Purpose
This work explores synthesis of novel cholesterol derivative for the preparation of cationic liposomes and its interaction with Paclitaxel (PTX) within liposome membrane using molecular dynamic (MD) simulation and in-vitro studies.

Methods
Cholesteryl Arginine Ethylester (CAE) was synthesized and characterized. Cationic liposomes were prepared using Soy PC (SPC) at a molar ratio of 77.5:15:7.5 of SPC/CAE/PTX. Conventional liposomes were composed of SPC/cholesterol/PTX (92:5:3 M ratio). The interaction between paclitaxel, ligand and the membrane was studied using 10 ns MD simulation. The interactions were studied using Differential Scanning Calorimetry (DSC) and Small Angle Neutron Scattering analysis. The efficacy of liposomes was evaluated by MTT assay and endothelial cell migration assay on different cell lines. The safety of the ligand was determined using the Comet Assay.

Results
The cationic liposomes improved loading efficiency and stability compared to conventional liposomes. The increased PTX loading could be attributed to the hydrogen bond between CAE and PTX and deeper penetration of PTX in the bilayer. The DSC study suggested that inclusion of CAE in the DPPC bilayer eliminates Tg. SANS data showed that CAE has more pronounced membrane thickening effect as compared to cholesterol. The cationic liposomes showed slightly improved cytotoxicity in three different cell lines and improved endothelial cell migration inhibition compared to conventional liposomes. Furthermore, the COMET assay showed that CAE alone does not show any genotoxicity.

Conclusions
The novel cationic ligand (CAE) retains paclitaxel within the phospholipid bilayer and helps in improved drug loading and physical stability.

Parenteral administration of Busulfan (BU) conquers the bioavailability and biovariability related issues of oral BU by maintaining the plasma drug concentrationin therapeutic range with minimal fluctuations thereby significantly reducing the side effects. Busulfex^® is the only commercially available parenteral formulation of BU composed of organic solvents N, N-dimethylacetamide and polyethylene glycol 400. Since, BU is highly susceptible to hydrolytic degradation; Busulfex^® has poor physical and chemical stability in IV fluids. It is quintessential to develop organic solvent free formulation of BU using parenterally acceptable excipients to enhance its solubility and stability in IV fluids. The Proliposomal formulation of BU was prepared by adsorption-sonicaton method using egg phosphotidylcholine, cholesterol, tween 80and mannitol. Vesicle size and entrapment efficiency were optimized using 2⁴ full factorial design and characterized by DSC, PXRD and TEM. Optimized formulation spontaneously forms 74.0 ± 1.7 nm sized nanovesicles with 72.9 ± 1.5 % entrapment efficiency. DSC and PXRD studies revealed that BU was present in phospholipid bilayer in amorphized form and TEM images confirmed the multi lamellar vesicular structure. Physicochemical stability of BU was significantly enhanced with proliposomal formulation. In-vivo studies in Sprague Dawley rats showed proliposomal formulation has comparable immunosuppression activity and 110.62 % relative bioavailability as compared to marketed Busulfan formulation i.e. Busulfex^®.

Poly(lactic-co-glycolic acid) microspheres loaded with cholecalciferol (CL), more bioactive form of vitamin D was developed as an injectable controlled drug releasesystem and was evaluated for its feasibility of once a month delivery. The CL loaded microspheres (CL-MS) were prepared by simple oil in water (O/W) emulsion–solvent evaporation technique incorporated with a stabilizer, Tocopherol Succinate (TS). Different formulation as well as process parameters were investigated namely concentration of emulsifier, concentration of stabilizer and drug: polymer mass ratios. The prepared CL-MS were evaluated for particle size, drug loading, in–vitro drug release and in–vivo pharmacokinetics in rats. The optimized formulation was found to have a mean particle size of 28.62 ± 0.26 μm, Encapsulation Efficiency (EE) of 94.4 ± 5.4% and drug loading of 5.19 ± 0.29% with CL:TS ratio of 2:1. It was found that the EE drastically decreased (26 ± 5.9%) in the absence of stabilizer (TS) indicating its role in stabilization of CL during formulation. DSC and XRD studies indicated that CL existed in an amorphous structure in the polymer matrix. SEM of the CL-MS revealed the spherical morphology and confirmed the particle size. In–vitrorelease showed that the CL release from CL-MS followed near zero–order drug release kinetics over nearly 1 month. In–vivo pharmacokinetic study of CL-MS showed higher t_1/2 (239 ± 27.5 h) compared to oily CL depot (32.7 ± 4.8 h) with sustained release of CL plasma concentration for 1 month. The labile CL could thus be effectively encapsulated and protected against degradation during microspheres formulation, storage and release in presence of stabilizer. This novel CL loaded PLGA MS is stable and may have great potential for clinical use.

Present investigation explores the potential of nanostructured lipid carriers (NLCs) for nose to brain delivery of rivastigmine (RV), which is further enhanced by incorporating into an in situ gelling system, increasing retention in nasal cavity. NLCs having particle size of 123.2 ± 2.3 nm, entrapment efficiency of 68.3 ± 3.4%, and zeta potential of 32 ± 1.2 mV was fabricated by a scalable method. Pharmacokinetics showed sustained release of intranasal (IN) and intravenous (IV) NLCs compared with RV solution by same route, with significantly higher AUC and T_half. Biodistribution indicated blood brain barrier penetrating potential of IV NLCs (457.24 ± 38.41.12 ng/mL) and IN NLCs (736.42 ± 34.54 ng/mL) with 4.6 and 5.3-fold enhancement in brain concentrations compared with IV and IN solution of RV. Similar results reflected in pharmacodynamics, indicating faster regain of memory loss in amnesic mice with 5-fold decrease in escape latency with NLCs compared with plain RV solution by IV and IN routes respectively. Sub-acute toxicity studies demonstrated safety of developed formulations to vital organs without any hematological and biochemical changes compared with control group. Moreover, nasal toxicity studies of NLCs showed no signs of inflammation, maintaining the integrity of ciliary epithelial cells, thus confirming safety of the formulation for its intended nasal application.

Polymeric microneedle (MN) arrays continue to receive growing attention due to their ability to bypass the skin’s stratum corneum barrier in a minimally-invasive fashion and achieve enhanced transdermal drug delivery and “targeted” intradermal vaccine administration. In this research work, we fabricated biodegradable bilayer MN arrays containing nano – microparticles for targeted and sustained intradermal drug delivery. For this study, model drug (vitamin D₃, VD₃)-loaded PLGA nano- and microparticles (NMP) were prepared by a single emulsion solvent evaporation method with 72.8% encapsulation of VD₃. The prepared NMP were directly mixed 20% w/v poly(vinyl pyrrolidone) (PVP) gel, with the mixture filled into laser engineered micromoulds by high-speed centrifugation (30 min) to concentrate NMP into MN shafts. The particle size of PLGA NMP ranged from 300 nm to 3.5 μm and they retained their particle size after moulding of bilayer MN arrays. The relatively wide particle size distribution of PLGA NMP was shown to be important in producing a compact structure in bilayer conical, as well as pyramidal, MN, as confirmed by scanning electron microscopy. The drug release profile from PLGA NMP was tri-phasic, being sustained over 5 days. The height of bilayer MN arrays was influenced by the weight ratio of NMP and 20% w/v PVP. Good mechanical and insertion profiles (into a skin simulant and excised neonatal porcine skin) were confirmed by texture analysis and optical coherence tomography, respectively. Ex vivo intradermal neonatal porcine skin penetration of VD₃ NMP from bilayer MN was quantitatively analysed after cryostatic skin sectioning, with 74.2 ± 9.18% of VD₃ loading delivered intradermally. The two-stage novel processing strategy developed here provides a simple and easy method for localising particulate delivery systems into dissolving MN. Such systems may serve as promising means for controlled transdermal delivery and targeted intradermal administration.

In current study, supercritical processed starch nanosponge (SSNS) used as a carrier for poorly water soluble drug (fenofibrate) to enhance its in-vitro and in-vivo performance. SSNS was prepared by using sol- gel method and effective supercritical drying technique. Fenofibrate was loaded into the SSNS by using solvent immersion method with selected and optimized organic solvent. BET surface area of SSNS was evaluated by nitrogen adsorption/desorption analysis. SSNS and drug loaded SSNS were characterized by DSC, XRPD, FTIR, SEM, Contact angle study and evaluated for in-vitro, in-vivo studies. The results revealed that the formed SSNS material has high surface area (180m2/gm) with pore size (40 nm to 200nm). The DSC and XRPD study revealed the amorphization of drug within a SSNS. SEM study showed the continuous porous structure with differ nanosized pores of SSNS. Contact angle study showed improvement in aqueous wetting property of drug within a SSNS. In-vitro drug release study showed remarkable dissolution enhancement of SSNS formulation as compared to plain drug. In vivo pharmacodynamic study (hyperlipidaemia model) showed SNSS based formulation significantly improved the bioavailability of drug. Thus SSNS carrier system has good potential to be explored as a delivery system for poorly water soluble drugs.

The aim of present investigation was the preparation of dodecylamine template-based hexagonal mesoporous silica (HMS) as a carrier for poorly water-soluble drug (fenofibrate). HMS material has distinctive characteristics such as easy synthesis, high surface area and wormhole pores. These characteristics are highly admirable to make use of it as a carrier in drug delivery system. HMS was prepared by pH and temperature-independent process. Fenofibrate was loaded into the HMS by solvent immersion method using organic solvent. The BET surface area of HMS was evaluated by nitrogen adsorption/desorption analysis. HMS and drug-loaded HMS were characterized by differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and contact angle study. The HMS-based system was also evaluated for in vitro and in vivo study as compared to plain drug. The BET surface area of HMS was found 974 m2/g with a narrow pore size average of 2.6 nm. The DSC and XRD study confirmed the amorphization of drug within the HMS. SEM and TEM study showed morphological features of HMS as well as revealed the wormhole porous structure. Contact angle study showed improvement in aqueous wetting property of drug within the HMS (contact angle 46°). The In vitro drug release study showed a remarkable dissolution enhancement in HMS-based system as compared to plain drug. In vivo pharmacodynamic study (hyperlipidaemia model) exhibited HMS-based formulation was significantly improved the bioavailability of fenofibrate. Thus, HMS has admirable properties; makes it a potential carrier for delivery system of poorly water-soluble drugs.

A novel polymer–drug conjugate, polyethylene glycol–N-(acetyl)-glucosamine–doxorubicin (PEG-NAG-DOX) was evaluated in this study for its in vivo potential for treatment of tumours demonstrating improved efficacy and reduced toxicity. The proposed polymer–drug conjugate comprised of polyethylene glycol–maleimide (mPEG-MAL, 30000 Da) as a carrier, doxorubicin (DOX) as an anticancer drug and N-acetyl glucosamine (NAG) as a targeting moiety as well as penetration enhancer. Doxorubicin has a potent and promising anticancer activity; however, severe cardiotoxicity limits its application in cancer treatment. By modifying DOX in PEG-NAG-DOX prodrug conjugate, we aimed to eliminate this limitation. In vivo anticancer efficacy of the conjugate was evaluated using BDF mice-induced skin melanoma model by i.v. administration of DOX conjugates. Anticancer efficacy studies were done by comparing tumour volume, body weight, organ index and percent survival rate of the animals. Tumour suppression achieved by PEG-NAG-DOX at the cumulative dose of 7.5 mg/kg was two-fold better than that achieved by DOX solution. Also, the survival rate for PEG-NAG-DOX conjugate was >70% as compared to <50% survival rate for DOX solution. In addition, toxicity studies and histopathological studies revealed that while maintaining its cytotoxicity towards tumour cells, PEG-NAG-DOX conjugate showed no toxicities to major organs. Therefore, PEG-NAG-DOX conjugate can be suggested as a desirable candidate for targeted cancer therapy.

Background: Efficacy of anticancer drug is limited due to non-selectivity and toxicities allied with the drug; therefore the heart of the present work is to formulate drug delivery systems targeted selectively towards cancer cells with minimal toxicity to normal cells.

Purpose: Targeted drug delivery system of doxorubicin (DOX)-loaded niosomes using synthesized N-lauryl glucosamine (NLG) as a targeting ligand.

Methods: NLG-anchored DOX niosomes were developed using ethanol injection method.

Results: Developed niosomes had particle size <150 nm and high entrapment efficiency ∼90%. In vivo pharmacokinetics exhibited long circulating nature of targeted niosomes with improved bioavailability, which significantly reduced CL and Vd than DOX solution and non-targeted niosomes (35 fold and 2.5 fold, respectively). Tissue-distribution study and enzymatic assays revealed higher concentration of DOX solution in heart while no toxicity to major organs with developed targeted niosomes was observed. Solid skin melanoma tumor model in mice manifested the commendable targeting potential of targeted niosomes with significant reduction in tumor volume and high % survival rate without drop in body weight in comparison with DOX solution and non-targeted niosomes of DOX. Conclusion: The glucosamine-anchored DOX-loaded targeted niosomes showed its potential in cancer targeted drug therapy with reduced toxicity.

Current endeavor was aimed towards studying significance of lipid composition on free propofol concentration in aqueous phase and associated pain on injection. Three different nanoformulations, namely long-chain triglyceride (LCT)/medium-chain glyceride (MCG)-based nanoemulsion (ProNano), MCG-based self-nanoemulsifying formulation (PSNE), and lipid-free nanoformulation (PNS) were accessed for the same. In vitro and in vivo performances of developed formulations were compared with Diprivan®. ProNano showed minimum free propofol concentration (0.13%) and hence lower pain on injection (rat paw-lick test, 6 ± 2 s) compared to Diprivan®, PSNE, and PNS (0.21%, 0.23%, and 0.51% free propofol, respectively, and rat paw-lick test; 12 ± 3, 14 ± 2, and 22 ± 3 s, respectively). These results conjecture the role of MCG in effective encapsulation of propofol. Anesthetic action assessed by measuring duration of loss of righting reflex (LORR), which was found similar in case of ProNano and PSNE (14 ± 3 and 15 ± 3 min, respectively) compared to Diprivan® (13 ± 3 min). In case of lipid-free formulation, PNS, extended anesthetic action (21 ± 2 min) was observed which may be due to sustained release of propofol from nanosponges. Studies on effect of lipoproteins on propofol release highlighted significance of HDL (100% release with maximum concentration of about 1.2 μg/ml of HDL) from all three formulations.

Background: Efficacy of an anticancer drug is challenged by severe adverse effects persuaded by the drug itself; hence designing a tumour targeted delivery system is chosen as an objective of this research work.Purpose: We propose, glucose transporter targeting ligand, i.e. synthesised N-lauryl glucosamine (NLG) anchored doxorubicin (DOX) in niosomal formulation.Methods: Synthesised NLG was incorporated into niosomal formulation of DOX using Span 60 as surfactant, cholesterol as membrane stabilizer and dicetyl phosphate (DCP) as stabilizer.Results: The formulation was stable with particle size of 110 ± 5 nm, zeta potential -30 ± 5 mV and entrapment efficiency approximately 95%. DSC and XRD pattern of freeze-dried formulation demonstrated encapsulation of DOX in niosomal formulation. Cytotoxicity of targeted niosomal formulation (IC50 = 0.830 ppm) was higher than non-targeted niosomal formulation (IC50 = 1.369 ppm) against B6F10 melanoma cell lines. In vitro cellular internalization revealed that targeted niosomal formulation was internalised more efficiently with higher cellular retention by cancer cells compared to the non-targeted niosomal formulation and free DOX. In vitro receptor binding and docking study of targeted niosomal formulation had shown the comparative association potential with glucose receptor.Conclusion: NLG anchored niosomal formulation of DOX with enhanced cytotoxicity, internalization and receptor binding potential has implication in targeted cancer therapy. © 2015 Informa UK Ltd.

Present investigation is exploring structure-biocompatibility interaction of tumour targeted polyethylene glycol (PEG) based drug conjugate of doxorubicin using N-acetyl glucosamine as targeting ligand. The synthesized polymer drug conjugate was evaluated for particle size, zeta potential, molecular weight, haemolysis activity, cytotoxicity, protein binding and in vitro receptor (lectin) binding study. The particle size of synthesized conjugate was observed to be around 30 nm with polydispersability index of 0.213 indicating mono-disperse particles. Fluorescence quenching assay addressed relatively lower binding interactions of polymer drug conjugate to bovine serum albumin in comparison with free doxorubicin which may be governed to the hydrophilicity of polyethylene glycol and N-acetyl glucosamine. The cell compatibility and haemolysis study showed that PEG drug conjugate was nontoxic and biocompatible, which recommends the suitability of polymer drug conjugates for delivering biological active agents systemically. In vitro ligand-lectin receptor binding assays of synthesized targeted polymer conjugate suggest the possibility of promising interaction of N-acetyl glucosamine in vivo. Thus, the study indicated the suitability of N-acetyl glucosamine anchored targeted polymer drug conjugate in delivering bio-therapeutics for specifically targeting to tumour tissues. © 2015 Elsevier B.V. All rights reserved.

