Eudragit-Based Nanosuspension of Poorly Water-Soluble Drug: Formulation and In Vitro–In Vivo Evaluation

The present study was performed to investigate potential of Eudragit RLPO-based nanosuspension of glimepiride (Biopharmaceutical Classification System class II drug), for the improvement of its solubility and overall therapeutic efficacy, suitable for peroral administration. Nanoprecipitation method being simple and less sophisticated was optimized for the preparation of nanosuspension. Physicochemical characteristics of nanosuspension in terms of size, zeta potential, polydispersity index, entrapment efficiency (% EE) and in vitro drug release were found within their acceptable ranges. The size of the nanoparticles was most strongly affected by agitation time while % EE was more influenced by the drug/polymer ratio. Differential scanning calorimetry and X-ray diffraction studies provided evidence that enhancement in solubility of drug resulted due to change in crystallinity of drug within the formulation. Stability study revealed that nanosuspension was more stable at refrigerated condition with no significant changes in particle size distribution, % EE, and release characteristics for 3 months. In vivo studies were performed on nicotinamide–streptozotocin-induced diabetic rat models for pharmacokinetic and antihyperglycaemic activity. Nanosuspension increased maximum plasma concentration, area under the curve, and mean residence time values significantly as compared to aqueous suspension. Oral glucose tolerance test and antihyperglycaemic studies demonstrated plasma glucose levels were efficiently controlled in case of nanosuspension than glimepiride suspension. Briefly, sustained and prolonged activity of nanosuspensions could reduce dose frequency, decrease drug side effects, and improve patient compliance. Therefore, glimepiride nanosuspensions can be expected to gain considerable attention in the treatment of type 2 diabetes mellitus due to its improved therapeutic activity.KEY WORDS: diabetes mellitus, glimepiride, nanoprecipitation, poloxamer, sustained release     

Tween-Embedded Microemulsions—Physicochemical and Spectroscopic Analysis for Antitubercular Drugs

The microemulsion composed of oleic acid, phosphate buffer, ethanol, and Tween (20, 40, 60, and 80) has been investigated in the presence of antitubercular drugs of extremely different solubilities, viz. isoniazid (INH), pyrazinamide (PZA), and rifampicin (RIF). The phase behavior showing the realm of existence of microemulsion has been delineated at constant surfactant/co-surfactant ratio (K _m?=?0.55) with maximum isotropic region resulting in the case of Tween 80. The changes in the microstructure of Tween 80-based microemulsion in the presence of anti-TB drugs have been established using conductivty (σ) and viscosity (η) behavior. The optical microscopic images of the system help in understanding the effect of dilution and presence of drug on the structure of microemulsion. Partition coefficient, particle size analysis, and spectroscopic studies (UV–visible, Fourier transform infrared, and ¹H NMR) have been performed to evaluate the location of a drug in the colloidal formulation. To compare the release of RIF, PZA, and INH from Tween 80 formulation, the dissolution studies have been carried out. It shows that the release of drugs follow the order INH>PZA>RIF. The kinetics of the release of drug has been analyzed using the Korsmeyer and Peppas equation. The results have given a fair success to predict that the release of PZA and INH from Tween 80 microemulsion is non-Fickian, whereas RIF is found to follow a Fickian mechanism.     

Early-phase clinical trials of anti-HIV Drugs——understanding and discussion

Innovative anti-HIV drugs developed by local sponsors in China have come into the stage of early-phase clinical trials. How to systemically design the clinical trials of innovative anti-HIV drugs still remains a challenge for them. This article references the literature and the experience of reviewers, to introduce general considerations concerning early-phase clinical trials of innovative anti-HIV drugs.     

HUMAN TISSUE PRESERVATION—Development of Regulations and Removal of Some Legal Barriers

Human tissue must be obtained promptly postmortem if it is to be successfully preserved.Legal assistance toward this goal has been established by the California Legislature.To implement this legislation the State Board of Public Health has established regulations relating to human tissue preservation. These are the first such regulations in the nation.Tissue preservation is not yet fully developed. Much research is in progress to overcome many problems.The future may hold interesting developments. Present laws and regulations will implement them.     

