Ranendra N. Saha

Nanoparticulate drug delivery systems for cancer chemotherapy.

Abstract Nanoparticles (NPs) are, in general, colloidal particles, less than 1000 nm, that can be used for better drug delivery and prepared either by encapsulating the drug within a vesicle and or by dispersing the drug molecules within a matrix. Nanoparticulate drug delivery systems have been extensively studied in recent years for spatial and temporal delivery, especially in tumour and brain targeting. NPs have great promise for better drug delivery as found in both pharmaceutical and clinical research. As a drug carrier, NPs have significant advantages like better bioavailability, systemic stability, high drug loading, long blood circulation time and selective distribution in the organs/tissues with longer half life. The selective targeting of NPs can be achieved by the enhanced permeability and retention effect (EPR-effect), attaching specific ligands, or by making selective distribution due to change of the physiological conditions of specific systems like nature, pH, temperature, etc. It has been observed that drug-loaded NPs can have selective distribution to organs/tissues using different types of and proportions of polymers. The current aim of researchers is to prepare NPs that are long-lived with and that demonstrate the appropriate selective distribution for better therapy and thus improved clinical outcomes. Nanoparticulate drug delivery systems have the potential to deliver a drug to the target site with specificity and to maintain the desired concentration at the site for the intended time without untoward effects. In this review article, the methods for the preparation of NPs, their characterization, biodistribution, and pharmacokinetic characteristics are discussed.

Design and study of lamivudine oral controlled release tablets

The objective of this study was to design oral controlled release matrix tablets of lamivudine using hydroxypropyl methylcellulose (HPMC) as the retardant polymer and to study the effect of various formulation factors such as polymer proportion, polymer viscosity, and compression force on the in vitro release of drug. In vitro release studies were performed using US Pharmacopeia type 1 apparatus (basket method) in 900 mL of pH 6.8 phosphate buffer at 100 rpm. The release kinetics were analyzed using the zero-order model equation, Higuchi’s square-root equation, and the Ritger-Peppas empirical equation. Compatibility of the drug with various excipients was studied. In vitro release studies revealed that the release rate decreased with increase in polymer proportion and viscosity grade. Increase in compression force was found to decrease the rate of drug release. Matrix tablets containing 60% HPMC 4000 cps were found to show good initial release (26% in first hour) and extended the release up to 16 hours. Matrix tablets containing 80% HPMC 4000 cps and 60% HPMC 15 000 cps showed a first-hour release of 22% but extended the release up to 20 hours. Methematical analysis of the release kinetics indicated that the nature of drug release from the matrix tablets was dependent on drug diffusion and polymer relaxation and therefore followed non-Fickian or anomalous release. No incompatibility was observed between the drug and excipients used in the formulation of matrix tablets. The developed controlled release matrix tablets of lamivudine, with good initial release (20%–25% in first hour) and extension of release up to 16 to 20 hours, can overcome the disadvantages of conventional tablets of lamivudine.

Etoposide Loaded PLGA and PCL Nanoparticles II: Biodistribution and Pharmacokinetics after Radiolabeling with Tc-99m

Etoposide and nanoparticle formulations were labeled with Tc-99m and their biodistribution and pharmacokinetics were studied after intravenous administration in healthy mice and rabbits respectively. Etoposide was rapidly cleared from the body, while the disposition of nanoparticles was slower. A higher proportion of nanoparticles compared with etoposide was observed in different organs of mice. Scintigraphic images of rabbits concluded that the radioactivity shown by formulations is significantly higher after 4 and 24 h, as compared with etoposide administered in rabbits. AUC0 − ∞, clearance and MRT are better than those obtained with etoposide administration. The overall high residence of nanoparticles, compared with etoposide, signifies the advantage of PLGA and PCL nanoparticles as drug carriers for etoposide in enhancing the bioavailability and reducing the etoposide-associated toxicity.

Application of rotatable central composite design in the preparation and optimization of poly(lactic-co-glycolic acid) nanoparticles for controlled delivery of paclitaxel.

