Quercetin-Loaded Nanostructured Lipid Carrier In Situ Gel for Brain Targeting Through Intranasal Route: Formulation, In Vivo Pharmacokinetic and Pharmacodynamic Studies.

Quercetin (QT) shows potential for protecting against neurodegenerative diseases like Alzheimer's. However, its limited bioavailability and instability in physiological pH hinder its clinical use. The purpose of this work is to construct QT-filled nanostructured lipid carriers (QT-NLC) intranasal in situ gel to enhance pharmacokinetic and pharmacodynamic performance. NLCs were developed using a melt emulsification-high-pressure homogenization and were optimized using design expert software with the Box-Behnken design. NLCs were then incorporated into an in situ gel based on Lutrol F127 and further characterized. The pharmacodynamics of the formulation was evaluated in neurodegeneration induced by trimethyl tin (TMT) Wistar rats. The optimized QT in situ gel had spherical shape, entrapment efficiency of 96.1 ± 4.40%, and in vitro drug release of 83.74 ± 1.40%. The mean particle size was 123.3 ± 5.46 nm. After intranasal administration, in vivo single-dose pharmacokinetic studies demonstrated a significant therapeutic concentration of drug in CNS, having Cmax 183.41 ± 11.76 ng/mL and Tmax of 2 h. The more brain targeting efficiency of NLCs was proved by the developed QT in situ gel, which had a higher drug targeting efficiency (DTE) of 117.47% and drug targeting potential (DTP) of 88.9%. As compared to the neurodegeneration control group, the QT in situ gel-treated group had significantly decreased escape latency and pathlength. Biochemical analysis and histological investigations demonstrated that QT in situ gel exhibited superior anti-Alzheimer's potential compared to standard drug, donepezil. The promising results of the developed and optimized intranasal QT in situ gel suggest its potential and can be used in Alzheimer's disease management.

Stepping into small shoes: Gaining user perspective on appropriate administration devices for paediatric medication in India.

A cross sectional pan-India study about use of administration devices for paediatric oral and inhalation medicines was conducted with a diverse pool of participants of various age groups. Via 634 respondents from more than 15 states in India, this study has identified the administration devices commonly used by parents/caregivers for children 0 to 18 years and by children over 10 years. It has provided insights on device ease of use, challenges faced and recommendations to facilitate the correct use of administration devices for paediatric oral and inhalation medicines. Ethics approval (DPSRU-BREC/2020/A/008)) was obtained from the Biomedical Research Ethics Committee of Delhi Pharmaceutical Sciences and Research University. The survey was completed by parents only (n = 514) and jointly by both parents and children (n = 120). The mean age of the child was 7.2 ± 4.96 years. 72% of the respondents reported that an oral medicine had been taken recently, 6.3% reported that an inhaled medicine had been taken and the remaining 21.9% reported that both an oral and inhaled medicine had been taken. The use of measuring cup was most prevalent followed by household spoons. The mean of the score for ease of use was found to be highest 4.6 ± 0.50 for oral syringe and lowest (3.8 ± 0.76) for measuring cups. The majority of them found the oral device easy to use. Difficulties were reported mostly for measuring cups and household spoons and were related to a lack of user instructions and measuring difficulties. The respondents who found the device easy to use had mostly received clear instructions from healthcare professionals. Compared to oral devices, there were very limited responses for inhalation devices (n = 175/634). Nebulisers with facemasks were most frequently used followed by manually actuated Metered dose inhalers with and without spacer. The mean of the ease-of-use score for dry powder inhalers was found to be highest (4.2 ± 0.37) followed by mist inhalers (4.0 ± 0) and manually actuated pressurised metered dose inhalers (4.0 ± 0.71). The nebulisers with facemask were reported to be difficult to use by most of the respondents despite receiving clear instructions from healthcare professionals. The study findings add evidence to the understudied area of user experiences and perspectives on administration devices for oral and inhalation medicines in India. It highlights a need for initiatives to improve the usability, availability, and affordability of administration devices for children in India. Awareness on the importance of proper use of devices needs to be raised and sustained about the existence of affordable administration devices.

Buccal spray of standardized Berberis aristata extract causes tumour regression, chemoprotection and downregulation of inflammatory mediators in oral cancer hamster model.

