Drug Delivery Letters - Volume 5, Issue 3, 2015

Background: Natural polymers have been explored for drug delivery applications since decades, but limited success has been ascribed to their undesired physicochemical properties. Here, we demonstrate the grafting of an anionic and hydrophilic exopolysaccharide ‘gellan gum’with polyacrylamide using microwave irradiation and its potential in controlled delivery of aceclofenac. Methods: Grafting of gellan gum was optimized w.r.t. microwave temperature, exposure time, concentration of free radical initiator and characterized by FTIR, DSC, XRD and SEM analysis. Subsequently, gellan gum and gellan-g-poly(acrylamide) were formulated into aceclofenac tablets and subjected to in vitro drug release, swelling and stability studies. Results: The microwave temperature, exposure time and concentration of free radical initiator had synergistic effect on grafting efficiency up to 80 °C, 120 s and 5 g, respectively. The swelling studies carried out at different pH conditions support the potential of gellan-g-poly(acrylamide). Gellan gum and gellan-g-poly(acrylamide) formulations were compared with commercialized sustained release Zerodol-CR tablets. In vitro release studies revealed the superiority of gellan- g-poly(acrylamide) which was able to sustain the drug release up to 97% over 24 h by zero order kinetics with n value within the range of 1.38-1.80 indicating super case-II (non-Fickian) transport i.e. dominated by diffusion and erosion from polymeric matrix. Interestingly higher drug release was observed in acidic conditions. Conclusion: These findings validate the crucial role of co-polymerization in improving the efficacy of existing natural polymers and support the competence of gellan-g-poly(acrylamide) in the design of highly efficient controlled drug delivery system.

Background: Hypertension is the most common cardiovascular disease worldwide and number one cause of death. Its related morbidities also impose huge economic burdens on population. The aim of the present investigation was to prepare thermal gel of Diltiazem Hydrochloride (DTZ) with different ratios of Poloxamer 407 (PLM 407) and Hydroxypropyl methylcellulose K100M (HPMC K100M) and to characterize their in vitro parameters, ex vivo permeation and in vivo antihypertensive activity. Methods: Cold method was used to prepare thermal gel of DTZ. In vitro testing such as interaction study using FTIR and DSC method, bioadhesive strength was measured using modified balance method, in vitro release study performed using dialysis bag method. Ex vivo permeation study was carried out by using a cylindrical glass diffusion cell. Rabbit model was used to perform in vivo antihypertensive activity. Results: The FT-IR spectra and DSC thermograms demonstrated the absence of interaction between DTZ and selected polymers. Based on the results obtained from in vitro studies, formulation DT3 having 1% w/w of HPMC K100M and 25% w/w of PLM 407 was selected as optimized thermal gel. Among the permeation enhancers (PEs) used in this study (such as L-menthol, transcutol and isopropyl myristate (IPM) at 10% (w/w)) L-menthol present in gel formulation DTm showed highest flux of 355.234 μg/cm2/h across abdominal skin of rat. Rabbit group treated with DTm exhibited prolonged (up to 8 h) antihypertensive effect in normotensive rabbits compared to orally treated group. Conclusion: The optimized gel with L-menthol has a promising potential as an effective product in the treatment of hypertension and expected to provide a better alternative to oral DTZ formulations with improved patient compliance.