In the current research work, rivastigmine (RV)-loaded in situ gelling nanostructured lipid carriers (NLCs) were developed for nose to brain delivery. NLCs were fabricated by ethanol injection method using glyceryl monosterate, Capmul MCM C8, Lecithin and Tween 80. NLCs showed average particle size of 123.2 ± 2.3 nm with entrapment efficiency of 68.34 ± 3.4%. DSC, XRD and IR studies showed complete amorphization and incorporation of the drug into nanoparticles. NLCs were incorporated into an in situ gelling system using 0.8% gellan gum and 15% Lutrol F 127. RV in situ gel showed excellent elasticity, rheology, mucoadhesion and adhesiveness to facilitate its adhesion to the upper nasal mucosa. NLC-based in situ gel showed a 2-fold increase in nasal permeation of the drug over plain RV solution. In situ gelling NLCs showed a 3-fold increase in enzyme inhibition efficacy. © 2014 Informa Healthcare USA, Inc.

Several molecular inheritances have severely restrained the peroral delivery of taxanes. The main objective of the present investigation was to develop a paclitaxel (PTX) formulation which can circumvent the hurdles of its extremely poor solubility and permeability, Pgp efflux and high pre-systemic metabolism. Positively charged PTX nanocrystals of 209 nm were prepared by sonoprecipitation with high pressure homogenization technique, wherein an arginine based surfactant was explored as a stabilizer. The BET surface area analysis revealed that the surface area of PNC was 8.53 m2/gm, reflecting significant rise in surface area with nanonization of PTX. The DSC and XRD pattern suggested that the PTX is in the form of the most stable dihydrate crystal. The PNC showed very rapid dissolution profile compared to plain PTX in both sinks and non-sink conditions. Clarithromycin (CLM) was evaluated as a better alternative to cyclosporin A in improving PTX permeability. The PNC-CLM showed remarkable enhancement of 453% in relative bioavailability along with maintaining the therapeutic concentration of PTX for 8 h. Efficacy data in B16 F10 melanoma tumor bearing mice showed substantial reduction in tumor volume and improvement in percentage survival compared to the control group. © 2014 Published by Elsevier B.V.

The aim of the present study was to formulate serratiopeptidase (SER)-loaded chitosan (CS) nanoparticles for oral delivery. SER is a proteolytic enzyme which is very sensitive to change in temperature and pH. SER-loaded CS nanoparticles were fabricated by ionic gelation method using tripolyphosphate (TPP). Nanoparticles were characterized for its particle size, morphology, entrapment efficiency, loading efficiency, percent recovery, and in vitro dissolution study. SER-CS nanoparticles had a particle size in the range of 400–600 nm with polydispersity index below 0.5. SER association was up to 80 ± 4.2%. SER loading and CS/TPP mass ratio were the primary parameters having direct influence on SER-CS nanoparticles. SER-CS nanoparticles were freeze dried using trehalose (20%) as a cryoprotectant. In vitro dissolution showed initial burst followed by sustained release up to 24 h. In vivo anti-inflammatory activity was carried out in rat paw edema model. In vivo anti-inflammatory activity in rat paw edema showed prolonged anti-inflammatory effect up to 32 h relative to plain SER. © 2014, American Association of Pharmaceutical Scientists.

Oxybutynin is an antimuscarinic agent used for the treatment of an overactive bladder. Because of its poor chromophore, it is difficult to determine oxybutynin by HPLC-UV analysis The difficulty increases when the analysis involves a complex biological matrix like plasma. Precolumn derivatization with trifluoroacetic anhydride followed by GC separation and ECD was used to solve this problem. The developed GC-ECD method had good linearity in the concentration range 2-20 ng ml-1 with a correlation coefficient of 0.9959. The accuracy and sensitivity for the determination of the halogenated derivative by this method was better than that for GC-MS. NMR and mass spectroscopy data confirmed the derivatization reaction. The developed GC-ECD method was used to study the pharmacokinetic parameters of an oxybutynin transdermal patch (36 mg/39 cm2) and oxybutynin gel (10% w/w). The Cmax, Tmax and AUC0-96 values for the oxybutynin transdermal patch and oxybutynin gel were equivalent. © 2014 The Royal Society of Chemistry.

The present study discusses possibility of targeting an anti-Alzheimer’s drug rivastigmine tartarate (RT) to the brain using novel synthesized L-lactide-depsipeptide polymeric nanoparticles (NPs). Single emulsion-solvent evaporation technique was used for preparation of NPs. The mean particle size, zeta potential and entrapment efficiency of drug loaded NPs were found to be 142.2 ± 21.3 nm, +4.85 mV and 60.72 ± 3.72% respectively. Pharmacodynamic study showed faster regain of memory loss in amnesic rat with RT loaded NPs as compared to RT solution. In pharmacokinetic study, total concentration and mean residence time was increased up to 3.79 fold and 2 fold respectively while clearance was decreased to 1.91 fold on intravenous administration of RT loaded NPs as compared to RT solution. The biodistribution study demonstrated 5.45 fold and 2 fold increase in brain concentration of drug after administration of RT loaded NPs (i.v; 10.52 ± 1.31 ng/ml) as compared to plain RT solution by oral (1.93 ± 1.23 ng/ml) and intravenous (5.34 ± 1.22 ng/ml) route, respectively. Therefore, RT loaded L-lactide-depsipeptide polymeric NPs might be a potential drug delivery system in treatment of Alzheimer’s disease. Copyright © 2014 American Scientific Publishers.

The first objective of the proposed research work includes comparative bioavailability and bioequivalence evaluation of oxybutynin transdermal patch with respect to different permeation enhancers. The second objective was to evaluate different in vitro methods along with synthetic membranes toward development of an in vitro-in vivo correlation. Oleic acid (fatty acid), Soluphor P (2-pyrrolidone, cosolvent), menthol (volatile oil), and dipropylene glycol (plasticizer) were selected as representatives from different classes of permeation enhancers. A random, crossover, single-dose pharmacokinetic study was carried out on male New Zealand white rabbits to determine bioavailability and bioequivalence. The obtained pharmacokinetic data were correlated with in vitro drug release using convolution-deconvolution approach. All developed formulations were found to be bioequivalent with respect to the marketed patch (Oxytrol®) on the basis of level of C max, AUC0-96, and AUCtotal (0.8-1.25). A biphasic linear correlation was obtained pertaining to differential diffusion behavior of the drug in vivo during the experimental timeframe. Because of close resemblance to skin, Cuprophan® membrane was found to be more suitable for developing an IVIVC than Millipore® membrane. © 2013 Controlled Release Society.

A typical breakthrough pain episode is severe, categorized by a fast onset, typically reaches peak intensity instantly, and lasts for an average duration of about 30 min. The research work includes the use of opioid for the treatment of breakthrough pain with special emphasis on the development of rapidly dissolving sublingual film formulation of buprenorphine hydrochloride (BPH). BPH is an opioid analgesic with low oral bioavailability due to less absorption and first-pass metabolism. The clear and transparent sublingual films were prepared using a film-forming polymer (pullulan) with a plasticizer (PEG 400). The formulation was optimized statistically using 32 randomized full factorial design. The optimized film formulation showed desired mechanical properties (tensile strength of 25 N/m2) and a minimum disintegration time of 16 s. Differential scanning calorimetry and X-ray diffraction studies confirmed the uniform distribution of the drug in polymeric matrices. Morphological study showed the absence of drug crystals on polymeric surface. The relative bioavailability of the film formulation was increased by 10 % with respect to tablet formulation due to rapid T max (0.08 h for film while 0.15 h for tablet), which was confirmed by in vivo studies performed on rabbits. The present technology could be a promising alternative to conventional drug delivery systems and traditional routes of administration for breakthrough pain management. © 2013 Controlled Release Society.

The amalgamation of chemotherapy and gene therapy is promising treatment option for cancer. In this study, novel biocompatible self-assembled nanocomplexes (NCs) between carboxylmethylated pullulan t335 (CMP) with polyallylamine (CMP–PAA NCs) were developed for plasmid DNA (pDNA) and pH-sensitive doxorubicin (DOX) delivery. DOX was conjugated to CMP (DOX–CMP) via hydrazone and confirmed by FTIR and 1H-NMR. In vitro release studies of pH-sensitive DOX–CMP conjugate showed 23 and 85 % release after 48 h at pH 7.4 (physiological pH) and pH 5 (intracellular/tumoral pH), respectively. The CMP–PAA NCs or DOX–CMP–PAA NCs self-assembled into a nanosized (<250 nm) spherical shape as confirmed by DLS and TEM. The hemolysis and cytotoxicity study indicated that the CMP–PAA NCs did not show cytotoxicity in comparison with plain polyallylamine. Gel retardation assay showed complete binding of pDNA with CMP–PAA NCs at 1:2 weight ratio. CMP–PAA NCs/pDNA showed significantly higher transfection in HEK293 cells compared to PAA/pDNA complexes. Confocal imaging demonstrated successful cellular uptake of DOX–CMP–PAA NCs in HEK293 cells. Thus, NCs hold great potential for targeted pDNA and pH-sensitive intratumoral drug delivery. © 2014, Springer Science+Business Media Dordrecht.

The present research work explores an innovative technological solution to constraints in efficient oral delivery of poorly water-soluble anti-obesity drug orlistat. Nanoemulsion of orlistat and its subsequent transformation into multi-unit pellet system (MUPS) for improved oral delivery was developed. Orlistat nanoemulsion was developed with capryol PGMC as an oil phase and cremophor RH40 as an emulsifier using high-pressure homogenization. Influence of critical processing parameters on globule size distribution, polydispersity index and physical stability of nanoemulsion was evaluated. The optimized nanoemulsion was transformed into MUPS using an extrusion spheronization technique. Optimized formulation was characterized at nanoemulsion as well as MUPS stage. DLS and nanoparticle tracking analysis studies of orlistat nanoemulsion exhibited unimodal size distribution with polydispersity value <0.1. Confocal laser scanning microscopy (CLSM) studies confirmed the presence of uniform spherical nanosized oil droplets of nanoemulsified orlistat. DSC and PXRD studies of MUPS confirmed amorphization of embedded nanoemulsified orlistat. In-vitro dissolution studies in surfactant-reduced media demonstrated remarkable improvement in dissolution compared to pure orlistat and marketed formulation (Xenical Capsules 120 mg, Hoffman-La Roche, Basle, Switzerland). Comparative in-vitro bovine porcine pancreatic lipase inhibition studies of pure orlistat, marketed product and developed MUPS showed 13.57- and 2.41-fold higher lipase inhibition with developed MUPS compared to pure orlistat and marketed products, respectively. © 2014 Informa Healthcare USA, Inc.

The objective of this research work was to design, develop and optimize the self micro-emulsifying drug delivery system (SMEDDS) of Felodipine (FL) filled in hard gelatine capsule coated with polymer in order to achieve rapid drug release after a desired time lag in the management of hypertension. Microemulsion is composed of a FL, Lauroglycol FCC, Transcutol P and Cremophor EL. The optimum surfactant to co-surfactant ratio was found to be 2:1. The resultant microemulsions have a particle size in the range of 65-85 nm and zeta potential value of -13.71 mV. FL release was adequately adjusted by using pH independent polymer i.e. ethyl cellulose along with dibutyl phthalate as plasticizer. Influence of formulation variables like viscosity of polymer, type of plasticizer and percent coating weight gain was investigated to characterize the time lag. The developed formulation of FL SMEDDS capsules coated with ethyl cellulose showed time lag of 5-7 h which is desirable for chronotherapeutic application.

There is a need of an efficient and safe nonviral gene delivery carrier due to promising future of nucleic acid-based therapeutics in the treatment of intractable diseases. Cytotoxicity and cost are the major concerns with current quaternary ammonium-based cationic liposomes. The major aim of current research work was development and in vitro evaluation of arginine-anchored nanoliposomes for gene delivery. LArginine-fatty acid conjugate was synthesized and characterized using IR, NMR, and mass spectroscopy. Synthesized conjugate-lauroyl arginine ethyl ester (LAE) was successfully incorporated into liposomes. Effect of nanocarrier composition on DNA binding was evaluated by preparing solid lipid nanoparticle (SLN) and self nanoemulsifying system (SNES) using same LAE concentration. Effect of cationic head on DNA binding was also evaluated. Arginine-anchored nanoliposomes-arginoplexes (APX) showed superior DNA-binding affinity. Surface PEG was expected to cause hindrance in DNA binding in SLNs and SNES. Guanidino group was found to be a better cationic head for DNA binding compared to primary amine or quaternary amine. Gel retardation assay was performed to optimize the ratio of DNA to LAE in nanocarrier. Serum stability, haemolysis, cytotoxicity, and transfection studies were carried out to evaluate APX. Binding ofDNAtoAPXwas found to be stable in the presence of serum, and no degradation of DNA was observed. APX containing 2 mg/ml LAE which exhibited particle size of ∼72 nm with zeta potential of +57.5 mV, showed lower cytotoxicity and better transfection. APXcan be a promising carrier for gene delivery. © Springer Science+Business Media Dordrecht 2014.

The poly[La-(Glc-Leu)] copolymer was applied in the present investigation as polymeric carrier to fabricate naltrexone (NTX)-loaded poly[La-(Glc-Leu)] microspheres in the single emulsion solvent evaporation technique for the long-term treatment of alcohol dependence. Newly synthesized poly[La-(Glc-Leu)] copolymer exhibited diminished crystallanity, good biocompatibility and favorable biodegradability to be explored for drug delivery application. Scanning Electron Microscopy study revealed smooth and spherical-shaped NTX-loaded polymeric microspheres with a mean size of 10-90 μm. Influence of various decisive formulation variables such as amount of polymer, stabilizer concentration, homogenization speed, homogenization time, drug loading and organic-to-aqueous phase ratio on particle size, and entrapment efficiency was studied. Differential scanning calorimeter and X-ray diffractometry study confirmed the drug entrapment within polymer matrix into the microsphere environment. In vitro drug release showed the sustained drug release of formulation for the period of 28 d giving biphasic release pattern. Histological examination of NTX-loaded poly[La-(Glc-Leu)] microspheres injected intramuscularly into the thigh muscle of Wistar rats showed minimal inflammatory reaction, demonstrating that NTX-loaded microspheres were biocompatible. Insignificant increase in the serum creatine phosphokinase level (p<0.05) as compared with the normal value revealed good muscle compatibility of the poly[La-(Glc-Leu)] microsphere system. Biocompatible nature and sustained drug-release action of poly[La-(Glc-Leu)] microspheres may have potential application in depot therapy. © 2014 Informa Healthcare USA, Inc.

Niosomes are reported to increase the skin permeation and bioavailability of topically applied drug molecules. However, very few studies were reported for nanometer-sized niosome vesicles. The aim of the present study was to prepare minoxidil-loaded niosomal formulation using ethanol injection method. Surfactant screening showed that only Span 60, Span 20, and Tween 20 with cholesterol have capability of nano size vesicle formation. The formed niosomes were characterized for entrapment efficiency, vesicle size, scanning electron microscope, and physical stability. By modulation of surfactant and cholesterol ratio maximum entrapment up to 34.70 ± 1.1 % with size of 470 ± 27 nm was obtained (Span 60/cholesterol ratio of 1:2). The vesicle size obtained was between 150 and 800 nm that was depending on cholesterol ratio and type of nonionic surfactant employed. The in vitro skin permeation study showed that an increase in cholesterol concentration in niosome vesicles increases minoxidil skin retention. Niosome formulation prepared with 1:2 ratio of Span 60 and cholesterol showed 17.21 ± 3.2 % skin retention of minoxidil, which is more than eightfold as compared to control minoxidil gel. © 2012 Controlled Release Society.

The current work was aimed to develop Medium Chain Triglyceride (MCT) rich self nanoemulsifying preconcentrate of paclitaxel (PTX) for parenteral delivery. Very high concentrations of Cremophor EL and ethanol in Taxol® have rendered patients to severe side effects. Years of extensive research on development of cost effective and safer vehicle for PTX, have failed to provide a promising replacement for Taxol®. MCT was selected as oil owing to its parenteral acceptability, high solubilization capacity and multiple therapeutic benefits in cancer cachexia. PTX precipitation kinetics and reported toxicity profile of Kolliphor HS15 has favored its selection for PTX Self Nanoemulsifying Preconcentrate (PSNP). Presence of 30% free PEG in Kolliphor HS15 (PEG-15-hydroxystearate) restricts its miscibility with MCT, imposing significant challenge in development of MCT rich self nanoemulsifying preconcentrate. Removal of PEG layer from oil-surfactant mixture facilitated the formulation of PSNP with 51% w/w MCT. PSNP exhibited better precipitation kinetic profile, higher PTX loading with negligible hemolysis and histamine release compared to Taxol®. PSNP was bioequivalent to Taxol® , though Vd and MRT was significantly higher than Taxol®. PSNP showed distinctly better profile in inhibiting tumor growth and maintaining body weight with significantly higher % survival. Thus, PSNP can be a safer vehicle with potential clinical benefits. Copyright © 2013 American Scientific Publishers. All rights reserved.

