Jyotsana R. Madan

Development and evaluation of solid lipid nanoparticles of mometasone furoate for topical delivery

Introduction: Solid lipid nanoparticles (SLNs) are the new generation of submicron sized lipid emulsions where liquid lipid (oil) has been substituted by solid lipid. Lipids used in the formulation are safe, stable and biodegradable in nature. SLNs offer various advantages for topical drug delivery like ability of deposition into skin with the reduced systemic exposure and reduced local side-effects along with providing sustained release of drug. Mometasone furoate (MF) is a topical glucocorticoid having anti-inflammatory, anti-pruritic, anti-hyper proliferative activity. Owing to these properties it is recommended in chronic inflammation and psoriasis. In market, MF cream and lotion (0.1%) are available, which show slight skin irritation, burning and common side-effects due to steroids. Experimental: To overcome the shortcomings of conventional formulations, there is a need to develop a novel formulation that can reduce these side-effects and show maximum desired effects. Thus, SLN of MF can be prepared, which would help in increasing skin deposition as well as provide sustained release. In this study, SLNs were prepared by solvent - injection method. Results: The F8 batch had shown maximum entrapment up to55.59% and sustained drug release for more than 8 h. The skin permeability of SLN loaded gel was found to be 15.21times more than that of marketed cream. SLN loaded gel showed 83.52% of skin deposition which was 2.67 times more than marketed cream and 20 times more than plain drug loaded gel. The scanning electron microscopy and zeta potential study showed formation of good SLN dispersion. The stability study showed successful formation of stable SLNs. Thus, SLNs proved the potential for topical delivery of corticosteroid drug over the conventional formulations. Experimental: To overcome the shortcomings of conventional formulations, there is a need to develop a novel formulation that can reduce these side-effects and show maximum desired effects. Thus, SLN of MF can be prepared, which would help in increasing skin deposition as well as provide sustained release. In this study, SLNs were prepared by solvent - injection method.

Formulation and Evaluation of Transdermal Patches of Donepezil

AIMS AND BACKGROUND Donepezil (DNZ) is a centrally acting reversible acetyl cholinesterase inhibitor. The main therapeutic use of donepezil is in the treatment of Alzheimers disease. The present research work pertains to the preparation of transdermal patches of donepezil with the objective to improve its patient compliance, therapeutic efficacy and to reduce the frequency of dosing and side effects as well as to avoid its extensive first pass metabolism. The recent patents on Rivastigmine (WO2013150542A2), Xanomeline (US5980933A) and Propentofylline (CA2255580A1) helped in selecting the drug and polymers. MATERIALS AND METHODS The transdermal patches were prepared using various polymers in combination with the plasticizer and penetration enhancers. The physicochemical parameters like folding endurance, thickness, drug content, content uniformity, moisture absorption, weight variation, and drug permeation studies of the optimized patches were studied. RESULTS The system containing Eudragit S -100, Eudragit E -100 and HPMC as matrix forming agent and glycerine as plasticizer was the best formulation. The in vitro release data was treated with kinetic equations and it followed zero order release. The diffusion study was carried out using rat skin showed 89% drug was released within 72 hours. Tween-80 (0.83 % w/w) was found to be the best among all penetration enhancers. All the transdermal patches had the desired physical properties like tensile strength, folding endurance, flatness and water vapor transmission rate etc. CONCLUSION The study concluded that that transdermal patch can extend the release of donepezil for many hours and also ensure enhanced bioavailability, further it also helps in avoiding the first pass effect.

Formulation and evaluation of niosomal in-situ nasal gel of Buspirone Hydrochloride for brain delivery

BACKGROUND Buspirone Hydrochloride is an anxiolytic agent and serotonin receptor agonist belonging to azaspirodecanedione class of compounds used in the treatment of anxiety disorders. It has short half-life (2-3h) and low oral bioavailability (4%) due to extensive first pass metabolism. OBJECTIVE The nasal mucosa has several advantages viz., large surface area, porous endothelial membrane, high blood flow, avoidance of first-pass metabolism and ready accessibility that lead to faster and higher drug absorption. Keeping these facts in mind, the objective of the present study was to develop Buspirone hydrochloride loaded niosomal in-situ nasal gel. METHODS Buspirone hydrochloride niosomal in situ nasal gel was formulated, optimized and evaluated with the objective to deliver drug to the brain via intranasal route. Niosomes were prepared by thin film evaporation method and optimized using32 factorial design. Niosomes were characterized for particle size, zeta potential, entrapment efficiency and in vitro drug release. Buspirone hydrochloride loaded niosomes were further incorporated into Carbopol 934P and HPMC K4M liquid gelling system for the formation of in situ gel. The resultant solution was assessed for various parameters, viz., gelling time, gelling capacity, viscosity at pH 5 and pH 6. RESULTS The vesicle size of all niosomal suspension batches ranges between 168.3 -310.5 nm. The vesicle size of optimized niosomal suspension F5 batch is 181.9±0.36nm. For F5 batch, the value of zeta potential was found to be -15.4 mV; this specifies that prepared niosomes have sufficient surface charge to prevent aggregation of the vesicles. % entrapment efficiency for all batches was found in the range 72.44±0.18% to 87.7±0.66%. The cumulative percent release of niosomal suspension ranges from 66.34±0.39 to 84.26±0.26%. Ex vivo permeation of Buspirone hydrochloride through the sheep nasal mucosa showed that 83.49% w/w drug permeated after 8 h. The SEM and Zeta potential studies showed the formation of stable vesicles. CONCLUSION Thus, the application of niosomes proved the potential for intranasal delivery of Buspirone hydrochloride over the conventional gel formulations. Overall intranasal drug delivery for Buspirone hydrochloride has been successfully developed.

