V. Kusum Devi

Design and evaluation of matrix diffusion controlled transdermal patches of verapamil hydrochloride.

Abstract Transdermal patches of verapamil hydrochloride were prepared using four different polymers (individual and combination): Eudragit RL100 (ERL100), Eudragit RS100 (ERS100), hydroxypropyl methylcellulose 15 cps (HPMC), and ethyl cellulose (EC), of varying degrees of hydrophilicity and hydrophobicity. The effect of the polymers on the technological properties, i.e., drug release, water vapor transmission rate (WVTR), and percentage moisture loss (ML), percentage moisture absorption (MA), folding endurance, and thickness, was investigated. Different formulations were prepared in accordance with the 23 factorial design, with ERL100 being the parent polymer. The patch containing ERL100 alone showed maximum WVTR, % MA, and % ML, which could be attributed to its hydrophilic nature. As expected, substitution with ERS100, HPMC, and EC decreased all the above values in accordance with their decreasing degree of hydrophilicity. In vitro release studies showed zero-order release of the drug from all the patches, and the mechanism of release was diffusion mediated. Moreover, the release of the drug was sustained and it extended over a period of 24 hr in all formulations. A12 emerged as the most satisfactory formulation insofar as its technological properties were concerned. Further, release and permeation of the drug from the most satisfactory formulation (A12) was evaluated through different biological barriers (shed snake skin, rabbit skin, and rat skin) to get an idea of the drug permeation through human skin. Shed snakes skin was found to be most permeable (82.56% drug release at 24 hr) and rat skin was least permeable (52.38%). Percutaneous absorption studies were carried out in rabbits. The pharmacokinetic parameters calculated from blood levels of the drug revealed a profile typical of a sustained release formulation, with the ability to maintain adequate plasma levels for 24 hr. [AUC: 3.09 mg/mL hr, Cmax: 203.95 µg/mL, Tmax: 8 hr]. It can therefore be concluded that the patch containing ERL100 and HPMC in the ratio 8:2 has achieved the objectives of transdermal drug delivery system, such as avoidance of first pass effect, extended release, and reduced frequency of administration.

Response surface methodology and process optimization of sustained release pellets using Taguchi orthogonal array design and central composite design

Furosemide is a powerful diuretic and antihypertensive drug which has low bioavailability due to hepatic first pass metabolism and has a short half-life of 2 hours. To overcome the above drawback, the present study was carried out to formulate and evaluate sustained release (SR) pellets of furosemide for oral administration prepared by extrusion/spheronization. Drug Coat L-100 was used within the pellet core along with microcrystalline cellulose as the diluent and concentration of selected binder was optimized to be 1.2%. The formulation was prepared with drug to polymer ratio 1:3. It was optimized using Design of Experiments by employing a 32 central composite design that was used to systematically optimize the process parameters combined with response surface methodology. Dissolution studies were carried out with USP apparatus Type I (basket type) in both simulated gastric and intestinal pH. The statistical technique, i.e., the two-tailed paired t test and one-way ANOVA of in vitro data has proposed that there was very significant (P≤0.05) difference in dissolution profile of furosemide SR pellets when compared with pure drug and commercial product. Validation of the process optimization study indicated an extremely high degree of prognostic ability. The study effectively undertook the development of optimized process parameters of pelletization of furosemide pellets with tremendous SR characteristics.

Optimization of Pellets Containing Solid Dispersion Prepared by Extrusion/Spheronization Using Central Composite Design and Desirability Function

Furosemide is a class IV biopharmaceutical classification system drug having poor water solubility and low bioavailability due to the hepatic first-pass metabolism and has a short half-life of 2 h. To overcome the above drawback, this study was carried to prepare and evaluate the pellets containing furosemide solid dispersion (SD) for oral administration prepared by extrusion/spheronization. SD of furosemide was prepared with Eudragit L-100 at a drug-to-polymer ratio of 1:2 by employing a solvent evaporation method and characterized. Further, microcrystalline cellulose pellets containing SD were consequently prepared using a lab scale extrusion/ spheronizer and evaluated for in vitro drug release studies. The influence of process parameters used during extrusion/spheronization on the pellet properties was also studied using 2-factor, 3-level central composite design in order to improve the product quality. Additionally, the desirability function approach was applied to acquire the preeminent compromise between the multiple responses. Pellets containing solid dispersion (PSD) were prepared using optimal parameter settings demonstrated 88.52 ± 0.69% of the drug was released in a sustained release manner till 12 h. In vitro drug release data were fitted to various release kinetics models to study the mechanism of drug release. Drug release from the PSD was found to follow zero-order and Higuchi′s model. Both studied parameters had great influence on the responses. PSD showed augmentation in the drug release profile till 12 h. The final optimized formulation was obtained by encapsulating best SD formulation within the pellet core to release the drug in the most soluble form in stomach and a sustained fashion in intestine.

Potential of nanotechnology as a delivery platform against tuberculosis: current research review.