Physico-chemical properties of permeation enhancers like molecular weight/size, hydrophobicity/hydrophilicity, co-solvency, etc. are necessary during their selection for pharmaceutical product development. Chemical permeation enhancers modulate the viscoelastic properties of pressure sensitive adhesives. The extent of this modulation depends upon the molecular size and branching of the polymeric chains. The functional nature of this branching additionally changes the peel and tack properties of PSA’s. Chemical permeation enhancers alone are not able to modify viscoelastic properties of aqueous based PSA’s as compared with their solvent based counterparts. These modulated mechanical aspects need to be maintained throughout development of transdermal patch along with other pharmaceutical aspects like drug release and drug stability. © 2013 Elsevier B.V.

The present work was aimed at formulating a supersaturated triglyceride free drug delivery system (s-TFDDS) of lornoxicam and evaluating its in vitro and in vivo potential. s-TFDDS contain the drug above its saturation solubility and consists of a hydrophilic surfactant, a hydrophobic surfactant, solubiliser and pH modifier. D-optimal mixture experimental design was applied to optimise s-TFDDS. Three formulation variables, X 1 (Tween 20®), the surfactant X 2 (Capryl PGMC®) and X 3 (Transcutol P), were included in the design. The systems were assessed for light transmittance and solubility of lornoxicam. The values of optimised formulation components (X 1, X 2 and X 3) were 60.0, 10.0 and 30.0 %, respectively. The combination of components was optimised for maximum solubilisation capacity of lornoxicam by combined effect of pH and temperature. The optimised liquid preconcentrate was evaluated for particle size (small-angle neutron scattering study), robustness to precipitation, effect of polymer on precipitation inhibition and by in vitro dissolution. The liquid preconcentrate was adsorbed on solid carrier (Neusilin US2, Sylysia 320) and characterised by in vitro dissolution, X-ray diffraction, differential scanning calorimetry and scanning electron microscopy study. An increase in dissolution (DE15min, 100 %) in simulated gastric fluid at pH 1.2 was achieved without precipitation of lornoxicam. Spectral characterisation reveals no sign of lornoxicam precipitation on solid carriers. Comparative pharmacodynamic evaluation was investigated in terms of anti-inflammatory efficacy using a rat paw oedema model in rats. The s-TFDDS formulation showed the maximum percent inhibition of oedema as compared with plain and micronised lornoxicam. © 2012 Controlled Release Society.

The aim of this study was to develop a nanosuspension of a highly hydrophobic drug, isradipine (ISR) by combination of anti-solvent microprecipitation and high-pressure homogenization to achieve the superior in vitro dissolution and in vivo pharmacokinetic profile. The nanosuspension was formulated using combination of stabilizers as vitamin E TPGS and sodium lauryl sulfate. The developed nanosuspension was characterized for particle size, shape, and zeta potential. The particle size of the developed ISR nanosuspension was observed to be approximately 538 nm (by laser diffraction) and 469 nm (by photon correlation spectroscopy) with -33.3 mV zeta potential. Scanning electron microscopy study revealed the good correlation with particle size measured by photon correlation spectroscopy and laser diffraction. The X-ray diffraction and differential scanning calorimetry showed that ISR was present as an amorphous state in the lyophilized form of nanosuspension. In vitro dissolution and saturation solubility study showed the dissolution rate of nanosuspensions (98.60 %) and saturation solubility (98.76 μg/ml) compared with the coarse drug (11.53 % and 14.1 μg/ml, respectively) had been significantly enhanced. The pharmacokinetic study showed that the nanosuspension exhibits increased in AUC0-48 by 2.0-fold compared to coarse suspension. Further, there was increased in C max and decreased in t max of ISR nanosuspension compared to coarse suspension of ISR. These studies proved that particle size reduction can influence ISR absorption in gastrointestinal tract and thus nanosuspension technology is responsible for enhancing oral bioavailability in rats. © 2012 Controlled Release Society.

The present research work was aimed at developing solid lipid nanoparticle (SLN)-based formulation of budesonide (BDS) for nasal delivery. Melt emulsification method was chosen for fabrication of BDS-SLN using ultrasound dispersion and hot high-pressure homogenization techniques. The Compritol888 ATO was chosen as the lipid component for SLN formulation due to highest solubility for BDS. Different surfactants were screened and it was found that combination of Tween 80 and plurol oleique has shown desired particle size with improved stability and entrapment efficiency. The optimized SLN composition had a particle size of 185.2 nm with polydispersibility index of 0.387. Entrapment efficiency of the SLN composition was observed to be 61 %. Further, the optimized SLN dispersion was formulated into nasal spray. In vitro permeation study was carried out using Ovis aries (Indian sheep) nasal mucosa and it was observed that the permeability of BDS nasal spray of SLN was increased significantly by 3.4-fold as compared to the plain BDS and 1.8-fold as compared to the marketed nasal formulation. Thus, SLN-based nasal drug delivery was observed to be a promising approach for improving the bioavailability of hydrophobic drugs. © 2012 Controlled Release Society.

The main aim of the investigation was to explore a novel L-lactide-depsipeptide copolymer for the development of rivastigmine-loaded polymeric nanoparticles. L-lactide-depsipeptide synthesis was based on the ring opening polymerization reaction of L-lactide with the cyclodepsipeptide, cyclo(Glc-Leu), using tin 2-ethyl hexanoate as an initiator. Rivastigmine-loaded nanoparticles were prepared by the single emulsion-solvent evaporation technique. The influence of various critical formulation variables like sonication time, amount of polymer, amount of drug, stabilizer concentration, drug-to-polymer ratio, and organic-to-aqueous phase ratio on particle size and entrapment efficiency was studied. The optimized formulation having a particle size of 142.2 ± 21.3 nm with an entrapment efficiency of 60.72 ± 3.72% was obtained. Increased rivastigmine entrapment within the polymer matrix was obtained with a relatively low organic-to-aqueous phase ratio and high drug-to-polymer ratio. A decrease in the average size of the nanoparticles was observed with a decrease in the amount of polymer added and an increase in the sonication time. Prolonged sonication time, however, decreased rivastigmine entrapment. From the different lyoprotectant tested, only trehalose was found to prevent nanoparticle aggregation upon application of the freeze-thaw cycle. Drug incorporation into the polymeric matrix was confirmed by the DSC and XRD study. The spherical nature of the nanoparticles was confirmed by the SEM study. The in vitro drug release study showed the sustained release of more than 90% of the drug up to 72 h. Thus, L-lactide-depsipeptide can be used as an efficient carrier for the nanoparticle preparation of rivastigmine.

Lornoxicam is a potent oxicam class of non steroidal anti-inflammatory agent, prescribed for mild to moderate pain and inflammation. Niosomal gel of lornoxicam was developed for topical application. Lornoxicam niosomes (Lor-Nio) were fabricated by thin film hydration technique. Bilayer composition of niosomal vesicles was optimized. Lor-Nio dispersion was characterized by DSC, XRD, and FT-IR. Morphological evaluation was performed by scanning electron microscopy (SEM). Lor-Nio dispersion was incorporated into a gel using 2% w/w Carbopol 980 NF. Rheological and texture properties of Lor-Nio gel formulation showed suitability of the gel for topical application. The developed formulation was evaluated for in vitro skin permeation and skin deposition studies, occlusivity test and skin irritation studies. Pharmacodynamic activity of the Lor-Nio gel was performed by carragenan-induced rat paw model. Optimized Lor-Nio comprised of Span 60 and cholesterol in a molar ratio of 3:1 with 30 μM dicetyl palmitate as a stabilizer. It had particle size of 1.125 ± 0.212 μm (d 90), with entrapment efficiency of 52.38 ± 2.1%. DSC, XRD, and IR studies showed inclusion of Lor into niosomal vesicles. SEM studies showed spherical closed vesicular structure with particles in nanometer range. The in vitro skin permeation studies showed significant improvement in skin permeation and skin deposition for Lor-Nio gel (31.41 ± 2.24 μg/cm2, 30.079 ± 1.2 μg/cm2) over plain lornoxicam gel (7.37 ± 1.27 μg/cm2, 6.6 ± 2.52 μg/cm2). The Lor-Nio gel formulation showed enhanced anti-inflammatory activity by exhibiting mean edema inhibition (87.69 ± 1.43%) which was significantly more than the plain lornoxicam gel (53.84 ± 2.21%). © 2013 American Association of Pharmaceutical Scientists.

Objective: The objective of the present work was to enhance solubility, in vitro dissolution and in vivo pharmacodynamic activity of meloxicam (MLX) by preparation of lyophilized inclusion complexes with β-cyclodextrin. Methods: Phase solubility studies were conducted to analyze the influence of βCD on solubility of MLX. Inclusion complexes (ICs) of MLX & βCD were prepared in 2:1, 1:1 and 1:2M ratio followed by in vitro dissolution studies. The amorphous nature of the optimized IC and interaction of MLX with βCD was studied by differential scanning calorimetry (DSC), X-ray diffractometry (XRD) and Fourier transform Infra-Red Spectroscopy (FTIR). The in vivo anti-inflammatory ability of optimized IC was evaluated by carrageenan induced rat paw edema method while the analgesic study was conducted using acetic acid induced writhing test in mice. Results: Solubility of pure MLX in water at 25°C was found to be only 9.4 μg/mL. The AL type of phase solubility curve of MLX with β-CD confirmed the solubility enhancement capability of βCD. Based on the in vitro dissolution studies, 1:1M IC was found to be optimum for further studies. The in vivo anti-inflammatory ability of optimized IC was significantly higher and faster (edema inhibition of 63.36 ± 6.43% at the end of two hours) as compared to plain MLX (39.75 ± 4.73% at the end of four hours). Analgesic studies revealed rapid onset of action from optimized IC (73.9% inhibition of writhes in 20 minutes) as compared to that of plain MLX (38.14% inhibition of writhes in 40 minutes). Conclusion: These results prove that inclusion of MLX in βCD enhances not only the in vitro dissolution of the drug, but also improves its in vivo pharmacodynamic activity.

Nanosponges (NS) were synthesized by crosslinking of beta cyclodextrins with diphenyl carbonate. It is a hyper-branched polymer with an ultra high encapsulation efficiency leading to formation of colloidal systems. Dexamethasone (DEX) on the other hand is a poorly soluble drug with a poor corneal permeability. Excessive instillation of ocular suspension of dexamethasone leads to various complications thereby necessitating a novel nanotherapeutic system with greater ocular retention and permeation. This study aimed at formulating complexes of DEX with three types of beta-cyclodextrin NS obtained with different cross-linking ratio (viz. 1:2, 1:4 and 1:8 on molar basis with the cross-linker) for ocular applications. Nano-encapsulation was done by incubation-lyophilization technique to yield various formulations of Nanosponges (viz. F1:2, F1:4 and F1:8). From drug loading studies it was found that DEX was loaded in the highest amount in (NS 1:4), as much as 10% w/w as compared to 3% w/w and 5% w/w in 1:2 and 1:8 types of NS respectively. In vitro release studies showed that release of DEX was in a controlled manner for around 300 minutes. The particle sizes of the loaded NS formulations were between 350 and 660 nm with low polydispersity indices. The zeta potentials were sufficiently high (-20 to -27 mV) to obtain a stable colloidal nanosuspension. X-ray powder diffraction, differential scanning calorimetry and Fourier transform infra-red attenuated transmittance reflectance spectroscopy studies confirmed the interactions and encapsulation of DEX with NS. Transmission electron microscopy and atomic force microscopy studies confirmed its spherical colloidal nature. Ex vivo safety assessment done on bovine cornea showed no adverse reactions proving the safety of the system. Adhesion and retention properties of NS formulations were confirmed by use of 6-Coumarin as a model fluorescent marker. Corneal permeability of DEX from optimized formulations done on excised bovine cornea in corneal holders showed that the NS formulation showed higher permeability than the marketed formulation. Copyright © 2013 American Scientific Publishers All rights reserved.

Nanosponges (NS) are a recently developed class of hyper-branched polymers, nano-structured to form three dimensional meshwork; obtained by reacting cyclodextrins with a cross linker like diphenyl carbonate. Herein, we report an anomalous behavior of NS with regards to physical and morphological characteristics and drug encapsulation behavior by minor synthetic modification. Two distinct forms viz. crystalline and para-crystalline of NS were identified and extensively characterized by use of high resolution transmission electron microscopy (HR-TEM), X-ray powder diffraction (XRPD), scanning electron microscope, atomic force microscope, optical microscope and Fourier transform infra-red attenuated total reflectance spectroscopy (FTIR-ATR). Dimension of the crystal lattice was found to be equal to 0.61 nm. Higher magnifications clearly showed a zone axis with a hexagonal symmetry as that of beta-cyclodextrin. XRPD patterns were in concurrence with the HR-TEM results. Solubility studies with a model drug dexamethasone (DEX) showed more than three folds increase in the solubility of the drug in the crystalline NS as compared to the para-crystalline ones. Percent drug association and drug loading for DEX was found to be higher in the crystalline type of NS. An In vitro drug kinetic study evidenced a faster release of DEX from the crystalline type NS. The particle sizes of the formulations were as follows: crystalline NS: 688.6 ± 38.0 nm, para-crystalline NS: 702.2 ± 21.2 nm with polydispersity indices of 0.155 and 0.132; zeta-potential of -26.55 ± 1.7 and -23.42 ± 2.1 respectively. Differential scanning calorimetry and thermogravimetric analysis revealed that both forms encapsulated the drug satisfactorily. FTIR-ATR and Raman spectroscopy showed weak interactions. Crystallinity of NS was thus found to be an important factor in solubilization, in vitro kinetics and encapsulation behavior and can be tuned to give a tailored drug release profile or formulation characteristics. © 2012 Springer Science+Business Media B.V.

Background: Lumefantrine, an antimalarial molecule has very low and variable bioavailability owing to its extremely poor solubility in water. It is recommended to be taken with milk to enhance its solubility and bioavailability. The aim of present study was to develop a Self Nanoemulsifying Delivery system (SNEDs) of lumefantrine (LF) to achieve rapid and complete dissolution independent of food-fat and surfactant in dissolution media. Methods. Solubility of LF in oil, co-solvent/co-surfactant and surfactant solution and emulsification efficiency of surfactant were analyzed to optimize the LF loaded self nanoemulsifying preconcentrate. Effect of LF-oleic acid complexation on emulsification, droplet size, zeta potential and dissolution were investigated. Effect of milk concentration and fat content on saturation solubility and dissolution of LF was investigated. Dissolution of marketed formulation and LF-SNEDs was carried out in pH 1.2 and pH 6.8 phosphate buffer. Results: LF exhibited very high solubility in oleic acid owing to complexation between tertiary amine of LF and carboxyl group of oleic acid (OA). Cremophore EL and medium chain monoglyceride were selected surfactant and co-surfactant, respectively. Significantly smaller droplet size (37 nm), shift in zeta potential from negative to positive value, very high drug loading in lipid based system (> 10%), no precipitation after dissolution are the major distinguish characteristics contributed by LF-OA complex in the SNED system. Saturation solubility and dissolution study in milk containing media pointed the significant increment in solubility of LF in the presence of milk-food fat. LF-SNEDs showed > 90% LF release within 30 min in pH 1.2 while marketed tablet showed almost 0% drug release. Conclusion: Self nanoemulsification promoting ionic complexation between basic drug and oleic acid hold great promise in enhancing solubility of hydrophobic drugs. © 2013 Patel et al.; licensee BioMed Central Ltd.

The purpose of the present study was to develop Tamoxifen loaded β-cyclodextrin nanosponges for oral drug delivery. The three types of Tamoxifen loaded β-cyclodextrin nanosponges were synthesized by varying the molar ratios of β-cyclodextrin to carbonyldiimidazole as a crosslinker viz. 1:2, 1:4 and 1:8. The Tamoxifen nanosponge complex (TNC) with particle size of 400-600 nm was obtained by freeze drying method. Differential scanning calorimetry, Fourier transformed infra-red spectroscopy and X-ray powder diffraction studies confirmed the complexation of Tamoxifen with cyclodextrin nanosponge. AUC and Cmax of TNC formulation (1236.4 ± 16.12 μg · mL(-1) h, 421.156 ± 0.91 μg/mL) after gastric intubation were 1.44 fold and 1.38 fold higher than plain drug (856.079 ± 15.18 μg · mL(-1) h, 298.532 ± 1.15 μg/mL). Cytotoxic studies on MCF-7 cells showed that TNC formulation was more cytotoxic than plain Tamoxifen after 24 and 48 h of incubation.

