrug approaches, whereas physical strategies comprise formulation based approaches including application of absorption enhancers and metabolism modifiers along with delivering them via colloidal carrier systems such as nanoparticles, liposomes, microparticles, and micro- and nano-emulsions. This review stands to accomplish the diverse aspects of oral delivery of proteins/peptides and summarizes the key concepts involved in targeting the biodrugs to specific sites of the GI tract such as the intestine and colon. Furthermore some light has also been shed on the current industrial practices followed in developing oral formulations of such bioactives.

Nanoemulsion: Concepts, development and applications in drug delivery

ABSTRACT Nanoemulsions are biphasic dispersion of two immiscible liquids: either water in oil (W/O) or oil in water (O/W) droplets stabilized by an amphiphilic surfactant. These come across as ultrafine dispersions whose differential drug loading; viscoelastic as well as visual properties can cater to a wide range of functionalities including drug delivery. However there is still relatively narrow insight regarding development, manufacturing, fabrication and manipulation of nanoemulsions which primarily stems from the fact that conventional aspects of emulsion formation and stabilization only partially apply to nanoemulsions. This general deficiency sets up the premise for current review. We attempt to explore varying intricacies, excipients, manufacturing techniques and their underlying principles, production conditions, structural dynamics, prevalent destabilization mechanisms, and drug delivery applications of nanoemulsions to spike interest of those contemplating a foray in this field.

Mucoadhesive chitosan microspheres for non-invasive and improved nasal delivery of insulin

Novel mucoadhesive chitosan microspheres were developed to explore the possibilities of non invasive delivery of insulin. The mucoadhesive chitosan microspheres were prepared by emulsification method. Formulations were characterized for various physiochemical attributes, shape, surface morphology, size and size distribution, drug payload, swelling ability and mucoadhesion. Mucoadhesive chitosan microspheres bearing insulin were evaluated for in vitro drug release and in vitro drug permeation through mucosal membrane. In vivo performance was studied on blood plasma level of glucose. Glutaraldehyde cross-linked microspheres showed better reduction of blood glucose level than citric acid cross-linked microspheres. The in vivo performance of mucoadhesive microspheres showed prolonged and controlled release of drug as compared with the conventional dosage form.

Bridging small interfering RNA with giant therapeutic outcomes using nanometric liposomes

The scope of RNAi based therapeutics is unquestionable. However, if we dissect the current trend of clinical trials for afore mentioned drug class, some stark trends appear: 1) naked siRNA only exerts influence in topical mode whilst systemic delivery requires a carrier and 2) even after two decades of extensive efforts, not even a single siRNA containing product is commercially available. It was therefore felt that a perspective simplifying the unique intricacies of working with a merger of siRNA and liposomes from a pharmaceutical viewpoint could draw the attention of a wider array of interested researchers. We begin from the beginning and attempt to conduit the gap between theoretical logic and experimental/actual constraints. This, in turn could stimulate the next generation of investigators, gearing them to tackle the conundrum, which is siRNA delivery.

Polymeric colloidal particulate systems: intelligent tools for intracellular targeting of antileishmanial cargos

Introduction: Targeted cargo delivery systems can overcome drawbacks associated with antileishmanials delivery, by defeating challenges of physiological barriers. Various colloidal particulate systems have been developed in the past; few of them even achieved success in the market, but still are limited in some ways. Areas covered: This review is focused on the pathobiology of leishmaniasis, interactions of particulate systems with biological environment, targeting strategies along with current conventional and vaccine therapies with special emphasis on polymeric nanotechnology for effective antileishmanial cargo delivery. Expert opinion: The problems concerned with limited accessibility of chemotherapeutic cargos in conventional modes to Leishmania-harboring macrophages, their toxicity, and resistant parasitic strain development can be sorted out through target-specific delivery of cargos. Vaccination is another therapeutic approach employing antigen alone or adjuvant combinations delivered by means of a carrier, and can provide preventive measures against human leishmaniasis (HL). Therefore, there is an urgent need of designing site-specific antileishmanial cargo carriers for safe and effective management of HL. Among various colloidal carriers, polymeric particulate systems hold tremendous potential as an effective delivery tool by providing control over spatial and temporal distribution of cargos after systemic or localized administration along with enhancing their stability profile at a comparatively cost-effective price leading to improved chances of commercial applicability.

Perspectives of nanoemulsion assisted oral delivery of docetaxel for improved chemotherapy of cancer

Abstract Context: Nanoemulsions (NE) are one of the robust delivery tools for drugs due to their higher stability and efficacy. Objectives: The purpose of present investigation is to develop stable, effective and safe NE of docetaxel (DTX). Methods: Soybean oil, lecithin, Pluronic F68, PEG 4000 and ethanol were employed as excipients and NEs were prepared by hot homogenization followed by ultra-sonication. NEs were optimized and investigated for different in vitro and in vivo parameters viz. droplet size, poly dispersity index, charge; zeta potential, drug content and in vitro drug release, in vitro cytotoxicity, in vitro cell uptake and acute toxicity. Transmission electron microscopy was performed to study morphology and structure of NEs. Stability studies of the optimized formulation were performed. Results: Droplet size, poly dispersity index, zeta potential, drug content and in vitro drug release were found to be 233.23 ± 4.3 nm, 0.24 ± 0.010, −43.66 ± 1.9 mV, 96.76 ± 1.5%, 96.25 ± 2.1%, respectively. NE F11 exhibited higher cell uptake (2.83 times than control) and strong cytotoxic activity against MCF-7 cancer cells (IC50; 13.55 ± 0.21 µg/mL at 72 h) whereas no toxicity or necrosis was observed with liver and kidney tissues of mice at a dose of 20 mg/kg. Transmission electron microscopy ensured formation of poly-dispersed and spherical droplets in nanometer range. NE F11 (values indicated above) was selected as the optimized formulation based on the aforesaid parameters. Conclusion: Conclusively, stable, effective and safe NE was developed which might be used as an alternative DTX therapy.

