Convolutions in the rendition of nose to brain therapeutics from bench to bedside: Feats & fallacies.

Brain, a subtle organ of multifarious nature presents plethora of physiological, metabolic and bio-chemical convolutions that impede the delivery of biomolecules and thereby resulting in truncated therapeutic outcome in pathological conditions of central nervous system (CNS). The absolute bottleneck in the therapeutic management of such devastating CNS ailments is the BBB. Another pitfall is the lack of efficient technological platforms (due to high cost and low approval rates) as well as limited clinical trials (due to failures of neuro­leads in late-stage pipelines) for CNS disorders which has become a literal brain drain with poorest success rates compared to other therapeutic areas, owing to time consuming processes, tremendous convolutions and conceivable adverse effects. With the advent of intranasal delivery (via direct N2B or indirect nose to blood to brain), several novel drug delivery carriers viz. unmodified or surface modified nanoparticle based carriers, lipid based colloidal nanocarriers and drysolid/liquid/semisolid nanoformulations or delivery platforms have been designed as a means to deliver therapeutic agents (small and large molecules, peptides and proteins, genes) to brain, bypassing BBB for disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), epilepsy, schizophrenia and CNS malignancies primarily glioblastomas. Intranasal application offers drug delivery through both direct and indirect pathways for the peripherally administered psychopharmacological agents to CNS. This route could also be exploited for the repurposing of conventional drugs for new therapeutic uses. The limited clinical translation of intranasal formulations has been primarily due to existence of barriers of mucociliary clearance in the nasal cavity, enzyme degradation and low permeability of the nasal epithelium. The present review literature aims to decipher the new paradigms of nano therapeutic systems employed for specific N2B drug delivery of CNS drugs through in silico complexation studies using rationally chosen mucoadhesive polymers (exhibiting unique physicochemical properties of nanocarrier's i.e. surface modification, prolonging retention time in the nasal cavity, improving penetration ability, and promoting brain specific delivery with biorecognitive ligands) via molecular docking simulations. Further, the review intends to delineate the feats and fallacies associated with N2B delivery approaches by understanding the physiological/anatomical considerations via decoding the intranasal drug delivery pathways or critical factors such as rationale and mechanism of excipients, affecting the permeability of CNS drugs through nasal mucosa as well as better efficacy in terms of brain targeting, brain bioavailability and time to reach the brain. Additionally, extensive emphasis has also been laid on the innovative formulations under preclinical investigation along with their assessment by means of in vitro /ex vivo/in vivo N2B models and current characterization techniques predisposing an efficient intranasal delivery of therapeutics. A critical appraisal of novel technologies, intranasal products or medical devices available commercially has also been presented. Finally, it could be warranted that more reminiscent pharmacokinetic/pharmacodynamic relationships or validated computational models are mandated to obtain effective screening of molecular architecture of drug-polymer-mucin complexes for clinical translation of N2B therapeutic systems from bench to bedside.

Engineered Site-specific Vesicular Systems for Colonic Delivery: Trends and Implications.

Steering drug-loaded, site-specific, coated lipid vesicles to the target receptor sites have the potential of plummeting adverse effects and improving the pharmacological response in diverse pathologies of the large bowel, especially the colon. Colonic delivery via oral route has its own challenges, often governed by several glitches such as drug degradation or absorption in the upper GIT, instability of proteins/peptides due to high molecular weight, and peptidase activity in the stomach. Consequently, colon-specific coated liposomal systems (CSLS) offer a potential alternate for not only site-specificity, but protection from proteolytic activity, and prolonged residence time for greater systemic bioavailability. On the other hand, liposomal delivery via the oral route is also cumbersome owing to several barriers such as instability in GIT, difficulty in crossing membranes, and issues related to production at the pilot scale. New advancements in the field of CSLS have successfully improved the stability and permeability of liposomes for oral delivery via modulating the compositions of lipid bilayers, adding polymers or ligands. Despite this ostensible propitiousness, no commercial oral CSLS has advanced from bench to bedside for targeted delivery to the colon as yet. Nevertheless, CSLS has quite fascinated the manufacturers owing to its potential industrial viability, simplistic and low-cost design. Hence, this review aims to decipher the convolutions involved in the engineering process of industrially viable CSLS for colonic delivery.

