Biodistribution and efficacy of the anticancer drug, oxaliplatin palmitate acetate, in mice.

Oxaliplatin palmitate acetate (OPA), a platinum (IV) oxaliplatin derivative, was previously designed with the aim to improve the platinum-based anti-cancer therapy. In this work, we further explore the potential of OPA in extensive in vitro and in vivo studies. OPA in pancreatic (BxPC3-luc), lung (NCI-H1993) and liver (Hep3B) cancer cell lines showed a higher toxicity in comparison to oxaliplatin. The in vitro release kinetic experiments of OPA from the nanoparticles (NPs) under sink conditions exhibited a very rapid profile. Furthermore, OPA cannot be considered a prodrug of oxaliplatin, based on the OPA intact molecule pharmacokinetic profile study in rats. The formation of oxaliplatin from the biodegradation of OPA ranges only from 5% to 7% and both drugs were rapidly eliminated from the plasma. Pharmacokinetics of OPA PLGA nanoparticles in mice showed that nanoparticles failed to prolong the release of OPA in the plasma and did not add any therapeutic benefit over OPA solution, as suggested by the rapid in vitro release of OPA from nanoparticles. In pancreatic xenograft BxPC3-luc cancer model, both OPA in solution and OPA nanoparticles inhibited the tumor growth, equally and significantly, as compared to oxaliplatin. In liver xenograft Hep3B cancer model, OPA solution and cisplatin demonstrated good and similar antitumor efficacy. In lung xenograft NCI-H1993 cancer model, OPA solution, with a significant antitumor efficacy, was superior to cisplatin, which did not differ from the vehicle. In conclusion, OPA may offer a promising advance in platinum-based chemotherapy against various forms of cancers in an adequate dose and schedule.

Modified mesoporous silica nanoparticles for enhancing oral bioavailability and antihypertensive activity of poorly water soluble valsartan.

The aim was to improve the oral bioavailability and antihypertensive activity of poorly soluble drug valsartan (VAL) by modifying the design and delivery of mesoporous silica nanoparticles (MSNs). The synthesized MSNs were functionalized with aminopropyl groups (AP-MSN) through postsynthesis and coated with pH sensitive polymer Eudragit L100-55 (AP-MSN-L100-55) for pH dependant sustain release of anionic VAL. MSNs were characterized by Brauner-Emmett-Teller (BET) surface area analyzer, zeta sizer, Field Emission Scanning Electron Microscope (FESEM), Powder X-Ray Diffraction (PXRD) and Differential Scanning Calorimetry (DSC). Functionalized MSNs showed highest entrapment efficiency (59.77%) due to strong ionic interaction with VAL. In vitro dissolution of M-MSN [MSN-VAL and AP-MSN-VAL-L100-55 mixed equally] at physiological conditions demonstrated immediate release (MSN-VAL fraction) followed by sustained release (AP-MSN-VAL-L100-55 fraction) of 96% VAL in 960min. The dramatic improvement in dissolution was attributed to the amorphization of crystalline VAL by MSNs as evidenced by DSC and PXRD studies. No noticeable cytotoxicity was observed for MSN, AP-MSN and AP-MSN-L100-55 in MTT assay. Pharmacokinetic study of M-MSN confirmed 1.82 fold increases in bioavailability compared to commercial Diovan tablet in fasted male rabbits. Blood pressure monitoring in rats showed that the morning dosing of Diovan tablet efficiently controlled BP for just over 360min whereas the effect of M-MSN lasted for >840min.

Chronotherapeutically Modulated Pulsatile System of Valsartan Nanocrystals-an In Vitro and In Vivo Evaluation.

