Curcumin loaded mesoporous silica nanoparticles: assessment of bioavailability and cardioprotective effect.

Rhizomes of the plant Curcuma longa has been traditionally used in medicine and culinary practices in India. It possesses various pharmacological effect, namely, antioxidant, hepatoprotective, anti-inflammatory, anti-thrombosis, and anti-apoptotic. The study was undertaken to assess the effect of curcumin and curcumin loaded mesoporous silica nanoparticles (MSNs) against doxorubicin (DOX)-induced myocardial toxicity in rats. Furthermore, the study also included the bioavailability estimation of curcumin delivered alone and delivered via mesoporous technology. Cardiotoxicity was produced by cumulative administration of DOX (2.5 mg/kg for two weeks). Curcumin and curcumin loaded mesoporous nanoparticles (MSNs) each 200 mg/kg, po was administered as pretreatment for two weeks and then for two alternate weeks with DOX. The repeated administration of DOX induced cardiomyopathy associated with an antioxidant deficit and increased level of cardiotoxic biomarkers. Pretreatment with curcumin (alone and via MSNs) significantly protected myocardium from the toxic effects of DOX by significantly decreased the elevated level of malondialdehyde and increased the reduced level of reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) in cardiac tissue. MSNs based delivery was found superior compared to curcumin delivered alone. Moreover, the results of bioavailability assessment in rats clearly indicated higher Cmax and AUC values in rats when curcumin was administered via MSNs indicating superior bioavailability. The bioavailability of curcumin loaded MSNs, biochemical and histopathology reports support the good cardioprotective effect of curcumin which could be attributed to its increased bioavaibility lead to good antioxidant and anti-inflammatory activity.

Temperature influencing permeation pattern of alfuzosin: an investigation using DoE.

BACKGROUND AND OBJECTIVE: There has been relatively little investigation of the effect of temperature on skin permeation compared to other methods of penetration enhancement. A principal physicochemical factor which controls the passive diffusion of a solute from a vehicle into the skin arises from the skin temperature. The aim of this ex vivo study was to probe into the effect of heat on transdermal absorption of alfuzosin hydrochloride from ethyl cellulose-polyvinyl pyrrolidone (EC-PVP) based transdermal systems. MATERIALS AND METHODS: Principles of design of experiment (DoE) were used to systematically study the influence of temperature on transdermal permeation of alfuzosin. Ex vivo transdermal permeation studies were carried out at varied donor compartment temperatures. Permeation data analysis was carried out and activation energy for transdermal permeation was estimated. RESULTS: Temperature found to enhance ex vivo permeation parameters of alfuzosin hydrochloride from its transdermal systems. It was also noted that chemical permeation enhancers potentiate permeation enhancing effect of temperature. The permeation flux values approximately doubled after exposure to 45°C. The activation energy for transdermal permeation was found lower for the runs with chemical permeation enhancers indicating existence of a lower energy barrier in the presence of chemical permeation enhancers. CONCLUSION: The method reported here is a simple and useful tool for studying the effect of heat on percutaneous absorption. Such temperature dependent enhancement of flux can be more pronounced at skin surface temperatures >45°C.

Optimal delivery of poorly soluble drugs using electrospun nanofiber technology: Challenges, state of the art, and future directions.

Poor aqueous solubility of both, existing drug molecules and those which are currently in the developmental stage, have posed a great challenge to pharmaceutical scientists because they often exhibit poor dissolution behavior and subsequent poor and erratic bioavailability. This has triggered extensive research to explore nanotechnology-based technology platforms for possible rescue. Recently, nanofibers have been exploited widely for diverse biomedical applications including for drug delivery. Electrospun nanofibers are capable of preserving the homogeneously loaded therapeutic agents in amorphous state potentialy impairing devitrification. The present review aims at providing an overview of the various key factors that affect the electrospinning process and characteristics of the nanofibers while fabrication of drug loaded nanofibers for poorly soluble drug candidates. The review explores various methodological advancements in the electrospinning process and set-ups for production scale-up. The various types of electrospun nanofibers (like simple matrix, core-sheath, Janus, and inclusion complex nanofibers) that have been exploited for the delivery of poorly soluble drugs are also critically assessed. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Rise of gold nanoparticles as carriers of therapeutic agents.