Biocompatible Nanovesicular Drug Delivery Systems with Targeting Potential for Autoimmune Diseases.

Autoimmune diseases are collectively addressed as chronic conditions initiated by the loss of one's immunological tolerance, where the body treats its own cells as foreigners or self-antigens. These hay-wired antibodies or immunologically capable cells lead to a variety of disorders like rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, multiple sclerosis and recently included neurodegenerative diseases like Alzheimer's, Parkinsonism and testicular cancer triggered T-cells induced autoimmune response in testes and brain. Conventional treatments for autoimmune diseases possess several downsides due to unfavourable pharmacokinetic behaviour of drug, reflected by low bioavailability, rapid clearance, offsite toxicity, restricted targeting ability and poor therapeutic outcomes. Novel nanovesicular drug delivery systems including liposomes, niosomes, proniosomes, ethosomes, transferosomes, pharmacosomes, ufasomes and biologically originated exosomes have proved to possess alluring prospects in supporting the combat against autoimmune diseases. These nanovesicles have revitalized available treatment modalities as they are biocompatible, biodegradable, less immunogenic and capable of carrying high drug payloads to deliver both hydrophilic as well as lipophilic drugs to specific sites via passive or active targeting. Due to their unique surface chemistry, they can be decorated with physiological or synthetic ligands to target specific receptors overexpressed in different autoimmune diseases and can even cross the blood-brain barrier. This review presents exhaustive yet concise information on the potential of various nanovesicular systems as drug carriers in improving the overall therapeutic efficiency of the dosage regimen for various autoimmune diseases. The role of endogenous exosomes as biomarkers in the diagnosis and prognosis of autoimmune diseases along with monitoring progress of treatment will also be highlighted.

Novel synergistic approach to exploit the bactericidal efficacy of commercial disinfectants on the biofilms of Salmonella enterica serovar Typhimurium.

Combined effect of malic acid and ozone as sanitizer to inhibit the biofilm formation by Salmonella typhimurium on different food contact surfaces was investigated in this study. Different surfaces used in food industry including PVC pipes, polyethylene bags, plastic surfaces and fresh produce were analyzed for the biofilm formation by S. typhimurium ST1 and ST2. Malic acid alone was not able to inhibit biofilm formation in all the samples. However, combination of malic acid with ozone reduced the biofilm formation on plastic bags as well as on PVC pipes suggesting as an effective disinfectant for food contact surfaces. Five- and six-fold reduction in biofilm formation was observed in microtitre plates after 20 h and 40 h. Scanning electron micrographs of carrot and turnip showed control over the biofilms. Malic acid as sanitizer in food industry was effective for the complete inhibition of biofilm in carrot and other food contact surfaces, besides this, combined sanitizer (malic acid and ozone) was effective in turnip. Biofilms in food-processing industries can survive even after the sanitizer treatment and may represent reservoirs of product contamination leading to subsequent spoilage and/or food safety risks.

In silico predicative studies for cytotoxic potential of NSAIDs using self-organizing molecular field analysis.

Antiproliferative potential of nonsteroidal anti-inflammatory drugs (NSAIDs) has generated an immense interest among the scientific fraternity to assess its broader role in the chemoprevention of colon cancer. Due to serious adverse events associated with the chemotherapy, NSAIDs have been exploited as adjuvants to synergize the cytotoxic potential of conventional chemotherapeutic agents at low-dose regimens. The present investigation has been focused on in silico model generation for in vitro cytotoxicity activity of the clinically active NSAIDs using self-organizing molecular field analysis (SOMFA) studies. A statistically validated robust model for a diverse group of NSAIDs having flexibility in structure and cytotoxicity activity was obtained using SOMFA. The statistical measures having good cross-validated correlation coefficient r (2) (cv) (.8291), noncross-validated correlation coefficient r (2) values (.8686), and high F test value (41.8722) proved significance in the generated model. Analysis of 3-dimensional quantitative structure activity relationship (3D-QSAR) models through electrostatic and shape grids provided additional valuable information regarding shape and electrostatic potential influence on in vitro cytotoxicity profile. The analysis of SOMFA results provided a better insight about the generation of molecular architecture of novel NSAIDs yet to be synthesized, with optimum in vitro cytotoxicity activity and improved therapeutic profile.

