Piroxicam loaded polymer hybrid microspheres based tablets with modified release kinetics: Development, characterization and in vivo evaluation.

Piroxicam (PC) is a non-steroidal anti-inflammatory drug characterized by poor aqueous solubility and reported to cause and impart crucial GIT irritation, bleeding, peptic and duodenal ulcer. Engineering of PC loaded microcapsules and its surface modification using different polymers has become the popular approach to address the said issues. The purpose of the study was to develop new PC loaded gastro-protective polymer hybrid microspheres (PHM) with subsequent conversion to tablet dosage form having modified dissolution rate and improved bioavailability. The crystallinity of the PC loaded PHM were established through powder X-ray diffraction. The optimised microspheres, PC-M1 with particle size 32±3.0µm, entrapment efficiency 83.78±2.5% and in vitro drug release 87.1±2.6% were further subjected to tablets development and in vivo evaluation. The in vitro drug release study conducted for PHM at pH media 1.2 and 6.8 demonstrated retarded and enhanced drug release rates (P<0.001) respectively. Both accelerated and real time stability studies confirmed stability of the PC loaded PHM based tablets. A substantial improvement in the drug plasma concentration 12.6±2.36 (P<0.001) was observed for the produced tablets compared to the marketed formulations.

Creatinine-based non-phospholipid vesicular carrier for improved oral bioavailability of Azithromycin.

CONTEXT: Novel, safe, efficient and cost effective nano-carriers from renewable resources have got greater interest for enhancing solubility and bioavailability of hydrophobic dugs. OBJECTIVES: This study reports the synthesis of a novel biocompatible non-phospholipid human metabolite "Creatinine" based niosomal delivery system for Azithromycin improved oral bioavailability. METHODS: Synthesized surfactant was characterized through spectroscopic and spectrometric techniques and then the potential for niosomal vesicle formation was evaluated using Azithromycin as model drug. Drug loaded vesicles were characterized for size, polydispersity index (PDI), shape, drug encapsulation efficiency (EE), in vitro release and drug-excipient interaction using zetasizer, atomic force microscope (AFM), LC-MS/MS and FTIR. The biocompatibility of surfactant was investigated through cells cytotoxicity, blood hemolysis and acute toxicity. Azithromycin encapsulated in niosomes was investigated for in vivo bioavailability in rabbits. RESULTS: The vesicles were spherical with 247 ± 4.67 nm diameter hosting 73.29 ± 3.51% of the drug. Surfactant was nontoxic against cell cultures and caused 5.80 ± 0.51% hemolysis at 1000 µg/mL. It was also found safe in mice up to 2.5 g/kg body weight. Synthesized surfactant based niosomal vesicles revealed enhanced oral bioavailability of Azithromycin in rabbits. CONCLUSIONS: The results of the present study confirm that the novel surfactant is highly biocompatible and the niosomal vesicles can be efficiently used for improving the oral bioavailability of poor water soluble drugs.

Evaluation of analgesic, antiamnesic and antidiarrheal potentials of Medicago denticulata extract using animal model.

