Ashwini R. Madgulkar

Formulation Design and Optimization of Novel Taste Masked Mouth-Dissolving Tablets of Tramadol Having Adequate Mechanical Strength

The purpose of this work was to develop novel taste masked mouth-dissolving tablets of tramadol that overcomes principle drawback of such formulation which is inadequate mechanical strength. Tramadol is an opioid analgesic used for the treatment of moderate to severe pain. Mouth-dissolving tablets offer substantial advantages like rapid onset of action, beneficial for patients having difficulties in swallowing and in conditions where access to water is difficult. The crucial aspect in the formulation of mouth-dissolving tablets is to mask the bitter taste and to minimize the disintegration time while maintaining a good mechanical strength of the tablet. Mouth-dissolving tablets of tramadol are not yet reported in the literature because of its extreme bitter taste. In this work, the bitter taste of Tramadol HCl was masked by forming a complex with an ion exchange resin Tulsion335. The novel combination of a superdisintegrant and a binder that melts near the body temperature was used to formulate mechanically strong tablets that showed fast disintegration. A 32 full factorial design and statistical models were applied to optimize the effect of two factors, i.e., superdisintegrant (crospovidone) and a mouth-melting binder (Gelucire 39/01). It was observed that the responses, i.e., disintegration time and percent friability were affected by both the factors. The statistical models were validated and can be successfully used to prepare optimized taste masked mouth-dissolving tablets of Tramadol HCl with adequate mechanical strength and rapid disintegration.

Design of potential reverse transcriptase inhibitor containing Isatin nucleus using molecular modeling studies

Two Dimensional (2D) and Three Dimensional (3D) Quantitative Structure-Activity Relationship (QSAR) studies were performed for correlating the chemical composition of Isatin analogues and their anti-HIV activity using Multiple Linear Regression (MLR) Analysis and k Nearest Neighbor Molecular Field Analysis (kNN MFA), respectively. New Chemical Entities (NCEs) were designed using results of QSAR studies. Binding affinities of designed NCEs were studied on Reverse Transcriptase enzyme using docking studies and their ADME properties were also predicted. Finally most promising compounds were selected from molecular modeling studies. Five compounds containing Isatin nucleus were synthesized and tested for their anti-HIV activity by performing Reverse Transcriptase Assay. Three compounds showed significant Reverse Transcriptase inhibiting activity compared to standard Navirapine. Structure-Activity Relationships were also discussed bases on obtained molecular modeling and experimental data.

Synthesis and characterization of a novel mucoadhesive derivative of xyloglucan

A novel polymer in the form of a thiolated derivative of natural tamarind seed polysaccharide or xyloglucan was synthesized and its chacteristics as a mucoadhesive polymer were studied as a part of the study undertaken herein. The synthetic route followed involves a two-step reaction mechanism of firstly oxidizing xyloglucan and then further conjugating it with l-cysteine to form thiolated xyloglucan or thiomer via imine linkage. The thiomer thus formed was characterized using various analytical techniques as differential scanning calorimetry (DSC), X-ray diffraction analysis (XRD), and nuclear magnetic resonance (NMR). Ellmans method was used to determine the numbers of thiol groups/g of thiolated xyloglucan. Zeta potential measurements were carried out for thiolated xyloglucan. Viscosities of the formulated xyloglucan and thiolated xyloglucan gels were comparatively evaluated along with the evaluation of mucoadhesive properties of the gels using ex vivo bioadhesion study employing freshly excised sheep intestinal mucosa.

Formulation and optimization of sustained release tablets of venlafaxine resinates using response surface methodology

The aim of the current study was to design sustained release matrix tablets of venlafaxine hydrochloride using ion exchange resin with the incorporation of hydrophilic and hydrophobic polymer combinations. Venlafaxine HCl was loaded onto Indion 244 by batch method and then resinate were wet granulated with ethyl cellulose and blended with hydroxypropylmethylcellulose and compressed. A central composite design for 2 factors at 3 levels each was employed to systematically optimize drug release profile at 2 h and at 18 h. Hydroxypropylmethylcellulose and ethylcellulose were taken as the independent variables. Response surface plots and contour plots were drawn, and optimum formulations were selected by feasibility and grid searches. Resinate shows inadequate sustained release profile. Compressed matrices exhibited the anomalous release mechanism, as the value of release rate exponent (n) varied between 08109 and 08719, resulting in regulated and complete release until 20 h. Validation of optimization study, performed using five confirmatory runs, indicated very high degree of prognostic ability of response surface methodology, with mean percentage error as 1.152±1.88%. Regulated drug release study indicates that the hydrophilic and hydrophobic matrix tablets of venlafaxine resinate prepared using hydroxypropylmethylcellulose and ethylcellulose, can successfully be employed as a once-a-day oral controlled release drug delivery system.