Fabrication and optimization of fast disintegrating tablets employing interpolymeric chitosan-alginate complex and chitin as novel superdisintegrants.

The objective of the present work was to optimize the formulation of fast disintegrating tablets (FDTs) of ondansetron HCl containing novel superdisintegrants, possessing sufficient mechanical strength and disintegration time comparable to those containing crospovidone or croscarmellose sodium. The FDTs were formulated using a novel superdisintegrant (chitosan-alginate (1:1) interpolymer complex and chitin) to achieve a sweet tasting disintegrating system. The results revealed that chitin (5-20%) increased the porosity and decreased the DT of tablets. At higher concentrations chitin maintained tablet porosity even at 5.5 kg crushing strength. Ondansetron HCl was found to antagonize the wicking action of glycine. Further, evaluation of the mechanism of disintegration revealed that glycine transported the aqueous medium to different parts of the tablets while the chitosan-alginate complex swelled up due to transfer of moisture from glycine. This phenomenon resulted in breakage of the tablet within seconds. For preparing optimized FDTs, the reduced model equations generated from Box-Behnken design (BBD) were solved after substituting the known disintegration time of FDTs containing superdisintegrants in the reduced model equations. The results suggested that excipient system under investigation not only improved the disintegration time but also made it possible to prepare FDTs with higher crushing strength as compared to tablets containing known superdisintegrants.

Molecular simulation of hydroxypropyl-beta-cyclodextrin with hydrophobic selective Cox-II chemopreventive agent using host-guest phenomena.

The present investigation outlays the host-guest penetration of hydrophobic selective Cox-II chemopreventive agent, celecoxib (CXB), with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) using inclusion complexation phenomena. Phase solubility studies conducted at 37 degrees C and 25 degrees C revealed typical A(L)-type curve for the HP-beta-CD indicating the formation of soluble complexes. The inclusion complexes in the molar ratio of 1:1 and 2:1 (CXB-HP-beta-CD) were prepared by kneading technique. The formation of inclusion complexes and the molecular simulation of CXB protons with HP-beta-CD cavity in all samples were testified by 1H-NMR, DSC, powder-XRD, SEM and FTIR and UV/visible spectroscopy. The results of these studies indicated that complex (prepared by kneading method) in molar ratio of 1:1 exhibited better improvement in in vitro dissolution profiles as compared to 1:2 complex. Mean in vitro dissolution time indicated significant difference in the release profiles of CXB from complexes and physical mixtures as compared to pure CXB.

Assessment of biological half life using in silico QSPkR approach: a self organizing molecular field analysis (SOMFA) on a series of antimicrobial quinolone drugs.

The quinolones belong to a family of synthetic potent broad-spectrum antibiotics and particularly active against gram-negative organisms, especially Pseudomonas aeruginosa. A 3D-QSPkR approach has been used to obtain the quantitative structure pharmacokinetic relationship for a series of quinolone drugs using SOMFA. The series consisting of 28 molecules have been investigated for their pharmacokinetic performance using biological half life (t(1/2)). A statistically validated robust model for a diverse group of quinolone drugs having flexibility in structure and pharmacokinetic profile (t(1/2)) obtained using SOMFA having good cross-validated correlation coefficient r(cv)(2) (0.6847), non cross-validated correlation coefficient r(2) values (0.7310) and high F-test value (33.9663). Analysis of 3D-QSPkR models through electrostatic and shape grids provide useful information about the shape and electrostatic potential contributions on t(1/2). The analysis of SOMFA results provide an insight for the generation of novel molecular architecture of quinolones with optimal half life and improved biological profile.

In vivo bioavailability and therapeutic assessment of host-guest inclusion phenomena for the hydrophobic molecule etodolac: pharmacodynamic and pharmacokinetic evaluation.

