Munish Ahuja

Topical Ocular Delivery of NSAIDs

In ocular tissue, arachidonic acid is metabolized by cyclooxygenase to prostaglandins which are the most important lipid derived mediators of inflammation. Presently nonsteroidal anti-inflammatory drugs (NSAIDs) which are cyclooxygenase (COX) inhibitors are being used for the treatment of inflammatory disorders. NSAIDs used in ophthalmology, topically, are salicylic-, indole acetic-, aryl acetic-, aryl propionic- and enolic acid derivatives. NSAIDs are weak acids with pKa mostly between 3.5 and 4.5, and are poorly soluble in water. Aqueous ophthalmic solutions of NSAIDs have been made using sodium, potassium, tromethamine and lysine salts or complexing with cyclodextrins/solubilizer. Ocular penetration of NSAID demands an acidic ophthalmic solution where cyclodextrin could prevent precipitation of drug and minimize its ocular irritation potential. The incompatibility of NSAID with benzalkonium chloride is avoided by using polysorbate 80, cyclodextrins or tromethamine. Lysine salts and α-tocopheryl polyethylene glycol succinate disrupt corneal integrity, and their use requires caution. Thus a nonirritating ophthalmic solution of NSAID could be formulated by dissolving an appropriate water-soluble salt, in the presence of cyclodextrin or tromethamine (if needed) in mildly acidified purified water (if stability permits) with or without benzalkonium chloride and polyvinyl alcohol. Amide prodrugs met with mixed success due to incomplete intraocular hydrolysis. Suspension and ocular inserts appear irritating to the inflamed eye. Oil drop may be a suitable option for insoluble drugs and ointment may be used for sustained effect. Recent studies showed that the use of colloidal nanoparticle formulations and the potent COX 2 inhibitor bromfenac may enhance NSAID efficacy in eye preparations.

Carboxymethyl tamarind kernel polysaccharide nanoparticles for ophthalmic drug delivery

Tropicamide-loaded carboxymethyl tamarind kernel polysaccharide (CMTKP) nanoparticles were prepared and evaluated for ocular delivery. Preparation of ionotropically gelled CMTKP nanoparticles was optimized employing three-levels, two-factor central composite design. Concentration of polymer and crosslinker had significant synergistic effect on particle size and % encapsulation efficiency. The optimal calculated parameters were concentrations of CMTKP 0.10% (w/v) and calcium chloride 0.11% (w/v). The optimized tropicamide-loaded CMTKP formulation showed ex vivo corneal permeation of tropicamide across isolated goat cornea comparable to its aqueous solution. Further, the mucoadhesive and non-irritant nature of CMTKP nanoparticles indicate their suitability as ocular delivery system.

Synthesis, characterization and evaluation of thiolated tamarind seed polysaccharide as a mucoadhesive polymer

In the present study, thiol-functionalization of tamarind seed polysaccharide was carried out by esterification with thioglycolic acid. Thiol-functionalization was confirmed by SH stretch in Fourier-transformed infra-red spectra at 2586 cm(-1). It was found to possess 104.5 mM of thiol groups per gram. The results of differential scanning calorimetry and X-ray diffraction study indicate increase in crystallinity. Polymer compacts of thiolated tamarind seed polysaccharide required 6.85-fold greater force to detach from the mucin coated membrane than that of tamarind seed polysaccharide. Comparative evaluation of Carbopol-based metronidazole gels containing thiolated tamarind seed polysaccharide with gels containing tamarind seed polysaccharide for mucoadhesive strength using chicken ileum by modified balance method revealed higher mucoadhesion of gels containing thiolated tamarind seed polysaccharide. Further, the gels containing tamarind seed polysaccharide and thiolated tamarind seed polysaccharide released the drug by Fickian-diffusion following the first-order and Higuchis-square root release kinetics, respectively.

Carboxymethyl gum kondagogu: Synthesis, characterization and evaluation as mucoadhesive polymer

The objective of the study was to modify gum kondagogu by carboxymethylation and to evaluate it for potential pharmaceutical applications. Carboxymethylation of gum kondagogu was carried out by reacting gum kondagogu with monochloroacetic acid under alkaline conditions. The results of characterization studies revealed that carboxymethylation of gum kondagogu increases its degree of crystallinity and surface roughness, reduces its viscosity and improves its mucoadhesive properties. Further, carboxymethyl gum kondagogu was explored for pharmaceutical applications by formulating ionotropically gelled beads using metformin as the model drug and calcium chloride as cross-linking agent. Ex vivo bioadhesion study conducted using isolated chick-ileum by wash-off test revealed bioadhesion of >80% over a period of 24 h. It was observed that increasing the concentration of cross-linking agent increases the % drug entrapment and reduces the release rate. The beads were found to release the drug by Fickian-diffusion mechanism and following zero-order release kinetics.