Sugars as solid dispersion carrier to improve solubility and dissolution of the BCS class II drug: clotrimazole

Abstract Solid dispersion of poorly soluble BCS class II drug, clotrimazole, was prepared with the aim of enhancing its dissolution profile. Solid dispersions were prepared using various sugars as carriers at different weight ratio to drug-like d-mannitol, d-fructose, d-dextrose and d-maltose by fusion method. The solubility of plain clotrimazole in different percent of sugar solutions was measured. Also, its solubility in solid dispersion and their physical mixture were assessed. The dissolution of all the prepared SD tablets, direct compressed clotrimazole tablet and plain drug were tested using the U.S. Pharmacopeia convention (USP) apparatus II. The dissolution profiles were characterized by parameters like area under curve (AUC), mean residence time (MRT), mean dissolution time (MDT) and percent dissolution efficiency (% DE). The release kinetics study was performed using DD Solver TM software. The selected solid dispersions (SDs) were evaluated for antifungal activity. A 100% solution of mannitol showed 806-fold increases in solubility as compared with plain clotrimazole in water. It was observed that the dissolution profile of clotrimazole was improved by mannitol SD at drug to sugar ration of 1:3. The percent DE value for mannitol SD tablet was found to be 77.3516% as against plain drug and directly compressed tablet of clotrimazole at 50.9439% and 31.33%, respectively. Also the antifungal activity indicated by inhibition zone was found to be 54 mm indicating enhance activity against Candida albicans as compared with plain CTZ at 6.6 mm. Thus, it can be concluded that the sugar alcohol, that is, mannitol is a more promising hydrophilic carrier for solid dispersion preparation to improve the solubility and dissolution of poorly soluble drugs.

Fabrication and efficacy evaluation of chloroquine nanoparticles in CFA-induced arthritic rats using TNF-α ELISA.

Rheumatoid arthritis (RA), a chronic systemic autoimmune disease, stimulates various immune cells especially macrophages, causing release of various proinflammatory cytokines such as TNF-α leading to persistent synovitis. Chloroquine, an anti-malarial drug inhibits the production of TNF-α, thus, halting the disease progression. The aim of the present study was fabrication, characterization and demonstration of kinetic and dynamic efficacy of chloroquine loaded solid lipid nanoparticles (CQ-SLNs) in arthritic rats and in lowering TNF-α levels. CQ-SLNs were prepared using melt homogenization method and subjected to lyophilization. The particle size, zeta potential, PDI and entrapment efficiency were found to be 113.6±0.15nm, -27.8±1.21mV, 0.125±0.03 and 93.45±0.43% respectively. Ex vivo endocytic uptake studies revealed engrossment of endocytic pathways in the uptake of SLN from intestine. Plasma drug profile upon pharmacokinetic evaluation demonstrated increased AUC, half-life and decreased elimination rate of the drug. Pharmacodynamic studies revealed reduction in the paw volume, bone erosion and cartilage destruction, the same was also reflected in histopathological studies. The TNF-α ELISA concluded that the TNF-α level was significantly reduced in the synovial fluid upon treatment with CQ-SLN, thus, leading to the conclusion that CQ-SLN could be used as a potential in reducing inflammatory TNF-α at the arthritic site and halting the disease progression.

Formulation and evaluation of Adapalene-loaded nanoparticulates for epidermal localization.

