Padma V. Devarajan

Lipomer of doxorubicin hydrochloride for enhanced oral bioavailability

The present study discusses design of doxorubicin hydrochloride (Dox) loaded lipid based nanocarrier (LIPOMER) for oral delivery. High entrapment (>90 %) and high loading (38.11 ± 0.37 %w/w) of hydrophilic Dox in lipid nanocarrier of polyglyceryl-6-distearate was achieved using poly(methyl vinyl ether-co-maleic anhydride) (Gantrez AN 119) and a modified nanoprecipitation method. Dox-LIPOMER revealed nanosize (314 ± 16.80 nm) and negative zeta potential (-25.00 ± 2.41 mV). Dox-LIPOMER exhibits sustained release in vitro and was influenced by ionic strength of dissolution medium. DSC and XRD studies suggested amorphous nature of Dox in LIPOMER. TEM revealed spherical morphology of Dox-LIPOMER. Dox-LIPOMER was stable up to 12 months at 25 °C/60 % RH. A 384 % enhancement in oral bioavailability compared to Dox solution was observed following Dox-LIPOMER administration at 10 mg/kg body weight. Superoxide dismutase (SOD), catalase (CAT) and malondialdehyde (MDA) assay data of heart and kidney tissues of rats treated with Dox-LIPOMER were comparable with untreated rats. Dox-LIPOMER represents a potential safe drug delivery system for oral administration.

Particle Shape: A New Design Parameter for Passive Targeting In Splenotropic Drug Delivery

The role of particle size and surface modification on biodistribution of nanocarriers is widely reported. We report for the first time the role of nanoparticle shape on biodistribution. Our study demonstrates that irregular shaped polymer lipid nanoparticles (LIPOMER) evade kupffer cells and localize in the spleen. We also demonstrate the macrophage-evading characteristic of the irregular-shaped LIPOMER. Our results suggest particle shape as an important tool for passive targeting of nanocarriers in splenotropic drug delivery.

Polyethylene sebacate-doxorubicin nanoparticles for hepatic targeting

The present study discusses polyethylene sebacate (PES)-doxorubicin (DOX) nanoparticles (PES-DOX NP) using pullulan as asialoglycoprotein receptor (ASGPR) ligand for hepatic targeting. Pullulan, a hydrophilic polymer served as ligand and as stealth agent. PES-DOX NP were prepared by modified nanoprecipitation using PES and Gantrez AN 119 (Gantrez), as complexing agent in the organic phase, while DOX was dissolved in the aqueous phase. Pullulan was adsorbed on the formed nanoparticles (PES-DOX-PUL). Intimate association of PES and Gantrez, and ionic complexation of DOX with Gantrez (confirmed by FTIR), coupled with rapidity of nanoprecipitation resulted in nanoparticles with high entrapment efficiency and high drug loading. Nanoparticles were successfully freeze dried. Drug release from PES NP followed zero order kinetics. PES-DOX NP and PES-DOX-PUL exhibited low hemolytic potential and good serum stability. Comparative biodistribution study in rats using (99m)Tc labeled formulations revealed higher blood concentration and lower liver concentration of PES-DOX-PUL, confirming the long circulating nature of PES-DOX-PUL, and thereby the possibility of improved targeting to hepatocytes. Nanoparticles revealed lower DOX concentration in the heart suggestive of low cardiotoxicity. Our study presents a radically different yet simple approach for the design of PES-DOX nanoparticles with high drug loading for improved therapy in hepatic cancer.