Background: Ciprofloxacin hydrochloride-encapsulated poly[LA-(Glc-Leu)] copolymeric nanoparticles were prepared to provide sustained release and ameliorate shortcomings associated with eye drops. Methods: Poly[LA-(Glc-Leu)] copolymer was synthesized by ring opening copolymerization of l-lactide with a cyclodepsipetide. Ciprofloxacin hydrochloride-loaded polymeric nanoparticles were prepared by double emulsification-solvent evaporation technique with emphasis on optimization of different process and formulation variables. Results: Optimized formulation showed encapsulation efficiency of approximately 63.08 ± 5.88% and a positive zeta potential of +17.46 mV. Scanning electron microscope study revealed the spherical shape of the nanoparticles with a particle size 300-400 nm. In vitro drug-release studies showed sustained release for 24 h with biphasic release pattern. In vivo ocular tolerability study in rabbits demonstrated no signs of toxicity or irritation parallel to the results obtained with the marketed formulation. Conclusion: Poly[LA-(Glc-Leu)] copolymer can be used as an efficient carrier for nanoparticle preparation of ciprofloxacin. © 2013 Future Science Ltd.

The aim of the present investigation was to develop Monolithic Osmotic Tablet System (MOTS) of pH dependent and poorly water soluble lornoxicam (LOR) for controlled drug release. MOTS of LOR comprised freeze dried ternary amorphous complex of drug as core and cellulose acetate with pore former as release controlling membrane. LOR has a poor water (61 μg/ml) and pH dependant (3 μg/ml in pH 1.2) solubility. Freeze dried amorphous ternary complex of drug containing β-cyclodextrin and arginine (LOR:β- CD:Arg) in stoichiometry ratio of 1:1:1 was found to give 30 fold and 300 fold increase in solubility of LOR in water and in 1.2 pH buffer respectively as compared to plane drug which is prerequisite for MOTS. Amorphization of LOR was confirmed by XRD, DSC and SEM study. LOR has a half-life of 3-4 hr which necessitates developing controlled release system of drug for longer period of time. Different formulation variables like type of polyethylene oxide, concentration of pore former, coating weight gain, concentration of osmotic agent and aperture diameter were optimized to achieve zero order drug release. Optimized MOTS of LOR was found to be delivering drug at controlled zero order rate up to 24 hr. pH independent controlled drug release behaviour was revealed by carrying out dissolution in 1.2 pH, 4.5 pH and 6.8 pH dissolution medium. Hence, the developed monolithic osmotic system of LOR utilizing freeze dried amorphous ternary complex was found to be promising approach for controlled release of pH dependent and poorly water soluble drug candidates.

Cyclodextrin-based nanosponges (NS) are solid nanoparticles, obtained from the cross-linking of cyclodextrins that have been proposed as delivery systems for many types of drugs. Various NS derivatives are currently under investigation in order that their properties might be tuned for different applications. In this work, new carboxylated cyclodextrin-based nanosponges (Carb-NS) carrying carboxylic groups within their structure were purposely designed as novel Acyclovir carriers. TEM measurements revealed their spherical shape and size of about 400 nm. The behaviour of Carb-NS, with respect to the incorporation and delivery of Acyclovir, was compared to that of NS, previously investigated as a drug carrier. DSC, XRPD and FTIR analyses were used to investigate the two NS formulations. The results confirm the incorporation of the drug into the NS structure and NS-Acyclovir interactions. The Acyclovir loading into Carb-NS was higher than that obtained using NS, reaching about 70% (w/w). In vitro release studies showed the release kinetics of Acyclovir from Carb-NS to be prolonged in comparison with those observed with NS, with no initial burst effect. The NS uptake into cells was evaluated using fluorescent Carb-NS and revealed the nanoparticle internalisation. Enhanced antiviral activity against a clinical isolate of HSV-1 was obtained using Acyclovir loaded in Carb-NS. © 2012 Elsevier B.V. All rights reserved.

The present research work explores formulation design, critical scale-up considerations and bio-equivalence studies of soluble itraconazole (ITZ) in a tablet form using disordered drug delivery approach. Disordered system of ITZ with a lower viscosity grade of hydroxypropyl methyl cellulose (Pharmacoat 603) was developed for the first time and extensively characterised at three different stages, namely development of glass system, pellet coating and tablet compression using advanced analytical techniques. Complete molecular embedment of ITZ resulting in amorphisation was observed and found to be sustained until end of the real-time and accelerated stability studies. Developed formulation exhibited comparative in vitro dissolution profile (similarity factor >70) with reference product (Sporanox, Janssen Pharmaceutica) in simulated gastric fluid without enzymes. Formulation was scaled up in three batches (50,000 tablets/batch) with detailed validation of critical process parameters using process capability index method. Critical scale-up considerations like control of residual solvent content, effect of pellet size on dissolution, process variables in pellet coating, compressibility of coated pellets and cushioning effect required for desired compressibility were thoroughly discussed. Bioequivalence study of single dose of test and reference product in seven healthy human volunteers under fed condition exhibited significant bioequivalence with results (AUClast and AUC∞) lying between 90% confidence interval. With increase in number of subjects to 24, a significant effect on pharmacokinetic parameters of both reference as well as developed ITZ tablets was observed. © 2013 American Association of Pharmaceutical Scientists.

The objective of the present investigation was to develop in situ gelling nasal spray formulation of carvedilol (CRV) nanosuspension to improve the bioavailability and therapeutic efficiency. Solvent precipitation- ultrasonication method was opted for the preparation of CRV nanosuspension which further incorporated into the in situ gelling polymer phase. Optimized formulation was extensively characterized for various physical parameters like in situ gelation, rheological properties and in vitro drug release. Formation of in situ gel upon contact with nasal fluid was conferred via the use of ion-activated gellan gum as carrier. In vivo studies in rabbits were performed comparing the nasal bioavailability of CRV after oral, nasal, and intravenous administration. Optimized CRV nanosuspension prepared by combination of poloxamer 407 and oleic acid showed good particle size [d (0.9); 0.19 μm], zeta potential (+10.2 mV) and polydispersity (span; 0.63). The formulation containing 0.5% w/v gellan gum demonstrated good gelation ability and desired sustained drug release over period of 12 h. In vivo pharmacokinetic study revealed that the absolute bioavailability of in situ nasal spray formulation (69.38%) was significantly increased as compared to orally administered CRV (25.96%) with mean residence time 8.65 h. Hence, such in situ gel system containing drug nanosuspension is a promising approach for the intranasal delivery in order to increase nasal mucosal permeability and in vivo residence time which altogether improves drug bioavailability. © 2012 American Association of Pharmaceutical Scientists.

Curcumin is the source of the spice turmeric having potential application in tumor treatment but has limited therapeutic utility because of its poor aqueous solubility. Curcumin suppresses the onset of tumors as well as their growth and metastasis. Cyclodextrin-based nanosponges (NS) have been used to increase the solubility of curcumin and to control its release. The aim of the study was to formulate the complex of curcumin with β-cyclodextrin nanosponge obtained with dimethyl carbonate as a cross linker. The particle size of loaded nanosponge was found to be 487.3 nm with minimum polydispersibility index (0.476). The loaded NS have shown more solubilization efficiency (20.89 μg/ml) in comparison with plain curcumin (0.4 μg/ml) and β-CD complex (5.88 μg/ml). The zeta potential was sufficiently high (-27 mV) which indicates formation of a stable colloidal nanosuspension. The curcumin nanosponge complex (CrNS) was characterized for FTIR, XRD and DSC studies and it confirmed the interactions of curcumin with NS. The in vitro drug release of curcumin was controlled over a prolonged period of time. The in vitro hemolysis study showed that the complex was non-hemolytic. CrNS sample showed only a slight reduction in cytotoxicity against MCF-7 cells, which concludes that there is no change in molecular structure of curcumin in CrNS formulation. © 2012 Springer Science+Business Media B.V.

Despite of advancements in dosage form design and use of multifunctional excipients, improvement in dissolution characteristics of molecules like Telmisartan (TEL) having exceedingly pH dependent and poor solubility profile is still challenging. The present research work explores an innovative particle engineering approach which synergistically coalesce two principally different solubility enhancement strategies namely ternary β-cyclodextrin complexation and top-down nanonization in a unit process. The research was aimed to improve solubility and reduce in vivo variability in pharmacokinetic parameters of TEL irrespective to physiological pH conditions. Ternary β-cyclodextrin nanocomposites of TEL were prepared with high pressure homogenization using meglumine as ternary component. TEL nanocomposites were thoroughly characterized for particle size, surface topology, surface charge, inclusion complexation, crystalinity, dissolution and in vivo pharmacokinetic performance in male wistar rats at fed and fasted state. TEL nanocomposites exhibited average particle size of 698 ± 23 nm. Remarkable improvement in in vitro dissolution characteristics in multimedia and biorelevant media was observed in comparison with plain drug and marketed formulation. Results of in vivo pharmacokinetic studies revealed that, nanocomposites effectively bypass variation in pharmacokinetic parameters at fed and fasted states with 346%, 315%, 301% and 321% increase in relative bioavailability compared to marketed formulation and pure TEL in fed and fasted conditions respectively. © 2012 Elsevier B.V. All rights reserved.

The purpose of the research was to prepare and evaluate a topical nanolipidgel (NLH) of terbinafine hydrochloride (TRB), an antimycotic agent, for enhanced skin deposition and improved antifungal activity. Topical solid lipid nanoparticles (SLN) based nanolipidgel was formulated and evaluated. TRB-loaded SLNs were formulated by high-pressure homogenization technique. The stable TRB SLN dispersion was incorporated into a gel using 1% Carbopol 980 NF. Rheological evaluation and texture analysis of the TRB NLH was carried out. Skin permeation, skin deposition, antifungal activity, and occlusivity studies of the nanolipidgel formulation were carried out. The safety of the TRB NLH gel was evaluated using acute skin irritation test on New Zealand White rabbits. The SLN dispersion containing 10% of glyceryl monostearate, 3% of Tween 80, and 1% Plurol Oleique was the most stable. The optimized TRB SLN had a particle size and zeta potential value of 148.6 ± 0.305 nm and -20.4 ± 1.2 mV, respectively. TRB NLH had excellent rheological and texture properties to facilitate its topical application. TRB NLH showed increased skin deposition of the drug over plain (3-fold) and marketed TRB formulation (2-fold). TRB NLH had significantly enhanced antifungal activity against Candida albicans. TRB NLH showed efficient occlusivity and was non-irritant to the rabbit skin with no signs of erythema or edema. Solid lipid nanoparticles-based topical nanolipidgel of terbinafine can be an efficient, industrially scalable, and cost-effective alternative to the existing conventional formulations. © 2012 American Association of Pharmaceutical Scientists.

The present research work deals with the development of a time delayed chronotherapeutic formulation of felodipine (FD) aimed at rapid drug release after a desired lag time in the management of hypertension. The developed system comprises a drug core embedded within a swellable layer and coated with an insoluble, water permeable polymeric system. FD cyclodextrin complex was used as an active core while ethyl cellulose was used as an effective coating layer. Dissolution studies of the complex revealed that there was a 3-fold increase in dissolution of the complex compared to plain FD. This dissolution enhancement and rapid drug release resulted from FD amorphisation, as confirmed by XRD, DSC and SEM studies. FTIR and 1H NMR studies confirmed the complex formation between FD and cyclodextrin based on the observed hydrogen bond interactions. FD release was adequately adjusted by using a pH independent polymer, i.e., ethyl cellulose, along with dibutyl phthalate as plasticizer. Influence of formulation variables like polymer viscosity, plasticizer concentration, super disintegrant concentration in the swellable layer and percent coating weight gain was investigated to characterize the lag time. Upon permeation of water, the core tablet swelled, resulting in the rupture of the coating layer, followed by rapid drug release. The developed formulation of FD showed a lag time of 5-7 h, which is desirable for chronotherapeutic application.

Efficacy of anticancer drug is limited by the severe adverse effects induced by drug; therefore the crux is in designing delivery systems targeted only to cancer cells. Toward this objectives, we propose, synthesis of poly(ethylene glycol) (PEG)-doxorubicin (DOX) prodrug conjugates consisting N-acetyl glucosamine (NAG) as a targeting moiety. Multicomponent system proposed here is characterized by 1H NMR, UV spectroscopy, and HPLC. The multicomponent system is evaluated for in vitro cellular kinetics and anticancer activity using MCF-7 and MDA-MB-231 cells. Molecular modeling study demonstrated sterically stabilized conformations of polymeric conjugates. Interestingly, PEG-DOX conjugate with NAG ligand showed significantly higher cytotoxicity compared to drug conjugate with DOX. In addition, the polymer drug conjugate with NAG and DOX showed enhanced internalization and retention effect in cancer cells, compared to free DOX. Thus, with enhanced internalization and targeting ability of PEG conjugate of NAG-DOX has implication in targeted anticancer therapy. © 2012 Elsevier B.V. All rights reserved.

[No abstract available]

The aim of the present investigation was to develop controlled porosity osmotic system for poorly water-soluble drug based on drug in polymer-surfactant layer technology. A poorly water-soluble drug, glipizide (GZ), was selected as the model drug. The technology involved core of the pellets containing osmotic agent coated with drug dispersed in polymer and surfactant layer, finally coated with release-retardant layer with pore former. The optimized drug-layer-coated pellets were evaluated for solubility of GZ at different pH conditions and characterized for amorphous nature of the drug by differential scanning calorimetry and X-ray powder diffractometry. The optimized release-retardant layer pellets were evaluated for in vitro drug release at different pH, hydrodyanamic, and osmolality conditions. The optimized drug layer showed improvement in solubility (10 times in pH 1.2, 11 times in pH 4.5, and 21 times in pH 6.8), whereas pellets coated with cellulose acetate (15.0%, w/w, weight gain) with pore former triethyl citrate (10.0%, w/w, of polymer) demonstrated zero-order drug release for 24h at different pH conditions; moreover, retardation of drug release was observed with increment of osmolality. This system could be a platform technology for controlled delivery of poorly water-soluble drugs. © 2012 Wiley Periodicals, Inc.

In the present investigation, cyclodextrin complexation process was explored for development of tablet formulation of WHO approved fixed dose combination of lopinavir and ritonavir with reduced tablet size, shorter disintegration time and higher bio-availability in comparison to reference product. In preliminary studies, we found that lopinavir solubility and dissolution rate is poor into the dissolution medium recommended by FDA, whereas ritonavir solubilized fairly into dissolution medium with adequate dissolution rate. Solid-state cyclodextrin complexation technology was used for enhancement of dissolution rate of lopinavir into dissolution medium. Various cyclodextrins were screened by comparison on basis of enhancement of dissolution rate of lopinavir (LPV) and the order was found as gamma cyclodextrin (γ-CD) > hydroxypropyl beta-cyclodextrin (HP-β-CD) > methyl beta-cyclodextrin (M-β-CD) > beta-cyclodextrin (β-CD), with Q 120 values (i.e. percentage of dissolved drug at 120 min.) were 10.1 for the pure LPV and 56.3, 51.3, 30.3 and 10.3 for LPV/γ-CD, LPV/HP-β-CD, LPV/M-β-CD and LPV/β-CD, respectively. Anomalous results were found between stability constant, dissolution rate and saturation solubility. It was found that cyclodextrin having higher stability constant value with LPV, provides higher saturated solubility of LPV in aqueous media but at slow dissolution rate and vice versa. The γ-CD was selected for complexation with lopinavir in the stoichiometric ratio 1:1.5 M of LPV to γ-CD. Various processes such as kneading method, milling technique, sonication, freeze drying and autoclaving were tried, from which kneading method was found to give best dissolution results. The corresponding solid complexes were characterized by differential scanning calorimetric, X-ray powder diffraction and scanning electron microscopy studies. Based on various studies, the complexation phenomenon between LPV and γ-CD was found to follow non-inclusion behavior. Pharmacokinetic studies were carried out in Sprague-Dawley rats using cross over design with a 3 day wash out period. The bioavailability of lopinavir was found to be enhanced significantly using cyclodextrin complex tablet formulation. Graphical Abstract: [Figure not available: see fulltext.] © 2011 Springer Science+Business Media B.V.

Surmounting the constraints of limited solubilization efficiency and prime requisite of antioxidant for conventional lipid formulations, the research work explores an edge over formulation utilizing potential applicability of rice germ oil (RGO) as a multifunctional excipient. Self-microemulsifying drug delivery system (SMEDDS) of tacrolimus (TAC) was formulated with RGO, an indigenous source of gamma-oryzanol. Being the same biological source, RGO and rice bran oil (RBO) were compared and it was found that RGO have more solubilization potential for TAC (2.2-fold) as well as higher antioxidant activity (8.06-fold) than the RBO. TAC-SMEDDS was prepared using RGO/Capmul PG8 (2:3) as an oil phase, Cremophore EL as a surfactant, and Transcutol P as a cosurfactant. The approximate particle size of TAC-SMEDDS was found to be 38 nm by dynamic light scattering and 12 nm by small angle neutron scattering. The in vitro dissolution studies showed complete and rapid drug release in 30 min compared to a plain drug (<5%) and marketed capsule (<50%). AUC and Cmax were found to be 45.05±15.64 ng h/ml and 3.91±1.2 ng/ml for TAC-SMEDDS, 12.59±5.54 ng h/ml and 0.48±0.12 ng/ml for plain TAC, and 30.23± 10.34 ng h/ml and 2.31±0.68 ng/ml for marketed formulation, respectively. The improved pharmacokinetic profile of TAC-SMEDDS is correlating to the dissolution results. Thus, gamma-oryzanol-enriched RGO acts as a potential multifunctional excipient for lipid formulations. © 2012 American Association of Pharmaceutical Scientists.