Adapalene (ADP), a topically administered antiacne drug, finds limitation due to poor penetration, limited localization, and associated incompatibility of photosensitization and skin irritation. To explicate an innovative and safe method for ADP administration and alleviating the associated limitations, solid lipid nanoparticles (SLN) of ADP have been fabricated and evaluated for efficacy in the present work. The SLN were prepared using pre-emulsion sonication method and incorporated into convenient topical dosage form, hydrogels. In vitro permeation studies of the hydrogels through HCS indicated gel containing ADP-SLN showed 2-fold more accumulation in skin layers as compared to conventional ADP gel. Rheological studies demonstrated ADP-SLN gel to possess pseudoplastic behavior, occlusion and hydration studies revealed permeation effectiveness of ADP-SLN gel over conventional ADP gel while primary skin irritation studies established safety of the ADP-SLN gel upon topical application. Hence, it was concluded that the studied ADP-SLN formulation with skin localizing ability may be a promising carrier for topical delivery of ADP.

Synthesis of MCC-PEG Conjugate and Its Evaluation as a Superdisintegrant

PEGylated conjugate of microcrystalline cellulose (MCC) was synthesized by reacting MCC with polyethylene glycol (PEG) 200 in the presence of catalyst at elevated temperature. Conjugation between MCC and PEG was confirmed by FT-IR and 1H NMR studies. The conjugate showed 61% PEG content increase in molecular weight determined by mass spectroscopy. PEGylation did not improve solubility of cellulose significantly. The physico-chemical properties of conjugate were compared against MCC. This conjugate was evaluated for water vapor uptake isotherms, maximum water saturation, water penetration rate, disintegration time, superdisintegration power, and dissolution study. After comparing its results with that of commercial superdisintegrants, it can be concluded that MCC–PEG conjugate can prove to be a good superdisintegrant.

Formulation of piperine solid lipid nanoparticles (SLN) for treatment of rheumatoid arthritis

Abstract The purpose of this work was to formulate piperine solid lipid nanoparticle (SLN) dispersion to exploit its efficacy orally and topically. Piperine SLN were prepared by melt emulsification method and formula was optimized by the application of 32 factorial design. The nanoparticulate dispersion was evaluated for particle size, entrapment efficiency and zeta potential (ZP). Optimized batch (128.80 nm average size, 78.71% entrapment efficiency and −23.34 mV zeta potential) was characterized for differential scanning calorimetry (DSC), X-ray diffraction which revealed amorphous nature of piperine in SLN. The prepared SLN were administered orally and topically to CFA-induced arthritic rats. Ex vivo study using Franz diffusion cell indicate that piperine from SLN gel formulation accumulates in the skin. Pharmacodynamic study result indicates both the topical and oral piperine evoked a significant response compared to orally administered chloroquine suspension. The results of ELISA show significant reduction in TNFα in treated rat which might be the reason behind the DMARD action of piperine SLN.

Formulation and optimisation of sustained release spray-dried microspheres of glipizide using natural polysaccharide.

The objective of this study was to investigate the combined influence of three independent variables in the preparation of glipizide microspheres by the spray-drying method. A three factor, three level Box-Behnken design was used to derive polynomial equations and construct response surface plots to predict responses. The independent variables selected were concentration of polymer (xyloglucan) (X1), amount of crosslinking agent (X2), and feed rate (X3). Fifteen batches were prepared and evaluated for percentage drug entrapment and time for 80% drug release (t80). Response surface plots were constructed to demonstrate the combined effects of factors X1, X2, and X3 on response percent entrapment. The optimal microsphere preparations displayed a percent entrapment between 96.96 and 98.11 and a t80 between 420 and 439 min. The microspheres had particle size between 3 and 6 microns, and differential scanning chromatography thermograms showed the presence of glipizide in amorphous form in microspheres. LAY ABSTRACT: Multiparticulate dosage forms are pharmaceutical formulations in which the active substance is present as number of small independent subunits. The microspheres as drug delivery systems are especially suitable for providing oral controlled release formulations with low risk of dose dumping, Microspheres can be blended suitably to attain different release patterns. Glipizide is recommended orally for treatment of type II diabetes and is administered in 2 or 3 doses of 2.5 to 10 mg per day. The development of controlled-release dosage form would offer effective control by releasing drug over period of time. The present work describes formulation of microspheres containing glipizide using the tamarind seed polysaccharide or xyloglucan as carrier. The spray-drying method was used to formulate the microspheres and variables (concentration of xyloglucan, amount of crosslinking agent, and feed rate) affecting performance parameters such as time for 80% drug release and percent drug entrapment were optimized using a statistical design (Box Behnken design). The microspheres had particle size between 3 and 6 microns, had entrapment between 97 and 99%, and sustained the drug release beyond 7 hours.