The analgesic, antidiarrheal, and neuro-pharmacological potentials of Medicago denticulata leaves extract were screened in animal models. Potential analgesic response was noted (*P < 0.05, **P < 0.01, ***P < 0.001) in formalin, acetic acid and heat-induced pain models in a dose-dependent manner. Maximum activity by means of writhing inhibition was documented for Medicago denticulata at 300 mg/kg that was found to be 71.79% (17.43 ± 1.31). In first phase, the Medicago denticulata at a dose of 150 and 300 mg/kg showed analgesic activity and reduced the pain by 54.18% (18.39 ± 1.67) and 62.90% (14.89 ± 1.56), respectively. In second phase, the Medicago denticulata at a dose of 150 and 300 mg/kg showed analgesic activity and reduced the pain by 69.48% (19.78 ± 1.44) and 70.89% (18.86 ± 1.58), respectively. In hot plate method, the Medicago denticulata at a dose of 150 and 300 mg/kg showed the maximum response of 61.16% (8.47 ± 1.23) and 67.39% (10.09 ± 1.04), respectively at 60 min. Scopolamine significantly reduces spontaneous alteration in Y-maze model for antiamnesic activity. Medicago denticulata significantly increased the discrimination index in a dose-dependent manner using novel object recognition test (NORT) model. Exploration time in sec for the novel object was increased significantly (P < 0.001) by donepezil decreased for familiar one with a discrimination index (DI) of 62.18%. Medicago denticulata significantly increased the discrimination index by 60.86% and 57.24% at 300 and 150 mg/kg b.w, respectively. The lowest DI of 53.80% at 75 mg/kg was observed in comparison to the amnesic group. The Medicago denticulata significant decreased the elevated levels of acetylcholinesterase (AChE) and malondialdehyde (MDA and enhancing level of acetylcholine (ACh), superoxide dismutase (SOD) and catalase (CAT) acting as an antioxidant agent. Medicago denticulata reduced the total number of diarrheal feces to lesser extent at dose-dependent manner. From the study results, it is suggested that the Medicago denticulata extract possess good analgesic and antiamnesic activity however the antidiarrheal effects of plant were negligible. In the current study, the traditional use of the plant as a source of medicine has been validated.

PEGylation: a promising strategy to overcome challenges to cancer-targeted nanomedicines: a review of challenges to clinical transition and promising resolution.

On account of heterogeneity, intrinsic ability of drug resistance, and the potential to invade to other parts of the body (malignancy), the development of a rational anticancer regimen is dynamically challenging. Chemotherapy is considered the gold standard for eradication of malignancy and mitigation of its reoccurrence; nevertheless, it has also been associated with detrimental effects to normal tissues owing to its nonselectivity and nominal penetration into the tumor tissues. In recent decades, nanotechnology-guided interventions have been well-acclaimed due to their ability to facilitate target-specific delivery of drugs, avoidance of nontarget distribution, alleviated systemic toxicity, and maximized drug internalization into cancer cells. Despite their numerous biomedical advantages, clinical translation of nanotechnology-mediated regimens is challenging due to their short plasma half-life and early clearance. PEGylation of nanomedicines has been adapted as an efficient strategy to extend plasma half-life and diminished early plasma clearance via alleviating the opsonization (uptake by monocytes and macrophages) of drug nanocarriers. PEGylation provides "stealth" properties to nanocarrier's surfaces which diminished their recognition or uptake by cellular immune system, leading to longer circulation time, reduced dosage and frequency, and superior site-selective delivery of drugs. Therefore, this review aims to present a comprehensive overview of the pharmaceutical advantages and therapeutic feasibility of PEGylation of nanocarriers in improving tumor-specific targetability, reversing drug resistance, and improving pharmacokinetic profile of drugs and anticancer efficacy. Challenges to PEGylated cancer nanomedicines, possible adaptations to resolve those challenges, and pivotal requirement for interdisciplinary research for development of rational anticancer regimen have also been pondered.

Domperidone nanocrystals with boosted oral bioavailability: fabrication, evaluation and molecular insight into the polymer-domperidone nanocrystal interaction.

The aim of this study was to employ experimental and molecular modelling approaches to use molecular level interactions to rationalise the selection of suitable polymers for use in the production of stable domperidone (DOMP) nanocrystals with enhanced bioavailability. A low-energy antisolvent precipitation method was used for the preparation and screening of polymers for stable nanocrystals of DOMP. Ethyl cellulose was found to be very efficient in producing stable DOMP nanocrystals with particle size of 130 ± 3 nm. Moreover, the combination of hydroxypropyl methylcellulose and polyvinyl alcohol was also shown to be better in producing DOMP nanocrystals with smaller particle size (200 ± 3.5 nm). DOMP nanosuspension stored at 2-8 °C and at room temperature (25 °C) exhibited better stability compared to the samples stored at 40 °C. Crystallinity of the unprocessed and processed DOMP was monitored by differential scanning calorimetry and powder X-ray diffraction. DOMP nanocrystals gave enhanced dissolution rate compared to the unprocessed drug substance. DOMP nanocrystals at a dose of 10 mg/kg in rats showed enhanced bioavailability compared to the raw drug substance and marketed formulation. A significant increase in plasma concentration of 2.6 µg/mL with a significant decrease in time (1 h) to reach maximum plasma concentration was observed for DOMP nanocrystals compared to the raw DOMP. Molecular modelling studies provided underpinning knowledge at the molecular level of the DOMP-polymer nanocrystal interactions and substantiated the experimental studies. This included an understanding of the impact of polymers on the size of nanocrystals and their associated stability characteristics.