Background: The practical applicability of solid dispersions (SD) for improvement of oral bioavailability of poorly water-soluble drugs has still remained limited because of lack of feasibility for scale-up of manufacturing processes. The present research work deals with the preparation of SDs of meloxicam (MLX) with β-cyclodextrin (β-CD) by the ball-milling technique to overcome the scale-up issues. Methods: Phase-solubility studies were conducted to analyze the influence of β-CD on solubility of MLX. In vitro dissolution studies on various complexes as well as tablets prepared on pilot scale in an industrial set up were performed and compared with the marketed products. Physicochemical characterization of optimized complexes was done using various methods to study drug-β-CD interaction. Results: Solubility of pure MLX in water at 25°C was found to be only 9.4 g/mL. The AL type of phase-solubility profile of MLX with β-CD [stability constant (K1:1)=22.056M -1 and Gibbs free energy (ΔF o)=7.665 KJ/mole] confirmed the solubility enhancement capability of β-CD. Milling time of 6h was considered to be optimum and showed maximum enhancement of drug dissolution. The amorphous nature of the milled complex and mode of interaction of MLX with β-CD was confirmed by differential scanning calorimetry (DSC), x-ray diffractometry (XRD), Fourier transform infrared spectroscopy (FTIR) and proton nuclear magnetic resonance spectrophotometry ( 1HNMR). Tablets containing MLX-β-CD (1:1.5M) milled complexes showed the best release (T90%=10.94min) compared to the marketed products (T90% ≥ 450min). Stability studies performed confirmed the integrity of the amorphous complex. Conclusion: Stable inclusion complexes of MLX-β-CD with enhanced aqueous solubility and dissolution rate were prepared by a highly efficient and controlled large-scale milling technique. © 2011 Informa Healthcare USA, Inc.

Cyclodextrin based carbonate nanosponges were synthetized starting from native β-cylodextrin and active carbonyl compounds i.e. carbonildiimidazole. In this work they were used to form inclusion complexes with three different gases i.e. 1-methylcyclopropene, oxygen and carbon dioxide. The encapsulation of gases were proved by direct reaction to known adduct (1-methylcyclopropene), by gravimetric analysis (CO2) and by oxymeter (Oxygen). The complexetion of oxygen or carbon dioxide could be useful for many biomedical applications. In particular the oxygen-filled nanosponges could supply oxygen to the hypoxic tissues which are present in various deseases. 1-methylcyclopropene included in β-cyclodextrin nanosponges showed superior antiethylenic performances in long lasting cut flowers in comparison with marketed products. © 2011 Springer Science+Business Media B.V.

Reproducible delivery of drugs through bioencapsulation in cellular carriers is severely limited by biovariability in cellular carriers and effects of decisive formulation variables. Surmounting the constraints in reproducible results, our work explores optimization methodology for precise and reproducible cellular bioencapsulation technology for poorly water soluble drug. Active-dried baker’s yeast cells were selected as cellular carriers for poorly soluble antimycotic agent itraconazole (ITZ). Pre-treatment of yeast cells with various techniques exhibited substantial augmentation in bioencapsulation efficiency (%BE). Sequentially optimized values of formulation variables like bioencapsulation temperature (40-50°C), stirring rate (350?rpm) and time (5?h) exhibited highest %BE with desired reproducibility. In comparison with marketed product, bioencapsulated itraconazole demonstrated marked increase in solubility with more than 70% release in 10?min. Compression pressure equivalent to tablet hardness of 2.0-3.5?kg/cm2 was optimum to maintain integrity of biocapsules. Resulting biocapsules exhibited safe residual solvent content, inertness for fermentation ability and excellent stability at accelerated conditions. © 2011 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.

The purpose of the present study was to investigate the influence of an amino acid, arginine, as a ternary component on the complexation of Lornoxicam, a poorly water-soluble and weakly acidic anti-inflammatory agent, with β-cyclodextrin (β-CD). The molecular inclusion of Lornoxicam with βCD alone and in combination with ternary component was aimed at improvement in solubility and, subsequently, dissolution rate limited oral absorption. The solid complexes of Lornoxicam and β-CD with or without arginine (binary and ternary systems, respectively) were prepared as Freeze dried product in different stoichiometric ratios. The formation of inclusion complexes in solid state was confirmed by using classical instrumental techniques like IR, DSC, XRD, and in liquid state by phase solubility analysis, UV spectroscopy, HPLC and 1H NMR. The in vitro dissolution and the saturation solubility of complex are determined analyzing by UV spectrophotometer. Assay and level of related substance was monitored by developed RP-HPLC method. Inclusion ternary complex of Lornoxicam with β-CD and arginine showed significant improvement in dissolution compared with uncomplexed drug and binary system. This improved physicochemical behavior of ternary complex with the novel inclusion of an arginine translated into enhanced in vitro dissolution of Lornoxicam compared with standard rapid marketed formulation. © 2010 Springer Science+Business Media B.V.

The present study was aimed at synthesizing and characterizing star copolymers of β-cyclodextrin and exploring their application as nanocarriers. The copolymers of β-cyclodextrin and polypropylene oxide were synthesized by using ring opening polymerization, catalyzed by base, under high temperature and pressure. The polymers of different molecular weight were synthesized by increasing chain length of polypropylene oxide at optimized temperature, pressure and concentration of catalyst. The structure of synthesized polymer was confirmed by IR and NMR. Molecular weight and molecular weight distribution was evaluated by hydroxyl number and gel permeation chromatography respectively. Amphiphilic nature of the polymers was evaluated by determining the solubility in water and different organic solvents. For the evaluation of polymer as a nanocarrier, Ibuprofen was selected as model drug. Loading efficiency and release of Ibuprofen from the complex were also investigated. It was observed that, with increase in the molecular weight of the polymers, loading capacity was increased. © 2010 Springer Science+Business Media B.V.

The aim of this work was to increase the solubility, stability and permeation of resveratrol by complexation with cyclodextrin-based nanosponges (NS). Nanosponges are recently developed hyper-cross-linked cyclodextrin polymers nanostructured to form three-dimensional networks; they are obtained by reacting cyclodextrin with a cross-linker such as carbonyldiimidazole. They have been used to increase the solubility and stability of poorly soluble actives. This study aimed at formulating complexes of resveratrol with β-cyclodextrin nanosponges in different weight ratios. DSC, FTIR and X-ray powder diffraction (XRPD) studies confirmed the interaction of resveratrol with NS. XRPD showed that the crystallinity of resveratrol decrease after encapsulation. The particle sizes of resveratrol-loaded NS are in between 400 to 500 nm with low polydispersity indices. Zeta potential is sufficiently high to obtain a stable colloidal nanosuspension. TEM measurement also revealed a particle size around 400 nm for NS complexes. The in vitro release and stability of resveratrol complex were increased compared with plain drug. Cytotoxic studies on HCPC-I cell showed that resveratrol formulations were more cytotoxic than plain resveratrol. The permeation study indicates that the resveratrol NS formulation showed good permeation in pigskin. The accumulation study in rabbit mucosa showed better accumulation of resveratrol NS formulation than plain drug. These results signify that resveratrol NS formulation can be used for buccal delivery and topical application. © 2011 American Association of Pharmaceutical Scientists.

Beta cyclodextrin (β-CD) based nanosponges were synthesized and paclitaxel inclusion complex with nano-sponges were prepared using techniques of inclusion complex formation. The paclitaxel nanosponge’s complexes were evaluated for their release. The nanosponges complexes were also evaluated using DSC, FTIR, and NMR techniques for confirmation of inclusion complex formation between paclitaxel and nanosponges. Particle size and morphology of paclitaxel nanosponge’s complex were estimated using SEM, TEM and dynamic light scattering techniques. The particle sizes were found out to be in range of 400 to 600 nm. Cytotoxic efficacy of paclitaxel nanosponge complex was determined against MCF-7 cells and paclitaxel nanosponge’s complex was found to be cytotoxic and more effective against this cell line. © 2011 Bentham Science Publishers Ltd.

Purpose: The present study deals with evaluation of crosslinked poly vinyl alcohol (PVA) as a potential disintegrant. Methods: Crosslinking of PVA was carried out using glutaraldehyde as a crosslinker, in presence of acidic conditions. The crosslinking reaction was optimized for a) polymer: crosslinker ratio; b) temperature requirement and c) reaction duration. Certain physical parameters of the disintegrant (including sedimentation volume, hydration capacity, specific surface area and bulk and tap density) were determined and compared to the known disintegrants. Characterization was carried out using FT-IR, DSC, XRD, SEM and Photo microscopy studies. The developed excipient was also studied for acute toxicity in rats and found to be safe for oral use. Results: Disintegration property of formed product was found to give better results. As compared to known disintegrant (Ac-Di-Sol). The disintegration mechanism of developed disintegrant was postulated based on results obtained from various physical evaluations. Hausner’s ratio & Carr’s index value of 1.12 and 10.61 suggested excellent flowability. Wetting time and distintegration time of 21.90 ± 0.1 and 26.20 ± 0.2 seconds was obtained at the disintegrant level of 5 % w/w. Conclusions: By changing the condition parameters of well known crosslinking reaction of PVA, we obtained a crosslinked product which had excellent disintegration activity, good flow and optimal tableting properties.

Three types of cyclodextrin nanosponges were synthetized cross-linking α, β or γ cyclodextrin with carbonyldiimidazole as cross-linker. Nanosponges are solid nanoparticles previously used as drug carriers. In this studies cyclodextrin nanosponges were developed as oxygen delivery system. For this purpose the three types of nanosponges suspended in water were saturated with oxygen and in vitro characterized. The nanosponge safety was tested on Vero cells. Their ability to release oxygen in the presence and in the absence of ultrasound (US) was determined over time. Oxygen permeation through a silicone membrane was obtained using a β-cyclodextrin nanosponge/hydrogel combination system. Nanosponge formulations might be potential gas delivery systems showing the ability to store and to release oxygen slowly over time. © 2010 Elsevier B.V.

New swellable cyclodextrin-based poly(amidoamine) nanosponges, named PAA-NS10 and PAA-NS11, were synthesized by crosslinking β-cyclodextrin with either 2,2-bisacrylamidoacetic acid or with polyamidoamine segments deriving from 2,2-bisacrylamidoacetic acid and 2-methylpiperazine, respectively. Water uptake studies showed a tremendous swelling capacity of both nanosponges, forming hydrogels. Time dependent swelling experiments in various aqueous media showed that the nanosponge hydrogels were stable over a period of at least 72 h maintaining their integrity. Thermal analysis showed that the two nanosponges were stable up to 250 and 300 °C, respectively. Both PAA-NS10 and PAA-NS11 were converted to aqueous nanosuspensions using the High Pressure Homogenization technique. Bovine serum albumin (BSA) was used as model protein to study the encapsulating capacity of these new β-cyclodextrin-based PAA-nanosponges. High protein complexation capacity was observed, as confirmed by UV spectroscopy. BSA encapsulation efficiency was greater than 90% on w/w basis for both nanosponges. In vitro BSA release studies were carried out showing a prolonged release of albumin from the two swollen BSA loaded β-CD PAA-NS over a period of 24 h. © 2010 Springer Science+Business Media B.V.

A new kind of gastro-retentlve dosage form for drugs with poor aqueous solubility was developed and evaluated, with the aim of achieving gastro-retention, enhancing aqueous solubility and achieving controlled release of the active. Furosemide with an absorption window in the upper gastro-intestinal tract and limited aqueous solubility was selected as the model drug and was enhanced by preparing a self microemulsifying drug delIvery system (SMEDDS) of furosemide. The idea generated in the present study can be used as a general model for designing gastro retentive dosage forms of drugs with limited solubility.

Camptothecin (CAM), a plant alkaloid and a potent antitumor agent, has a limited therapeutic utility because of its poor aqueous solubility, lactone ring instability and serious side effects. Cyclodextrin-based nanosponges (NS) are a novel class of cross-linked derivatives of cyclodextrins. They have been used to increase the solubility of poorly soluble actives, to protect the labile groups and control the release. This study aimed at formulating complexes of CAM with three types of β-cyclodextrin NS obtained with different cross-linking ratio (viz. 1:2, 1:4 and 1:8 on molar basis with the cross-linker) to protect the lactone ring from hydrolysis and to prolong the release kinetics of CAM. Crystalline (F1:2, F1:4 and F1:8) and paracrystalline NS formulations were prepared. XRPD, DSC and FTIR studies confirmed the interactions of CAM with NS. XRPD showed that the crystallinity of CAM decreased after loading. CAM was loaded as much as 21%, 37% and 13% w/w in F1:2, F1:4 and F1:8, respectively while the paracrystalline NS formulations gave a loading of about 10% w/w or lower. The particle sizes of the loaded NS formulations were between 450 and 600 nm with low polydispersity indices. The zeta potentials were sufficiently high (-20 to -25 mV) to obtain a stable colloidal nanosuspension. The in vitro studies indicated a slow and prolonged CAM release over a period of 24 h. The NS formulations protected the lactone ring of CAM after their incubation in physiological conditions at 37 °C for 24 h with a 80% w/w of intact lactone ring when compared to only around 20% w/w of plain CAM. The cytotoxicity studies on HT-29 cells showed that the CAM formulations were more cytotoxic than plain CAM after 24 h of incubation. © 2009 Elsevier B.V. All rights reserved.

The aim of this study was to evaluate the pharmacokinetics of paclitaxel-loaded nanosponges (PLN) in rats. The study also evaluates the intrinsic effect of the dosage form on the improvement of paclitaxel oral bioavailability. Paclitaxel-loaded nanosponges were prepared and characterized in terms of size distribution, drug solubilization, and the kinetics of paclitaxel sedimentation. Taxol® and paclitaxel-loaded nanosponges were administered orally to rats. The plasma concentration of paclitaxel was determined using liquid chromatography. The average size of PLN was 350±25nm. The drug payload of paclitaxel was 500±0.27mg/g of lyophilized powder. The encapsulation efficiency was 99.1±1.0%, and 1.7±0.2% of paclitaxel was crystallized after 48h. The relative oral bioavailability of paclitaxel-loaded nanosponges was 256. After oral administration of paclitaxel-loaded PLN, the area under the plasma concentration time curve was significantly increased (∼ 3-fold) in comparison to the control group (p<0.05). The results indicated that PLN provided a promising new formulation to enhance the oral bioavailability of paclitaxel while avoiding the use of cremophore El: Ethanol in Taxol®. © 2010 Informa UK Ltd.

Aim: We did a prospective study to investigate pharmacokinetics of a single intramuscularly (i.m.) administered Valdecoxib (VC) polymeric microparticles in New Zealand white rabbits. Method: Poly[lac(glc-leu)] microparticles encapsulating a potent cyclooxygenase-2- selective inhibitor, VC, were prepared by emulsion and solvent evaporation technique and administered i.m. to rabbits for pharmacokinetic study. Results: A single i.m. dose of drug-loaded poly[lac(glc-leu)] microparticles resulted in sustained therapeutic drug levels in the plasma for 49 days. The relative bioavailability was increased severalfold as compared with unencapsulated drug. Conclusions: Injectable poly[lac(glc-leu)] microparticles hold promise for increasing drug bioavailability and reducing dosing frequency for better management of rheumatoid arthritis. © Informa UK, Ltd.

Valdecoxib has been entrapped in sub-5 μm particles of poly[Lac(Glc-Leu)] copolymer using a oil-in-water (o/w) emulsification-solvent evaporation technique. To achieve monodispersed sized particles, a microfluidizer was used as ultrasonication device. Formulation parameters such as effect of polymer load, ultrasonication time, stabilizer concentration and stirring rate have a profound effect on particle size, and polydispersity. By adjustment of these parameters, microparticles ranging from about 0.8 to more than 4 μm have been prepared. © 2009 Elsevier B.V. All rights reserved.

[No abstract available]

Purpose: The present study was undertaken to develop a validated, rapid, simple and economic stability indicating reverse phase HPLC method for estimating meloxicam (MLX) in bulk and commercial preparations. Method: Reversed phase chromatographic analysis was performed on a C18 Hi Q Sil column with acetonitrile-water-glacial acetic acid [55:40:5 (% v/v)] at a flow rate of 1ml/min and detection wavelength of 355 nm. System suitability tests essential for the assurance of quality performance of the method were performed. The drug was subjected to stress degradation studies under acidic, basic and oxidative conditions. The method was validated for accuracy, precision, reproducibility, specificity, robustness, limit of detection (LOD) and limit of quantification (LOQ) , as per International Conference on Harmonization (ICH) guidelines. Results: A single sharp peak was obtained for MLX at Rt of 6.8 ± 0.01min. The polynomial regression data for the calibration plots exhibited good linear relationship (r = 0.9995) over a concentration range of 4-20 μg/ml and the linear regression equation was y = 57257.38x + 3443.07. Accuracy ranged from 99.27 to 100.78% and the % coefficient of variation (CV) for both intra-day and inter-day precision was less than 2%. MLX showed minor degradation peak in acidic conditions at Rt of 2.24min. The LOD and LOQ values were 360 ng/ml and 510 ng/ml, respectively. Conclusion: The proposed method gave good resolution of MLX and its degradants. System suitability tests and statistical analysis performed prove that the method is precise, accurate and reproducible, and hence can be employed for routine analysis of MLX in bulk and commercial formulations. © Pharmacotherapy Group, Faculty of Pharmacy, University of Benin. All rights reserved.