ETHNOPHARMACOLOGICAL RELEVANCE: Berberis aristata (BA) has been described in Ayurveda in formulations for treating conditions related to the buccal cavity, including tumours and inflammation. Oral cancer (OC) is a major global health problem with high rates of recurrence and metastasis. Natural product based therapies are being explored as safer therapeutic strategies for OC. AIM OF THE STUDY: Evaluating the potential of standardized BA extract loaded buccal spray formulation in OC. MATERIAL AND METHODS: BA stem bark extract was prepared using sonication and standardized with respect to Berberine. The standardized extract was characterized and formulated as a buccal spray (SBAE-BS) using hydroxyl propyl methyl cellulose K15M, polyethylglycol 400, Miglyol®812N and ethanol. The SBAE-BS was characterized and evaluated in vitro in KB cell line and in vivo in OC hamster model. RESULTS: The SBAE-BS had pH, viscosity, mucoadhesive strength and BBR content corresponding to 6.8, 25.9 cP, 345 dyne/cm2 and 0.6 mg/mL respectively. In vitro cytotoxicity of SBAE-BS was comparable to 5 fluorouracil (5FU). In hamsters, SBAE-BS treatment lead to tumour regression (p = 0.0345), improved body weights (p < 0.0001), no organ toxicity, downregulation of inflammatory mediators and improved survival outcomes as compared to standard systemic 5FU. CONCLUSION: Thus, SBAE-BS showed cytotoxic and chemo-protective effects in the OC hamster model, evidencing its ethnopharmacological use and demonstrating translational potential to be developed as therapy for OC.

Exosomes as New Generation Vehicles for Drug Delivery: Biomedical Applications and Future Perspectives.

Currently, particular interest among the scientific community is focused on exploring the use of exosomes for several pharmaceutical and biomedical applications. This is due to the identification of the role of exosomes as an excellent intercellular communicator by delivering the requisite cargo comprising of functional proteins, metabolites and nucleic acids. Exosomes are the smallest extracellular vesicles (EV) with sizes ranging from 30-100 nm and are derived from endosomes. Exosomes have similar surface morphology to cells and act as a signal transduction channel between cells. They encompass different biomolecules, such as proteins, nucleic acids and lipids, thus rendering them naturally as an attractive drug delivery vehicle. Like the other advanced drug delivery systems, such as polymeric nanoparticles and liposomes to encapsulate drug substances, exosomes also gained much attention in enhancing therapeutic activity. Exosomes present many advantages, such as compatibility with living tissues, low toxicity, extended blood circulation, capability to pass contents from one cell to another, non-immunogenic and special targeting of various cells, making them an excellent therapeutic carrier. Exosome-based molecules for drug delivery are still in the early stages of research and clinical trials. The problems and clinical transition issues related to exosome-based drugs need to be overcome using advanced tools for better understanding and systemic evaluation of exosomes. In this current review, we summarize the most up-to-date knowledge about the complex biological journey of exosomes from biogenesis and secretion, isolation techniques, characterization, loading methods, pharmaceutical and therapeutic applications, challenges and future perspectives of exosomes.

Risk Assessment and QbD-Based Optimization of Sorafenib Tosylate Colon Targeted Bilayer Tablet: In Vitro Characterization, In Vivo Pharmacokinetic, and In Vivo Roentgenography Studies.

The employment of site-specific administration in colon is a promising technique to improve efficacy and reduce systemic side effects of anticancer medications used in colorectal cancer. However, the physiology of the gastrointestinal tract and colonic environment limit the efficient delivery of orally administered anticancer drugs to the colon. These prerequisites can be fulfilled by a release modulated colon targeted drug delivery system (CTDDS) based on pH-dependent chronotherapeutic bilayer tablet of sorafenib tosylate (ST). Quality by design (QbD) was used to examine the risk assessment. The Box-Behnken design was used to optimize the core uncoated bilayer tablet, whereas the 22 factorial design was used to optimize the coating process. The amount of croscarmellose sodium, Eudragit® RLPO, and tablet hardness all had a significant impact on disintegration time and drug release, according to the results of the core uncoated bilayer optimization. The amount of Eudragit® S 100 and PEG 400 in the final coated tablet had a considerable impact on drug release. The optimized formulation demonstrated 5-h lag time, a peculiar feature of CTDDS. The pharmacokinetic studies of coated tablet in rabbits showed lower Cmax (4.45 ± 0.40 µg/mL) and AUC (148.52 ± 3.96 h µg/mL), whereas Tmax was substantially delayed (8.0 ± 0.57 h) compared to core uncoated tablet. The tablet remained intact until it reached the colon (> 4 h), according to the in vivo roentgenography studies. The present study revealed that a QbD approach can be useful to develop a rugged and scalable CTDDS.