Methotrexate Bearing Calcium Pectinate Microspheres: A Platform to Achieve Colon-Specific Drug Release

In the present work calcium pectinate (Ca-pectinate) microspheres were prepared to deliver methotrexate in the environment of colon. Calcium pectinate microspheres were prepared by modified emulsification method using calcium chloride as cross linker. All the formulations were evaluated for various physicochemical parameters. Particle size of the microspheres was determined using laser diffraction particle size analyzer. Encapsulation efficiency was determined by digesting with enzyme pectinase for 24 hours and swellability by equilibrium swelling in simulated gastrointestinal fluid. The in vitro drug release studies were performed in simulated gastric fluid for 2 hours and simulated intestinal fluid for 3 hours. In vitro release rate studies were also carried out in simulated colonic fluid in presence of rat caecal contents. Moreover, release rate studies were also carried out after enzyme induction by treating the rats with 1 ml of 1% w/v aqueous dispersion of pectin for 7 days. Mean particle size of the microspheres was found to be in the range of 20.82+/-1.34 to 32.26+/-1.59 microm whereas the entrapment efficiency varied from 52.28+/-0.32 to 74.01+/-3.32%. The in vitro drug release studies in simulated gastric fluid and simulated intestinal fluid showed that only 8.15+/-0.49% drug was released in 5 hours whereas most of the loaded drug was released in simulated colonic fluid containing pectinase. In vitro release rate study showed release of 69.94+/-3.46% of drug in presence of 3% rat caecal contents, which was further increased to 94.43+/-4.48% when enzyme induction was carried out for 7 days. Thus, it is concluded that calcium pectinate microspheres can be used to effectively localize the release of drug in the physiological environment of colon.

Chondroitin nanocapsules enhanced doxorubicin induced apoptosis against leishmaniasis via Th1 immune response.

Current leishmaniasis treatment is strangled due to concealed residence of parasite and reduced host cell mediated immune response. To circumvent above challenges, novel macrophage targeted oily core polymeric shell based doxorubicin (DOX) loaded nanocapsules (NCAPs) were fabricated employing chondroitin sulphate (CHD) for complimentary immunotherapy coupled chemotherapy against leishmaniasis. Excellent encapsulation efficiency along with pH dependent drug release was demonstrated by NCAPs. Improved cell cycle arrest at G1-S phase (1.56 folds) and apoptosis against promastigotes (6.26 folds), support the remarkable in-vitro antileishmanial activity of NCAPs (IC50: 0.254±0.038 μg/ml) compared to free DOX (IC50: 0.543±0.012 μg/ml). In-vivo antileishmanial activity in hamsters represented a significantly enhanced parasitic inhibition by NCAPs (1.42 folds). Improved activity was mediated via immunotherapeutic activity of NCAPs which up-regulated Th1 immune response (IL-12, INF-γ, and TNF-α) and down-regulated Th2 immune response (IL-4, IL-10, and TGF-β). In conclusion, current novel nano-formulation could be a viable option against leishmaniasis.

Chitosan Coated Hydroxypropyl Methylcellulose- Ethylcellulose Shell Based Gastroretentive Dual Working System to Improve the Bioavailability of Norfloxacin

This investigation was aimed to formulate, evaluate and optimize a gastroretentive dual working system based on mucoadhesion and floating mechanisms to improve the bioavailability of norfloxacin (NFX). Floating microballoons (FMB) were prepared by a non-aqueous emulsification–solvent evaporation method employing hydroxypropyl methylcellulose (HPMC) and ethylcellulose (EC) to develop a core matrix. Furthermore, FMB were coated with chitosan by an ionotropic gelation method to impart mucoadhesive characteristics. Prior to incorporation of NFX into mucoadhesive floating microballoons (MFMB), a solid dispersion (SD) of NFX was prepared using a spray–freeze drying method in order to improve the solubility of NFX. The morphological characteristics of the microballoons were assessed using scanning electron microscopy (SEM) which revealed the spherical shape of the microballoons with a smoother, dense and less porous surface. The developed microballoons were evaluated for various physicochemical parameters such as particle size, surface morphology, entrapment efficiency (EE), in vitro-dissolution, in vitro buoyancy and mucoadhesion. The optimized microballoons were developed with good in vitro-buoyancy coupled with high EE. Microballoons exhibited a zero-order release in simulated gastric fluid (SGF) demonstrating drug release in the range from 64.99 ± 3.26 to 99.94 ± 8.45% after 10 h through various formulations. Chitosan coating over FMB imparted excellent mucoadhesion in rat gut wall and results were also supported by mucin glycoprotein assay. MFMB were able to achieve higher mean plasma concentrations compared to FMB and pure NFX in Wistar rats. Keeping in mind the comprehensible advantages of a developed gastroretentive dual working system over a conventional gastroretentive drug delivery system, it can be concluded that the developed system can be used to target drugs in the gastric cavity.