Objective: The aim of the present study was to investigate the effect of lauroyl macrogolglycerides (Gelucire 44/14) on Fluconazole (FZ) loaded solid lipid nanoparticles (SLN). Methods: FZ SLN were prepared using Glyceryl monostearate (GMS) and Gelucire 44/14 (GL) by microemulsion technique. The effect of concentration of GL on FZ SLN was studied. Similarly, the effect of formulation variables, drug content in lipid phase (X1) and Surfactant mixture: lipid ratio (X2), on particle size (Y1), entrapment (Y2) and release (Y3) of FZ loaded SLN was also studied using 32 full factorial design. SLN was characterized for particle size, entrapment efficiency, drug content, drug release, morphology by TEM and in-vitro antifungal efficacy. The solid state characterization of optimized lyophilized formulation was performed by DSC and XRD. Results: For the optimized formulation, particle size was 143 nm, PDI 0.38, drug entrapment 75.2% and FZ release after 8 h of dissolution 84.9%. Incorporation of GL in SLN not only decreased the particle size, increased the percent entrapment efficiency and enhanced the drug release but also stabilized the formulation. In-vitro antifungal activity revealed significant reduction in Candida count with FZ SLN [from 4.51 log CFU/ml (T0) to 3.64 log CFU/ml (T24)]. Conclusion: Present study suggests that the developed system might serve as a potential system of drug delivery for Candidiasis.

Background: Colorectal cancer claims the life of millions of people globally. Chemoprevention is among the upcoming approaches for the treatment of colorectal cancer. It involves the use of therapeutic agents which are essentially not cytotoxic drugs but, however, impedes the carcinogenesis. Meloxicam (MLX) is one such agent which has the potential to be employed in the chemopreventive therapy of colorectal cancer. The aim of this study was to formulate MLX into a formulation so as to exploit its potential to the fullest. Method: Conventional (M-MM) and PEGylated mixed micelles (M-PMM) of MLX were prepared using hydrogenated soy phosphatidylcholine (HSPC) and 1, 2-Distearoyl-phosphatidylethanolamine-methyl-polyethyleneglycol conjugate- 2000 sodium salt (MPEG 2000 DSPE) by the film casting method. The mixed micelles were fabricated using Quality by Design (QbD) approach and were optimized for parameters such as particle size and entrapment efficiency. The optimized formulation was further characterized for parameters such as particle size, percent entrapment efficiency, zeta potential, long-term stability, morphology, in vitro release and in vitro cytotoxic activity. Results: The optimized PEGylated mixed micelles had high percent entrapment efficiency of 73.6%±0.72% and mean particle size of 132 nm±67nm and had a sustained release profile releasing 62.7%±0.37% drug in 24h. The M-PMM mixed micellar formulations revealed uniform size in the Small Angle Neutron Scattering (SANS) analysis and were found to be ellipsoidal shaped vesicles by transmission electron microscopy (TEM) as well as SANS studies. The entrapment of the MLX in the formulations was confirmed by Differential Scanning Calorimetry (DSC), Fourier Transform Infrared spectroscopy (FT-IR) and Powder X-Ray diffraction (PXRD) studies. Long term stability study indicated that the formulation was stable for three months. The cytotoxicity assay carried out in HT-29 cell lines showed that the PEGylated mixed micellar formulations had higher cytotoxicity than the conventional mixed micelles after 48 hours of incubation. Conclusion: MLX loaded PEGylated mixed micelles had superior in vitro release as well as in vitro cytotoxicity. Hence, PEGylated mixed micelles can be considered to be a promising system for the delivery of MLX.

Background: The objective of this study was to develop liposomal mucoadhesive drug delivery system for the delivery of curcumin via nasal route, to avoid hepatic first pass metabolism, to increase residence time and to investigate its nose to brain delivery potential. Methodology: The liposomes were prepared by solvent dispersion method using soya lecithin and cholesterol as a lipid phase and xanthan gum as a mucoadhesive polymer. The liposomes were evaluated for particle size, entrapment efficiency, mucoadhesion, DSC, ex vivo permeation, histopathological study, in vitro drug release, and in vivo study for the estimation of drug in brain after intranasal administration. Results and Discussion: The particle size was in the range of 100.2-150 nm with good stability and controlled release characteristics without any deleterious effect on nasal mucosa of rat. When administered via intranasal route the liposomes showed higher drug distribution in brain (1240 ng) compared to drug solution (65 ng). Conclusion: The results of the in vivo study suggests that the xanthan gum coated curcumin liposomes is a promising drug delivery system to deliver drug to the brain through nasal route.