The objective was to improve the dissolution of valsartan by developing valsartan nanocrystals and design a pulsed release system for the chronotherapy of hypertension. Valsartan nanocrystals were prepared by sonication-anti-solvent precipitation method and lyophilized to obtain dry powder. Nanocrystals were directly compressed to minitablets and coated to achieve pulsatile valsartan release. Pharmacokinetic profiles of optimized and commercial formulations were compared in rabbit model. The mean particle size and PDI of the optimized nanocrystal batch V4 was reported as 211 nm and 0.117, respectively. DSC and PXRD analysis confirmed the crystalline nature of valsartan in nanocrystals. The dissolution extent of valsartan was markedly enhanced with both nanocrystals and minitablets as compared to pure valsartan irrespective of pH of the medium. Core minitablet V4F containing 5% w/w polyplasdone XL showed quickest release of valsartan, over 90% within 15 min. Coated formulation CV4F showed two spikes in release profile after successive lag times of 235 and 390 min. The pharmacokinetic study revealed that the bioavailability of optimized formulation (72.90%) was significantly higher than the commercial Diovan tablet (30.18%). The accelerated stability studies showed no significant changes in physicochemical properties, release behavior, and bioavialability of CV4F formulation. The formulation was successfully designed to achieve enhanced bioavailability and dual pulsatile release. Bedtime dosing will more efficiently control the circadian spikes of hypertension in the morning.

pH responsive cylindrical MSN for oral delivery of insulin-design, fabrication and evaluation.

OBJECTIVE: The objective of the present study was to develop novel PMV [poly (methacrylic acid-co-vinyl triethoxylsilane)]-coated mesoporous silica nanoparticles (MSN) with improved hypoglycemic effect for oral insulin (INS) delivery. METHODS: MSN was synthesized under acidic condition using Pluronic® P 123 and Tetra ethoxy orthosilane. Surfactant was removed by calcination. Calcined MSN was coated with pH sensitive polymer PMV. Cytotoxicity of this coated MSN was evaluated by MTT assay using CHO-K1 cell line. Different MSN samples were characterized with BET surface area analyzer, FESEM, TEM, FT-IR, XRD, TG-DTA. In vivo study was performed using male rats. Pharmacokinetic study was conducted using HPLC. RESULTS AND DISCUSSION: Highest surface area (304.3921 m2/g) was observed in case of calcined sample. Adsorption pore width of final coated sample was highest (64.7844 nm) compared with others. No noticeable cytotoxicity was observed for this coated support. The entrapment efficiency of insulin was found to be 39.39%. In vitro studies were done at different pH using Franz-diffusion cell. Results showed significant release at pH 7.4. Cumulative drug release over a period of 6 h was more than 48% at this systemic pH. Effect of this MSN-PMV-INS on blood glucose level was retained for 16 h. This novel formulation has shown 73.10% relative bioavailability of insulin. CONCLUSION: A novel-coated mesoporous silica support was successfully developed for delivery of insulin through oral route.

In Vitro Evaluation of pH Responsive Doxazosin Loaded Mesoporous Silica Nanoparticles: A Smart Approach in Drug Delivery.

OBJECTIVE: To develop a pH responsive drug delivery system (DDS) for controlled release of therapeutic cargo, Doxazosin Mesylate (DZM) which was loaded into carrier material mesoporous silica nanoparticle (MSN) and subsequently coated with Eudragit S-100(ES-100) to release the drug at pH 7.4. MATERIAL AND METHODS: We have synthesized cylindrical MSN under acidic condition using non-ionic surfactant (Pluronic(®) P 123) and Tetraethoxysilane (TEOS). After post synthesis treatment (PST) surfactant was removed by calcination. To obtain pH sensitive release calcined MSN was coated with ES-100 (MSN-DZMES100). The Brauner-Emmett-Teller (BET) surface area, adsorption isotherm, t-plot, pore volume of MSN were done in surface area analyzer to characterize different MSN samples (as synthesized, calcined, and coated). RESULT AND DISCUSSION: Highest surafce area (427.114 m(2)/g) was observed in case of calcined sample when compared to as synthesized (3.1198m(2)/g) and coated MSN (8.8480m(2)/g). Adsorption pore width of final coated sample was 12.58 nm whereas as synthesized and calcined samples possessed pore width 36.82 nm and 7.32 nm respectively. All uncoated and coated MSN samples were further characterized with FESEM, TEM, FTIR. No significant interaction between drug and MSN was found from FTIR studies. The drug loading into coated mesoporous support was found to be 43.7%. In vitro studies were done at different pH using Franz-diffusion cell. Results showed significant release at pH 7.4 from MSNDZM- ES100. Cumulative drug release over a period of 10 hr was 81% at this systemic pH. CONCLUSION: ES-100 coated mesoporous silica nanoparticle is a smart carrier for pH responsive release of guest molecule.