Preparation and In Vitro/In Vivo Evaluation of Gliclazide Loaded Eudragit Nanoparticles as a Sustained Release Carriers

ABSTRACT The aim of this study was to formulate and optimize gliclazide-loaded Eudragit nanoparticles (Eudragit L100 and Eudragit RS) as a sustained release carrier with enhanced efficacy. Eudragit L 100 nanoparticles (ELNP) were prepared by controlled precipitation method whereas Eudragit RSPO nanoparticles (ERSNP) were prepared by solvent evaporation method. The influence of various formulation factors (stirring speed, drug:polymer ratio, homogenization, and addition of surfactants) on particle size, drug loading, and encapsulation efficiency were investigated. The developed Eudragit nanoparticles (L100 and RS) showed high drug loading and encapsulation efficiencies with nanosize. Mean particle size altered by changing the drug:polymer ratio and stirring speed. Addition of surfactants showed a promise to increase drug loading, encapsulation efficiency, and decreased particle size of ELNP as well as ERSNP. Dissolution study revealed sustained release of gliclazide from Eudragit L100 as well as Eudragit RSPO NP. SEM study revealed spherical morphology of the developed Eudragit (L100 and RS) NP. FT-IR and DSC studies showed no interaction of gliclazide with polymers. Stability studies revealed that the gliclazide-loaded nanoparticles were stable at the end of 6 months. Developed Eudragit NPs revealed a decreased tmin (ELNP), and enhanced bioavailability and sustained activity (ELNP and ERSNP) and hence superior activity as compared to plain gliclazide in streptozotocin induced diabetic rat model and glucose-loaded diabetic rat model. The developed Eudragit (L100 and RSPO) NP could reduce dose frequency, decrease side effects, and improve patient compliance.

HPTLC determination of ketorolac tromethamine

A High Performance Thin Layer Chromatography (HPTLC) method for quantification of ketorolac tromethamine, a non-narcotic and non-steroidal agent was developed. The mobile phase composition was chloroform-ethyl acetate-glacial acetic acid (3:8:0.1, v/v/v). Spectrodensitometric analysis of ketorolac tromethamine was carried out at 323 nm. The calibration curve was linear in the range of 200-700 ng. The mean values of slope, intercept and correlation coefficient were, 2941, 749583, 0.99. The method was validated for method precision, system precision, marketed sample analysis and recovery studies. The % CV for method precision studies was 1.98 (n = 6) and system precision study was 1.83 (n = 6). The average recovery was found to be 99.2%. Acid and base degraded products were adequately separated from the drug. The method was successfully used for the determination of drug from saliva. The results indicate that the method is simple, specific, selective and reliable for quantitative analysis of ketorolac tromethamine as bulk drug and from formulations. It can also be applied for the stability study of the drug and analysis of drug in biological fluids.

Design, synthesis and antimycobacterial activity of cinnamide derivatives: a molecular hybridization approach.

A series of cinnamide derivatives was designed as potential antimycobacterial agents using molecular hybridization approach. The diamine moiety, a key feature of ethambutol and its other analogs, and certain structural features of cerulenin and cinnamic acid were hybridized to obtain cinnamide derivatives. The minimum inhibitory concentration (MIC) of all synthesized compounds was determined against M. tuberculosis H(37)R(v) using Resazurin Microtitre plate Assay (REMA) method. The synthesized molecules showed good to moderate activity with MIC in the range of 5-150 μM and good safety profile. Additionally, the most potent compound 1a, having MIC 5.1 μM exhibited synergy with rifampicin.

Simultaneous determination of lignocaine hydrochloride and phenylephrine hydrochloride by HPTLC

A high performance thin layer chromatographic (HPTLC) method for the simultaneous quantification of lignocaine hydrochloride (LIG) and phenylephrine hydrochloride (PHE) is described. The mobile phase consisted of ethyl acetate-methanol ammonia (4:1:0.4 v/v/v). The densitometric determination of LIG and PHE was carried out at 262 nm and 291 nm, respectively. The calibration curves of LIG and PHE were linear in the range of 8-18 microg and 4-9 microg, respectively. The method was validated with respect to system precision, method precision, recoveries, intra-day and inter-day variation. The system was applied for the simultaneous determination of LIG and PHE from a new drug delivery system. The results indicate that the method is simple, specific, selective and reliable for simultaneous quantitative determination of LIG and PHE as bulk drug and from formulations.