QbD-based optimization of raloxifene-loaded cubosomal formulation for transdemal delivery: ex vivo permeability and in vivo pharmacokinetic studies.

Raloxifene (RLX) is a drug that is commonly recommended to postmenopausal women at high risk of invasive breast cancer and to prevent osteoporosis. However, limited water solubility (0.000512 mg/ml) and low oral bioavailability (2%) of RLX limit its therapeutic utility. The objective of the present study was to develop an alternative transdermal delivery of RLX to improve its absorption, bypass first pass metabolism, and subsequently improve bioavailability. RLX-loaded cubosomes were prepared using the ethanol injection method followed by microfluidization technique and optimized using the QbD-based 23 factorial design. The average particle size, entrapment efficiency, and zeta potential of the optimized formulation were found to be 110.6 nm, 98.23%, and 26.2 mV, respectively. In vitro dissolution study indicated that the RLX-loaded cubosomes released 98.26% of the drug compared to pure RLX dispersion (58.6%). Histopathological examination revealed no sign of inflammation, indicating the safety of the developed formulation. Accelerated stability study as per ICH guidelines displayed no significant change in the formulation characteristics and drug-related performance of the developed formulation. Ex vivo permeability studies demonstrated a prolonged release from cubosomal formulation. In vivo pharmacokinetic studies revealed that the relative bioavailability of the optimized transdermal RLX-loaded cubosomes increased by 2.33-fold and 1.22-fold when compared with the oral RLX dispersion and transdermal RLX hydro-ethanolic solution respectively. IVIVC showed level C correlation with linear regression. Thus, the developed RLX-loaded cubosomes may have potential to overcome the problems associated with the existing marketed oral dosage forms of RLX.

Acceptability of different oral dosage forms in paediatric patients in hospital setting.

OBJECTIVE: The understanding of acceptability of existing dosage forms is limited in most of the world and hinders the development of acceptable, age-appropriate medicines. The attributes of paediatric medicine acceptability may differ from country to country based on culture, healthcare infrastructure and health policies. This study was designed to map the acceptability of oral medicines in paediatric patients treated in hospital in India. METHODS: An observational, cross-sectional study was conducted in patients aged below 18 years and taking any form of oral medication. Acceptability scores were obtained using CAST-ClinSearch Acceptability Score Test tool. FINDINGS: 490 patients were recruited and 193 evaluations of different pharmaceutical products available in 20 dosage forms and 7 routes of administration were studied. Oral liquids (50%) and tablets (35%) were the most commonly prescribed and administered forms. Regardless of the therapeutic class and age, the oral liquids were 'positively accepted' in infants and toddlers. Acceptability of tablets improved with age and appeared to be generally good from the age of 6. CONCLUSION: This study indicates the limited progress towards adoption of age-appropriate dosage forms in India and thus impact on the acceptability of existing oral dosage forms. The key challenges posed by the adoption of age-appropriate formulations in India are (1) awareness of importance of appropriate administration and acceptability of medicines to children in India, (2) availability of age-appropriate dosage forms and (3) lack of child-appropriate medicine policies.

Optimization of Diltiazem hydrochloride osmotic formulation using QBD approach

Abstract Diltiazem hydrochloride (DLH) is a calcium channel blocker useful for the treatment of angina pectoris, arrhythmia, and hypertension. DLH having a short half-life needs frequent administration for successful treatment but this poses a problem of poor patient compliance. These requirements are served by elementary osmotic pump tablets (EOP) based controlled-release (CR) systems. Quality by design (QbD) approach assists in screening various factors with subsequent assessment of critical parameters that can have a major impact on the scalability of EOP. Tablets were formulated using wet granulation method followed by osmotic coating. Factorial design based QbD strategy aided in defining the risk assessment of influential variables such as hydrophilic polymers and osmotic coat component on the in-vitro release kinetics of the designed EOP tablets. These formulated EOP systems followed zero-order kinetics, a characteristic feature of EOPs. EOP tablets were formulated applying a systematic QbD statistical approach. The formulated DLH EOP systems with improved concentration-independent behavior helped to address the challenges of IR formulation. Application of QbD strategy in ascertaining the scalability of DLH EOP formulation would help pharmaceutical industries in the translation of EOP based drug delivery systems from R&D to market.