Tapioca starch blended alginate mucoadhesive-floating beads for intragastric delivery of Metoprolol Tartrate.

The objective of the study was to develop tapioca starch blended alginate mucoadhesive-floating beads for the intragastric delivery of Metoprolol Tartrate (MT). The beads were prepared by ionotropic gelation method using calcium chloride as crosslinker and gas forming calcium carbonate (CaCO3) as floating inducer. The alginate gel beads having 51-58% entrapped MT showed 90% release within 45 min in gastric medium (pH 1.2). Tapioca starch blending markedly improved the entrapment efficiency (88%) and sustained the release for 3-4 h. A 12% w/w HPMC coating on these beads extended the release upto 9-11 h. In vitro wash off and buoyancy test in gastric media revealed that the beads containing CaCO3 has gastric residence of more than 12 h. In vitro optimized multi-unit formulation consisting of immediate and sustained release mucoadhesive-floating beads (40:60) showed good initial release of 42% MT within 1h followed by a sustained release of over 90% for 11 h. Pharmacokinetic study performed in rabbit model showed that the relative oral bioavailability of MT after administration of oral solution, sustain release and optimized formulation was 51%, 67% and 87%, respectively. Optimized formulation showed a higher percent inhibition of isoprenaline induced heart rate in rabbits for almost 12 h.

Recent advancement of gelatin nanoparticles in drug and vaccine delivery.

Novel drug delivery system using nanoscale materials with a broad spectrum of applications provides a new therapeutic foundation for technological integration and innovation. Nanoparticles are suitable drug carrier for various routes of administration as well as rapid recognition by the immune system. Gelatin, the biological macromolecule is a versatile drug/vaccine delivery carrier in pharmaceutical field due to its biodegradable, biocompatible, non-antigenicity and low cost with easy availability. The surface of gelatin nanoparticles can be modified with site-specific ligands, cationized with amine derivatives or, coated with polyethyl glycols to achieve targeted and sustained release drug delivery. Compared to other colloidal carriers, gelatin nanoparticles are better stable in biological fluids to provide the desired controlled and sustained release of entrapped drug molecules. The current review highlights the different formulation aspects of gelatin nanoparticles which affect the particle characteristics like zeta potential, polydispersity index, entrapment efficacy and drug release properties. It has also given emphasis on the major applications of gelatin nanoparticles in drug and vaccine delivery, gene delivery to target tissues and nutraceutical delivery for improving the poor bioavailabity of bioactive phytonutrients.

Pulse release of doxazosin from hydroxyethylcellulose compression coated tablet: mechanistic and in vivo study.

Chronotherapeutically programmed hydroxyethylcellulose (HEC) based compression coated doxazosin tablets were prepared and the influence of disintegrants croscarmellose sodium, L-hydroxypropylcellulose (L-HPC), gellan gum on drug release and in vivo performance were investigated. Infrared spectroscopy and differential scanning calorimetric studies did not indicate any excipient incompatibility in the tablets. The disintegrants induced a continuous water influx resulting in a rapid expansion of the membrane. The subsequent formation of fractures into the coats leads to a fast drug release after an initial lag time. Release rates indicated that croscarmellose sodium and L-HPC were directly proportional to their concentration in the formulations. In vitro optimized croscarmellose sodium-HEC matrix showed significantly faster (p < 0.05) drug release (t90% = 46 min) after an initial lag of 243 min. Disintegrant-HEC blended matrices were found significantly superior (p < 0.05) in terms of in vitro release and bioavailability in comparison to plain HEC matrices. Drug release kinetics followed modified power law and Weibull model (r > 0.99). The mechanism involved in release was anomalous transport and super case II transport with matrix swelling. The pulsatile tablets showed no changes either in physicochemical appearance, drug content or in dissolution pattern during its accelerated stability studies.

Nonionic surfactant vesicles in ocular delivery: innovative approaches and perspectives.

