Gemcitabine-Phospholipid Complex Loaded Lipid Nanoparticles for Improving Drug Loading, Stability, and Efficacy against Pancreatic Cancer.

This study aims to encapsulate gemcitabine (GEM) using a phospholipid complex (PLC) in lipid nanoparticles (NPs) to achieve several desirable outcomes, including high drug loading, uniform particle size, improved therapeutic efficacy, and reduced toxicities. The successful preparation of GEM-loaded lipid NPs (GEM-NPs) was accomplished using the emulsification-solidification method, following optimization through Box-Behnken design. The size of the GEM-NP was 138.5 ± 6.7 nm, with a low polydispersity index of 0.282 ± 0.078, as measured by a zetasizer and confirmed by transmission electron and atomic force microscopy. GEM-NPs demonstrated sustained release behavior, surpassing the performance of the free GEM and phospholipid complex. Moreover, GEM-NPs exhibited enhanced cytotoxicity, apoptosis, and cell uptake in Panc-2 and Mia PaCa cells compared to the free GEM. The in vivo pharmacokinetics revealed approximately 4-fold higher bioavailability of GEM-NPs in comparison with free GEM. Additionally, the pharmacodynamic evaluation conducted in a DMBA-induced pancreatic cancer model, involving histological examination, serum IL-6 level estimation, and expression of cleaved caspase-3, showed the potential of GEM-NPs in the management of pancreatic cancer. Consequently, the lipid NP-based approach developed in our investigation demonstrates high stability and uniformity and holds promise for enhancing the therapeutic outcomes of GEM.

Molecular Complex of HSIM-loaded Polymeric Nanoparticles: Potential Carriers in Osteoporosis.

BACKGROUND: Statins, especially simvastatin promote bone formation by stimulating the activity of osteoblasts and suppressing osteoclast activity via the BMP-Smad signaling pathway. Statins present the liver first-pass metabolism. This study attempts to fabricate and evaluate simvastatin functionalized hydroxyapatite encapsulated in poly(lactic-co-glycolic) acid (PLGA) nanoparticles (HSIM-PLGA NPs) administered subcutaneously with sustained release properties for effective management of osteoporosis. METHODS: Simvastatin functionalized hydroxyapatite (HSIM) was prepared by stirring and validated by docking studies, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and X-ray diffraction (XRD). Further, HSIM-loaded PLGA nanoparticles (HSIM-PLGA NPs) were developed via the solvent emulsification method. The nanoparticles were evaluated for zeta potential, particle size, entrapment efficiency, stability studies, and in vitro drug release studies. in vitro binding affinity of nanoparticles for hydroxyapatite was also measured. Bone morphology and its effect on bone mineral density were examined by using a glucocorticoid-induced osteoporosis rat model. RESULTS: The optimized nanoparticles were found to be amorphous and showed no drug-polymer interaction. The particle size of formulated nanoparticles varied from 196.8 ± 2.27nm to 524.8 ± 5.49 nm and the entrapment efficiency of nanoparticles varied from 41.9 ± 3.44% to 70.8 ± 4.46%, respectively. The nanoparticles showed sustained release behaviour (75% in 24 hr) of the drug followed by non-fickian drug release. The nanoparticles exhibited high binding affinity to bone cell receptors, increasing bone mineral density. A significant difference in calcium and phosphorous levels was observed in disease and treatment rats. Porous bone and significant improvement in porosity were observed in osteoporotic rats and treated rats, respectively (P < 0.05). CONCLUSION: Bone-targeting nanoparticles incorporating functionalized simvastatin can target bone. Thus, in order to distribute simvastatin subcutaneously for the treatment of osteoporosis, the developed nanoparticles may act as a promising approach.

Lipid- and TPGS-Based Core-Shell-Type Nanocapsules Endowed with High Paclitaxel Loading and Enhanced Anticancer Potential.