The aim of this study was to formulate and characterize a microparticulate system of progestin-only contraceptive. Another objective was to evaluate the effect of gamma radio-sterilization on in vitro and in vivo drug release characteristics. Levonorgestrel (LNG) microspheres were fabricated using poly(lactide-co-glycolide) (PLGA) by a novel solvent evaporation technique. The formulation was optimized for drug/polymer ratio, emulsifier concentration, and process variables like speed of agitation and evaporation method. The drug to polymer ratio of 1:5 gave the optimum encapsulation efficiency. Speed of agitation influenced the spherical shape of the microparticles, lower speeds yielding less spherical particles. The speed did not have a significant influence on the drug payloads. A combination of stabilizers viz. methyl cellulose and poly vinyl alcohol with in-water solvent evaporation technique yielded microparticles without any free drug crystals on the surface. This aspect significantly eliminated the in vitro dissolution "burst effect". The residual solvent content was well within the regulatory limits. The microparticles passed the test for sterility and absence of pyrogens. In vitro dissolution conducted on the product before and after gamma radiation sterilization at 2.5 Mrad indicated no significant difference in the drug release patterns. The drug release followed zero-order kinetics in both static and agitation conditions of dissolution testing. The in vivo studies conducted in rabbits exhibited LNG release up to 1 month duration with drug levels maintained within the effective therapeutic window. © American Association of Pharmaceutical Scientists 2009.

Polymeric nanoparticle suspensions (NS) were prepared from poly(lactide-co-glycolide) and poly(lactide-co-glycolide-leucine) {poly[Lac(Glc-Leu)]} biodegradable polymers and loaded with diclofenac sodium (DS), with the aim of improving the ocular availability of the drug. NS were prepared by emulsion and solvent evaporation technique and characterized on the basis of physicochemical properties, stability, and drug release features. The nanoparticle system showed an interesting size distribution suitable for ophthalmic application. Stability tests (as long as 6 months’ storage at 5°C or at 25°C/60% relative humidity) or freeze-drying were carried out to optimize a suitable pharmaceutical preparation. In vitro release tests showed a extended-release profile of DS from the nanoparticles. To verify the absence of irritation toward the ocular structures, blank NS were applied to rabbit eye and a modified Draize test performed. Polymer nanoparticles seemed to be devoid of any irritant effect on cornea, iris, and conjunctiva for as long as 24 hours after application, thus apparently a suitable inert carrier for ophthalmic drug delivery. © 2009 Elsevier Inc. All rights reserved.

A Levonorgestrel-loaded microparticulate system was developed with gelatin and bovine serum albumin using triple emulsion technique coupled with chemical cross-linking thermal rigidization method. The formulation was optimized for various formulation variables and process parameters. The microparticulate system was characterized by scanning electron microscopy, encapsulation efficiency, moisture content, IR, DSC, XRD, residual solvent content and evaluated for sterility, abnormal toxicity and absence of pyrogens. Microparticles were sterilized by gamma irradiation at 2.5 Mrad. The system was injected intramuscularly in rabbits and drug blood levels estimated using radioimmunoassay technique. An optimized drug to polymer ratio of 0.4:0.75 w/w gave drug encapsulation efficiency of about 40%. The in vitro drug release followed Higuchi square root kinetics. In in vivo studies the AUC0-t was found to be 12849.25 pg/mL.day-1 with mean residence time calculated to be about 16 days and Kel of 0.02 day-1. Levonorgestrel (LNG) levels were maintained between 200 and 400 pg/mL. The pharmacokinetic results indicate that LNG is released from the injectable microparticles for a period of one-month duration. © 2009 Informa UK Ltd.

The present study was carried out to evaluate potentials of alkyl polyglucoside (APG) as an alternative surfactant/stabilizer in the preparation of peptide-loaded nanoparticles. hGF2 (human gel filtration fraction 2) was used as a model peptide and APG based on C10 fatty alcohol (decyl polylglucoside) was used as a representative surfactant. PLA (poly D,L-lactide) and PLGA (poly D,L-lactide-co-glycolide) based nanoparticles were prepared and the effect of APG on particle size, entrapment efficiency and biological activity was evaluated. At a concentration as low as 0.05% w/v, APG provided an excellent stabilization effect, resulting in nanoparticles with better encapsulation efficiency and particle size well below 450 nm. The effective concentration of APG was found to be much less (10-fold) as compared to PVA. Moreover, APG also showed low residual content as compared to PVA. In-vitro and in-vivo biological activity evaluation confirmed that encapsulated peptide was compatible with APG. These preliminary results suggest that APGs can be used as alternate surfactants for nanoparticle preparation.

An injectable system of levonorgestrel (LNG) was developed using biodegradable polymer of natural origin. The parenteral system was optimized for particle size and higher drug loading. The microparticulate system was characterised by scanning electron microscopy, encapsulation efficiency, moisture content, IR, DSC, XRD, residual solvent content, sterility testing, test of abnormal toxicity and test for pyrogens. The microparticles were sterilised by gamma irradiation (2.5 Mrad). The system was injected intramuscularly in rabbits and the blood levels of LNG were determined using radioimmunoassay technique. An optimized drug to polymer ratio of 0.3-1.0 (w/w ratio) gave improved drug loading of about 52%. In vivo studies in rabbits showed that the drug was released in a sustained manner for a period of 1 month. The AUC0-t was found to be 9363.6 ± 2340 pg/mL day-1 with MRT calculated to be about 16 days and Kel of 0.01 day-1. LNG levels were maintained between 200 and 400 pg/mL. In vivo release exhibited an initial burst effect which was not observed in the in vitro dissolution. This promising "Progestin-only" long-term contraceptive with improved user compliance is an alternative to the synthetic expensive polymeric carriers. © 2008 Elsevier B.V. All rights reserved.

Ranitidine hydrochloride is a H2 receptor blocker used in the treatment of gastric ulcers. Pharmacological factors, in addition to the dosage regimen, favor development of a sustained-release system for ranitidine especially in the therapeutic condition of erosive esophagitis. This investigation delves into the development of bioadhesive type of gastroretentive formulation (tablets) of ranitidine. The effect of mucoadhesive polymers such as Carbopol, hydroxypropyl methyl cellulose, and dextrose were studied. Mucoadhesion, in vitro drug release profile, water uptake, and swelling of the tablet were evaluated. Alkalizing agents were incorporated in an attempt to maintain an alkaline microenvironment within the tablet and improve the stability of the drug in acidic medium. The stability was evaluated using dye test and degradation studies. The drug release profiles were fit into various kinetic models. Copyright © Informa UK, Ltd.

The main aim of the present study was to evaluate potential of ternary complexation (comprising of drug, cyclodextrin and polymer) as an approach for taste masking. For this purpose famotidine with property of bitter taste was selected as a model drug. Improvement in taste masking capability of cyclodextrin towards famotidine was evaluated by formulating a ternary complex including hydrophilic polymer hydroxyl propyl methyl cellulose (HPMC 5 cps) as the third component. Phase solubility analysis at 25 Deg;C was carried out for both the binary systems (viz. drug-cyclodextrin and drug-polymer) and the ternary system (drug-cyclodextrin-polymer). Ternary complex was prepared using solution method and was further characterized using XRD, DSC, FT-IR and microscopic studies. In vitro dissolution study was carried out to see the effect of ternary complexation on drug release. Taste perception study was carried out on human volunteers to evaluate the taste masking ability of ternary complexation. Results obtained from phase solubility analysis showed that the combined use of polymer and cyclodextrin effectively increased the stability constant of the complex [from 538 M-1 for binary system to 15,096 M-1 for ternary system]. Ternary system showed effective taste masking as compared to binary complex and at the same time showed no limiting effect on the drug release (D.E15min=90%). The effective taste masking was attributed to the enhanced complexation of famotidine in ternary system compared to binary system and the same was confirmed from the characterization studies. In conclusion, the study confirmed that ternary complexation can be utilized as an alternative approach for effective taste masking. © American Association of Pharmaceutical Scientists 2008.

Inclusion complexation of danazol with β-cyclodextrin (BCD) in aqueous solution, in solid state and in silico state was investigated to examine the interactions of danazol with BCD. The study also explored the potential application of danazol-β-cyclodextrin complex as an oral antiovulatory agent. Phase solubility analysis suggested formation of first-order soluble complex with stability constant 972.03 M-1 while Job’s plot affirmed 1:1 stoichiometry. Solution state complexation in water was studied by ultra violet absorption, circular dichroism and nuclear magnetic resonance (1H NMR) spectroscopy. The solid state complexes were evaluated by differential scanning calorimetry, powder X-ray diffractometry, fourier transform infrared spectroscopy and scanning electron microscopy. Thermodynamic studies in water indicated exothermic nature of inclusion complexation. Molecular modeling was used to help establish the mode of interaction of BCD with danazol. 1H NMR analysis suggested that the protons of steroidal skeleton of danazol are preferably involved in the complexation with BCD, which was confirmed by molecular dynamic simulations. An inclusion complex model has been established for explaining the observed enhancement of solubility of danazol in water by BCD. Moreover, in mouse model, danazol-β-cyclodextrin complex at 51.2 mg/kg (equivalent to 400 mg human dose) showed 100% anovulation when given orally. © 2007 Elsevier B.V. All rights reserved.

The present work was aimed at formulating a SMEDDS (self-microemulsifying drug delivery system) of fenofibrate and evaluating its in vitro and in vivo potential. The solubility of fenofibrate was determined in various vehicles. Pseudoternary phase diagrams were used to evaluate the microemulsification existence area, and the release rate of fenofibrate was investigated using an in vitro dissolution test. SMEDDS formulations were tested for microemulsifying properties, and the resultant microemulsions were evaluated for clarity, precipitation, and particle size distribution. Formulation development and screening was done based on results obtained from phase diagrams and characteristics of resultant microemulsions. The optimized formulation for in vitro dissolution and pharmacodynamic studies was composed of Labrafac CM10 (31.5%), Tween 80 (47.3%), and polyethylene glycol 400 (12.7%). The SMEDDS formulation showed complete release in 15 minutes as compared with the plain drug, which showed a limited dissolution rate. Comparative pharmacodynamic evaluation was investigated in terms of lipid-lowering efficacy, using a Triton-induced hypercholesterolemia model in rats. The SMEDDS formulation significantly reduced serum lipid levels in phases I and II of the Triton test, as compared with plain fenofibrate. The optimized formulation was then subjected to stability studies as per International Conference on Harmonization (ICH) guidelines and was found to be stable over 12 months. Thus, the study confirmed that the SMEDDS formulation can be used as a possible alternative to traditional oral formulations of fenofibrate to improve its bioavailability.

This study explored the potential of β-cyclodextrin to improve the aqueous solubility and dissolution of danazol, investigated a simple and less expensive method for preparation of a danazol-β-cyclodextrin binary system, and explored the potential application of a danazol-β-cyclodextrin binary system as a single-dose emergency contraceptive. Phase solubility analysis indicated formation of a first-order soluble complex with stability constant 972.03 M-1, while Job’s plot affirmed 1:1 stoichiometry. The hyperchromic shift in the UV-Vis spectrum of danazol in the presence of β-cyclodextrin indicated solubilization capability of β-cyclodextrin for danazol. The extrinsic Cotton effect with a negative peak at 280.7 nm confirmed the inclusion of danazol in the asymmetric locus of β-cyclodextrin. 1H-nuclear magnetic resonance analysis suggested that the protons of the steroidal skeleton of danazol display favorable interactions with the β-cyclodextrin cavity. The danazol-β-cyclodextrin binary system was prepared by kneading, solution, freeze-drying, and milling methods. The extent of the enhancement of dissolution rate was found to be dependent on the preparation method. Dissolution studies showed a similar relative dissolution rate (2.85) of the danazol-β-cyclodextrin binary system prepared by the freeze-drying and milling (in the presence of 13% moisture) methods. In a mouse model, the danazol-β-cyclodextrin binary system at 51.2 mg/kg (equivalent to a 400-mg human dose) showed 100% inhibition of implantation when given postcoitally. Moreover, the danazol-β-cyclodextrin binary system is safe up to 2000 mg/kg in the mouse (15.52 g/70 kg human) as a single oral dose. Thus, the danazol-β-cyclodextrin binary system could serve as a new therapeutic application: an oral emergency contraceptive at a physiologically acceptable single dose.

The purpose of present investigation was to understand the interactions involved in complexation of Nelfinavir Mesylate (NM)-a protease inhibitor, used in the treatment of HIV/AIDS with Beta-cyclodextrin (β-CD) and its subsequent effect on its absorption properties and bioavailability. Milling method was used for complexation. The inclusion complexes were characterized by 2D NOESY NMR and ITC studies. The feasibility of findings was further confirmed by using Cerius2 software of Tripos Inc. using Silicon Graphics O2. Pharmacokinetic studies were carried out in rabbits and data was treated by Student’s t Test. 2D NOESY NMR studies showed very intricate behavior showing interactions amongst drug and β-CD molecule as well as amongst β-CD-β-CD molecules. This fact of formation of molecular aggregates was further confirmed by ITC studies. Computer simulation studies further supported the finding of forming shallow complex. The percent relative bioavailability of complex at the dose of 400 mg/kg in rabbits was 185.37 as compared to the plain NM at 400 mg/kg dose. The studies were conducted at low dose of 200 mg/kg of drug in the form of complex in rabbit does not show statistically significant difference in AUC, T 1/2 and Kel. as compared to plain drug at 400 mg/kg of rabbit. © 2007 Springer Science+Business Media, Inc.

Nanosponges are betacyclodextrins crosslinked with carbonate bonds. The polymer formed is nanoparticulate in nature. Itraconazole is a BCS Class II drug that has a dissolution rate limited poor bioavailability. Rationale of the work was to enhance the solubility of Itraconazole so that the bioavailability problems are solved. Solid dispersion technique has been used for drug incorporation. The effect of a ternary component copolyvidonum on solubility of itraconazole has been studied. Phase solubility studies has been carried out with a rationale of comparing the solubilization efficiency of nanosponges, copolyvidonum and combination. The dispersions were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and photon correlation spectroscopy (PCS). It was found that the solubility of itraconazole was enhanced more than 50-folds with a ternary solid dispersion system. Using copolyvidonum in conjunction with nanosponges helps to increase the solubilization efficiency of nanosponges as evident from the phase solubility studies. © 2007 Springer Science+Business Media, Inc.

This study aimed to investigate the effect of β-cyclodextrin on aqueous solubility and dissolution rate of valdecoxib and also to get an insight of molecular interactions involved in formation of valdecoxiβ-β- cyclodextrin inclusion complex. Phase solubility analysis indicated complex with possible stoichiometry of 1:1 and a stability constant of 234.01 M -1. Thermodynamic studies in water indicated exothermic nature of inclusion complexation. Valdecoxiβ-β-cyclodextrin complexes (1:1 M) were prepared by kneading method, solution method and freeze-drying method. The complex was characterized by differential scanning calorimetry (DSC), powder X-ray diffractometry (P-XRD), Fourier transform infrared (FTIR) spectroscopy and nuclear magnetic resonance (1H-NMR) spectroscopy. Molecular modeling was used to help establish the mode of interaction of β-cyclodextrin with valdecoxib. 1H-NMR analysis suggested that the unsubstituted phenyl ring of valdecoxib display favorable interaction with the hydrophobic cavity of β-cyclodextrin, which was confirmed by molecular dynamic simulations. An inclusion complex model has been established for explaining the observed enhancement of solubility of valdecoxib in water by β-cyclodextrin. Dissolution studies in water showed that the valdecoxib in freeze-dried complex dissolved much faster than the uncomplexed drug and physical mixture. This improvement in dissolution rate is attributed to the increased solubility and wettability due to encapsulation along with decreased crystallanity caused by complex formation, which is evident by DSC and P-XRD studies. © 2006 Springer.