Context: Polymeric carrier systems of paclitaxel (PCT) offer advantages over only available formulation Taxol® in terms of enhancing therapeutic efficacy and eliminating adverse effects. Objective: The objective of the present study was to prepare poly (lactic-co-glycolic acid) nanoparticles containing PCT using emulsion solvent evaporation technique. Methods: Critical factors involved in the processing method were identified and optimized by scientific, efficient rotatable central composite design aiming at low mean particle size and high entrapment efficiency. Twenty different experiments were designed and each formulation was evaluated for mean particle size and entrapment efficiency. The optimized formulation was evaluated for in vitro drug release, and absorption characteristics were studied using in situ rat intestinal permeability study. Results: Amount of polymer and duration of ultrasonication were found to have significant effect on mean particle size and entrapment efficiency. First-order interactions of amount of miglyol with amount of polymer were significant in case of mean particle size, whereas second-order interactions of polymer were significant in mean particle size and entrapment efficiency. The developed quadratic model showed high correlation (R2 > 0.85) between predicted response and studied factors. The optimized formulation had low mean particle size (231.68 nm) and high entrapment efficiency (95.18%) with 4.88% drug content. The optimized formulation showed controlled release of PCT for more than 72 hours. In situ absorption study showed faster and enhanced extent of absorption of PCT from nanoparticles compared to pure drug. Conclusion: The poly (lactic-co-glycolic acid) nanoparticles containing PCT may be of clinical importance in enhancing its oral bioavailability.

Determination of celecoxib in pharmaceutical formulations using UV spectrophotometry and liquid chromatography

A new UV spectrophotometric method (UV method) and a reversed phase liquid chromatographic method (LC method) for the quantitative estimation of celecoxib, a selective COX-2 inhibitor, in pure form and in solid dosage form were developed in the present study. The linear regression equations obtained by least square regression method, were Abs=4.949 x 10(-2).Conc. (in microg/ml)+1.110 x 10(-2) for the UV method and Area under the curve=5.340 x 10(1).Conc. (in ng/ml)+3.144 x 10(2) for the LC method, respectively. The detection limit, as per the error propagation theory, was found to be 0.26 microg/ml and 25 ng/ml, respectively, for the UV and LC methods. The developed methods were employed with a high degree of precision and accuracy for the estimation of total drug content in three commercial capsule formulations of celecoxib. The results of analysis were treated statistically, as per International Conference on Harmonisation (ICH) guidelines for validation of analytical procedures, and by recovery studies. The results were found to be accurate, reproducible and free from interference and better than the earlier reported methods.

Oral matrix tablet formulations for concomitant controlled release of anti-tubercular drugs: design and in vitro evaluations.

The aim of the present investigation was to develop controlled release (C.R.) matrix tablet formulations of rifampicin and isoniazid combination, to study the design parameters and to evaluate in vitro release characteristics. In the present study, a series of formulations were developed with different release rates and duration using hydrophilic polymers hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC). The duration of rifampicin and isoniazid release could be tailored by varying the polymer type, polymer ratio and processing techniques. Further, Eudragit L100-55 was incorporated in the matrix tablets to compensate for the pH-dependent release of rifampicin. Rifampicin was found to follow linear release profile with time from HPMC formulations. In case of formulations with HPC, there was an initial higher release in simulated gastric fluid (SGF) followed by zero order release profiles in simulated intestinal fluid (SIFsp) for rifampicin. The release of isoniazid was found to be predominantly by diffusion mechanism in case of HPMC formulations, and with HPC formulations release was due to combination of diffusion and erosion. The initial release was sufficiently higher for rifampicin from HPC thus ruling out the need to incorporate a separate loading dose. The initial release was sufficiently higher for isoniazid in all formulations. Thus, with the use of suitable polymer or polymer combinations and with the proper optimization of the processing techniques it was possible to design the C.R. formulations of rifampicin and isoniazid combination that could provide the sufficient initial release and release extension up to 24h for both the drugs despite of the wide variations in their physicochemical properties.