Animal Experiments—An Essential Component for the Development of Liposomal Anticancer Agents

The poor selectivity of anticancer drugs often leads to their multiplicate dose-limiting toxicities in humans, which severely restricts their clinical application. In this study, a novel liposomal formulation of zedoary turmeric oil (ZTO) targeting the insulin receptor (IR) was prepared by covalently conjugating insulin to the terminal of the polyethylene glycol (PEG) chain of sterically stabilized liposomes. In vitro assays indicated that a higher uptake of insulin-modified sterically stabilized liposomes (ISSLs) was observed in SMMC-7721 hepatocarcinoma cells overexpressing insulin receptors. IC₅₀ values of ISSLs, NTLs (nontargeted liposomes), and ZTO injection (free ZTO) against SMMC-7721, determined by MTT assays, were 157.2, 256.7, and 43.3?μg·ml^?1, respectively. Plasma-clearance profiles of ZTO in the liposomal formulations were then compared with that of ZTO injection. The liposomal formulations showed much longer terminal half-lives (11.24 and 14.73 hours for ISSLs and NTLs, respectively) than that of ZTO injection (1.45 hours). All results above indicated the ISSLs were potentially useful for the treatment of IR (+) tumors and are worthy of further investigation.     

The Influence of Drivers and Barriers on Urban Adaptation and Mitigation Plans—An Empirical Analysis of European Cities

Cities are recognised as key players in global adaptation and mitigation efforts because the majority of people live in cities. However, in Europe, which is highly urbanized and one of the most advanced regions in terms of environmental policies, there is considerable diversity in the regional distribution, ambition and scope of climate change responses. This paper explores potential factors contributing to such diversity in 200 large and medium-sized cities across 11 European countries. We statistically investigate institutional, socio-economic, environmental and vulnerability characteristics of cities as potential drivers of or barriers to the development of urban climate change plans. Our results show that factors such as membership of climate networks, population size, GDP per capita and adaptive capacity act as drivers of mitigation and adaptation plans. By contrast, factors such as the unemployment rate, warmer summers, proximity to the coast and projected exposure to future climate impacts act as barriers. We see that, overall, it is predominantly large and prosperous cities that engage in climate planning, while vulnerable cities and those at risk of severe climate impacts in the future are less active. Our analysis suggests that climate change planning in European cities is not proactive, i.e. not significantly influenced by anticipated future impacts. Instead, we found that the current adaptive capacity of a city significantly relates to climate planning. Along with the need to further explore these relations, we see a need for more economic and institutional support for smaller and less resourceful cities and those at high risk from climate change impacts in the future.     

Barriers and Bridges to Prevention and Control of Dengue: The Need for a Social–Ecological Approach

This article critically examines how programs for the prevention and control of dengue fever have been conducted in the absence of an integrated approach, and considers the social and ecological factors influencing their effectiveness. Despite recognition of dengue fever as the most important arboviral disease affecting humans, and in spite of a greater emphasis on community-based control approaches, the burden placed on the communities, countries, and regions affected by this disease continues to rise. In considering historical experience in the Americas and the Asia-Pacific region, as well as the global forces that are exerting new pressures, the important elements of successful control programs are identified as community ownership, partnership with government, leadership, scalability, and control of immature mosquitoes. The key barriers to the exchange of knowledge and the transdisciplinary cooperation necessary for sustainable dengue control are rooted in differences in values among policy-makers, citizens, and scientists and are repeatedly expressed in technical, economic, cultural, geographic, and political dimensions. Through consideration of case studies in Cuba, Guatemala, Singapore, Thailand, Indonesia, and Vietnam, the limitations of control approaches that fail to take into account the complexities of ecological and social systems are presented. Bridges to effective control are identified as the basis for adaptability, both of control programs to the mosquito vector’s changing behavior and of education programs to public, regional and local particularities, as well as transdisciplinarity, community empowerment, the ability to scale local experiences up to the macro-level, and the capacity to learn from experience to achieve sustainability.     

Dual Activity of Hydroxypropyl-β-Cyclodextrin and Water-Soluble Carriers on the Solubility of Carvedilol

Carvedilol (CAR) is a non-selective α and β blocker categorized as class II drug with low water solubility. Several recent studies have investigated ways to overcome this problem. The aim of the present study was to combine two of these methods: the inclusion complex using hydroxypropyl-β-cyclodextrin (HPβCD) with solid dispersion using two carriers: Poloxamer 188 (PLX) and Polyvinylpyrrolidone K-30 (PVP) to enhance the solubility, bioavailability, and the stability of CAR. Kneading method was used to prepare CAR-HPβCD inclusion complex (KD). The action of different carriers separately and in combination on Carvedilol solubility was investigated in three series. CAR-carrier and KD-carrier solid dispersions were prepared by solvent evaporation method. In vitro dissolution test was conducted in three different media: double-distilled water (DDW), simulative gastric fluid (SGF), and PBS pH 6.8 (PBS). The interactions between CAR, HPβCD, and different carriers were explored by Fourier transform infrared spectroscopy (FTIR), powder X-ray diffractometry (XRD), and differential scanning colorimetry (DSC). The results showed higher solubility of CAR in KD-PVP solid dispersions up to 70, 25, and 22 fold compared to pure CAR in DDW, SGF, and PBS, respectively. DSC and XRD analyses indicated an improved degree of transformation of CAR in KD-PVP solid dispersion from crystalline to amorphous state. This study provides a new successful combination of two polymers with the dual action of HPβCD and PLX/PVP on water solubility and bioavailability of CAR.     

