Chetan G. Shinde

Mucosal vaccines: a paradigm shift in the development of mucosal adjuvants and delivery vehicles.

Mucosal immune responses are the first‐line defensive mechanisms against a variety of infections. Therefore, immunizations of mucosal surfaces from which majority of infectious agents make their entry, helps to protect the body against infections. Hence, vaccinization of mucosal surfaces by using mucosal vaccines provides the basis for generating protective immunity both in the mucosal and systemic immune compartments. Mucosal vaccines offer several advantages over parenteral immunization. For example, (i) ease of administration; (ii) non‐invasiveness; (iii) high‐patient compliance; and (iv) suitability for mass vaccination. Despite these benefits, to date, only very few mucosal vaccines have been developed using whole microorganisms and approved for use in humans. This is due to various challenges associated with the development of an effective mucosal vaccine that can work against a variety of infections, and various problems concerned with the safe delivery of developed vaccine. For instance, protein antigen alone is not just sufficient enough for the optimal delivery of antigen(s) mucosally. Hence, efforts have been made to develop better prophylactic and therapeutic vaccines for improved mucosal Th1 and Th2 immune responses using an efficient and safe immunostimulatory molecule and novel delivery carriers. Therefore, in this review, we have made an attempt to cover the recent advancements in the development of adjuvants and delivery carriers for safe and effective mucosal vaccine production.

Methotrexate: A Gold Standard for Treatment of Rheumatoid Arthritis

ABSTRACT Rheumatoid arthritis (RA) is a painful, debilitating disease characterized by inflammation of the joints, with the proliferation of the synovium and the progressive erosion of cartilage and bone. The treatment of RA is still unsatisfactory, but a number of powerful disease-modifying antirheumatic drugs have become available, such as methotrexate (MTX). Even in the current era of biological targeted therapies, MTX remains the initial preferred antirheumatic drug and is considered to be the gold standard for treatment of RA. The combination of its perceived efficacy, acceptable safety profile, and low cost, as well as decades of clinical experience, makes MTX the cornerstone of treatment for RA and the anchor drug in combination with various biological agents. In this review, the authors aim to summarize the research done in the field of drug delivery systems of MTX according to its routes of administration for treatment of RA. The last part of the review addresses combination therapy with MTX and future direction in the drug delivery of MTX. This review also provides the reader with a general overview of RA and its therapeutic strategies with respect of MTX, which may bring uniformity in medical practice for effective management of RA.

Intra-articular delivery of a methotrexate loaded nanostructured lipid carrier based smart gel for effective treatment of rheumatic diseases

A nanostructured lipid carrier (NLC) based smart gel of methotrexate (MTX) was developed as a potential system for the treatment of rheumatic diseases (RD). NLC composed of Compritol ATO 888 as the solid lipid, Capmul MCM EP as the liquid lipid, Tween 80 as the surfactant and PEG 400 as the co-surfactant was prepared by modified hot homogenization followed by melt ultrasonication. The prepared NLC dispersion was characterized for particle size, polydispersity index (PDI), entrapment efficiency and zeta potential. The nanoparticulate dispersion was suitably gelled into the polymer matrices of Pluronic F-127 (PF-127) and Pluronic F-68 (PF-68). Two-factor three-level full factorial design was employed to determine the optimum concentrations of PF-127 and PF-68. The prepared NLC based smart gel was evaluated for viscosity, sterility, thermosensitivity, syringeability, content uniformity and in vitro release behaviour. The efficacy and biocompatibility of the NLC based smart gels were established using an adjuvant arthritis model and histology analysis, respectively. The NLCs had an average particle size of 107 ± 6 nm with a PDI of 0.365 ± 0.03, entrapment efficiency of 69.53% ± 1.23% and zeta potential of −13.54 ± 1.1 mV. The optimized NLC based smart gel (F-10) was found to be thermo-sensitive and exhibited 92.41% drug release at 108 h. The results demonstrated that MTX was evenly distributed in the optimized formulation, which was sterile and syringeable through an 18 gauze needle. A significant decrease in rat joint swelling was observed using the MTX-NLC based gel during a 28 day period. In conclusion, this MTX-NLC based gel could be a potential formulation for intra-articular treatment of inflammation in rheumatic conditions.

A 32 full factorial design for development and characterization of a nanosponge-based intravaginal in situ gelling system for vulvovaginal candidiasis

Clotrimazole (CTZ) is a Biopharmaceutics Classification System (BCS) Class II drug having a limited therapeutic potential because of its poor aqueous solubility and relatively short half-life. The rationale behind the present research effort was to enhance the solubility and efficacy of CTZ by having it form a complex with hydroxypropyl β-cyclodextrin (HP-β-CD) nanosponges. Nanosponges (NSs) are hyper-cross linked cyclodextrin polymer-based colloidal structures with three-dimensional networks. Herein, NSs were prepared using dimethyl carbonate as a cross linker, suitably gelled, and were assessed for in vitro release, in vitro bioadhesion, in vivo antifungal activity and in vivo irritation using female Wistar albino rats. Nine formulations were prepared based on a 32 full factorial design using different Pluronic F-127: Pluronic F-68 ratios. The prepared CTZ-HP-β-CD NS samples were characterized by carrying out SEM, TEM, and FT-IR spectroscopy studies, as well as DSC and XRPD studies. The average particle size of loaded NS (N6) was found to be 455.6 nm. This sample displayed the lowest polydispersity index of the samples tested, and displayed a high zeta potential (−21.32 ± 1.3 mV), indicative of a stable colloidal nanosuspension. The optimized CTZ NS-based in situ gel (F-10) demonstrated prolonged drug release (up to 15 h), considerably longer than that of the conventional in situ gel, whose drug release only lasted for less than 6 h. The CTZ-NS gel showed higher in vivo antifungal activity and in vitro bioadhesion than did the conventional in situ gel. Furthermore, in vivo irritation studies showed the optimized CTZ NS gel formulation to be a non-irritant. All of these results signified the promising applicability of the formulated CTZ NS gel as a novel delivery system for the local treatment of vaginal candidiasis and other similar infections.

Fabrication and characterization of carboxymethylated bael fruit gum with potential mucoadhesive applications

A study was conducted to enhance the mucoadhesive potential of bael fruit gum by carboxymethylation. Carboxymethylation of bael fruit gum was achieved through its reaction with monochloroacetic acid in the presence of sodium hydroxide as a catalyst under different reaction conditions. The optimal degree of substituted carboxymethyl in the carboxymethylated bael fruit gum was found to be 0.68. The resulting product was characterized by FT-IR, DSC, XRD and SEM analyses. The results revealed that the carboxymethylated derivative of bael fruit gum showed an improved mucoadhesive potential compared to unmodified gum, with a slightly increased degree of crystallinity, surface roughness and decreased viscosity. Additionally, metformin-loaded, ionotropically gelled beads of bael fruit gum and carboxymethylated bael fruit gum were formulated using calcium chloride as a cross-linking agent. An ex vivo bioadhesion study performed by a wash-off test using goat intestinal mucosa showed higher bioadhesion times for carboxymethylated bael fruit gum compared to bael fruit gum. In vitro release studies conducted using phosphate buffer (pH 6.8) showed a faster release of metformin from carboxymethylated bael fruit gum than from bael fruit gum. These results have demonstrated that carboxymethylated bael fruit gum is a promising mucoadhesive excipient.