Background: Tablets are conventional dosage forms in health care systems and lot of efforts are made to control the release and subsequent oral absorption of drug via sustained release matrix tablets. Different polymers, natural and synthetic, are explored in this dimension to optimize the control over drug release and absorption. Different polymers presents different response to hydration, depending upon their swelling index. This study explores the use of hydrophilic and hydrophobic natural biodegradable polymers to control the drug release and oral absorption from simple matrix tablets, without involving the complex manufacturing processes and high cost polymeric excepients. Methods: Tizanidine HCl as model drug with low pharmacokinetic half-life was selected as cargo drug in this study. Xanthan gum and olibanum gum were used as release controlling natural hydrophilic and hydrophobic polymers with different swelling index. The underlying hypothesis was to optimize the drug release and absorption profile from matrix tablets, with different proportions of hydrophilic and hydrophobic polymers. Tablets were prepared by direct compression technique and optimized by using swelling behavior of gums upon hydration in compliance with 32 factorial models. Tablets were evaluated for in-vitro drug release, USP specifications for physical properties of tablets and oral absorption via single sample plasma Pharmacokinetics. Results: Pre-compression and post-compression physical parameters of bulk mixture and compressed tablets were found within USP specified limits. Oral absorption study was performed in rats to develop relationship in ratios of hydrophilic/ hydrophobic gums and oral absorption of drug. Single plasma sample was collected and analyzed after 2 h of oral administration. Formulation with more proportion of hydrophilic xanthan gum showed relatively better oral absorption of drug: increased plasma level and onset of Tinazidine associated sedation in animal was observed. In-vitro release studies were carried out at pH 1.2 for first 2 h and then pH 6.8 up to 12 h. Collective higher proportion of both gums was able to sustain the drug releasing properties of tablets and both gums showed their individual effect on drug release. A percentage drug release at T25%, T50%, T90% along with mean dissolution time was determined which showed a linear relationship among all the batches. Conclusion: Study explained the effect of relative concentration of gums with different swelling, eroding and hydration behavior-on oral absorption and controlled drug release behavior of tablets. It was concluded that both polymers worked in independent manner to optimize drug release and oral absorption.

Background: Chitosan is a semi-synthetic biopolymer obtained by the alkaline deacetylation of chitin by the use of concentrated NaOH. It exhibits excellent biological properties such as biocompatibility, bioactivity biodegradation in the human body, immunological, antimicrobial and wound-healing activity. Chitosan is a unique amino carbohydrate, as it has dual-functionality as hydroxyl and amino groups in it. It is soluble in dilute acidic media and insolubility of chitosan in basic media confines its biomedical applications as cannot interact with the cationic amenities. So as to increase its locale of biomedical applications the graft modification of chitosan is becoming progressively more imperative for developing smart materials based on this amino polysaccharide. Methods: In this current work, we have synthesized and characterized the graft copolymers of chitosan grafted with binary monomer mixture of acrylic acid with other vinyl monomers like acrylamide and acrylonitrile by free radical initiation method. The binary graft copolymers were investigated for swelling at different pH in order to define their end uses in the sustainable and controlled release of anti-inflammatory drug, Diclofenac sodium (DS). Results: The synthesized graft copolymers were characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), thermal analysis (TGA/DTA), scanning electron microscopy(SEM) and swelling studies. It is observed that the sorption of drug on polymeric samples is directly linked with swelling properties of polymeric samples. Ch-gpoly( AAc-co-AAm) load maximum drug in it as it swell maximum in all solutions of different pH. Conclusion: Graft copolymers were also studied for the sustainable release of anti-inflammatory drug, diclofenac sodium as a function of time and pH and found that polymeric samples Ch-g-poly(AAc-co-AAm) showed best results for sustained drug release.