Microemulsions and Nanoemulsions for Targeted Drug Delivery to the Brain

Brain disorders including neurological disorders, inflammatory and infectious conditions of brain, brain cancer and brain stroke pose a significant challenge globally. The blood brain barrier (BBB) an important physiological barrier limits access of drug to the site of action. While passive diffusion and endogenous carrier mediated transport are two important mechanisms for the transport of substances across the BBB into the luminal side, efflux transporters severely limit drug concentration. Drug delivery strategies must address on one hand methods to bypass the BBB and on the other hand methods to overcome efflux transporters. Lipid based nanocarriers, liposomes and solid lipid nanoparticles are widely investigated for brain targeting. Emulsion based lipid nanocarriers like microemulsions (ME) and nanoemulsions (NE) provide an additional advantage of greater bypass of the reticulo-endothelial system with improved brain targeting. More recently the promise of ME and NE for brain delivery has been cited. Oil, surfactants and water are the primary components of ME and NE. ME may additionally comprise cosurfactants. The reviews discusses the development of ME/NE, design of functional ME/NE by appropriate selection of primary ME/NE components which could provide improved brain delivery by functioning as stealth agent, absorption enhancer, efflux transporter inhibitor or even facilitate receptor mediated endocytosis. Engineering functional ME/NE into multifunctional ME/NE as a strategy to further enhance brain targeting is also presented. Functional and multifunctional excipients have been discussed. The possible routes of delivery namely intravenous, oral and intranasal and therapeutic applications of ME/NE designed for brain targeting is also reviewed.

High-performance thin-layer chromatographic determination of ibuprofen in plasma

A high-performance thin-layer chromatographic (HPTLC) method for quantitation of ibuprofen from plasma is described. The drug was extracted from acidified plasma with hexane-isopropanol (85:15). The mobile phase composition was n-hexane-ethyl acetate-anhydrous acetic acid (75:25:2). Densitometric analysis of ibuprofen was carried out at 222 nm. The calibration curves of ibuprofen in chloroform and in plasma were linear over the range 2-20 micrograms. The mean values of intercept, slope and correlation coefficient were 0.0422 +/- 0.0018. 1.0356 +/- 0.0213 and 0.9976 +/- 0.0013 for standard curves in chloroform and 0.1044 +/- 0.003, 0.8759 +/- 0.0213 and 0.9939 +/- 0.001 for standard curves in plasma, respectively. The limit of detection of ibuprofen from human plasma (assay sensitivity) was 50 ng and no interference was found from endogenous compounds. The recovery of ibuprofen from human plasma using the described extraction procedure was about 85%. The mean relative standard deviations for within-day and between-day analyses were 2.24 and 2.6% for 5 micrograms and 3.67 and 3.2% for 15 micrograms ibuprofen concentration, respectively. The method was utilized to monitor the plasma concentration of ibuprofen post administration of sustained release capsules in human patient volunteers.

A bioadhesive delivery system as an alternative to infiltration anesthesia

OBJECTIVE The aim of this study was to determine the feasibility of a novel saliva-activated bioadhesive drug delivery system of lidocaine hydrochloride as a viable alternative to infiltration anesthesia in dentistry. STUDY DESIGN The study was carried out in three stages. First, the drug delivery system (DDS) was subjectively evaluated for adherence to the gingival mucosa and peak effect of anesthesia. In the second stage, a comparative subjective and objective evaluation of the DDS with a marketed topical gel preparation was carried out. Finally an open label, nonblinded clinical trial was carried out using the exodontia model. A total of 49 extractions were attempted in 41 patients. The effect of the following variables was investigated in the study: (1) jaw (maxillary and mandibular), (2) overall mobility, (3) position-notation of tooth (1, 2, 3, 4 ...). The positive extractions were statistically analyzed by the t test comparison of means of two independent variables. RESULTS Subjective evaluation revealed that the DDS adheres to the gingiva within a minute and produces peak effect in 15 minutes. Comparative study revealed that the DDS produces greater depth of anesthesia than the marketed topical gel. Of 49 extractions attempted with the DDS, 40 were successful, giving an efficacy of 81.63%. CONCLUSION The novel saliva-activated bioadhesive drug delivery system of lidocaine hydrochloride exhibits potential as a feasible alternative to infiltration anesthesia in dentistry.