With the recent advancement in the field of ocular therapy, drug delivery approaches have been elevated to a new concept in terms of nonionic surfactant vesicles (NSVs), that is, the ability to deliver the therapeutic agent to a patient in a staggered profile. However the major drawbacks of the conventional drug delivery system like lacking of permeability through ocular barrier and poor bioavailability of water soluble drugs have been overcome by the emergence of NSVs. The drug loaded NSVs (DNSVs) can be fabricated by simple and cost-effective techniques with improved physical stability and enhance bioavailability without blurring the vision. The increasing research interest surrounding this delivery system has widened the areas of pharmaceutics in particular with many more subdisciplines expected to coexist in the near future. This review gives a comprehensive emphasis on NSVs considerations, formulation approaches, physicochemical properties, fabrication techniques, and therapeutic significances of NSVs in the field of ocular delivery and also addresses the future development of modified NSVs.

Maltodextrin based proniosomes of nateglinide: bioavailability assessment.

The present study delineates the fabrication of maltodextrin based proniosomes of nateglinide and their potential as controlled delivery system for diabetic therapy. New Zealand albino male rabbits have been used as animal model for in vivo study. To evaluate the bioavailability of nateglinide proniosome, a rapid, simple and sensitive HPLC method with photodiode array detection was developed and validated to determine nateglinide in rabbit plasma. Chromatographic separation was achieved by a reverse phase C18 column using a mixture of acetonitrile:methanol:10mM phosphate buffer (pH 3.5) in the ratio of 56:14:30 (%v/v) as the mobile phase at a flow rate of 1.0ml/min and quantified based on drug/IS peak area ratios. Gliclazide was used as the internal standard. The intra- and inter-day relative standard deviations of four tested concentrations were below 2%. The nateglinide proniosome formulation exhibited significantly higher plasma concentration than those of pure drug. The study revealed that the rate and extent of absorption of nateglinide from the proniosomal formulation was comparatively enhanced that of pure drug. Maltodextrin based proniosomes of nateglinide is not only simple and cost efficient delivery but also offers a useful and promising carrier for diabetic therapy through oral administration.

Chronotherapeutic delivery of hydroxypropylmethylcellulose based mini-tablets: an in vitro-in vivo correlation.

The purpose of the study was to develop and internally validate a nonlinear in vitro-in vivo correlation model for a chronotherapeutically programmed HPMC based propranolol HCl (PHCl) mini-tablet. A simple and sensitive HPLC method was developed for the determination of PHCl content in rabbit plasma. The influence of tri-sodium citrate (TSC) on release behaviour was investigated through in vitro dissolution and in vivo absorption. Linear and nonlinear (quadratic, cubic, sigmoid functions) deconvolution based in vitro-in vivo correlation (IVIVC) models were developed using in vitro dissolution data and bioavailability profile. Prediction errors were investigated for Cmax and AUC in the light of US FDA guidelines for average percent prediction error. Release rate indicated that TSC was directly proportional to its concentration in the formulation. In vitro optimized formulation showed nearly 4.5h lag time and 5.24 ± 1.74% drug releases in initial 4.5h following rapid release 97.11 ± 1.87% in 6h. The deconvolution based IVIVC model appeared to be curvilinear for all three pulsatile formulations. Among various functions investigated the model using cubic function showed a better correlation (r>0.99) and satisfies the US FDA guidelines for average percent prediction error of less than 10%.

Development and in vitro/in vivo evaluation of controlled release provesicles of a nateglinide-maltodextrin complex.

The aim of this study was to characterize the provesicle formulation of nateglinide (NTG) to facilitate the development of a novel controlled release system of NTG with improved efficacy and oral bioavailability compared to the currently marketed NTG formulation (Glinate™ 60). NTG provesicles were prepared by a slurry method using the non-ionic surfactant, Span 60 (SP), and cholesterol (CH) as vesicle forming agents and maltodextrin as a coated carrier. Multilamellar niosomes with narrow size distribution were shown to be successfully prepared by means of dynamic laser scattering (DLS) and field emission scanning electron microscopy (FESEM). The absence of drug-excipient interactions was confirmed by Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC) and X-ray diffraction (XRD) studies. In vitro release of NTG in different dissolution media was improved compared to pure drug. A goat intestinal permeation study revealed that the provesicular formulation (F4) with an SP:CH ratio of 5:5 gave higher cumulative amount of drug permeated at 48 h compared to Glinate™ 60 and control. A pharmacodynamic study in streptozotocin-induced diabetic rats confirmed that formulation F4 significantly (P<0.05) reduced blood glucose levels in comparison to Glinate 60. Overall the results show that controlled release NTG provesicles offer a useful and promising oral delivery system for the treatment of type II diabetes.