This review focusses on the current ongoing research in the field of tuberculosis comprising the resistant strains. It specifies a proper data analysis with results in concise form from areas gripping in: diagnostic nanotechnology, vaccine nanotechnology and the prime field of interest i.e., therapeutic nanotechnology. Primarily, therapeutic area recollects the research findings from advanced drug delivery (primary era) to the targeted drug delivery (modern era). The vaccine-based area derives the immune-specific targeting with enhanced emphasis on vaccine extraction and preparation of nanoparticles. Finally, the diagnostic area signifies the imaging techniques that may be employed in the diagnosis of TB. Not only that, there are some researches that emphasized on finding the comparable diagnostic differences between normal and resistant strains. With the advent of carbon nanotubes, metallic NPs, a newer hope has emerged out in diagnostic research, which may extend to therapeutic research applications too. Modifications of natural polymers, least or no use of organic solvents, size controlled NPs, optimized methodology, etc., are fields that need more effort to bypass toxicity. If above desired possibilities get the priority during research, it may lead to shift in the timeline towards much more oriented research.

Development of Extended Zero-Order Release Gliclazide Tablets by Central Composite Design

The purpose of this study was to develop an extended release tablet formulation containing gliclazide as a model drug by optimization technique. A central composite design was employed with pH-dependent matrix forming polymers like keltone®-HVCR (X1) and eudragit®-EPO (X2) as independent variables. Five dependent variables were considered: hardness, percent drug release after 1 hr, percent drug release after 6 hr, diffusion exponent and time required for 50% of drug release. Response surface methodology and multiple response optimization utilizing a quadratic polynomial equation were used to obtain an optimal formulation. The results indicate that Factor X1 along its interaction with Factor X2 was found to be significantly affecting the studied response variables. An optimized formulation, containing 8 mg of keltone®-HVCR and 14.10mg of eudragit®-EPO, provides a sufficient hardness (> 4.5 kg/cm2) and optimal release properties. The desirability function was used to optimize the response variables, each having a different target and the observed responses were highly agreed with experimental values. The release kinetics of gliclazide from optimized formulation followed zero-order release pattern. The dissolution profiles of optimized formulation before and after stability studies were evaluated by using similarity factor (f2) and were found to be similar. The results demonstrate the feasibility of the model in the development of extended release dosage form.

Nanocarrier-based interventions for the management of MDR/XDR-TB

Abstract Emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB over the past decade presents an unprecedented public health challenge to which countries of concern are responding far too slowly. Global Tuberculosis Report 2014 marks the 20th anniversary of the Global Project on Anti-Tuberculosis Drug Resistance Surveillance, indicating the highest global level of drug-resistance ever recorded detection of 97 000 patients with MDR-TB resulting in 170 000 deaths in 2013. Treatment of MDR-TB is expensive, complex, prolonged (18–24 months) and associated with a higher incidence of adverse events. In this context, nanocarrier delivery systems (NDSs) efficiently encapsulating considerable amounts of second-line anti tubercular drugs (sATDs), eliciting controlled, sustained and more profound effect to trounce the need to administer sATDs at high and frequent doses, would assist in improving patient compliance and avoid hepatotoxicity and/or nephrotoxicity/ocular toxicity/ototoxicity associated with the prevalent sATDs. Besides, NDSs are also known to inhibit the P-glycoprotein efflux, reduce metabolism by gut cytochrome P-450 enzymes and circumnavigate the hepatic first-pass effect, facilitating absorption of drugs via intestinal lymphatic pathways. This review first provides a holistic account on MDR-TB and discusses the molecular basis of Mycobacterium tuberculosis resistance to anti-tubercular drugs. It also provides an updated bird’s eye view on current treatment strategies and laboratory diagnostic test for MDR-TB. Furthermore, a relatively pithy view on patent studies on second-line chemotherapy using NDSs will be discussed.

Formulation and Optimization of Mucoadhesive Nanodrug Delivery System of Acyclovir

Acyclovir is an antiviral drug used for the treatment of herpes simplex virus infections, with an oral bioavailability of only 10-20% [limiting absorption in gastrointestinal tract to duodenum and jejunum] and half-life of about 3 h, and is soluble only at acidic pH (pKa 2.27). Mucoadhesive polymeric nanodrug delivery systems of acyclovir have been designed and optimized using 2 3 full factorial design. Poly (lactic-co-glycolic acid) (PLGA) (50:50) was used as the polymer along with polycarbophil (Noveon AA-1) as the mucoadhesive polymer and pluronic F68 as the stabilizer. From the preliminary trials, the constraints for independent variables X 1 (amount of PLGA), X 2 (amount of pluronic F68) and X 3 (amount of polycarbophil) have been fixed. The dependent variables that were selected for study were particle size (Y 1 ), % drug entrapment (Y 2 ) and % drug release in 12 h (Y 3 ). The derived polynomial equations were verified by check point formulation. The application of factorial design gave a statistically systematic approach for the formulation and optimization of nanoparticles with the desired particle size, % drug release and high entrapment efficiency. Drug: Polymer ratio and concentration of stabilizer were found to influence the particle size and entrapment efficiency of acyclovir-loaded PLGA nanoparticles. The release was found to follow Fickian as well as non-Fickian diffusion mechanism with zero-order drug release for all batches. In vitro intestinal mucoadhesion of nanoparticles increased with increasing concentration of polycarbophil. These preliminary results indicate that acyclovir-loaded mucoadhesive PLGA nanoparticles could be effective in sustaining drug release for a prolonged period.