3D-Printed Drugs for Children—Are We Ready Yet?

The first medicine manufactured by three-dimensional (3D) printing was recently approved by the Food and Drug Administration (FDA). The advantages of printing as a manufacturing route enabling more flexibility regarding the dose, and enlarging individual treatment options, have been demonstrated. There is a particular need for flexible drug delivery solutions when it comes to children. Printing as a new pharmaceutical manufacturing technology brings manufacturing closer to the patient and can easily be adjusted to the required dosing scheme, offering more flexibility for treatments. Printing of medicine may therefore become the manufacturing route of choice to provide tailored and potentially on-demand treatments for patients with individual needs. This paper intends to summarize and discuss the state of the art, the crucial aspects which should be taken into account, and the still-open questions, in order to make 3D printing a suitable manufacturing route for pediatric drugs.     

Anticancer Activity for Targeting Telomeric G-Quadruplex and Antiangiogenesis of a Novel Ru(II)–Se Complex

A new Ru(II)–Se complex, Ru(bpy)₂L₂Cl₂ (bpy?=?2,2′-bipyridine, L?=?1,10-phenanthrolineselenazole) (Ru-Se) has been synthesized and characterized. The G-quadruplex DNA-binding properties of the complex and its selenium ligand (Phen-Se) were evaluated by thermal denaturation study, polymerase chain reaction (PCR) stop assay, and telomerase repeat amplification protocol (TRAP). The results showed that the obtained complex could induce and stabilize G-quadruplex structure as well as exhibit potent inhibitory activity against telomerase. In vitro cytotoxicity studies showed that complex Ru-Se inhibited the cancer cell growth through apoptosis. However, the presence of the ligand Phen-Se did not appear to have a significant effect either on G-quadruplex binding or on biological activity. Furthermore, the cell migration assay and the tube formation assay also demonstrated that the complex Ru-Se significantly inhibited human umbilical vascular endothelial cell (HUVEC) proliferation, migration, and tube formation. These findings indicate that the Ru–Se complex may be a potential telomerase inhibitor and a viable drug candidate in antiangiogenesis for anticancer therapies.     

Co-solvent Evaporation Method for Enhancement of Solubility and Dissolution Rate of Poorly Aqueous Soluble Drug Simvastatin: In vitro–In vivo Evaluation

A number of synthesized chemical molecules suffer from low aqueous solubility problems. Enhancement of aqueous solubility, dissolution rate, and bioavailability of drug is a very challenging task in drug development. In the present study, solubility and dissolution of poorly aqueous soluble drug simvastatin (SIM) was enhanced using hydrophilic, low viscosity grade polymer hydroxypropyl methylcellulose (HPMC K₃LV). The co-solvent evaporation method was developed for efficient encapsulation of hydrophobic drug in polymer micelles of HPMC K₃LV. Spray drying and rotaevaporation method were applied for solvent evaporation. Co-solvent-evaporated mixture in solid state was determined by differential scanning calorimetry (DSC), X-ray diffraction studies (XRD), scanning electron microscopy, and Fourier-transform infrared spectroscopy. In vitro–in vivo studies were performed on co-solvent-evaporated mixture and compared with SIM. In vivo study was conducted on healthy albino rats (Wister strain), and formulations were administered by oral route. Results of the study show the conversion of crystalline form of SIM into amorphous form. The dissolution rate was remarkably increased in co-solvent-evaporated mixtures compared to SIM. co-solvent-evaporated mixtures showed better reduction in total cholesterol and triglyceride levels than the SIM. The low-viscosity grade HPMC acts as a surfactant, which enhances the wetting of drug and thus improves the solubility of drug. The co-solvent evaporation method provides good encapsulation efficiency and produces amorphous form of SIM, which gave better solubility and dissolution than the crystalline SIM.