Karthik Arumugam

A study of rivastigmine liposomes for delivery into the brain through intranasal route

A study of rivastigmine liposomes for delivery into the brain through intranasal route The present study is mainly aimed at delivering a drug into the brain via the intranasal route using a liposomal formulation. For this purpose, rivastigmine, which is used in the management of Alzheimers disease, was selected as a model drug. Conventional liposomes were formulated by the lipid layer hydration method using cholesterol and soya lecithin as lipid components. The concentration of rivastigmine in brain and plasma after intranasal liposomes, free drug and per oral administration was studied in rat models. A significantly higher level of drug was found in the brain with intranasal liposomes of rivastigmine compared to the intranasal free drug and the oral route. Intranasal liposomes had a longer half-life in the brain than intranasally or orally administered free drug. Delivering rivastigmine liposomes through the intranasal route for the treatment of Alzheimers disease might be a new approach to the management of this condition. Liposomi rivastigmina za isporuku u mozak intranazalnim putem Glavni cilj rada je razvoj liposoma za intranazalnu primjenu za isporuku lijeka u mozak. U tu svrhu izabran je rivastigmin kao modelni lijek koji se upotrebljava u terapiji Alzheimerove bolesti. Liposomi su pripravljeni metodom hidratacije lipidnog sloja koristeći kolesterol i lecitin iz soje kao lipidne komponente. Praćena je koncentracija rivastigmina u mozgu i plazmi nakon intranazalne i peroralne primjene liposoma i slobodnog lijeka. S intranazalnim liposomima rivastigmina postignuta je značajno veća koncentracija lijeka u mozgu. Osim toga intranazalni liposomi imaju dulje vrijeme poluživota u mozgu. Intranazalna primjena liposoma rivastigmina mogla bi predstavljati novi pristup terapiji Alzheimerove bolesti.

Preparation, in vitro characterization, pharmacokinetic, and pharmacodynamic evaluation of chitosan-based plumbagin microspheres in mice bearing B16F1 melanoma

The present study was aimed to evaluate the anti-tumor efficacy and systemic toxicity of chitosan-based plumbagin microspheres in comparison to free plumbagin. The optimized formulation had a mean particle size of 106.35 μm with an encapsulation efficiency of 80.12%. Pharmacokinetic studies showed a 22.2-fold increase in elimination half-life (t1/2) of plumbagin from chitosan microspheres as compared to free plumbagin. Administration of plumbagin microspheres resulted in a significant tumor growth inhibition and reduced systemic toxicity. These results suggest that chitosan-based microspheres could be a promising strategy for the systemic delivery of anti-cancer agents like plumbagin.

Multiparticulate Drug Delivery System of Aceclofenac: Development and In Vitro Studies

The aim of this study was to develop an enteric-coated multiunit dosage form containing aceclofenac, a nonsteroidal anti-inflammatory drug. The pellets were prepared by using extrusion/spheronization method, and the core pellets were coated with a pH-sensitive poly(meth) acrylate copolymer (Eudragit L100-55) to achieve site-specific drug release. The formulated pellets were characterized for percentage yield, size distribution, surface morphology studies, drug content, and flow properties. In vitro dissolution test was used for comparison of drug release profiles of various coated pellets. The practical yield was found to be 90–95%. The particle size of enteric-coated pellets was found to be in the range of 0.59–0.71 mm. The pellets were spherical in shape and surfaces of pellets were found to be rough and showing micropores. Enteric-coated pellets showed good flow properties and in vitro dissolution profile. Dissolution tests were carried out in a USP type II dissolution apparatus in media-simulating pH conditions of the gastrointestinal tract. The release of the aceclofenac from formulated pellets was established to be minimum in the pH 1.2 (<5%) for a period of 2 h, and at pH 6.8, it shows the maximum release (85 ± 5% release within 1 h) which indicates gastric resistance of the formulated pellets. The 20% wt/wt enteric-coated pellets were compared to that of marketed product (tablets), it was observed that pellets showed better release profile. The study concluded that the formulated multiparticulate dosage forms can be used as an ideal drug delivery system for the aceclofenac.