A nanoparticle is the simplest structural component due to its nanometer-sized diameter. Nanoparticles are typically atoms or molecules that generate a radius (or diameter) of less than 100 nm when bonded collectively. The latest developments in nanotechnology provide a wide range of methods for studying and monitoring various medical and biological processes at the nanoscale. Nanoparticles can help diagnose and treat diseases, such as cancer, by carrying drugs directly to cancer cells. They can also be used to detect disease biomarkers in the body, helping to provide early diagnosis. It is likely that the data will have a positive effect on biology and medicine. It is plausible that nanoparticles could be used in theranostic applications and targeted drug delivery. This could significantly improve patient outcomes and reduce the amount of time, effort, and money needed to diagnose and treat diseases. It could also reduce the side effects of treatments, providing more precise and effective treatments. Nanoparticles for biomedical applications include polymeric and metal nanoparticles; liposomes and micelles; dendrimers and quantum dots; etc. Among the nanoparticles, gold nanoparticles have emerged as a promising platform for drug delivery applications. Gold nanoparticles are highly advantageous for drug delivery applications due to their excellent biocompatibility, stability, and tunable physical and chemical properties. The present review provides an in-depth discussion of the various approaches to gold nanoparticle synthesis and drug delivery applications.

A Critical Appraisal of Lipid Nanoparticles Deployed in Cancer Pharmacotherapy.

Treatment modalities of various cancers and the delivery strategies of anticancer agents have evolved significantly in the recent past. The severity and fatality of the disease and hurdles to the effective delivery of therapeutic agents have drawn the attention of researchers across the world for proposing novel and effective drug delivery strategies for anticancer therapeutics. Attempts have been made to propose solutions to the diverse limitations like poor pharmacokinetics and higher systemic toxicities of the traditional delivery of anticancer agents. Nanotechnology-based drug delivery systems including lipid-based nanocarriers have demonstrated significant efficiency in this scenario. The review critically assessed the different types of lipid nanocarrier systems for the effective and optimal delivery of anticancer therapeutic agents. The diverse synthesis approaches are discussed for the laboratory scale and commercial development of different categories of lipid nanocarriers. Further, their application in anticancer drug delivery is illustrated in detail followed by a critical appraisal of their safety and toxicity.

Ibuprofen Loaded Electrospun Polymeric Nanofibers: A Strategy to Improve Oral Absorption.

The poor aqueous solubility of candidate drugs has presented a great challenge to formulation scientists for their effective oral delivery. Poor solubility is often associated with poor dissolution behavior and, subsequently, poor bioavailability for those drugs when intestinal absorption is dissolution rate limited. In the present study electrospun polymeric nanofibers were developed to address the poor aqueous solubility of ibuprofen, a Biopharmaceutic Classification System (BCS) class-II drug. Hydrophilic spinnable polymers like polyvinyl pyrrolidone were deployed as a carrier system for the fabrication of nanofibers. The electrospinning parameters like flow rate, voltage, and spinneret to collector distance were optimized. The fabricated ibuprofen-loaded nanofibers were characterized using scanning electron microscopy and differential scanning calorimetry. Drug release studies and ex vivo intestinal absorption studies were also carried out. The nanofiber-based platform significantly improved in vitro absorption of ibuprofen compared to pure ibuprofen crystals.

Influence of chemical permeation enhancers on transdermal permeation of alfuzosin: an investigation using response surface modeling.

CONTEXT: A nonoral alternative such as transdermal system is desired to improve bioavailability and to maintain a constant and prolonged drug level with reduced frequency of dosing. OBJECTIVE: The objective of the investigation is to develop a transdermal therapeutic system for alfuzosin hydrochloride and to study the influence of chemical permeation enhancers (CPEs) on the percutaneous permeation pattern. MATERIAL AND METHODS: A D-optimal mixture design was used to study the influence of CPE with oleic acid (OA), lauric acid, and propylene glycol (PG) as mixture components. The influence of chemical enhancers on skin permeation was compared using one-way analysis of variance followed by multiple comparison analysis. Criterion of desirability was used to optimize the therapeutic system. Preclinical studies in rabbits were also carried out to establish an ex vivo-in vivo correlation (EVIVC). RESULTS: The drug permeation pattern suggested Higuchian diffusion as predominant mode followed by case II to super case II transport as drug transport mechanism. The optimized formulation was obtained using 5% (w/w) CPE consisting of a blend of 62.41% OA and 37.59% PG. About twofold increase in alfuzosin permeation was achieved with the optimized transdermal patch. An approximate linear EVIVC was established (R(2) = 0.971). DISCUSSION: The optimized blend of enhancers could improve skin permeation parameters. A higher extent of in vivo skin permeation compared with cadaver skin permeation may be due to more permeable nature of rabbit skin. CONCLUSION: The investigations suggest an effective alternative delivery strategy such as transdermal systems for alfuzosin hydrochloride.