The purpose of present investigation was to investigate the effect of complexation of Nelfinavir Mesylate (NM) – an Anti-HIV drug with Betα-cyclodextrin (β-CD) on its dissolution characteristics and subsequent effect on its absorption properties and bioavailability. Phase solubility studies were conducted to find the interaction of NM with β-CD. Physical mixing and milling method were used for complexation. The inclusion complexes were characterized by X-ray diffractometry, FT-IR and NMR studies and further studied by in-vitro dissolution testing. The plain NM and complex was subjected to intestinal absorption studies by using Everted intestinal sac model. Data was treated statistically by Mann-Whitney U test. Pharmacokinetic studies were carried out in rabbits using cross over design and data was treated by Student’s t test. Phase solubility studies confirmed 1:1 complex formation of NM with β-CD with stability constant of 204.84 M-1. In-vitro dissolution studies of inclusion complexes of NM with β-CD prepared by milling method (T90=60.89 min) showed better dissolution rate kinetics in distilled water in comparison with plain NM (T90=374.31). The increased solubility with decreased crystallinity is attributed by inclusion of NM in the cavity of β-CD, which was further confirmed by instrumental studies. Intestinal absorption studies further supports these findings by showing 2.13 times enhancement in the absorption rate of complex as compared to plain NM. The percent relative bioavailability of complex in rabbits was 185.37 as compared to the plain NM. © 2006 Springer.

The present work investigates the possibility of improvement of the complexation efficiency of cyclodextrin towards a drug by adding a third auxiliary component (hydrophilic polymer). Phase solubility Analysis at 25 °C was used to investigate the interaction of the drug in both the binary systems (viz. Drug-Cyclodextrin and Drug-Polymer) and the ternary system (Drug-Cyclodextrin-Polymer). The combined use of polymer and cyclodextrin was clearly more effective in enhancing the aqueous solubility of the fenofibrate in comparison with the corresponding drug-cyclodextrin or drug-polymer binary systems. Hydrophilic polymers increased the complexation efficacy of cyclodextrin towards fenofibrate (as shown by the increased stability constants of the complexes). Polyvinyl Pyrollidone (PVP) was found to be most effective in enhancing the solubilization of fenofibrate by β-Cyclodextrin, the best results were obtained in ternary system with β-Cyclodextrin in presence of 1%w/v (PVP). Formulated ternary system with optimized drug:cyclodextrin:polymer ratio of 1:3.5:1 w/w resulted in a significant improvement in the dissolution rate of fenofibrate and showed 90% dissolution efficiency (D.E) as compared to around 15% and 83% of the plain drug and binary system respectively. DSC studies was carried out to characterize the ternary complex. © 2006 Springer.

Oral sustained release gastroretentive dosage forms offer many advantages for drugs having absorption from upper gastrointestinal tract and improve the bioavailability of medications that are characterized by a narrow absorption window. A new gastroretentive sustained release delivery system was developed with floating, swellable and bioadhesive properties. All these properties were optimized and evaluated. Various release retarding polymers like psyllium husk, HPMC K100M and a swelling agent, crosspovidone in combinations were tried and optimized to get the release profile for 24 h. Formulations were evaluated for in vitro drug release profile, swelling characteristics and in vitro bioadhesion property. The in vitro drug release followed Higuchi kinetics and the drug release mechanism was found to be of anomalous or non-Fickian type. For the developed formulation, the value of n was found to be 0.5766 while for the marketed formulation the value was 0.5718 indicating the anomalous transport. The high water uptake leading to higher swelling of the tablet supported the anomalous release mechanism of ofloxacin. The similarity factor f2 was found to be 91.12 for the developed formulation indicating the release was similar to that of the marketed formulation (Zanocin OD). The swelling properties were increased with increasing crosspovidone concentration and contributed significantly in drug release from the tablet matrix. The bioadhesive property of the developed formulation was found to be significant (P < 0.005) in combination as compared to HPMC K100M and psyllium husk alone. © 2006 Elsevier B.V. All rights reserved.

Sustained release (SR)-gastroretentive dosage forms (GRDF) enable prolonged and continuous input of the drug to the upper parts of the gastrointestinal (GI) tract and improve the bioavailability of medications that are characterized by a narrow absorption window. A new strategy is proposed for the development of gastroretentive dosage forms for ofloxacin preferably once daily. The design of the delivery system was based on the sustained release formulation, with floating and swelling features in order to prolong the gastric retention time of the drug delivery systems. Different polymers, such as psyllium husk, HPMC K100M, crospovidone and its combinations were tried in order to get the desired sustained release profile over a period of 24 h. Various formulations were evaluated for buoyancy lag time, duration of buoyancy, dimensional stability, drug content and in vitro drug release profile. It was found that dimensional stability of the formulation increases with the increasing psyllium husk concentration. It was also found that in vitro drug release rate increased with increasing amount of crospovidone due to the increased water uptake, and hence increased driving force for drug release. The optimized formulation was subjected to stability studies at different temperature and humidity conditions as per ICH guidelines. In vivo studies were carried out for the optimized formulation in 24 healthy human volunteers and the pharmacokinetic parameters of developed formulations were compared with the marketed once daily (Zanocin) formulation. Based on the in vivo performance in a parallel study design in healthy subjects, the developed formulation shows promise to be bioequivalent to the marketed product (Zanocin). The percent relative bioavailability of developed formulation was found to be 97.55%. © 2005 Elsevier B.V. All rights reserved.

The purpose of this work was to increase the nasal absorption of sumatriptan succinate by using bile salts. A rat in situ nasal perfusion technique was used to examine the rate and extent of absorption of sumatriptan succinate. In vitro enzymatic drug degradation studies were carried out with rat nasal washings. Various experimental conditions such as nasal perfusion rate, pH of the perfusion medium and concentrations of absorption enhancers such as sodium deoxycholate, sodium caprate, sodium tauroglycocholate and EDTA were optimized. In vivo studies were carried out for the optimized formulation in rabbits and the pharmacokinetics parameters of nasal solution were compared with marketed nasal solutions. Nasal absorption of sumatriptan succinate was pH dependent. It was found maximum at pH 5.5 and decreased at higher pH values. In in vitro enzymatic degradation studies, no measurable degradation was observed during the first week. The extent of drug absorption was increased by absorption enhancers. Sodium deoxycholate appeared to be more effective for enhancing the nasal absorption of sumatriptan succinate than the other absorption enhancers. The order of increasing absorption of sumatriptan succinate caused by the enhancers was sodium deoxycholate > sodium caprate > sodium tauroglycocholate > EDTA.

The objective of this work was to increase the nasal absorption of acyclovir by using absorption enhancers. Acyclovir was selected as a model drug. A rat in situ nasal perfusion technique was utilized in the investigation to examine the rate and extent of absorption of acyclovir. In vitro enzymatic drug degradation study was carried out with rat nasal washings. Various experimental conditions such as nasal perfusion rate, pH of the perfusion medium and concentrations of absorption enhancers such as sodium deoxycholate, hydroxypropyl β-cyclodextrin, sodium caprate, sodium tauroglycocholate and EDTA were optimized. Nasal absorption of acyclovir was pH dependent. Initial absorption rate constants were determined by the plot of log% remaining amount of drug in perfusate vs time. It was found maximum at pH 7.4 and decreased at lower and higher pH conditions. In in vitro enzymatic degradation study, no measurable degradation was observed during first week. The extent of drug absorption was increased via absorption enhancers. In vivo studies were carried out for the optimized formulation in rabbits and the pharmacokinetics parameters of nasal solution were compared with oral solution. Hydroxypropyl β-cyclodextrin appeared to be more effective for enhancing the nasal absorption of acyclovir than the other absorption enhancers. The order of increasing absorption of acyclovir caused by the enhancers was hydroxypropyl β-cyclodextrin>sodium deoxycholate>sodium caprate>sodium tauroglycocholate>EDTA. © 2004 Elsevier B.V. All rights reserved.

The development of a transdermal delivery system for isosorbide dinitrate (ISDN) using electron beam irradiation was studied. The solid state stability of the drug to irradiation was assessed. The drug was dissolved in 2-ethylhexylacrylate (EHA)-acrylic acid (AA) system and this solution was directly irradiated on a backing membrane (Scotchpak®1006) at different doses to get transdermal patches. The developed systems were evaluated for residual monomer content, equilibrium weight swelling ratios (EWSR), differential scanning calorimetry (DSC), weight uniformity, thickness uniformity, drug content and content uniformity, peel strength, in vitro release, skin permeation kinetics and skin irritation potential. The developed system possessed excellent adhesive properties. Increase in the irradiation doses did not have a significant effect on the peel strength values. The systems exhibited promising skin permeation kinetics and no skin irritating potential, both of which are important properties for transdermal drug delivery. The ISDN-EHA-AA system developed at an irradiation dose of 50kGy showed a higher skin permeation profile as compared to an internationally marketed transdermal matrix system of ISDN. © 2003 Elsevier B.V. All rights reserved.

The preparation of nanoparticles (NP) as an improved colloidal carrier system for the hydrophilic drug (Diclofenac Sodium) was investigated. Owing to the solubility of the drug in water, the double emulsion technique was used for the encapsulation of the drug. To achieve submicron size as well as increasing monodispersity, a microfluidizer was used as ultrasonication device. A biodegradable polymer, poly[lactide-co-glycolide] 50:50 (PLGA) was used in the process. The loading was improved by varying the concentration of the drug in the inner aqueous phase, whereupon the polydispersity and the particle size were slightly affected. But encapsulation efficiency decreased with higher drug loading in the inner aqueous phase. All release profiles were characterized by an initial burst effect followed by a sustained release. © 2003 Indian Society for Surface Science and Technology.

An acrylate-based pressure sensitive adhesive (PSA) was synthesized to incorporate in a design of a drug-inadhesive (DIA) type transdermal therapeutic system (TTS) for nitrendipine and nicorandil in treatment of hypertension and angina pectoris, respectively. Solutions of 2-ethylhexyl acrylate (EHA; 85% w/w), methyl methacrylate (MMA; 10% w/w), acrylic acid (AA; 3% w/w) and vinyl acetate (VA; 2% w/w) in either ethyl acetate, acetone or methanol were polymerized under free radical conditions to synthesize the PSA. The effects of solvent, reaction time, initiator concentration and reaction temperature on polymerization were studied. The resultant copolymers were characterized by 7H-NMR, IR, differential scanning calorimetry (DSC) and gel permeation chromatography (GPC) and the intrinsic viscosities, refractive index, peel strength, moisture uptake and skin irritation potential were determined. The PSA was used to develop DIA type patches for delivery of nitrendipine and nicorandil. The TTS were evaluated for thickness, weight, peel strength, moisture uptake, in vitro release and in vitro skin permeation through guinea-pig skin. The copolymer found to effectively control the rate of drug release and the corresponding TTSs could be successfully employed in transdermal delivery of nitrendipine and nicorandil. © 2003 John Wiley and Sons, Ltd.

A controlled porosity osmotic pump-based drug delivery system has been described in this study. Unlike the elementary osmotic pump (EOP) which consists of an osmotic core with the drug surrounded by a semipermeable membrane drilled with a delivery orifice, controlled porosity of the membrane is accomplished by the use of different channeling agents in the coating. The usual dose of pseudoephedrine is 60 mg to be taken three or four times daily. It has a short plasma half life of 5-8 h. Hence, pseudoephedrine was chosen as a model drug with an aim to develop a controlled release system for a period of 12 h. Sodium bicarbonate was used as the osmogent. The effect of different ratios of drug:osmogent on the in-vitro release was studied. Cellulose acetate (CA) was used as the semipermeable membrane. Different channeling agents tried were diethylphthalate (DEP), dibutylphthalate (DBP), dibutylsebacate (DBS) and polyethyleneglycol 400 (PEG 400). The effect of polymer loading on in-vitro drug release was studied. It was found that drug release rate increased with the amount of osmogent due to the increased water uptake, and hence increased driving force for drug release. This could be retarded by the proper choice of channeling agent in order to achieve the desired zero order release profile. Also the lag time seen with tablets coated using diethylphthalate as channeling agent was reduced by using a hydrophilic plasticizer like polyethyleneglycol 400 in combination with diethylphthalate. This system was found to deliver pseudoephedrine at a zero order rate for 12 h. The effect of pH on drug release was also studied. The optimized formulations were subjected to stability studies as per ICH guidelines at different temperature and humidity conditions. © 2003 Published by Elsevier Science B.V.

The objective of the present research investigation was to fabricate an acrylate-based transdermal therapeutic system (TTS) of nitrendipine, which could deliver drug at maximum input rate so as to deliver drug in minimum patch size. Transdermal patches were fabricated using synthesized acrylate pressure-sensitive adhesives (PSAs): PSA1, PSA2, and commercially available PSA3 and PSA4 using d-limonene as permeation enhancer. Effect of concentration of d-limonene on permeation kinetics of nitrendipine in PSAs was studied. Fabricated TTS in mentioned PSAs were evaluated for in-vitro release and permeation kinetics through guinea-pig skin. Cumulative release of drug in PSA1, PSA2, PSA3, and PSA4 was observed to be 45%, 40%, 25%, and 25%, respectively, upto 24hr. Flux of drug through guinea-pig skin calculated at 48 hr in PSA1, PSA2, PSA3, and PSA4, with and without d-limonene, was observed to be 0.346±0.10, 0.435±0.17, 0.410±0.17, and 0.162±0.06, and 0.625±0.19, 1.161±0.46, 0.506±0.17, and 0.520±0.18 (μg/cm2/hr), respectively. The TTS in PSA2 showed comparatively high flux and could deliver drug at high input rate through transdermal route. PSA2 was found to have good rate-controlling property and could be successfully employed in transdermal delivery of nitrendipine.

Electron beam irradiation was used to synthesize a matrix type transdermal system of isosorbide dinitrate, an effective anti-anginal agent. The drug was dissolved in two monomeric systems, 2-ethylhexyl acrylate (EHA) and 2-ethylhexyl acrylate:methyl methacrylate (9:1). The solutions were then directly irradiated on a backing membrane (Scotchpak®1006) at different doses to get transdermal patches. The developed systems were evaluated for residual monomer content, equilibrium weight swelling ratio, weight uniformity, thickness uniformity, drug content, peel strength, in vitro release and skin permeation kinetics. They possessed excellent tack and adhesive properties. In the case of isosorbide dinitrate-EHA systems, an increase in the peel strength values with respect to the skin was observed with increasing radiation doses. The systems exhibited promising skin permeation kinetics favorable for transdermal drug delivery. The radiation stability of the drug in the pure solid state form was also assessed. © 2002 Elsevier Science Ltd. All rights reserved.

The purpose of the present work was to investigate the effect of complexation of rofecoxib with β-cyclodextrin on its dissolution characteristics and bioavailability. Inclusion complexes of rofecoxib with β-cyclodextrin were made by freeze-drying technique. Phase solubility studies were conducted as suggested by Higuchi and Connors. The samples were characterized by performing dissolution studies, X-ray Diffraction studies and Differential Scanning Calorimetry. The complexes were compressed into tablets and compared in-vitro with various marketed formulations. A single dose study on healthy human volunteers was performed in comparison with a marketed formulation of rofecoxib (without β-cyclodextrin) to investigate the relative bioavailability. Phase solubility studies confirmed the formation of a 1:1 complex in solution of rofecoxib with β-cyclodextrin. Tablets of solid inclusion complexes of rofecoxib with β-cyclodextrin prepared by freeze drying technique showed enhanced dissolution rate in distilled water in comparison with all the marketed formulations analyzed. This is attributed to the increased solubility and wettability along with decreased crystallinity caused by complex formation, which is confirmed, by XRD and DSC studies. The bioequivalence studies performed showed statistically significant enhancement in bioavailability as compared to the marketed formulation. Apparently, tablets containing complexes of rofecoxib with β-cyclodextrin shows faster onset of action due to improved solubility, enhanced dissolution and faster absorption of the molecule. The results of this investigation with rofecoxib in β-cyclodextrin lend ample credence to its better oral bioavailability on complexation.

The objective of this work was to increase the nasal absorption of acyclovir by using cyclodextrins as absorption enhancers. Acyclovir was selected as a model drug. A rat in situ nasal perfusion technique was utilized in the investigation to examine the rate and extent of absorption of acyclovir. The remaining analyte concentrations in the nasal perfusate were quantitated by reversed phase high performance liquid chromatography. In vitro enzymatic drug degradation study was carried out with rat nasal washings. Various experimental conditions were optimized such as nasal perfusion rate, pH of the perfusion medium, and concentrations of cyclodextrins such as α, β, γ, methyl-β, hydroxypropyl-β-cyclodextrins. Nasal absorption of acyclovir was pH dependent. Initial absorption rate constants were determined by the plot of log % remaining amount of drug in perfusate vs time. It was maximum at pH 7.4 and decreases at lower and higher pH conditions. The uptake of analyte by flow circuit component was assessed prior to the animal study to minimize system artifacts. In in-vitro enzymatic degradation study, no measurable degradation was observed during first week. The extent of drug absorption was increased via absorption enhancers. From the above absorption enhancers, hydroxypropyl-β-cyclodextrin appeared to be more effective for enhancing the nasal absorption of acyclovir than the other absorption enhancers. The order of increasing absorption of acyclovir caused by the enhancers was hydroxypropyl-β-cyclodextrin (5%) > methyl-β-cyclodextrin (5%) > α-cyclodextrin (1.3%) > γ-cyclodextrin (1.5%) > β-cyclodextrin (2%).