Fabrication and in vitro evaluation of bidirectional release and stability studies of mucoadhesive donut-shaped captopril tablets.

OBJECTIVE: To obtain controlled release of captopril in the stomach, coated, mucoadhesive donut-shaped tablets were designed. MATERIALS AND METHODS: Donut-shaped tablet were made of different ratios of diluents to polymer or combination of polymers by direct compression method. Top and bottom portions of the tablet were coated with water-insoluble polymer followed by mucoadhesive coating. Time of water penetration, measurement of tensile strength, mucoadhesion studies (static ex vivo and ex vivo wash-off) were taken into account for characterization of respective films. In vitro study has been performed at different dissolution mediums. Optimized batches were also prepared by wet granulation. Stability studies of optimized batches have been performed. RESULTS: The results of time of water penetration and tensile strength indicated positive response against water impermeation. Mucoadhesive studies showed that film thickness of 0.12 mm was good for retention of tablet at stomach. At pH 1.2, optimized batch of tablet made with hydroxypropyl methyl cellulose (HPMC) E15 as binder showed 80% w/w drug release within 4­5 h with maximum average release of 97.49% w/w. Similarly, maximum average releases of 96.36% w/w and 95.47% w/w were obtained with nearly same dissolution patterns using combination of HPMC E5 and HPMC E50 and sodium salt of carboxy methyl cellulose (NaCMC) 500­600 cPs instead of HPMC E15. The release profiles in the distilled water and pH 4.5 followed the above pattern except deviation at pH 6.8. Stability studies were not positive for all combinations. CONCLUSION: Coated, mucoadhesive donut-shaped tablet is good for controlled release of drug in the stomach.

In vitro-in vivo correlation and bioavailability studies of captopril from novel controlled release donut shaped tablet.

A controlled release formulation of captopril which was coated and fabricated into a donut shaped tablet formulation, was investigated in rabbit for pharmacokinetic and in vitro-in vivo correlation studies. Coated donut shaped tablets were prepared and in vitro release was studied in simulated gastric fluid at three different RPMs. New Zealand albino male rabbits have been used as animal model for in vivo study. A sensitive and simple HPLC method was developed for the determination of captopril content in rabbit plasma. In vitro release studies showed that release patterns followed zero order for around 4h. Single oral administration of coated donut shaped tablets in rabbit illustrated retained availability of captopril to the injected drug. Captopril content could pursue the same release pattern over the same time course in in vivo study. The in vivo-in vitro correlation coefficients obtained from point-to-point analysis were greater than 99% between concentrations at certain time points obtained from release study in simulated gastric fluid at different RPMs and HPLC analysis of rabbit's plasma. From the in vitro-in vivo correlation prediction it was evident that the coated donut shaped tablet is a good device for controlled delivery of captopril.

Drug delivery system based on chronobiology--A review.

With the advancement in the field of chronobiology, modern drug delivery approaches have been elevated to a new concept of chronopharmacology i.e. the ability to deliver the therapeutic agent to a patient in a staggered profile. However the major drawback in the development of such delivery system that matches the circadian rhythm requires the availability of precise technology (pulsatile drug delivery). The increasing research interest surrounding this delivery system has widened the areas of pharmaceutics in particular with many more sub-disciplines expected to coexist in the near future. This review on chronopharmaceutics gives a comprehensive emphasis on potential disease targets, revisits the existing technologies in hand and also addresses the theoretical approaches to emerging discipline such as genetic engineering and target based specific molecules. With the biological prospective approaches in delivering drugs it is well understood that safer and more realistic approaches in the therapy of diseases will be achieved in the days to come.

Niosome: A future of targeted drug delivery systems.

Over the past several years, treatment of infectious diseases and immunisation has undergone a revolutionary shift. With the advancement of biotechnology and genetic engineering, not only a large number of disease-specific biological have been developed, but also emphasis has been made to effectively deliver these biologicals. Niosomes are vesicles composed of non-ionic surfactants, which are biodegradable, relatively nontoxic, more stable and inexpensive, an alternative to liposomes. This article reviews the current deepening and widening of interest of niosomes in many scientific disciplines and, particularly its application in medicine. This article also presents an overview of the techniques of preparation of niosome, types of niosomes, characterisation and their applications.