Evaluation of carboxymethyl gellan gum as a mucoadhesive polymer

The study was conducted to evaluate carboxymethyl gellan gum as bioadhesive polymer for drug delivery applications. Gellan gum was carboxymethylated by reacting it with monochloroacetic acid. Degree of carboxymethyl substitution was found to be 1.18. Further, carboxymethylation of gellan gum was found to increase its degree of crystallinity, surface roughness and diminish the cation-induced gelation. On comparative evaluation carboxymethyl gellan gum showed 2.71-fold higher mucoadhesive strength than gellan gum. Evaluation of ex vivo ocular tolerance using chorioallantoic membrane of hens egg and cytotoxicity screening on Vero cells using resazurin assay revealed that caroboxymethyl gellan gum is non-irritant and biocompatible. Ionotiropically gelled beads of carboxymethyl gellan gum formulated using metformin as the model drug and calcium chloride as the cross-linking agent showed ex vivo bioadhesion of 100% over 24h. Further, it was observed that carboxymethyl gellan gum beads released metformin at a rate faster than gellan gum.

Isonicotinic acid hydrazide derivatives: synthesis, antimicrobial activity, and QSAR studies

A series of isonicotinic acid hydrazide derivatives (1–19) was synthesized and tested in vitro for antimycobacterial activity against Mycobacterium tuberculosis and antimicrobial activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Candida albicans, and Aspergillus niger and the results indicated that the compounds with OH, SCH3, and OCH3 groups were found to be active against the tested strains. None of the test compounds were active against a broad variety of RNA and DNA viruses at subtoxic concentrations, except 8, that showed some selective anti-reovirus-1 activity. The multi-target QSAR models were found to be effective in predicting the antimicrobial activity of the isoniazid derivatives and indicated the importance of nuclear repulsion energy (Nu.E) in explaining the antimicrobial activity of isoniazid derivatives. The developed QSAR models were validated using the external test set of synthesized derivatives.

Synthesis, antimycobacterial, antiviral, antimicrobial activities, and QSAR studies of isonicotinic acid-1-(substituted phenyl)-ethylidene/cycloheptylidene hydrazides

A series of isonicotinic acid-1-(substituted phenyl)-ethylidene/cycloheptylidene hydrazide derivatives (1–12) was tested for their, in vitro antimycobacterial activity against Mycobacterium tuberculosis, and compound 2 was found to be more active than isoniazid. The antiviral screening results indicated that none of the tested compounds was active against a broad variety of DNA and RNA viruses at subtoxic concentrations, except compounds 8 and 10 that proved to be active against DNA viruses at concentrations close to their cytostatic potential. The synthesized compounds were also screened for their antimicrobial potential against S. aureus, B. subtilis, E. coli, C. albicans and A. niger, and the results indicated that compounds having Br, OCH3 and Cl groups were highly active. The multi-target QSAR models indicated the importance of lipophilic (log P) and topological parameters (3χv) in describing the antimicrobial activity.

Carboxymethyl gum kondagogu–chitosan polyelectrolyte complex nanoparticles: Preparation and characterization

The interaction between carboxymethyl gum kondagogu and chitosan was optimized to prepare polyelectrolyte complex nanoparticles using ofloxacin as the model drug. The effect of concentrations of carboxymethyl gum kondagogu and chitosan on the particle size and % drug entrapment was screened using 2-factor, 3-level central composite experimental design. The results revealed that the concentration of carboxymethyl gum kondagogu has a pronounced effect on the particle size while the concentration of chitosan affected the drug entrapment prominently. The optimized concentrations of carboxymethyl gum kondagogu and chitosan were 0.031% (w/v) and 0.059% (w/v) respectively. The optimized batch of nanoparticles had a particle size of 285.9 nm, entrapment efficiency of 63% and was observed to be ovoid in shape. Screening of ofloxacin-loaded nanoparticles for antibacterial activity with aqueous ofloxacin solution revealed no significant difference between the two formulations. Nanoparticles provided a sustained release with 50% of the drug getting released in 24 h following Higuchis square-root kinetics.

Evaluation of tropicamide-loaded tamarind seed xyloglucan nanoaggregates for ophthalmic delivery

The present study was aimed to prepare tamarind seed nanoaggregates and its evaluation for ophthalmic delivery. The preparation of tropicamide-loaded tamarind seed xyloglucan nanoaggregates was optimized using face centred central composite experimental design, employing the concentrations of tamarind seed xyloglucan and Poloxamer-407, as independent variables. The results revealed that concentration of TSX has a significant antagonistic effect on particle size, while poloxamer displayed a significant synergistic effect on encapsulation efficiency. The optimal concentrations of TSX and poloxamer were found to be 0.45% (w/v) and 0.5% (w/v) respectively. The optimized formulation of tropicamide-loaded TSX nanoaggregates showed a significantly higher corneal permeation of tropicamide across the isolated goat cornea compared to commercial conventional aqueous formulation. The results revealed excellent mucoadhesive properties of TSX nanoaggregates. Further, the tropicamide-loaded TSX nanoaggregates formulation showed excellent ocular tolerance and biocompatibility as determined by hens egg test chorioallantoic membrane and resazurin assay on Vero cell lines.

Isoniazid: the magic molecule

The resurgence of tuberculosis and emergence of multidrug resistant isolates has focused attention on the need for an improved understanding of molecular aspects of the disease, and for elucidation of the factors responsible for drug action and resistance. Isoniazid is the frontline drug employed in the treatment of tuberculosis. Recent research has probed the mechanism of action of isoniazid (INH), a key drug in the chemotherapy of tuberculosis and also the anti-mycobacterial potential of derivatives of isoniazid has been evaluated. We have made an attempt to compile an account of various derivatives of isoniazid reported for their diverse biological activities like anti-mycobacterial, -bacterial, -fungal and -viral activities.