The current study elucidates the improved drug loading of paclitaxel (PTX) in lipid- and D-α-tocopheryl polyethylene glycol succinate (TPGS)-based core-shell-type lipid nanocapsules (PTX-TPGS-LNC) for augmenting the therapeutic efficacy and curbing the toxicity. PTX-TPGS-LNCs were formulated by employing anti-solvent precipitation technique and displayed a particle size of 162.1 ± 4.70 nm and % practical drug loading of 15.04 ± 2.44%. Electron microscopy revealed that PTX-TPGS-LNCs have spherical morphology and the inner core was surrounded by a relatively lighter region, i.e., layer of lipids and TPGS. The nature of loaded PTX inside the PTX-TPGS-LNC was also confirmed using DSC and PXRD analysis. The in vitro release study showed biphasic and sustained release pattern of PTX from PTX-TPGS-LNC and it showed ~ threefold higher PTX uptake in MCF-7 cell line in comparison to free PTX. Moreover, it was apparent from the cytotoxicity assay that PTX-TPGS-LNC displayed higher cytotoxicity in MCF-7 cells and revealed ~ 2.92-fold decrease in IC50 value as against free PTX when incubated for 72 h. The apoptotic index in case of PTX-TPGS-LNC was ~ twofold higher than free PTX. The pharmacokinetic profile of PTX-TPGS-LNC revealed a ~ 3.18-fold increase in t1/2 and a ~ 2.62-fold higher AUC(0→∞) compared to Intaxel®. Finally, treatment with PTX-TPGS-LNC demonstrated significant lowering in the % tumor burden and serum toxicity markers compared to marketed formulation Intaxel®. Thus, the lipid- and TPGS-based core-shell-type LNC with high PTX loading can advance the existing standards of therapy for overshadowing cancer.

Nanomaterials in Dentistry: Current Applications and Future Scope.

Nanotechnology utilizes the mechanics to control the size and morphology of the particles in the required nano range for accomplishing the intended purposes. There was a time when it was predominantly applied only to the fields of matter physics or chemical engineering, but with time, biological scientists recognized its vast benefits and explored the advantages in their respective fields. This extension of nanotechnology in the field of dentistry is termed 'Nanodentistry.' It is revolutionizing every aspect of dentistry. It consists of therapeutic and diagnostic tools and supportive aids to maintain oral hygiene with the help of nanomaterials. Research in nanodentistry is evolving holistically but slowly with the advanced finding of symbiotic use of novel polymers, natural polymers, metals, minerals, and drugs. These materials, in association with nanotechnology, further assist in exploring the usage of nano dental adducts in prosthodontic, regeneration, orthodontic, etc. Moreover, drug release cargo abilities of the nano dental adduct provide an extra edge to dentistry over their conventional counterparts. Nano dentistry has expanded to every single branch of dentistry. In the present review, we will present a holistic view of the recent advances in the field of nanodentistry. The later part of the review compiled the ethical and regulatory challenges in the commercialization of the nanodentistry. This review tracks the advancement in nano dentistry in different but important domains of dentistry.

Lipid and Biosurfactant Based Core-Shell-Type Nanocapsules Having High Drug Loading of Paclitaxel for Improved Breast Cancer Therapy.

The current investigation illustrates high drug loading of Paclitaxel (PTX) in lipid- and biosurfactant-based core-shell-type nanocapsules for improving therapeutic potential and reducing toxicity of PTX. The nanocapsules were prepared using the antisolvent precipitation technique having a particle size of 253.8 ± 15.4 nm and drug loading of ∼19%. The microscopic evaluation revealed the spherical shape of the nanocapsules and corroborated with the particle size obtained from Zetasizer. It also revealed the drug core enveloped by the relatively lighter shadowed region, that is, the layer of lipids and the biosurfactant. The in vitro release study showed biphasic and sustained release pattern of PTX from core-shell-type nanocapsules. In case of nanocapsules, the cellular uptake in the MCF-7 cell line was augmented ∼3.17-fold as compared to free PTX. Further, it was evident from the cytotoxicity assay that nanocapsules displayed greater cytotoxicity in MCF-7 cells and ∼2.98-fold decrease in the IC50 value as compared to free PTX. The apoptotic index observed in case of nanocapsules was ∼2.04-fold higher than that of free PTX. Furthermore, the pharmacokinetic profile of nanocapsules revealed a ∼7.21-fold increase in t1/2 and a ∼3.27-fold higher AUC(0→∞) compared to Intaxel. Finally, treatment with PTX core-shell-type nanocapsules demonstrated significant cutback in the % tumor burden and serum toxicity markers compared to marketed formulation. Thus, the current approach of core-shell-type nanocapsules with high drug loading can improve the current standards of PTX therapy for treatment of cancer.