Etoposide-Loaded PLGA and PCL Nanoparticles I: Preparation and Effect of Formulation Variables

Etoposide-loaded nanoparticles were prepared using nanoprecipitation and emulsion solvent evaporation techniques using polylactide-co-glycolic acid and poly(ε -caprolactone) in presence of Pluronic F68, respectively. Effect of formulation variables like stabilizer concentration, amount of polymer, and drug was studied. These parameters were found to affect particle size, zeta potential, drug content, and entrapment efficiency of nanoparticles. The methods produced nanoparticles with good entrapment efficiency of around 80%. Recovery of nanoparticles was as high as 95% and drug content was around 1.5%. Increase in lactide content decreased the release of etoposide in vitro and poly(ε -caprolactone) nanoparticles retarded etoposide release for 48 hr. The results show the suitability of polylactide-co-glycolic acid and poly(ε -caprolactone) nanoparticles as potential carriers for controlled delivery of etoposide.

A Comparative Study of Controlled Release Matrix Tablets of Diclofenac Sodium, Ciprofloxacin Hydrochloride, and Theophylline

The need for controlled release formulations for diclofenac sodium, ciprofloxacin, and theophylline is well recognized. In our study, controlled release tablets of the three drugs were formulated by the matrix-embedding technique using ethyl cellulose as retardant. Tablets of all the drugs were of good physical quality with respect to appearance, drug content uniformity, hardness, weight variation, and friability. In vitro release rate studies showed that ethyl cellulose extended the release of the three drugs to 12 hr or more. Release patterns from formulations of the three drugs followed Higuchis square root kinetics. At pH 6.8, the release rate was higher in all three drugs, probably due to increased solubility of the drugs and/or increased swelling of ethyl cellulose at the higher pH. The formulations were highly stable and possessed reproducible release kinetics across batches.The need for controlled release formulations for diclofenac sodium, ciprofloxacin, and theophylline is well recognized. In our study, controlled release tablets of the three drugs were formulated by the matrix-embedding technique using ethyl cellulose as retardant. Tablets of all the drugs were of good physical quality with respect to appearance, drug content uniformity, hardness, weight variation, and friability. In vitro release rate studies showed that ethyl cellulose extended the release of the three drugs to 12 hr or more. Release patterns from formulations of the three drugs followed Higuchis square root kinetics. At pH 6.8, the release rate was higher in all three drugs, probably due to increased solubility of the drugs and/or increased swelling of ethyl cellulose at the higher pH. The formulations were highly stable and possessed reproducible release kinetics across batches.

Oral Controlled Release Formulations of Rifampicin. Part II: Effect of Formulation Variables and Process Parameters on In Vitro Release

Hydrophilic controlled release matrix tablets of rifampicin, a poorly soluble drug, have been formulated using hydroxypropyl methylcellulose (HPMC) polymer (low, medium, and high viscosity) by direct compression method. Influence of formulation variables and process parameters such as drug:HPMC ratio, viscosity grade of HPMC, drug particle size, and compression force on the formulation characters and drug release has been studied. Our results indicated that the release rate of the drug and the mechanism of release from the HPMC matrices are mainly controlled by the drug:HPMC ratio and viscosity grade of the HPMC. In general, decrease in the drug particle size decreased the drug release. Lower viscosity HPMC polymer was found to be more sensitive to the effect of compression force than the higher viscosity. The formulations were found to be stable and reproducible.

Development and Validation of High‐Performance Liquid Chromatographic Method for Estimation of Lercanidipine in Rabbit Serum

Abstract A new, simple, and sensitive reverse‐phase liquid chromatographic method was developed and validated for the estimation of Lercanidipine hydrochloride in rabbit serum using UV detector under isocratic conditions. After subjecting serum to simple and efficient one‐step extraction procedure, 100 µl of sample was injected onto high‐performance liquid chromatography system. The detector response was linear in the concentration range of 25–1000 ng/ml. The developed method was validated as per standard guidelines. Validation demonstrated accuracy, precision, and selectivity of the proposed method. The drug was found to be stable under various processing and storage conditions.