Hydrophilically modified self-assembling α-tocopherol derivative as niosomal nanocarrier for improving clarithromycin oral bioavailability.

Synthesis of biocompatible and cost-effective novel nonionic surfactants from renewable resources has been the subject of greater scientific interest for enhancing the bioavailability of less water-soluble drugs. The present study focuses on the synthesis of α-tocopherol-based novel biocompatible nonionic surfactant and its evaluation for forming clarithromycin-loaded niosomal drug delivery system. α-tocopherol was hydrophilically modified through multistep reactions and characterized using mass and 1H NMR spectroscopic techniques. Drug-loaded niosomal vesicles were investigated for entrapment efficiency (%EE), size, polydispersity index (PDI), zeta potential (ζ) and morphology using LC-MS, dynamic light scattering (DLS) and atomic force microscopy (AFM). Blood haemolysis, cell culture and acute toxicity tests were performed to investigate its biocompatibility. In vivo oral bioavailability of clarithromycin loaded in niosomal formulation was studied in rabbits. The vesicles were spherical in shape and entrapped up to 75 ± 2.57% of the drug. They exhibited a homogeneous size distribution with a mean diameter of 245 ± 4.66 nm. The surfactant was quite haemocompatible, low cytotoxic and safe in mice. Improved oral bioavailability of clarithromycin was achieved when carried in α-tocopherol-based niosomes. Results obtained showed that the synthesized amphiphile is biocompatible and has excellent capability for formation of niosomal vesicles and enhancing oral bioavailability of less water-soluble drugs like clarithromycin.

Development of a biocompatible creatinine-based niosomal delivery system for enhanced oral bioavailability of clarithromycin.

CONTEXT: Nonionic surfactant vesicles have gained increasing scientific attention for hydrophobic drugs delivery due to their biocompatibility, stability and low cost. OBJECTIVE: The aim of the present study was to synthesize and evaluate a novel creatinine-based nonionic surfactant in terms of its ability to generate biocompatible niosomal system for the delivery of Clarithromycin. MATERIALS AND METHODS: The surfactant was synthesized by reacting creatinine with lauroyl chloride followed by characterization using 1HNMR and MS. The drug-loaded niosomal vesicles of the surfactant were characterized for drug encapsulation efficiency (EE) using LC-MS, vesicle size using dynamic light scattering (DLS) and vesicle shape using atomic force microscopy (AFM). The surfactant was also investigated for blood hemolysis, in vitro cytotoxicity against different cell lines and in vivo acute toxicity in mice. Furthermore, the in vivo bioavailability of Clarithromycin encapsulated in the novel niosomal formulation was investigated using rabbits and quantified through validated LC-MS/MS method. RESULTS AND DISCUSSION: Findings showed that vesicles were able to entrap up to 67.82 ± 1.27% of the drug, and were rounded in shape with a size around 202.73 ± 5.30 nm and low polydispersity. The surfactant caused negligible blood hemolysis, very low cytotoxicity and was found to be safe up to 2500 mg/kg body weight using mice. The niosomal formulation showed twofold enhanced oral bioavailability of Clarithromycin as compared to commercial formulations of the drug. CONCLUSION: The study has shown that the creatinine-based niosomes developed in our laboratory were biocompatible, safe and increased the oral bioavailability of the model hydrophobic Clarithromycin using experimental animals.