Design and Toxicity Evaluation of Novel Fatty Acid-Amino Acid-Based Biocompatible Surfactants.

Surfactants occupy an important place owing to their wide application, but primarily compromised due to its toxicity issues. This raises the need for exploration of newer surfactants with increased biocompatibility. Novel fatty acid- and amino acid-based surfactants were prepared using standard carbodiimide chemistry. Pyrene assay was implemented to confirm the amphiphilic nature of the surfactants and to calculate their CMC (critical micellar concentration). In vitro hemolytic and cell culture study in MCF-7 and HEK cell line were done to check the in vitro biocompatibility of the developed surfactants in comparison to marketed surfactants Triton X-100 and Tween ® 80. In vivo biocompatibility test in female Swiss albino mice was carried out in comparison to marketed surfactants with respect to serum markers, organ histology, and RBC morphology. Surfactant synthesis provided more than 60% yield in all the conjugates. Pyrene assay concluded the amphiphilic nature of the surfactants with lowest CMC of 0.083% w/v in the case of stearic acid and valine conjugate. In vitro hemolytic and cell culture study depicted highest biocompatibility in vitro as compared to marketed surfactants. Similar results were obtained in in vivo biocompatibility with respect to AST (aspartate transaminase), ALT (alanine transaminase), BUN (blood urea nitrogen), and creatinine serum levels and histology of spleen, liver, and kidney in comparison to marketed surfactants Triton X-100 and Tween ® 80. The developed surfactant also depicted least RBC morphology changes in vivo. Stearic acid valine conjugate thus depicted potential for further application in formulation development replacing the commercially available surfactants.

Drug-Phospholipid Complex-a Go Through Strategy for Enhanced Oral Bioavailability.

Among many, the oral route of delivery is considered to be the most favorable route with the highest patient compliance. The main issue with oral delivery is the environmental vulnerability of gastro intestinal tract (G.I.T). The bioavailability could further decrease when drug has poor aqueous solubility and permeability through biological membrane. This drawback could be resolved by employing drug-phospholipid complex strategy, as they utilize mechanism which is similar to the absorption mechanism of nutritional constituents form G.I.T. The drug-phospholipid complexes are considered ideal for oral delivery as they are biodegradable and non-toxic, which enable them to be employed as solubilizer, emulsifier, and as a matrix forming excipient for dugs with poor solubility and/or permeability. The present review compiles the basic know how about the phospholipids and the mechanism through which it improves the bioavailability of drugs. Further, it also compiles the crucial formulation aspects and methods of preparations of drug-phospholipid complex along with its physical and in silico characterization techniques. The increase in number of recent reports involving the utilization of drug-phospholipid complex to improve oral bioavailability of drugs thus explains how vital the strategy is for a successful oral delivery.

Lipid and TPGS based novel core-shell type nanocapsular sustained release system of methotrexate for intravenous application.