Exploring Acceptability Drivers of Oral Antibiotics in Children: Findings from an International Observational Study.

Antibiotics are among the most commonly prescribed drugs in children. Adherence to the treatment with these drugs is of the utmost importance to prevent the emergence of resistant bacteria, a global health threat. In children, medicine acceptability is likely to have a significant impact on compliance. Herein we used a multivariate approach, considering simultaneously the many aspects of acceptability to explore the drivers of oral antibiotic acceptability in children under twelve, especially in toddlers and in preschoolers. Based on 628 real-life observer reports of the intake of 133 distinct medicines, the acceptability reference framework highlighted the influence of many factors such as age and sex of patients, previous exposure to treatment, place of administration, administration device, flavor agent in excipients and active pharmaceutical ingredient. These findings from an international observational study emphasize the multidimensional nature of acceptability. Therefore, it is crucial to consider all these different aspects for assessing this multi-faceted concept and designing or prescribing a medicine in order to reach adequate acceptability in the target population.

Nanocarrier-Based Approaches for the Efficient Delivery of Anti-Tubercular Drugs and Vaccines for Management of Tuberculosis.

Drug-resistant species of tuberculosis (TB), which spread faster than traditiona TB, is a severely infectious disease. The conventional drug therapy used in the management of tuberculosis has several challenges linked with adverse effects. Hence, nanotherapeutics served as an emerging technique to overcome problems associated with current treatment. Nanotherapeutics helps to overcome toxicity and poor solubility issues of several drugs used in the management of tuberculosis. Due to their diameter and surface chemistry, nanocarriers encapsulated with antimicrobial drugs are readily taken up by macrophages. Macrophages play a crucial role as they serve as target sites for active and passive targeting for nanocarriers. The surface of the nanocarriers is coated with ligand-specific receptors, which further enhances drug concentration locally and indicates the therapeutic potential of nanocarriers. This review highlights tuberculosis's current facts, figures, challenges associated with conventional treatment, different nanocarrier-based systems, and its application in vaccine development.

Global Pediatric Regulations: An Overview.

The purpose of the present review is to summarize the current pediatric regulatory requirements and also the regulatory efforts that need to be taken for the potential benefits of safety and efficacy to the pediatric patients. The importance of pediatric regulations came into existence as adult physiological conditions differ from that of children; therefore, the same dosage regimen cannot be recommended for both. Children deviate from adults with respect to pharmacokinetic and pharmacodynamic characteristics, and hence the effect of the drug has to be reconfirmed for pediatrics. Drugs used in pediatric clinics are often considered as "therapeutic orphans" throughout the world as they are difficult to develop and are not provided with sufficient information. The number of clinical trials performed in children is not sufficient. At present, laws and regulations aimed at drug development in the pediatric field have not been focused significantly. There are different regulatory bodies that administrate the pediatric regulations for a particular region.

Stimuli-responsive biodegradable polyurethane nano-constructs as a potential triggered drug delivery vehicle for cancer therapy.

Polyurethanes (PUs) constitute an essential class of stimuli-responsive and biodegradable material, which has significantly contributed to the advancement of polymers utilization in the biomedical field. The bio-erodible PUs construct an active corridor for facilitating drug into tumor cells, which has significantly impacted the progression of nano-micellar delivery systems. The self-assembledcolloidal PUs pose distinctive features such as enhancing the solubility of hydrophobic chemotherapeutics, rapid cellular uptake, triggered erosion and drug release, bio-stimulus sensitivity, improvement in the targeting and proficiency ofbioactive. Cationic PUs can easily be condensed with genetic material to form polyplexes and have shown excellent transfection efficiency for potential gene therapy against various cancers. Their modifiable chemistry offers a tool to impart the desired multifunctionality such as biocompatibility, sensitivity to pH, redox, temperature, enzyme, etc. and ligand conjugation for active targeting. These diverse exceptional properties make them excellent nano-carrier for a variety of bioactive, including chemotherapeutic drugs, DNA, RNA, and diagnostic moieties to the target tissue or cells. The PUs based nano-devices have certainly uncovered the path to achieve ideal systems for controlled personalized therapy. The literature discussed in this review shed light on the research innovations carried out in the last ten years for the development of multifunctional PUs for triggered delivery of bioactive to treat various cancers.