Preclinical evaluation of drug in adhesive type ondansetron loaded transdermal therapeutic systems.

The in vivo assessment of percutaneous absorption of molecules is a very important step in the evaluation of any transdermal drug delivery system and a key goal in the design and optimization of transdermal dosage forms lies in understanding the factors that determine a good in vivo performance. The objective of the present investigation is to assess the in vivo performance of an optimized transdermal system of ondansetron hydrochloride in rabbits and to generate preclinical pharmacokinetic data. The pharmacokinetic performance of ondansetron hydrochloride following intravenous and transdermal administration was studied in rabbits following non compartmental pharmacokinetic analysis. The pharmacokinetic parameters such as area under the curve, elimination rate constant, elimination half life and mean residence time, were significantly (P < 0.01) different following transdermal administration compared to intravenous administration. Absolute bioavailability of the transdermal film studied was estimated to be 0.37 ± 0.06 which is quite low because a very high drug loading in the transdermal system was essential to achieve sufficient thermodynamic activity for transdermal permeation. Though in vivo studies in rabbits are found promising, investigations in healthy human subjects are essential to confirm the performance of the developed transdermal films.

Alfuzosin hydrochloride transdermal films: evaluation of physicochemical, in vitro human cadaver skin permeation and thermodynamic parameters.

PURPOSE: The main objective of the investigation was to develop a transdermal therapeutic system for alfuzosin hydrochloride and to study the effects of polymeric system and loading dose on the in vitro skin permeation pattern. MATERIALS AND METHODS: Principles of experimental design have been exploited to develop the dosage form. Ratio of ethyl cellulose (EC) and polyvinyl pyrrolidone (PVP) and loading dose were selected as independent variables and their influence on the cumulative amount of alfuzosin hydrochloride permeated per cm2 of human cadaver skin at 24 h (Q24), permeation flux (J) and steady state permeability coefficient (PSS) were studied using experimental design. Various physicochemical parameters of the transdermal films were also evaluated. Activation energy for in vitro transdermal permeation has been estimated. RESULTS: Ratio of EC and PVP was found to be the main influential factor for all the dependent variables studied. Drug loading dose was also found to influence the dependent variables but to a lesser extent. Physicochemical parameters of the prepared films were evaluated and found satisfactory. Activation energy for alfuzosin permeation has also been estimated and reported. CONCLUSION: The therapeutic system was found to be dermatologically non-irritant and hence, a therapeutically effective amount of alfuzosin hydrochloride can be delivered via a transdermal route.

Influence of hydroxypropyl methylcellulose on drug release pattern of a gastroretentive floating drug delivery system using a 3(2) full factorial design.

In the present investigation, controlled release gastroretentive floating drug delivery system of theophylline was developed employing response surface methodology. A 3(2) randomized full factorial design was developed to study the effect of formulation variables like various viscosity grades and contents of hydroxypropyl methylcellulose (HPMC) and their interactions on response variables. The floating lag time for all nine experimental trial batches were less than 2 min and floatation time of more than 12 h. Theophylline release from the polymeric matrix system followed non-Fickian anomalous transport. Multiple regression analysis revealed that both viscosity and content of HPMC had statistically significant influence on all dependent variables but the effect of these variables found to be nonlinear above certain threshold values.

Formation of physically stable amorphous phase of ibuprofen by solid state milling with kaolin.