Core shell nanocapsules present an interesting system for attaining high loading of drug. In an attempt, lipid and TPGS based novel core-shell nanocapsule were prepared to achieve high drug loading with sustained release of model hydrophilic drug methotrexate (MTX). Antisolvent nanoprecipitation was utilized for the formulation of nanoparticles. Optimized formulation depicted 223.6 ± 24.1 nm particle size, 0.243 ± 0.034 PDI, zeta potential -2.07 ± 0.51 mV and 15.03 ± 1.92%drug loading. In vitro release showed biphasic release for 12 h with initial burst phase followed by sustained release phase. Haemolytic study on RBCs revealed haemocompatible nature of MTX-TPGS nanoparticles compared to Biotrexate® (Zydus). In vitro cell culture studies depicted 3 folds and 2.66 folds increase in cellular uptake of MTX at 10 µg/ml and 15 µg/ml respectively for developed nanoparticles with 3.81 folds decrease in IC50 value as compared to Biotrexate®. Higher apoptosis and increased lysosomal membrane permeability were also depicted by MTX-TPGS nanoparticles. 2.45 folds increase in AUC and 3.68 folds increase in T1/2 was achieved in pharmacokinetic study. Significant reduction in tumor burden and serum biochemical parameters depicted efficacy and safety respectively of the formulation as compared to Biotrexate®. RBCs morphology was retained after MTX-TPGS exposure proving its haemocompatibility in vivo.

Novel biosurfactant and lipid core-shell type nanocapsular sustained release system for intravenous application of methotrexate.

In an attempt to prepare novel core shell nanocapsules, lipid and Stearic acid-Valine conjugate (Biosurfactant) based nanosystem was prepared to attain high drug loading of hydrophilic drug methotrexate (MTX), with sustained release. Antisolvent nanoprecipitation technique was employed for the formulation of nanoparticles (NPs). Optimized formulation depicted 209.6 ±â€¯31.3 nm particle size, 0.209 ±â€¯0.072 PDI and 14.98 ±â€¯1.33 %w/w drug loading. In vitro release depicted biphasic release for 12 h with initial burst phase followed by sustained release phase. In vitro Haemolytic study on RBCs revealed haemocompatible nature of MTX-Biosurfactant NPs compared to Biotrexate® (Zydus). In vitro cell culture studies showed 3.33 folds and 3.50 folds increase in cellular uptake of MTX at 10 µg/ml and 15 µg/ml concentration respectively for developed nanoparticles with 4.16 folds decrease in IC50 value. Higher apoptosis and increased lysosomal membrane permeability were obtained in MTX-Biosurfactants NPs. AUC and T1/2 was found to increase by 2.55 and 3.25 folds respectively in pharmacokinetic study. Significant reduction in tumor burden and serum toxicity marker level depicted efficacy and safety respectively of the formulation as compared to Biotrexate®. RBCs morphology was retained after MTX-Biosurfactants NPs exposure proving its haemocompatibility in vivo.

Co-delivery of docetaxel and gemcitabine by anacardic acid modified self-assembled albumin nanoparticles for effective breast cancer management.

In the present study, we have modified bovine serum albumin (BSA) by covalently conjugating with anacardic acid (AA) and gemcitabine (GEM) and further used for development of docetaxel (DTX) loaded nanoparticles (AA-GEM-BSA NPs). AA is supposed to provide tumor targeting through VEGF receptors overexpressed in tumors, while the combination of GEM and DTX is supposed to provide synergistic activity by targeting multiple pathways. The conjugate was synthesized via carbodiimide chemistry and characterized by 1H NMR, FTIR, MALDI-TOF and elemental analysis. Conformational changes owing to conjugation of AA and GEM were estimated via fluorescence, Raman and CD spectroscopy, while changes in physiochemical properties were studied by differential scanning calorimetry (DSC), thermogravimetry (TGA) and contact angle goniometry (CAG). Synthesized conjugate was further transformed into DTX loaded NPs and freeze dried. Scanning Electron Microscopy (SEM) and Atomic Force Microscopy (AFM) demonstrated formation of spherical NPs having particle size, 163 ±â€¯8 nm, PDI, 0.13 ±â€¯0.09 and ZP, -27 ±â€¯1 mV. Cellular uptake in MCF-7 and MDA-MB-231 revealed hNTs, OATP1B3 independent, clathrin mediated internalization followed via nuclear co-localization of C-6 loaded AA-GEM-BSA NPs, responsible for significantly higher apoptosis index. Pharmacokinetic profile of DTX loaded AA-GEM-BSA NPs revealed 6.12 and 3.27-fold and 6.28 and 8.9-fold higher AUC and T1/2 values of DTX and GEM as compared to Taxotere® and Gemzar®, respectively. Interestingly, the developed NPs were found safe with no marked effect on RBCs, lower hepato and nephro toxicity. Data in hand suggest promising potential of developed NPs in ameliorating the pharmacokinetic and therapeutic profile of combinatorial regimen of DTX and GEM. STATEMENT OF SIGNIFICANCE: The present report is the original state of art technology to selectively target dual drug (DTX and GEM) loaded BSA NPs via exploring tumor targeting potential of AA, having high affinity towards VEGF receptors (angiogenesis marker) overexpressed in tumor. The AA and GEM bio-conjugated BSA was synthesized and further used to develop DTX loaded nanoparticles (AA-GEM-BSA NPs). The optimized NPs were further evaluated via extensive in vitro and in vivo studies, demonstrating ameliorated cellular uptake, pharmacokinetic and toxicity profile of drugs. Conclusively, DTX loaded AA-GEM-BSA NPs, holds promising potential in increasing the therapeutic efficiency of drugs and overcoming solvent and drug mediated side effects and can be explored further as a scalable platform technology for difficult to deliver drugs.