The aim of present investigation was 1) to evaluate the in vivo bioavailability of an Etodolac (ETD)-Î-cyclodextrin (Î-CD) inclusion complex system prepared by kneading and spray drying techniques in rats, 2) to study the pharmacodynamic parameters in various animal models for analyzing the therapeutic response and, 3) to evaluate the pharmacokinetic profile of the drug administered. Inclusion complexation with Î-CD enhanced the solubility of the drug, improved bioavailability and reduced ulcerogenicity of ETD in rats. Pharmacodynamic studies were carried out in normal LACA mice and pharmacokinetic evaluation was done in male Wistar rats. Pharmacokinetic parameters evaluated for the inclusion complexes revealed good correlation. The minimum dose necessary to produce analgesic or anti-arthritic activity was also decreased, indicating that the host-guest strategy that uses Î-CD and ETD was very effective and could be successfully employed in the preparation of pharmaceutical formulations of anti-arthritics and analgesics.

Formulation development of stronger and quick disintegrating tablets: a crucial effect of chitin.

A well known superdisintegrant like croscarmellose sodium or crospovidone loses their quick disintegration property when compressed at more than 4 kg tablet crushing strength (TCS). Therefore, the objective of the present work was to develop a disintegrating system that could be used for preparing fast disintegrating tablets (FDTs) of highly water soluble drug, metoclopramide, without compromising on the mechanical strength, irrespective of the TCS used for compressing the granules. For this purpose disintegrating system consisting of chitosan-alginate (CTN-ALG) complex (1:1): glycine and chitin was developed. The results revealed that when CTN-ALG and glycine were mixed in the ratio of 30:70, the granules exhibited a minimum water sorption time and maximum effective pore radius (R(eff.p)). The addition of chitin (5-10% w/w) into this mixture further enhanced the R(eff.p). Further, increase in the concentration of chitin from 10% to 20% w/w did not produce any significant effect (p>0.05) on the R(eff.p). The FDTs prepared by using CTN-ALG:glycine (30:70) and chitin exhibited increased porosity and lower disintegration time (DT). Further, chitin was found to neutralize the effect of TCS on DT of FDTs. This property of chitin was also observed in FDTs prepared by using croscarmellose sodium (5% w/w) or crospovidone (5% w/w). The reduction in DT of FDTs by chitin was also observed in tablets prepared without the drug. Hence, the effect was not influenced by the solubility component present in the tablets. Overall, the results suggested incorporation of chitin (5-10% w/w) while preparing FDTs of metoclopramide to enhanced the disintegration without compromising their mechanical strength of the tablets.

Formulation of orodispersible tablets of ondansetron HCl: investigations using glycine-chitosan mixture as superdisintegrant.

The objective of this investigation was to prepare orodispersible tablets (ODTs) of ondansetron HCl using a direct compression method. A combination of glycine and chitosan was used as a disintegrating system and these tablets were compared for mechanical strength and disintegration time with those containing superdisintegrants. The Plackett-Burman screening design was used to screen the independent variables [concentration of glycine (X(1)), concentration of chitosan (X(2)), concentration of ondansetron HCl (X(3)) and tablet crushing strength (X(4))] which were found to actively influence the dependent variables [disintegration time in the oral cavity (DT), wetting time (WT), and water absorption ratio (WAR)]. Further, a central composite design was used to formulate additional ODTs of ondansetron HCl for estimating response in the extended spherical domain. The regression analysis (performed using Statistica-7.0) of quadratic fit revealed that DT or WT and WAR were 99% and 98% correlated with active factors (X(1), X(2) or X(3)), respectively. The data showed that disintegration time of optimized ondansetron HCl ODTs was not significantly different (p<0.05) from ODTs prepared using Croscarmellose sodium or Crospovidone.

Understanding the mechanism for paradoxical effect of ionized and unionized chitosan: Orodispersible tablets of Ondansetron Hydrochloride.