Development of Sustained Release Oseltamivir Phosphate Dry Powder Inhaler: In-Vitro Characterization and In-Vivo Toxicological Studies.

BACKGROUND: Oseltamivir Phosphate (OP) is an ethyl ester prodrug prescribed for the treatment of influenza virus infection. Current marketed formulations of OP have been observed to be supplemented with an adverse effect during post-marketing surveillance. These prerequisites are sufficed by developing a sustained release Dry Powder for Inhalation (DPI). OBJECTIVE: The objective of the present study was to develop OP-DPI by an innovative formulation approach comprising of Immediate (IR) and Sustained (SR) Release portions. METHODS: DPI formulation comprising IR and SR portions were prepared by spray drying technique using Hydroxy Propyl Methyl Cellulose (HPMC) as the rate-controlling polymer for SR portion. The spray-dried product was further characterized for various pharmaco-technical, in-vitro and in-vivo parameters. RESULTS: OP-DPI showed a burst release of 49% within 15 min further sustaining the drug release up to 9 hrs. The in-vitro aerodynamic performance of OP-DPI showed maximum deposition at stage 3 and Fine Particle Dose (FPD) of 1.08 mg indicating deposition in the upper respiratory tract. Solid-state characterization by DSC and XRD indicated the partial amorphization of OP due to spray drying. In-vivo toxicological examination revealed no sign of inflammation, indicating the safety of the developed formulation. Accelerated stability study as per ICH guidelines displayed no significant change in the solid-state characterization and drug-related performance of OP-DPI. CONCLUSION: Prepared novel and scalable OP-DPI may have the potential to overcome the problems associated with existing marketed dosage forms of OP. Further, localized drug delivery of the antiviral drug through the pulmonary route might be clinically beneficial in controlling the viral proliferation.

Exploring micellar-based polymeric systems for effective nose-to-brain drug delivery as potential neurotherapeutics.

Non-invasive nose-to-brain delivery presents a competitive strategy for effective drug targeting. This strategy can potentially evade the blood-brain barrier (BBB) depending on the pathway the drug and/or drug/micelle composite travels, thereby allowing direct drug delivery to the brain. This delivery strategy was employed for lurasidone, a clinically USFDA-approved neurotherapeutic molecule in bipolar disorders and schizophrenia treatments. The aim of this study was to develop mixed polymeric micelles of lurasidone HCl (LH) for targeted brain delivery via intranasal route. Lurasidone HCl-loaded mixed micelles (LHMM) were prepared by solvent evaporation method and optimized by 32 factorial design to quantify the effects of excipients on micelle size and entrapment efficiency. Fourier transform infrared spectroscopy helped in scrutinizing drug-excipient interactions whereas transmission electron microscopy images showed particle size and shape. Further, LHMM and LHMM hydrogel were evaluated for in vitro diffusion, histopathology, ex vivo permeation, in vivo pharmacokinetics and stability studies. Optimized LHMM exhibited 175 nm particle size and 97.8% entrapment efficiency with improved in vitro drug diffusion (81%). LHMM hydrogel showed 79% ex vivo drug permeation without any significant signs of nasociliary toxicity to sheep nasal mucosa. Single dose in vivo pharmacokinetic studies showed improved therapeutic concentration of drug in the brain post intranasal administration with 9.5 ± 0.21 µg/mL Cmax and T1/2 of 19.1 ± 0.08 h as compared to pure drug. LHMM, when administered by intranasal route, demonstrated significant increase in the drug targeting efficiency as well as potential (%DTE and %DTP) of drug as compared to pure lurasidone. Thus, nanosized mixed micelles were useful in effective brain delivery of lurasidone HCl via intranasal route. Graphical abstract.

Global Pediatric Regulations: An Overview.

The purpose of the present review is to summarize the current pediatric regulatory requirements and also the regulatory efforts that need to be taken for the potential benefits of safety and efficacy to the pediatric patients. The importance of pediatric regulations came into existence as adult physiological conditions differ from that of children; therefore, the same dosage regimen cannot be recommended for both. Children deviate from adults with respect to pharmacokinetic and pharmacodynamic characteristics, and hence the effect of the drug has to be reconfirmed for pediatrics. Drugs used in pediatric clinics are often considered as "therapeutic orphans" throughout the world as they are difficult to develop and are not provided with sufficient information. The number of clinical trials performed in children is not sufficient. At present, laws and regulations aimed at drug development in the pediatric field have not been focused significantly. There are different regulatory bodies that administrate the pediatric regulations for a particular region.