Improved oral bioavailability and therapeutic efficacy of erlotinib through molecular complexation with phospholipid.

The current study was aimed to prepare a molecular complex of erlotinib (ERL) with phospholipid (PC) for enhancement of solubility and thus bioavailability, therapeutic efficacy and reducing the toxicity of erlotinib. Phospholipid complex of drug was prepared by solvent evaporation method and characterized by differential scanning calorimetry (DSC), Fourier transform infra-red spectroscopy (FT-IR), proton and phosphorus nuclear magnetic resonance spectroscopy (1H NMR and 31P NMR), powder X-ray diffraction (P-XRD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM), which all explained the interactions of two components, validating the complexation phenomenon. In silico study also supported the phase change and molecular interactions for the establishment of ERL-PC. Spherical shaped nanostructures with 183.37±28.61nm size, -19.52±6.94mV potential and 28.59±2.66% loading efficiency were formed following dispersion of ERL-PC in aqueous media. In vitro release study revealed the higher release of ERL-PC due to amorphization and solubilization of drug. Caco-2 cell uptake resulted in ∼2 fold higher uptake of ERL-PC than free drug. In vitro cell culture studies were performed using human pancreatic adenocarcinoma cell lines, which demonstrated the higher cytotoxicity and apoptosis in case of ERL-PC. In vivo pharmacokinetics also supported the in vitro observations and showed ∼1.7 fold higher bioavailability with ERL-PC than ERL. Finally, in vivo efficacy and toxicity studies explained the superiority of ERL-PC over the free drug. Based on the results, phospholipid complex appears to be a promising tool to enhance bioavailability, efficacy, cytotoxicity and safety of erlotinib.

Novel Gemcitabine Conjugated Albumin Nanoparticles: a Potential Strategy to Enhance Drug Efficacy in Pancreatic Cancer Treatment.