Controlled release chitosan microspheres of mirtazapine: In vitro and in vivo evaluation

The purpose of the study was to formulate and evaluate controlled release chitosan microspheres of mirtazapine (MTZ) to improve the bioavailability by altering the pharmacokinetic profiles of the drug. Chitosan microspheres were prepared to prolong the release of the drug into the systemic circulation. Microspheres were prepared by a single water in oil (w/o) emulsion technique varying the chitosan/drug ratio, stirring speed and concentration of the crosslinking agent (glutaraldehyde). Drug-polymer compatibility studies were carried out using fourier transform infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC). The microspheres were evaluated for encapsulation efficiency, particle size, surface morphology, swelling index, in vitro release, as well as erosion and in vivo studies in rats. The FT-IR and DSC studies revealed no interaction between drug and polymer. The encapsulation efficiency of different formulation varied from 53 ± 1.2% to 78 ± 1.5%. The mean particle size of the optimized formulation F-14 was 106.4 ± 0.5 μm. Surface morphology revealed that chitosan microspheres were discrete and spherical in shape with a porous surface. The release of MTZ from chitosan microspheres was rapid up to 4 h, and then it was continuously and slowly released up to 48 h. Optimized formulation (F-14) was found to be stable under accelerated storage conditions based on International Conference on Harmonisation guidelines. Pharmacokinetic studies revealed that the optimized formulation showed significant increases in systemic exposure (AUC = 177.70 ± 7.39 μg·h/mL), half-life (4.72 ± 0.46 h) and reduced clearance (0.009 ± 0.0001 L/h) compared to pure drug administration. Hence, the present study demonstrates that controlled release formulation of MTZ microspheres using chitosan can improve pharmacokinetic profiles of MTZ.

Evaluation of Pharmacokinetic, Biodistribution, Pharmacodynamic, and Toxicity Profile of Free Juglone and Its Sterically Stabilized Liposomes

The present study was aimed to formulate and compare the pharmacokinetic, biodistribution, pharmacodynamic, and toxicity profiles of free 5-hydroxy-1,4-naphthoquinone (juglone) with sterically stabilized liposomal form. The liposomes were optimized for size, zeta potential, entrapment efficiency (EE), and in vitro release properties. The optimized formulation had a mean size, zeta potential, and EE value of 137.1 nm, -43.1 mV, and 67.2%, respectively. In vitro release studies showed biphasic pattern with initial burst followed by sustained release over the study period, releasing about 61% after 24 h. In vitro cytotoxicity studies against melanoma cells indicated that liposomal juglone was more toxic than free juglone. Free juglone had short plasma half-life of about 2 h, whereas liposomal juglone exhibited significantly improved pharmacokinetics with a 12-fold increase in plasma half-life. Further, biodistribution studies indicated rapid renal elimination of free juglone, evidenced by its significant localization in kidneys. Conversely, the accumulation of liposomal juglone in kidneys reduced significantly with enhanced tumor localization, thereby resulting in enhanced antitumor activity. The histological studies revealed lower levels of nephrotoxicity for liposomal juglone compared with that of free juglone. To conclude, sterically stabilized liposomes could be a promising approach for the intravenous delivery of hydrophobic compounds such as juglone.

Development and validation of a HPLC method for quantification of rivastigmine in rat urine and identification of a novel metabolite in urine by LC‐MS/MS

A sensitive, specific and accurate HPLC method for the quantification of rivastigmine (RSM) in rat urine was developed and validated. The method involves the simple liquid-liquid extraction of RSM and pyridostigmine as an internal standard (IS) from rat urine with tertiary methyl butyl ether. The chromatographic separation of RSM and IS was achieved with 20  mm ammonium acetate buffer (pH 6.5) and acetonitrile (65:35, v/v) delivered at flow-rate of 1 mL/min on a Kromasil KR-100. The method was in linear range from 50 to 5000  ng/mL. The validation was done as per FDA guidelines and the results met the acceptance criteria. The method was successfully applied for the quantification of RSM in rat urine. Besides method validation, we have identified two metabolites of RSM in urine. Both the metabolites were characterized by HPLC-PDA and LC-MS/MS and it was found that one metabolite is novel.