Risk assessment and QbD based optimization of an Eprosartan mesylate nanosuspension: In-vitro characterization, PAMPA and in-vivo assessment.

Quality by design (QbD) principles were implemented to understand the product and process variables of sonoprecipitation technique, for preparation of eprosartan mesylate (EM) nanosuspension. Quality risk management approach was utilized to identify and assess high-risk attributes affecting critical quality attributes (CQA's), prioritizing the number of experiments. The effect of critical material attributes (CMA's) and critical process parameters (CPP's) (soluplus concentration, drug concentration ultrasonication amplitude) on z-average particle size and PDI were investigated using a central composite face-centered design (CCF). Further, design space with criteria set of CMA's and CPP's was established to offer assurance of quality. The optimal formulation, identified using numerical optimization method, was further lyophilized and evaluated for redispersibility, solubility saturation, dissolution kinetic and in-vitro dissolution behavior. The EM nanoparticles were in an amorphous state as confirmed by differential scanning calorimetry (DSC) and X-ray diffraction (XRD) studies. The stability study conducted for a span of 6 months attests physical and chemical stability of EM dry nanosuspension in an amorphous state when stored at 4 °C. The enhanced solubility and in-vitro dissolution of EM nanosuspension may be attributed to the reduced particle size and alteration of the physical state from a crystalline to an amorphous state. Further, the optimized formulation was subjected to in-vitro and ex-vivo transport study using parallel artificial membrane permeability assay (PAMPA) and rat everted gut sac model respectively. The transport studies revealed successful permeation enhancement of EM nanoparticle when compared with EM API and physical mixture (PM). The absolute bioavailability of EM API was 7.1% and improved to 39.9% for EM nanosuspension, suggesting that nanoformulation had overcome solubility and permeability limited bioavailability which was observed with EM API.

Enhanced dissolution/caco-2 permeability, pharmacokinetic and pharmacodynamic performance of re-dispersible eprosartan mesylate nanopowder.

Eprosartan mesylate is an angiotensin receptor blocker which suffers from extremely poor bioavailability owing to its poor solubility and poor permeability. The rationale of the present work was to design the drug delivery system capable of overcoming these constraints. Nanoformulation of eprosartan mesylate was developed using ultrasonic wave-assisted liquid-antisolvent technique. Nanoformulation was further freeze dried with the addition of 1% of mannitol resulting in formation of re-dispersible EPM nanopowder. To prove our proof of principle, the re-dispersed nanopowder with z-average particle size 165.2 ±â€¯1.8 nm was evaluated enormously for in-vitro dissolution behaviour and permeability assay through Caco-2 cell model. In-vitro dissolution study was performed at pH 1.2, pH 4.5 and pH 6.8. Result demonstrates enhanced dissolution from EPM nanopowder with negligible pH dependence. Transport studies accomplished using validated Caco-2 based cell model showed 11-fold enhanced apparent permeability of redispersed nanopowder when compared to pure EPM and corresponding physical mixture (p < 0.0001). In-vivo study reveals, exceptionally strong variations in plasma concentration of EPM through nanopowder (62 mg/kg) formulation when compared with physical mixture and pure EPM (62 mg/kg) group. Moreover, study manifests that 5-fold lower dose (12.4 mg/kg) of developed formulation yields higher exposure (4600 ±â€¯36 ng·mL-1·h) than pure EPM (2349 ±â€¯34 ng·mL-1·h) and corresponding physical mixture (2456 ±â€¯49 ng·mL-1·h) at therapeutic dose (62 mg/kg). Further, L-NAME induced hypertensive model was undertaken to investigate effect of reduced dose of EPM nanopowder on systolic blood pressure, biochemical analysis and histopathology of heart. Results revealed pronounced antihypertensive potential of re-dispersed EPM nanopowder at 5-fold lower dose (12.4 mg/kg). In conclusion, our study indicates that nanopowder delivery might be the promising approach for providing enhanced oral bioavailability at lower dose.

Galangin loaded galactosylated pluronic F68 polymeric micelles for liver targeting.