PURPOSE: The present study reports a novel conjugate of gemcitabine (GEM) with bovine serum albumin (BSA) and thereof nanoparticles (GEM-BSA NPs) to potentiate the therapeutic efficacy by altering physicochemical properties, improving cellular uptake and stability of GEM. METHODS: The synthesized GEM-BSA conjugate was extensively characterized by NMR, FTIR, MALDI-TOF and elemental analysis. Conjugation mediated changes in structural conformation and physicochemical properties were analysed by fluorescence, Raman and CD spectroscopy, DSC and contact angle analysis. Further, BSA nanoparticles were developed from BSA-GEM conjugate and extensively evaluated against in-vitro pancreatic cancer cell lines to explore cellular uptake pathways and therapeutic efficacy. RESULTS: Various characterization techniques confirmed covalent conjugation of GEM with BSA. GEM-BSA conjugate was then transformed into NPs via high pressure homogenization technique with particle size 147.2 ± 7.3, PDI 0.16 ± 0.06 and ZP -19.2 ± 1.4. The morphological analysis by SEM and AFM revealed the formation of smooth surface spherical nanoparticles. Cellular uptake studies in MIA PaCa-2 (GEM sensitive) and PANC-1 (GEM resistant) pancreatic cell lines confirmed energy dependent clathrin internalization/endocytosis as a primary mechanism of NPs uptake. In-vitro cytotoxicity studies confirmed the hNTs independent transport of GEM in MIA PaCa-2 and PANC-1 cells. Moreover, DNA damage and annexin-V assay revealed significantly higher apoptosis level in case of cells treated with GEM-BSA NPs as compared to free GEM. CONCLUSIONS: GEM-BSA NPs were found to potentiate the therapeutic efficacy by altering physicochemical properties, improving cellular uptake and stability of GEM and thus demonstrated promising therapeutic potential over free drug. Graphical Abstract ᅟ.

Improved metabolic stability and therapeutic efficacy of a novel molecular gemcitabine phospholipid complex.

The aim of the present research is to increase lipid solubility, metabolic stability and therapeutic efficacy of water soluble gemcitabine (GEM) via phospholipid complex (PC) formation. A novel phospholipid complex of GEM was successfully prepared and optimized. Physical interaction of GEM with phospholipid was evaluated by DSC, FT-IR, 1H NMR, 31P-NMR and P-XRD. SEM images of GEM-PC showed rough structure and TEM images of diluted aqueous dispersion of GEM-PC showed micellar structure. In silico study also revealed the significant interaction between drug and phospholipid. GEM-PC demonstrated sustained drug release pattern and high plasma stability (∼2.2 fold) in vitro as compared to GEM. Increased in vitro cytotoxicity and apoptosis were observed with GEM-PC, when incubated with human pancreas adenocarcinoma cell lines. In vivo pharmacokinetics showed the almost 2 fold increase in AUC0-∞ (area under curve) with phospholipid complex (8983.26ngh/ml) as compared with GEM (4371.18ngh/ml) and GEMITA (4689.29ngh/ml). Toxicity studies signify the safety of GEM-PC over GEMITA. Pharmacodynamics studies in pancreatic tumor model further revealed higher efficacy of GEM-PC than GEMITA. These findings suggested the higher potential of phospholipid based technology for the enhancement of metabolic stability and therapeutic efficacy of GEM.

Nanostructured lipid carriers of olmesartan medoxomil with enhanced oral bioavailability.

The current study explores the potential of nanostructured lipid carriers (NLCs) for oral bioavailability enhancement of olmesartan medoxomil (OLM) by systemic design approach. OLM-NLC was successfully prepared with optimized process parameters (i.e. amount of liquid lipid, total amount of lipid, drug content and surfactant concentration) using the Box-Behnken design of experiments for different response parameters (i.e. particle size, Polydispersity index and entrapment efficiency). Further, optimized formulation was validated which depicted nano size, homogenous distribution with optimum entrapment efficiency. OLM-NLC was characterized by different techniques viz. differential scanning calorimetry (DSC), powder X-Ray diffraction (PXRD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM), which showed reduced crystallinity of the drug with smooth spherical appearance of nanoparticles. Formulation was found to be stable in simulated gastric fluids as no significant changes were found in size, PDI and entrapment efficiency. In vitro release showed extended release of OLM from OLM-NLC. In vitro cellular uptake study revealed 5.2 folds higher uptake of nanoparticles as compare to the free drug, when incubated with Caco-2 cells. In vivo performance showed that AUCtotal and Cmax of OLM-NLC were found significantly (P<0.01) higher as compare to the free drug. Overall, the present study successfully reports the improvement of oral bioavailability of olmesartan medoxomil.

α-Tocopherol as functional excipient for resveratrol and coenzyme Q10-loaded SNEDDS for improved bioavailability and prophylaxis of breast cancer.