Development and Evaluation of Transdermal Organogels Containing Nicorandil

The objective of the study was to formulate a transdermal product containing Nicorandil as a model drug, because it has been first drug of choice to treat angina and hypertension. A further objective was to reduce its side effects. The transdermal product was prepared using various synthetic and natural gelling agents such as Carbopol 934p, Carbopol 974p, HPMC K15M and HPMC K100M. Various penetration enhancers were incorporated to enhance the diffusion across the rat skin. A further objective was to formulate organogels and minimize the concentration of penetration enhancer to 50% of the concentration used in gels and yet to achieve the maximum drug release. The prepared formulations were evaluated for their physical appearance, viscosity, spreadability, drug content and freeze thaw cycle. Based on in vitro studies across rat skin and human cadaver skin it was concluded that Nicrorandil transdermal organogel formulation using HPMC K100M with 2% w/w Transcutol-P shows increase in cumulative diffusion of Nicorandil amongst all other formulations.

Skin targeting of oxiconazole nitrate loaded nanostructured lipid carrier gel for fungal infections.

BACKGROUND The progression of fungal infections can be rapid and serious due to compromising with immune function. They may cause liver damage, affect estrogen levels or may cause allergic reactions. Oxiconazole nitrate (OXZN) is a broad spectrum commonly used antifungal drug. It acts by erogosterol biosynthesis inhibition, which causes lysis of the fungal cell membrane because of changes in both membrane integrity and fluidity and direct membrane damage of fungal cells. However, its poor water solubility and short half-life (3-5 h) limit its applications. OBJECTIVE This study aimed to develop and evaluate OXZN-loaded nanostructured lipid carrier (NLC) to improve its solubility and prolong its release for the treatment of fungal infection via topical administration. METHOD OXZN-NLC was prepared by ultrasonication method using 32 full factorial design. Glyceryl monostearate (GMS) (X1) and oleic acid (X2) were used as independent variables and particle size and percentage entrapment efficiency (% EE) as dependent variables. The OXZN-NLCs were characterized for particle size, particle morphology and entrapment efficiency. RESULTS The mean diameter of optimized OXZN-NLCs was found to be 124 ± 2 nm. Spherical shape and size were confirmed using scanning electron microscopy (SEM). Skin deposition study showed about 82.74% deposition as compared with the marketed formulation that showed 68.42% deposition. The developed NLCs show a sustained release pattern and high drug disposition in the infected area. CONCLUSION OXZN-NLC could be a potential alternative for the treatment of topical fungal infection after clinical evaluation in near future.

Formulation, Characterization and In-vitro Evaluation of Fast Dissolving Tablets Containing Gliclazide Hydrotropic Solid Dispersions

BACKGROUND Low aqueous solubility is a major problem faced with new drug molecules. The purpose of this research was to provide a fast dissolving oral dosage form of Gliclazide (GLZ) using the concept of mixed hydrotropy. The recent patents on Adenosine (US20140107059A1), Growth hormone releasing factor peptide (EP0984788A1) and Paclitaxel (WO2002030466A2) helped in selecting the hydrotropes. METHODS Solubility of GLZ was determined individually in sodium salicylate, nicotinamide, lactose, sodium acetate, urea, trisodium citrate and sodium benzoate. Highest solubility was obtained in 40% sodium benzoate solution. In order to decrease the individual hydrotrope amount, mixed hydrotropic agents were used. RESULTS Highest solubility was obtained in 25:15 ratio of sodium salicylate and sodium benzoate. This optimized combination was utilized in the preparation of solid dispersions which were evaluated for Xray diffractometry, Differential Scanning Calorimetry (DSC) and Fourier-transform infrared to show no drug-hydrotropes interaction. This solid dispersion was compressed to form fast dissolving tablets. Dissolution studies of prepared tablets were done using USP Type II apparatus. CONCLUSION The batch G3 tablets showed 86% cumulative drug release within 14min with in vitro dispersion time of 33sec. It was concluded that the enhancement in solubility of GLZ is a clear indication of the potential of mixed hydrotropy which is a novel, safe and cost-effective technique to be employed for other poorly water-soluble drugs having low bioavailability.