Galangin possess wide range of pharmacological activities including antiarthritic, hepatoprotective, anti-inflammatory, antibacterial, and anticancer especially in hepatocellular carcinoma. However, its biological use has been limited owing to its poor aqueous solubility, P-gp efflux and rapid in vivo metabolism by cytochrome enzymes. In order to address the drawbacks of galangin, the current work was designed with an objective to prepare liver targeted galangin loaded galactosylated pluronic F68 polymeric (GF68-Gal) micelles. Galactosylated pluronic F68 copolymer was successfully synthesized usi reduction amination method and used for micelle preparation. The prepared micelles were evaluated for micelle size, entrapment efficiency, zeta potential, in vitro galangin release and in vivo biodistribution. The average size of GF68-Gal micelles was found to be around 242±4.6 nm with an entrapment efficiency of about 77.5± 0.34% w/w. In vitro dissolution profile of GF68-Gal micelles revealed controlled release of galangin. Further, biodistribution studies of GF68-Gal micelles showed significant improvement in the amount of galangin in liver at 15 min (around 2.6 folds) and after 30 min (around 7.18 folds) as compared to galangin solution. Such significant increase in galangin amount in the liver for GF68-Gal micelles could be attributed to their efficient targeting to the liver by galactose moieties having affinity towards ASGPR receptor, P-gp and cytochrome enzyme inhibition activity of pluronic F68 reducing the rate of metabolism and in turn elimination. Thus, galactosylated pluronic F68 copolymer can act as a promising carrier system for improving liver targeting of hydrophobic drugs susceptible to P-gp efflux and cytochrome enzyme associated metabolism.

Positive effect of alendronate on bone turnover in ovariectomised rats' osteoporosis: comparison of transdermal lipid-based delivery with conventional oral administration.

Alendronate (ALD) is clinically indicated for the treatment of osteoporosis, but its therapeutic use has been marred by severe GIT adverse effects affecting quality of life in patients. In this study, we selected novel transdermal microemulsion (TDME) as a suitable carrier for ALD as the way of avoiding intestinal toxicity and highlighted its anti-osteoporotic efficacy with extensive pharmacokinetic and pharmacodynamic analysis. TDME achieved two fold increase in bioavailability as compared to oral administration in pharmacokinetic studies. To investigate the capability of TDME in alleviating symptoms of osteoporosis, it was administered to ovariectomised rats 2 months post-surgery. The results obtained after 2 months of treatment with ALD by trans-epidermal route exhibited improved bone density in DEXA scan of rats. These observations were further supported by biochemical investigations including analysis of bone formation and resorption markers. Moreover, TDME effectively suppressed the decline in bone mass of osteoporotic rats as determined through the biometric analysis and histopathological examination of bones. Additionally, skin histopath results showed no significant skin damage at the end of treatment. Overall, these findings demonstrate that the TDME system is a promising approach for the effective delivery of ALD, bypassing the adverse effects associated with oral administration.

Engineering of pectin-capped gold nanoparticles for delivery of doxorubicin to hepatocarcinoma cells: an insight into mechanism of cellular uptake.

In this study, we have reported the fabrication and evaluation of pectin-capped gold nanoparticles (PEC-AuNPs) for delivery of anticancer drug, doxorubicin (DOX) to cells overexpressing asialoglycoprotein receptor (ASGPR). Pectin was used as a reducing, stabilizing and targeting agent. The pectin-capped gold nanoparticles demonstrated surface plasmon resonance band at 519 nm. The PEC-AuNPs were spherical in shape with a particle size of 14 nm and zeta potential value of -33 mV and were biocompatible and non-cytotoxic. The PEC-AuNPs exhibited a high drug loading efficiency of 78%. The DOX-loaded gold nanoparticles (DOX-PEC-AuNPs) showed excellent stability under varying pH and electrolytic conditions. The cytotoxicity study of the DOX-PEC-AuNPs in human Caucasian hepatocyte cells demonstrated their greater potency in killing these cells as compared to free DOX. The uptake and targeting potential of DOX-PEC-AuNPs was thoroughly investigated. Further, it was found that the PEC-AuNPs were taken up by HepG2 cells via a clathrin-dependent receptor-mediated endocytosis by asialoglycoprotein receptor present of the surface of these cells. Thus, the PEC-capped AuNPs can prove a promising carrier for anticancer drug in the treatment of hepatocellular carcinoma.