The present study evaluates the prophylactic efficacy of α-tocopherol (α-TOH), resveratrol (RES), and coenzyme Q10 (CoQ10) co-loaded self-nanoemulsifying drug delivery system (α-TOH-RES-CoQ10 SNEDDS) in 7,12-Dimethylbenz[a]anthracene (DMBA) induced breast cancer model. SNEDDS formulation components were rationally selected and optimized for maximum drug loading by applying the design of experiments and further evaluated for stability in simulated gastrointestinal fluids, functional stability of antioxidants, in vitro release, Caco-2 cell uptake, oral bioavailability and prophylactic anticancer activity. The SNEDDS demonstrated excellent stability in stimulated gastrointestinal fluids. The functional activity of antioxidants was confirmed by 2,2-diphenylpicrylhydrazyl (DPPH) scavenging assay wherein significantly (p > .05) higher antioxidant activity was observed in case of SNEDDS as compared with free antioxidants. Coumarin 6 (C-6)-loaded SNEDDS formulation demonstrated remarkably higher Caco-2 cell uptake in comparison with free C-6, indicative of efficient internalization of sub-micron SNEDDS droplets by Caco-2 cells. In line with Caco-2 cell uptake observations, α-TOH-RES-CoQ10-SNEDDS showed ∼2.30- and ∼3.64-fold increase in the AUC0-∞ values of RES and CoQ10 in comparison with free antioxidants. Significantly lower (p < .001) tumor volume (∼327 mm3) was found in case of animals treated with α-TOH-RES-CoQ10-SNEDDS in comparison with free antioxidant combination (∼1070 mm3) and DMBA control (∼1540 mm3) groups. Conclusively, the proposed strategy posed great potential in improving the prophylactic activity of antioxidants and hold promise for further exploration.

Formulation, optimization, and in vitro-in vivo evaluation of olmesartan medoxomil nanocrystals.

The aim of the present study is to increase the saturation solubility and oral bioavailability of olmesartan medoxomil (OLM) using nano-sized crystals produced using a combination of antisolvent precipitation and high-shear homogenization. A response surface design comprising 46 runs was used to optimize the OLM nanocrystal formulation. The optimized formulation was produced using a combination of D-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS) (0.7% w/v), Pluronic F-68® (0.5% w/v), and drug concentration (0.2% w/v) and subjected to 10 and 15 homogenization cycles at 1000 and 1700 bar, respectively. The particle size, polydispersity index (PDI), and zeta potential of optimized formulation were found to be 140 ± 10.34 nm, 0.07 ± 0.016, and -21.43 ± 2.33 mV, respectively. The optimized formulation exhibited irregular morphology as evaluated by scanning electron microscopy and was crystalline as determined by thermal analysis and powder X-ray diffraction studies. OLM nanocrystals showed a marked increase in the saturation solubility as well as rapid dissolution rate in comparison with the pure drug. No significant change in the particle size, PDI, and zeta potential was observed when optimized formulation was stored at room and refrigeration conditions for 3 months. Lastly, in vivo pharmacokinetic studies in Sprague-Dawley rats substantiate the ability of OLM nanocrystal formulation to significantly improve (∼4.6-fold) the oral bioavailability of OLM in comparison with the free drug. This study has established a potential and commercial viable OLM formulation with enhanced saturation solubility and in vivo oral bioavailability.

Development of Novel Polymer-Lipid Hybrid Nanoparticles of Tamoxifen: In Vitro and In Vivo Evaluation.