High Performance Liquid Chromatographic Fluorescence Detection Method for the Quantification of Rivastigmine in Rat Plasma and Brain: Application to Preclinical Pharmacokinetic Studies in Rats

A highly sensitive and selective high performance liquid chromatographic fluorescence detection method has been developed and validated for the quantification of rivastigmine in rat plasma and brain. Protein precipitation and one-step liquid-liquid extraction techniques were utilized for the extraction of RSM from brain and plasma, respectively, along with an internal standard. The chromatographic separation was achieved with a column inertsil ODS-3V and a mobile phase consisting of ammonium acetate buffer (20 mM, pH 4.5) and acetonitrile (76:24, v/v) delivered at a flow rate of 1 ml/min. The lower limit of quantitation for the developed method was 10 ng/mL for both matrices. The method was found to be accurate and reproducible and was successfully used to quantify levels of RSM in plasma and brain following intravenous administration of RSM in rats.

Development of a sensitive bioanalytical method for the quantification of lacosamide in rat plasma. Application to preclinical pharmacokinetics studies in rats.

A sensitive and selective high performance liquid chromatographic (HPLC) method was developed and validated for quantification of lacosamide in rat plasma. A liquid-liquid extraction procedure was optimized to extract lacosamide from rat plasma. Chromatographic separation was accomplished using a reversed phase C18 Hichrom (250×4.6 mm, 5 µm) column with the mobile phase consisting of acetonitrile-phosphate buffer (pH 3.2±0.1; 20 mM) (21:79, v/v) at a flow rate of 1 mL/min. Both intra- and inter day assay precision and accuracy were lower than 15% CV. The lower limit of quantitation was 25 ng/mL for lacosamide and the response was linear in a concentration range from 25 to 10 000 ng/mL. The developed method was successfully used for the preclinical pharmacokinetic study of lacosamide in rats.

Gender Differences in the Pharmacokinetics of Rivastigmine in Rats

The effect of gender on the pharmacokinetics of rivastigmine (CAS 123441-03-2) was studied in male and female Wistar rats following intravenous bolus administration. The area under the plasma concentration-time curve (AUC), apparent volume of distribution (Vd), systemic clearance (CL), and terminal plasma halflife (t1/2) of rivastigmine were compared between male and female rats. Compared to male rats, female rats exhibited higher plasma rivastigmine levels showing significantly (p < 0.05) larger AUC (226.77 vs. 149.68 ng h/ml), Vd (6.70 vs. 4.13 L), t1/2 (0.84 vs. 0.34 h) and a lower CL (5.51 vs. 8.35 L/h). The male rats had a 2.5 fold greater elimination rate constant than female rats (2.02 vs. 0.82 h(-1)). Gender had a significant effect on the pharmacokinetics of rivastigmine. Gender differences were reported due to gonadal hormones, and the observed difference in pharmacokinetics of rivastigmine might be attributed to testosterone in male rats.

A sensitive and selective HPLC method for estimation of lamotrigine in human plasma and saliva: application to plasma-saliva correlation in epileptic patients

A sensitive and selective high performance liquid chromatographic (HPLC) method was developed and validated for estimation of lamotrigine (CAS 84057-84-1) in human plasma and saliva. The chromatographic separation was achieved with a reversed phase column and a mobile phase consisting of acetonitrile and 20 mM ammonium acetate buffer pH 6.5 (30:70) with a flow rate of 1 mL/min. The calibration curve was linear within the working range for both plasma and saliva. The validated method has been successfully applied for a study of lamotrigine in human plasma and saliva to establish the correlation between these two matrices. A scatter plot of plasma versus salivary lamotrigine concentrations showed a gold linear relationship between them (Pearson correlation coefficient, r = 0.6832, p < 0.001).