Ibuprofen was milled in the solid state with kaolin (hydrated aluminium silicate) in different ratio to examine the extent of transformation from crystalline to amorphous state. The physical stability of the resultant drug was also investigated. X-ray powder diffractometry (XRD) and birefringence by Scanning Electron Microscopy (SEM) studies indicated almost complete amorphization of the drug on ball milling with kaolin at 1:2 ratio. Fourier transform infrared spectroscopy (FTIR) data showed a reduction in the absorbance of the free and the hydrogen-bonded acid carbonyl peak of carboxylic acid group accompanied by a corresponding increase in the absorbance of the carboxylate peak, indicating an acid-base reaction between the carboxylic acid containing ibuprofen and kaolin on milling. The extent of amorphization and reduction in the carbonyl peak and increase in carboxylate peak was a function of kaolin concentration in the milled powder. On storage of milled powder (at 40 degrees C and 75% RH for 10 weeks), XRD and birefringence of SEM study showed the absence of reversion to the crystalline state and FTIR data revealed continued reduction of carbonyl peak, whereas, ibuprofen converted from its crystalline acid form to amorphous salt form on milling with kaolin. Kaolin-bound state of ibuprofen was physically stable during storage. In-vitro dissolution studies revealed that percent release of ibuprofen from the kaolin co-milled powder is in the order: 1:2>1:1>1:0.5>1:0.1>milled alone ibuprofen>crystalline ibuprofen.

Physicochemical characterization of interaction of ibuprofen by solid-state milling with aluminum hydroxide.

This present study is a preliminary exploration of the affinity between a carboxylic model drug ibuprofen and aluminum hydroxide. Ibuprofen was comilled with aluminum hydroxide in different weight ratios in the solid state and was characterized by scanning electron microscopy (SEM), X-ray powder diffractometry (XRD), Fourier transform infrared spectroscopy (FTIR), and in vitro dissolution studies. XRD and SEM studies indicated complete interaction of ibuprofen with aluminum hydroxide and complete amorphization of aluminum hydroxide-ibuprofen complexed salt as well, on comilling with aluminum hydroxide at 1:2 ratio. FTIR data showed the disappearance of acid carbonyl peak with the appearance and the corresponding increase in absorbance of new signal at 1,682 cm(-1) in the 1:1 and 1:2 ibuprofen-aluminum hydroxide-comilled powder. The accompanied increase in the absorbance of carboxylate peak in the ibuprofen-aluminum hydroxide physical mixture, and 1:0.1, 1:0.5, 1:1, and 1:2 (IBA(pm), and IB(1)A(0.1), IB(1)A(0.5), IB(1)A(1), and IB(1)A(2), respectively) comilled powder indicated an acid-base reaction between ibuprofen and aluminum hydroxide. On storage at 40 degrees C and 75% relative humidity (RH) for 10 weeks, XRD study showed the absence of reversion to the crystalline state and FTIR data revealed continued increase of new signal at 1,682 cm(-1) relative to carboxylic acid peak and no reappearance of carboxylic acid peak. In vitro dissolution studies revealed that the percent release of ibuprofen from the aluminum hydroxide-comilled powder is in the following order: IB(1)A(2) < IB(1)A(1) < ibuprofen crystal < ibuprofen milled alone < IB(1)A(0.1) < IB(1)A(0.5). Aluminum metal cation might have interacted to form a complex through the carboxyl and carbonyl groups of ibuprofen. Improved dissolution of drug associated with IB(1)A(0.1) and IB(1)A(0.5) is because of the absence of a new signal at 1,682 cm(-1) and improved amorphization of the drug to some extent. Dissolution of drug affected in IB(1)A(2) and IB(1)A(1) may be because of the insoluble stable complex formation.

Graphene and graphene-based nanocomposites: biomedical applications and biosafety.

Graphene is the first carbon-based two dimensional atomic crystal and has gained much attention since its discovery by Geim and co-workers in 2004. Graphene possesses a large number of material parameters such as superior mechanical stiffness, strength and elasticity, very high electrical and thermal conductivity, among many others. It is the strongest and the most stretchable known material, which has the record thermal conductivity and very high intrinsic mobility, as well as being completely impermeable. Numerous favorable properties of graphene make it a potential promising material for applications in biomedicine. A large surface area, chemical purity and the possibility for its easy functionalization allow graphene to provide opportunities for drug delivery. Its unique mechanical properties suggest applications in tissue engineering and regenerative medicine. However, like other nanomaterials, graphene may pose a bio-hazard. In this article, we present a systematic review on the synthesis of graphene, various approaches for the fabrication of nanocomposites of graphene and their applications in biomedicine. A very detailed review is presented on how graphene and its nanocomposites are currently exploited for drug delivery, cancer therapy, gene delivery, biosensing and regenerative medicine. Finally, the safety and toxicity associated with graphene are also discussed.