Improving the solubility of nevirapine using a hydrotropy and mixed hydrotropy based solid dispersion approach

BACKGROUND Nevirapine, an antiviral drug, is a potent reverse transcriptase inhibitor (NNRTI). It is used in combination with nucleoside analogues for treatment of HIV type-1 (HIV-1) infection and AIDS. Nevirapine is a BCS class II drug which shows dissolution rate limited absorption. OBJECTIVES The aim of the present research was to provide a fast dissolving solid dispersion of nevirapine. MATERIAL AND METHODS The solubility of nevirapine was initially determined individually in four hydrotropic agents - namely urea, lactose, citric acid and mannitol - at a concentration of 10, 20, 30 and 40% w/v solutions using purified water as a solvent. The highest solubility was obtained in the 40% citric acid solution. Then different combinations of 2 and 3 hydrotropic agents in different ratios were used to determine solubility, so that the total concentration of hydrotropic agents was always 40%. RESULTS The highest solubility was obtained in a solution of lactose and citric acid at the optimum ratio of 15:25. This optimized combination was utilized in preparing solid dispersions by a common solvent technique using distilled water as a solvent. The solid dispersions were evaluated for XRD, DSC and FTIR to show no drug-hydrotrope interaction. CONCLUSIONS It was concluded that the concept of mixed hydrotropic solid dispersion is a safe, novel and cost-effective technique for enhancing the bioavailability of poorly water-soluble drugs by dissolving the drug in a nonionized form. The enhancement in solubility of nevirapine using hydrotropy is a clear indication of its potential to be used in the future for other poorly water-soluble drugs in which low bioavailability is a major concern.

Development and evaluation of in situ gel of pregabalin

Aim and Background: Pregabalin (PRG), an analog of gamma-aminobutyric acid, reduces the release of many neurotransmitters, including glutamate, and noradrenaline. It is used for the treatment of epilepsy; simple and complex partial convulsion. The present research work aims to ensure a high drug absorption by retarding the advancement of PRG formulation through the gastrointestinal tract. The work aims to design a controlled release PRG formulation which is administered as liquid and further gels in the stomach and floats in gastric juice. Materials and Methods: In situ gelling formulations were prepared using sodium alginate, calcium chloride, sodium citrate, hydroxypropyl methylcellulose (HPMC) K100M, and sodium bicarbonate. The prepared formulations were evaluated for solution viscosity, drug content, in vitro gelling studies, gel strength, and in vitro drug release. The final formulation was optimized using a 32 full factorial design. Results: The formulation containing 2.5% w/v sodium alginate and 0.2% w/v calcium chloride were considered optimum since it showed minimum floating lag time (18 s), optimum viscosity (287.3 cps), and gel strength (4087.17 dyne/cm2). The optimized formulation follows Korsmeyer-Peppas kinetic model with n value 0.3767 representing Fickian diffusion mechanism of drug release. Conclusion: Floating in situ gelling system of PRG can be formulated using sodium alginate as a gelling polymer and calcium chloride as a complexing agent to control the drug release for about 12 h for the treatment of epilepsy.

Formulation and development of self-microemulsifying drug delivery system of pioglitazone

Self-microemulsifying drug delivery system (SMEDDS) is a promising system for the Biopharmaceutics Classification System (BCS) class II drugs. The current research aimed to improve the dissolution of poorly water-soluble antidiabetic drug pioglitazone HCl by formulating it in SMEDDS. Liquid SMEDDS of pioglitazone HCl were formulated with Capmul MCM C8 and oleic acid as oil phase, Cremophor RH 40 and Tween 80 as surfactant phase, and Transcutol P as cosurfactant phase after screening various vehicles. The prepared formulations were evaluated for self-emulsifying ability and phase diagram was constructed to optimize the system. These systems were further characterized for globule size, effect of pH and robustness, zeta potential, drug content, viscosity, self-emulsification time, polydispersity index, % transmittance, thermodynamic stability, surface morphology, and drug release. The system was robust to different pH media and dilution volumes. The optimized system possessed a mean globule size of 122.2 nm, zeta potential around -22.9 mV, drug content 99.66 ± 0.47%, viscosity 0.8874 ± 0.026 cP, emulsification time 38 s, polydispersity index value of 0.5, and transmittance value of 99.3 ± 0.6%. Drug release in hydrochloric acid buffer pH 2 was found to be 99.35 ± 0.38%. More than three-fold increase in dissolution characteristics of pioglitazone HCl in SMEDDS was observed as compared to pure and marketed formulation. Liquid SMEDDS filled in hard gelatin capsule (HGC) shell was found to be compatible. Stability studies show there was no sign of phase separation or precipitation and no change in drug content was observed.