Liquid Chromatographic Assay for the Analysis of Kanamycin sulphate nanoparticles in Rat after intramuscular administration: Application to a Pharmacokinetic Study -

A rapid reversed-phase high performance liquid chromatography (RP-HPLC) method was developed for the determination of Kanamycin sulphate (KS) in PLGA nanoparticle formulation. A new formulation of KS loaded PLGA nanoparticles (NPs) was prepared by double (multiple) emulsion process in our laboratory. The desired chromatographic separation was achieved on a Phenomenex C18 column under isocratic conditions using UV detection at 205 nm. The optimized mobile phase consisted of a mixture of 0.1 M disodium tetraborate (pH 9.0) and water (25:75, v/v) supplemented with 0.5 g/L sodium octanesulphonate at a flow rate of 1 mL/min. The linear regression analysis for the calibration curves showed a good linear correlation over the concentration range of 120-840 µg/ml, with correlation coefficients of (r2 0.9997). The system was found to construct sharp peaks for KS and IS with retention times of 4.08 and 5.49 min, respectively. Transmission electron microscopy studies on MFX NPs demonstrated particle size < 100 nm. An average encapsulation efficiency of 74.34% was obtained for NPs. In vitro studies showed zero-order release and about 95% drug being released within 12 days in PBS (pH 7.4). In conclusion, the proposed optimized method was successfully applied for the determination of in vitro and in vivo release studies of KS NPs.

Potential of novel drug delivery strategies for the treatment of hyperlipidemia

Abstract Emergence of hyperlipidemia in urban population of India and the world at large is very high and accounts to several fatal diseases. This condition is known to manifest elevated levels of lipids and/or lipoproteins. Serious limitations like inadequate solubility, less absorption, less bioavailability, ineffectiveness in lowering of cholesterol levels, patient incompliance and so on are noticed with majority of anti-hyperlipidemic drugs and dosage forms, which are used conventionally. To overcome these shortcomings, building technology platforms for development of appropriate dosage forms is the need of the hour. These efforts are required to maximize patient acceptability while maintaining safety, efficacy, accessibility and affordability. Hyperlipidemia, its types, etiology, pathophysiology and conventional dosage forms are discussed here. The current approaches and novel developments which illustrate controlled drug release and sustained therapeutic effect along with site specific and target oriented drug delivery with better patient compliance are also reviewed critically. Despite the incentives provided by the efforts of formulation scientists, there is still a need for implementation of pharmaceutical technologies that enable to combat limitations of anti-hyperlipidemic drugs and conventional dosage forms associated with it. The present review emphasize on applications of novel drug delivery systems in pharmacotherapy of anti-hyperlipidemic drugs demonstrating the advantages and disadvantages.

Kanamycin Sulphate Loaded PLGA-Vitamin-E-TPGS Long Circulating Nanoparticles Using Combined Coating of PEG and Water-Soluble Chitosan

Kanamycin sulphate (KS) is a Mycobacterium tuberculosis protein synthesis inhibitor. Due to its intense hydrophilicity, KS is cleared from the body within 8 h. KS has a very short plasma half-life (2.5 h). KS is used in high concentrations to reach the therapeutic levels in plasma, which results in serious nephrotoxicity/ototoxicity. To overcome aforementioned limitations, the current study aimed to develop KS loaded PLGA-Vitamin-E-TPGS nanoparticles (KS-PLGA-TPGS NPs), to act as an efficient carrier for controlled delivery of KS. To achieve a substantial extension in blood circulation, a combined design, affixation of polyethylene glycol (PEG) to KS-PLGA-TPGS NPs and adsorption of water-soluble chitosan (WSC) (cationic deacetylated chitin) to particle surface, was raised for surface modification of NPs. Surface modified NPs (KS-PEG-WSC NPs) were prepared to provide controlled delivery and circulate in the bloodstream for an extended period of time, thus minimizing dosing frequency. In vivo pharmacokinetics and in vivo biodistribution following intramuscular administration were investigated. NPs surface charge was close to neutral +3.61 mV and significantly affected by the WSC coating. KS-PEG-WSC NPs presented striking prolongation in blood circulation, reduced protein binding, and long drew-out the blood circulation half-life with resultant reduced kidney sequestration vis-à-vis KS-PLGA-TPGS NPs. The studies, therefore, indicate the successful formulation development of KS-PEG-WSC NPs with reduced frequency of dosing of KS indicating low incidence of nephrotoxicity/ototoxicity.