Effect of casting solvent on crystallinity of ondansetron in transdermal films.

The purpose of the present investigation is to assess the influence of casting solvent on crystallinity of ondansetron hydrochloride in transdermal polymeric matrix films fabricated using povidone and ethyl cellulose as matrix forming polymers. Various casting solvents like chloroform (CHL), dichloromethane (DCM), methanol (MET); and mixture of chloroform and ethanol (C-ETH) were used for fabrication of the transdermal films. Analytical tools like scanning electron microscopy (SEM), X-ray diffraction (XRD) studies, differential scanning calorimetry (DSC), etc. were utilized to characterize the crystalline state of ondansetron in the film. Recrystallisation was observed in all the transdermal films fabricated using the casting solvents other than chloroform. Long thin slab-looking, long wire-like or spherulite-looking crystals with beautiful impinged boundaries were observed in SEM. Moreover, XRD revealed no crystalline peaks of ondansetron hydrochloride in the transdermal films prepared using chloroform as casting solvent. The significantly decreased intensity and sharpness of the DSC endothermic peaks corresponding to the melting point of ondansetron in the formulation (specifically in CHL) indicated partial dissolution of ondansetron crystals in the polymeric films. The employed analytical tools suggested chloroform as a preferred casting solvent with minimum or practically absence of recrystallization indicating a relatively amorphous state of ondansetron in transdermal films.

Drug in adhesive type transdermal matrix systems of ondansetron hydrochloride: optimization of permeation pattern using response surface methodology.

The present investigation aims at development of pressure sensitive adhesive (PSA) based drug in adhesive type transdermal systems of ondansetron hydrochloride with higher permeation flux. The effect of mixture of two chemical permeation enhancers (oleic acid and lauric acid diethanolamide); and drug loading dose on the ex vivo human cadaver skin permeation from the transdermal patches has been investigated using a d-optimal combined mixture design. Incorporation of chemical permeation enhancers significantly improved the permeability parameters and it was also found that blend of permeation enhancers is more effective than either permeation enhancer. Criterion of desirability was employed to numerically optimize the transdermal system. Optimized formulation was achieved with 67.5% lauric acid diethanolamide, 32.5% oleic acid and 10% drug loading in an acrylate based PSA matrix. Optimized formulation was found to be nonirritating and safe for dermatological application.

Current perspectives of solubilization: potential for improved bioavailability.

This review focuses on the recent techniques of solubilization for the attainment of effective absorption and improved bioavailability. Solubilization may be affected due to cosolvent water interaction or altered crystal structure by cosolvent addition. Micellar solubilization could be affected by both ionic strength and pH. Addition of cosolvents to the surfactant solutions offers only a small advantage because of the decrease in the solubilization capacity of the micelles. Polymorphism is known to influence dissolution and bioavailability of the drugs. Molecular modeling study of cyclodextrin inclusion complexations can predict the inclusion modes, stoichiometry of the complex, and the relative complexing efficiency of cyclodextrins with various drug molecules.

Interaction characteristics and thermodynamic behaviour of gatifloxacin by aluminium hydroxide.

The interaction pattern of gatifloxacin was temperature-dependent Langmuir isotherm, and the Langmuir coefficients increased as the temperature was raised. The perturbation experiment conducted on this system showed that the nature of interaction was irreversible. The enthalpy change is a positive value, indicating the existence of increased activation energy as the temperature is raised. The entropy value, 24.21 e.u. obtained in this system, indicated that the hydration shells of the ions were rather tightly bound. Intestinal permeation study also revealed the decreased bioavailability of gatifloxacin relatively to the presence of aluminium hydroxide. The strong adsorption of gatifloxacin by aluminium hydroxide is due to formation of complexes with cations of aluminium hydroxide through carboxyl and carbonyl groups of gatifloxacin.