The objective of the present investigation was to formulate and evaluate orodispersible tablets (ODTs) of ondansetron HCl possessing sufficient mechanical strength by wet granulation or direct compression method. A combination of glycine and chitosan was employed for providing a sweet tasting disintegrating system. The evaluation of ODTs prepared by a wet granulation method revealed that in vitro disintegration time (DT) as well as wetting time (WT) increased and water absorption ratio (WAR) decreased with an increase in concentration of chitosan (as binder). However, an opposite relationship was obtained when ODTs were prepared by direct compression method. The FTIR spectra and DSC analysis indicated that the -NH3+ moieties of chitosan interacted with COO- moieties of glycine in ODTs prepared by the wet granulation method. However, chitosan was found to be present in the unionized state in ODTs prepared by direct compression method. Furthermore, in vitro as well as in vivo disintegration tests revealed that ODTs containing the chitosan-glycine mixture were superior to those containing well known superdisintegrants. The results suggested that the chitosan-glycine system not only improved disintegration time but also made it possible to prepare ODTs with higher crushing strength as compared to tablets containing superdisintegrants.

Orally disintegrating systems: innovations in formulation and technology.

Orally disintegrating systems have carved a niche amongst the oral drug delivery systems due to the highest component of compliance they enjoy in patients especially the geriatrics and pediatrics. In addition, patients suffering from dysphagia, motion sickness, repeated emesis and mental disorders prefer these medications because they cannot swallow large quantity of water. Further, drugs exhibiting satisfactory absorption from the oral mucosa or intended for immediate pharmacological action can be advantageously formulated in these dosage forms. However, the requirements of formulating these dosage forms with mechanical strength sufficient to with stand the rigors of handling and capable of disintegrating within a few seconds on contact with saliva are inextricable. Therefore, research in developing orally disintegrating systems has been aimed at investigating different excipients as well as techniques to meet these challenges. A variety of dosage forms like tablets, films, wafers, chewing gums, microparticles, nanoparticles etc. have been developed for enhancing the performance attributes in the orally disintegrating systems. Advancements in the technology arena for manufacturing these systems include the use of freeze drying, cotton candy, melt extrusion, sublimation, direct compression besides the classical wet granulation processes. Taste masking of active ingredients becomes essential in these systems because the drug is entirely released in the mouth. Fluid bed coating, agglomeration, pelletization and infusion methods have proven useful for this purpose. It is important to note that although, freeze dried and effervescent disintegrating systems rapidly disintegrate in contact with fluids, they do not generally exhibit the required mechanical strength. Similarly, the candy process cannot be used for thermolabile drugs. In the light of the paradoxical nature of the attributes desired in orally disintegrating systems (high mechanical strength and rapid disintegration), it becomes essential to study the innovations in this field and understand the intricacies of the different processes used for manufacturing these systems. This article attempts at discussing the patents relating to orally disintegrating systems with respect to the use of different formulation ingredients and technologies.

A novel approach to optimize and formulate fast disintegrating tablets for nausea and vomiting.

The aim of this study was to optimize and formulate fast disintegrating tablets (FDTs) for nausea and vomiting using aminoacetic acid, carmellose and sodium alginate with enough mechanical strength. Ondansetron HCl (water soluble) or domperidone (water insoluble) drug were added to FDTs and their disintegration behaviour was evaluated. Plackett Burman Screening Design was used to screen the independent active process variables [concentration of aminoacetic acid (X (1)), concentration of carmellose (X (2)) and tablet crushing strength (X (3))] which were found to actively influence the dependent variables [disintegration time in the mouth (DT), wetting time (WT), and water absorption ratio (WAR)] for both the drugs. Also, the coefficients of active variables (DT, WT and WAR) of FDTs containing domperidone was found to be significantly different (P < 0.05) from the coefficients of active factors (X (1), X (2) and X (3)) containing ondansetron HCl FDTs. Further, FDTs containing domperidone was prepared according to central composite design for estimating the effect of active factors (X (1), X (2), X (3)) in extended spherical domain. The regression analysis of quadratic fit revealed that DT, WT and WAR were 98% correlated with active factors (X (1), X (2) or X (3)). The optimized domperidone FDTs were further compared with superdisintegrants (croscarmellose sodium or crospovidone). The data revealed that optimized domperidone FDTs were better than domperidone FDTs containing croscarmellose or crospovidone. Hence, this novel excipients combination can be used for delivery of water insoluble drugs in place of superdisintegrants.