The aim of this research investigation was to fabricate acrylate-based stable transdermal therapeutic system (ITS) of nicorandil, which could deliver drug through transdermal route. Monolithic ITS was fabricated in pressure sensitive adhesives (PSAs)-(a) terpolymer (PSA1) of 2-ethylhexyl acrylate, methyl methacrylate, and acrylic acid, (b) copolymer (PSA2) of 2-ethylhexyl acrylate, methyl methacrylate, acrylic acid, and vinyl acetate, and (c) Eudragit E100® pressure sensitive adhesive (PSA3). To enhance the flux of nicorandil, skin permeation enhancer N-methyl-2-pyrrolidone (NMP) was investigated at different concentrations (0.05-5%) in PSAs. Fabricated TTS was evaluated for in-vitro release and skin permeation through guinea pig skin. Maximum flux of nicorandil was observed from Eudragit E100 based ITS and kept for stability study at refrigeration, 25°C/30% RH and 30°C/60% RH. Patches were evaluated for various physicochemical parameters. Formulation was observed to be relatively more stable at refrigeration. Shelf life of the formulation was found to be 270, 270, and 30 days at refrigeration, 25°C/30% RH and 30°C/60% RH conditions, respectively. Nicorandil could be successfully derived from Eudragit E100 based TTS, but attention needs to be given to improve its chemical stability in formulation.

Venlafaxine is a unique antidepressant that differs structurally from other currently available antidepressants. Sustained release tablets of venlafaxine to be taken once daily were formulated with venlafaxine hydrochloride equivalent to 75mg of venlafaxine base. Matrix system based on swellable as well as non-swellable polymers was selected for sustaining the drug release. Different polymers viz. hydroxypropylmethylcellulose (HPMC), cellulose acetate, Eudragit RSPO, ethylcellulose etc. were studied. Combinations of non-swellable polymers with HPMC were also tried in order to get the desired sustained release profile over a period of 16h. The effect of drug to polymer ratio on in vitro release was studied. The marketed formulation was evaluated for different parameters such as appearance, weight variation, drug content and in vitro drug release. The optimized formulation was subjected to stability studies at different temperature and humidity conditions as per ICH guidelines. These were evaluated for appearance, weight variation, thickness, hardness, friability, drug content and in vitro drug release at selected time intervals. In vivo studies were carried out for the optimized formulation in 12 healthy human volunteers and the pharmacokinetic parameters were compared with the marketed one. © 2002 Published by Elsevier Science B.V.

A rapid, selective and stability indicating high performance liquid chromatographic method was developed and validated for the estimation of venlafaxine in pharmaceutical dosage forms. The analysis was done on a Spherisorb C8 (4.6×250 mm, 5 μm) column. The mobile phase consisted of acetonitrile:sodium dihydrogen orthophosphate [0.04 M], pH 6.8 (75:25) at a flow rate of 1.5 ml/min. Detection was carried out at a wavelength of 224 nm. The developed method was found to give good separation between the pure drug and the degraded product. The polynomial regression data for the calibration plots showed good linear relationship in the concentration range of 1-10 μg/ml with r=0.9999. The method was validated for precision, accuracy, ruggedness and recovery. The minimum detectable and minimum quantifiable amounts were found to be 150 and 600 ng/ml, respectively. The drug was stable under basic and oxidative conditions. However, the sample treated with acid showed an additional peak at a retention time of 4.32 min other than the main peak at a retention time of 5.32 min. Statistical analysis proves that the method is reproducible and selective for the estimation of venlafaxine. As the method could effectively separate the drug from the degradation product, it can be employed as a stability indicating one. © 2002 Published by Elsevier Science B.V.

The present investigation was directed towards the synthesis of a copolymer of 2-ethylhexyl acrylate and acrylic acid to be exploited as a pressure sensitive adhesive (PSA) matrix in transdermal drug delivery systems. The polymer synthesis involved free radical solution polymerization using 2, 2′-azobisisobutyronitrile as the free radical initiator. The experimental methodology involved the optimization of reaction conditions for the polymer synthesis. The optimized copolymer was then characterized by IR, 1H-NMR, DSC, GPC and XRD. The PSA was also evaluated for percent free monomer content, intrinsic viscosity, refractive index, moisture uptake potential and film forming properties. To assess it suitability in the development of transdermal systems, peel strength values with respect to release liner as well as human skin and skin irritation potential were also determined. In addition, wear performance test was conducted to evaluate adhesion and adhesive transfer. The synthesized adhesive was found to have good peel strength; exhibited excellent adhesion and adhesive transfer on removal. It was found suitable for use in transdermals and could be further exploited either as an adhesive matrix or as a system component in the area of transdermal drug delivery. Copyright © 2002 John Wiley & Sons, Ltd.

A transdermal steroidal delivery system usually contains a high concentration of drug to obtain high drug fluxes. The present investigation involved the development of drug-in-adhesive transdermal systems of estradiol using synthesized acrylate copolymer (EA) of 2-ethylhexyl acrylate and acrylic acid. The effect of several variables such as varying drug polymer ratios, effect of Eudragit® RL PO and Eudragit® E PO and effect of drying temperatures on prevention of drug crystallization in the formulation matrix was investigated. The systems free from drug crystals were evaluated and compared with a marketed formulation with respect to its skin permeation profile. The optimized formulation was also subjected to accelerated stability testing. Eudragit® RL PO and Eudragit® E PO were found to be effective as crystallization inhibitors in the transdermal matrix systems tested. Formulations fabricated with Eudragit® E PO gave transparent systems with good film properties and a higher skin permeation profile as compared to that of the marketed system. Higher temperature and humidity conditions facilitated the formation of drug crystals, whereas no crystals were observed in the formulation matrix at 23±0.5°C and at 30±1°C for the period of 6 months studied. Copyright © 2001 Elsevier Science B.V.

A new kind of soluble structure-ordered ladder-like polysilsesquioxane with reactive side-chain 2-(-4-chloromethyl phenyl) ethyl groups (L) was first synthesized by stepwise coupling polymerization. The monomer, 2-(4-chloromethyl phenyl) ethyltrichlorosilane (M), was synthesized succesfully by hydrosilylation reaction with dicyclopentadienylplatinum(II) chloride (Cp2PtCl2) catalyst. Monomer and polymer structures were characterized by FT-IR, 1H-NMR, 13C-NMR, 29Si-NMR, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), vapor pressure osmometry (VPO) and X-ray diffraction (XRD). This novel reactive ladder-like polymer has promise potential applications as initiator for atom transfer radical polymerization, and as precursor for a variety of advanced functional polymers. Copyright © 2001 John Wiley & Sons, Ltd.

The combination of pseudoephedrine and cetirizine is widely used in the treatment of allergic rhinitis. A rapid, selective and stability indicating high performance thin layer chromatographic method was developed and validated for their simultaneous estimation in pharmaceutical dosage forms. The method employed TLC aluminium plates precoated with silica gel 60F-254 as the stationary phase. The solvent system consisted of ethyl acetate-methanol-ammonia (7:1.5:1, v/v/v). This system was found to give compact spots for both pseudoephedrine (Rf value of 0.69 ± 0.01) and cetirizine (Rf value of 0.38 ± 0.01). Also the degraded products were well separated from the pure drugs. Spectrodensitometric scanning-integration was performed at a wavelength of 240 nm. The polynomial regression data for the calibration plots showed good linear relationship with r2 = 0.9947 in the concentration range of 10-26 μg for pseudeophedrine and 200-1200 ng for cetirizine with r2 = 0.9973. The method was validated for precision, accuracy, ruggedness and recovery. The minimum detectable amounts were found to be 2 μg and 500 pg for pseudoephedrine and cetirizine, respectively. The limits of quantitation were found to be 6 μg for pseudoephedrine and 800 pg for cetirizine. Both the drugs do not undergo degradation under acidic and basic conditions. The samples degraded with hydrogen peroxide showed additional peaks at Rf values of 0.75 and 0.28 for pseudoephedrine and cetirizine, respectively. This indicates that both the drugs are susceptible to oxidation. Statistical analysis proves that the method is reproducible and selective for the simultaneous estimation of pseudoephedrine and cetirizine. As the method could effectively separate the drugs from their degradation products, it can be employed as a stability indicating one. © 2001 Elsevier Science B.V.

The objective of this study is to develop validated stability indicating HPLC (A), HPTLC (B) and spectrophotometric (C) method for the estimation of nitrendipine. The stability indicating capability of the assays is proved using forced degradation, by exposing drug solution to sunlight, acidic and alkaline medium. The chromatogram and UV spectrum showed nitrendipine well resolved from the degradation product. Degradation of drug is found faster in acidic (0.1 N hydrochloric acid) medium as compared to alkaline (0.1 N sodium hydroxide) medium at 100°C. Also, photodegradation is studied, with special emphasis on the effect of solvents like methanol (1), chloroform (2), dichloromethane (3), acetone (4) and ethyl acetate (5), on the rate of photodegradation. The degradation of title compound followed first order kinetics in all cases. Estimation of the drug is carried out by the stability indicating methods mentioned, using one point standardization within the linearity range of interest. The methods are compared in respect of performance precision and accuracy. Major route of degradation in all cases is found to be oxidation and degradation product is confirmed as dehydronitrendipine by the use of relevant UV, IR and 1H NMR spectrometry. © 2001 Elsevier Science B.V.

[No abstract available]

A new simple, rapid and selective high performance thin layer chromatography (HPTLC) method is developed for the quantitation of acyclovir during in vitro skin permeation studies. Separation of guinea pig skin proteins and acyclovir was achieved by employing a mobile phase consisting of chloroform-methanol-ammonia (15:9:4, v/v/v) on precoated silica gel 60F254 aluminum plates. Densitometnic analysis was carried out at 255 nm. The limit of detection and quantification were 30 and 50 ng, respectively. The calibration curve was linear in the range of 10-20 μg/ml (r=0.9965). The relative standard deviation for a sample of concentration 100 μg/ml were 1.15 and 2.85 for system and method precision, respectively. Intraday and interday variation studies gave an average 0.763 and 0.463% relative standard deviation for the three levels tested. Average recoveries of 101.8 and 100.1% were recorded for two marketed preparations studied. The method was employed to optirmize topical liposomal gel formulation of acyclovir on basis of maximum skin permeation. Copyright (C) 2000 Elsevier Science B.V.

Estradiol (ESD) is widely used in post climacteric replacement therapy. Most of the methods used for quantitation are expensive and time consuming. A rapid, selective and precise stability indicating high performance thin layer chromatography method was developed and validated for the estimation of ESD in bulk and pharmaceutical dosage forms. The method employed TLC aluminium plate precoated with silica gel 60F254 as the stationary phase. The solvent system employed consisted of chloroform-acetone-isopropyl alcohol-glacial acetic acid (9:1:0.4:0.1, v/v/v/v). Such a complex system was essential to obtain a dense and compact spot of the drug at an Rf value of 0.40±0.02. The drug on intentional degradation gave two products with Rf values of 0.52±0.01 and 0.58±0.01 respectively. Spectrodensitometric scanning-integration was performed on a Camag system using a wavelength of 286 nm. The polynomial regression data for the calibration plots exhibited good linear relationship (r=0.9947) over a concentration range of 1-8 μg. Recovery studies were also performed at three experimental levels. The recovery data reveals that the RSD for intra-day and inter-day analysis was found to be 1.27% and 1.75%, respectively. The proposed method was found to be stability indicating. Statistical analysis proves that the method is precise, accurate and reproducible, hence can be employed for the routine analysis of the drug. Copyright (C) 2000 Elsevier Science B.V.

Cyclodextrins (CDs) can be synthesized from starch by cyclodextrin glycosyltransferase (CGTase). This enzyme produces α-, β- and γ-CDs in varying proportions. In the production of cyclodextrins, purity as well as yield are important factors. A precise and reproducible method was developed and validated for the simultaneous determination of α-, β-, and γ-CDs. Optimum separation between the three CDs was achieved using a Finepak amino column with a mobile phase consisting of acetonitrile-water (70:30, v/v) at a flow rate of 1 ml/min. Detection was carried out using a differential refractive index detector. The developed method gave good chromatographic resolution of the three components with retention times of 13.16, 16.83 and 21.74 min for α-, β- and γ-CDs, respectively. The polynomial regression data for the calibration plots exhibited good linear relationship (coefficient of correlation r=0.9987 for α, r=0.9986 for β and r= 0.9998 for γ-CDs) over a concentration range of 2-10 mg/ml. Statistical analysis proves that the proposed LC method is precise, reproducible and accurate for the estimation of α-, β- and γ-cyclodextrins. The method can be employed for determination of percent purity as well as estimation of process yields of the cyclodextrins during the enzymatic production. Copyright (C) 2000 Elsevier Science B.V.

A rapid and sensitive HPTLC method was developed and validated for the estimation of Piroxicam (PM). Spectrodensitometric scanning-integration was performed at an absorbance wavelength of 360 nm. To justify the suitability, accuracy and precision of the proposed method, recovery studies were performed at three concentration levels. One of the degradation products of PM is 2-aminopyridine (2AP). It becomes imperative to separate this compound as it is a precursor during synthesis of the drug. A TLC aluminium plate precoated with silica gel 60F-254 was used as the stationary phase. The solvent system toluene-acetic acid (8:2 v/v) gave a dense and compact spot of PM with a Rf value of 0.58±0.01 which was well separated from 2AP (Rf 0.23±0.01). The polynomial regression data for the calibration plots exhibited good linear relationship (coefficient of correlation r=0.9982) over a concentration range of 400-800 ng. Statistical analysis proves that the proposed method is accurate and reproducible. The method is stability indicating and being economical can be employed for the routine analysis in bulk drug as well as pharmaceutical formulations. Copyright (C) 2000 Elsevier Science B.V.

The study involved the complexation of nimesulide with β-cyclodextrin (β-CyD) by milling. Nimesulide and β-CyD were mixed in the ratios 1: 1, 1: 2, 1: 3 and 1: 4 by weight. Each mixture was ground in a ball mill at 50 rev min-1 for 6, 12, 24 and 48 h. The samples were subjected to dissolution studies, differential scanning calorimetry and X-ray diffraction studies and were also evaluated for anti-inflammatory and analgesic activity. The sample containing the 1:4 ratio milled for 6 and 12h exhibited a lower T90 value compared with nimesulide, ball-milled nimesulide and the freeze-dried complex. Increasing the milling time to 24 or 48 h further increased the T90 (time required for 90% of the drug to dissolve) value. The dissolution rate constant for nimesulide increased with an increase in β-CyD concentration. Milled samples (1:4 ratio milled for 6 and 12 h) also showed significant anti-inflammatory and analgesic activity. The results showed an improved rate of nimesulide absorption and hence better bioavailability by inclusion complex formation of the drug with β-CyD.

Nimesulide (NM), a nonsteroidal anti-inflammatory drug (NSAID) has poor aqueous solubility. The present study describes the complexation of NM with β-cyclodextrin (β-CD) and its derivative hydroxypropyl β-cyclodextrin (HPβ-CD). The complexation was studied by phase solubility method. Fourier transformed infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), and X-ray diffractometry (XRD). The complexes were prepared by a freeze-drying technique. The in vitro dissolution rate of drug-HPβ-CD complex was faster compared to the drug-β-CD complex and drug alone.

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[No abstract available]

Therapeutic monitoring of theophylline can be accurately performed by radioimmunoassay (RIA). It is radioactive tracer as an essential reagent for the development of very sensitive RIA. Direct radiolabeling of theophylline with 125I is very difficult due to the absence of appropriate functional groups. Hence carboxylic acid of theophylline was tagged to tyrosine methyl ester and then radiolabeled. The derivatives of theophylline, bearing a propionic acid and butyric acid side chains at seventh and eight position of theophylline, were synthesised and coupled to tyrosine methyl ester. Theophylline-tyrosine methyl ester conjugates were labeled with 125I using chlora mine – T. Radiolabeled theophylline was purified by solvent extraction followed by thin layer chromatography. The purified radiolabeled compound were assessed for their radiochemical purity, specific activity and immunoreactivity. Stability studies of radiolabeled compounds were performed with different solvents at different temperatures. Theophylline serum samples analysed using developed and commercial kits showed the correlation coefficient of 0.961 (n = 9).

The preparation and characterization of an immunogen of estradiol is described. The 17-monosuccinate of estradiol (E-17MS) was coupled to bovine serum albumin (BSA) using carbodiimide. The immunogen was characterized for its chemical structure by various analytical methods. Rabbits were immunized, and the antisera collected was checked for immunoreactivity. A novel radiotracer was prepared by conjugation of E-17MS to tyrosine methyl ester hydrochloride (TME) using carbodiimide and radiolabeled by sodium iodide125. Incubation of raw antiserum was carried out in the presence of E-17MS-TME125I. Separation of free tracer from the bound form was achieved by a dextran-coated charcoal suspension. The percentage binding obtained was around 34%, thereby confirming the immunogenic potential of the antigen prepared.