This study was undertaken to develop and investigate the effect of tamoxifen polymer-lipid hybrid nanoparticles (Tmx-PLN) on its oral bioavailability and efficacy in the 7,12-dimethylbenzanthracene (DMBA)-induced breast cancer model. Modified solvent emulsification-evaporation method was optimized to obtain Tmx-PLN, composed of chitosan and lecithin, of 169.66 ± 4.84 nm particle size. The PLN exhibited prolonged in vitro release in phosphate-buffered saline. Further, PLN displayed enhanced oral bioavailability with considerable increase in AUC (1277.46 vs. 585.01 ng/ml · h), pro- longed t½ (27.87 ± 15.62 vs. 10.18 ± 6.5 h) and mean residence time (40.11 ± 25.72 vs. 17.42 ± 12.04 h) in comparison to pure Tmx. In addition, PLN exhibited significantly increased (P < 0.05) antitumor efficacy in DMBA-induced breast cancer model, when administered once in three days in comparison to Tmx daily dosing. This enhancement may be attributed to a probable reduction in Pgp efflux, decreased first-pass metabolism and lymphatic drug transport. Thus, Tmx-PLN exhibited enhanced potential to increase Tmx therapeutic efficacy in chronic treatment of breast cancer.

Potential of erlotinib cyclodextrin nanosponge complex to enhance solubility, dissolution rate, in vitro cytotoxicity and oral bioavailability.

The present study was envisaged to evaluate the effect of erlotinib ß-cyclodextrin nanosponge (ERL-NS) on the solubility, dissolution, in vitro cytotoxicity and oral bioavailability of erlotinib (ERL). Preliminary studies were conducted to select the optimized stoichiometry concentration of ERL and NS. The drug nanosponge complex comprising of 1:4 proportions of ERL and NS was prepared by freeze drying. ERL-NS formed nanoparticles of 372 ± 31 nm size with narrow size distribution (0.21 ± 0.07 PDI) and high zeta potential (-32.07 ± 4.58 mV). The complexation phenomenon was confirmed by DSC, SEM, PXRD, FTIR, and TEM studies. In vitro dissolution studies revealed an increased dissolution rate (2-folds) with an enhanced dissolution efficiency of the nanosponge complex in comparison to pure drug. In vitro cytotoxicity study and apoptosis assay in pancreatic cell lines (MIA PaCa-2 and PANC-1) indicates the increased toxicity of ERL-NS. Both, quantitative and qualitative cell uptake studies unveiled the higher uptake efficiency of ERL-NS than free drug. ERL-NS showed enhanced oral bioavailability with 1.8-fold higher Cmax (78.98 ± 6.2 vs. 42.36 ± 1.75 µg/ml), and ∼ 2-fold AUC0-∞ (1079.95 ± 41.38 vs. 580.43 ± 71.91), in comparison to pure ERL. Therefore, we conclude that the formation of a complex of nanosponge with ERL is a successful approach to increase its solubility, dissolution and oral bioavailability which may ultimately result in reduction in dose and dose related side-effects.

A novel nanogel formulation of methotrexate for topical treatment of psoriasis: optimization, in vitro and in vivo evaluation.

CONTEXT: Although several formulation strategies have been developed for the treatment of psoriasis, there is an unmet need for optimization of its therapy. OBJECTIVE: The objective was to develop a nanogel composed of methotrexate (MTX)-loaded nanostructured lipid carrier (MTX-NLC) and to evaluate its potential in imiquimod-induced psoriasis model to ameliorate symptoms of psoriasis. MATERIALS AND METHODS: MTX-NLC nanogel was prepared by hot-homogenization method and optimized by Design of Experiments. Particle size, polydispersity index (PDI) and entrapment efficiency were selected as the critical quality attributes. Antipsoriatic potential of MTX-NLC nanogel was evaluated by Psoriatic Area and Severity Index (PASI) score and histopathological examination in the imiquimod-induced psoriasis model. RESULTS AND DISCUSSION: Optimized MTX-NLC exhibited particle size of 278 ± 10 nm, PDI of 0.231 ± 0.05 and EE of 22.29 ± 1.23%. At the end of 48 h, MTX-NLC gel exhibited slow and prolonged release of MTX (47.32 ± 0.94% versus 94.23 ± 0.79%) compared to MTX gel. Furthermore, it significantly reduced the PASI score with recovery of normalcy of the mice's skin, while the MTX gel exhibited signs of hyper and parakeratosis at the end of the study. CONCLUSION: The developed MTX-NLC gel formulation can be a promising alternative to existing MTX formulation in treating psoriasis.