Indomethacin-containing interpolyelectrolyte complexes based on Eudragit® E PO/S 100 copolymers as a novel drug delivery system

Potential applications of a novel system composed of two oppositely-charged (meth)acrylate copolymers, Eudragit® ЕРО (EPO) and Eudragit® S100 (S100), loaded with indomethacin (IND) in oral drug delivery were evaluated. The particles based on drug-interpolyelectrolyte complexes (DIPEC), (EPO-IND)/S100, were prepared by mixing aqueous solutions of both copolymers at fixed pH. Particles of drug-polyelectrolyte complex (DPC), (EPO-IND) have a positive zeta potential, pointing to the surface location of free EPO chains and IND bound to EPO sequences. The formation and composition of both DPC and DIPEC were established by gravimetry, UV-spectrophotometry, capillary viscosity and elemental analysis. The structure and solid state properties of the formulated DIPEC were investigated using FTIR/NIR, Raman spectroscopy, XRPD and modulated DSC. DIPEC is a chemically homogenous material, characterized by a single Tg. DIPEC have an IR absorption band at 1560 cm−1, which can be assigned to the stretching vibration of the carboxylate groups (S100, IND) that form ionic bonds with the dimethylamino groups of EPO. XRPD, NIR and Raman-shifts confirm that during the preparation of this formulation, IND is converted into its amorphous form. The release of IND from DPC EPO/IND (3:1) and DIPEC EPO/L100/IND (4.5:1:1) is sustained and is completed within 7 hours under GIT mimicking conditions. However, S100 within DIPEC makes the release process slower making this system suitable for colon-specific delivery. Finally, DPC and DIPEC with indomethacin were used to prepare tablets, which can be potentially used as oral dosage forms for their slower indomethacin release in case of DIPEC which could be suitable for sustained delivery

The influence of crushing amorphous solid dispersion dosage forms on the in-vitro dissolution kinetics

Solid dosage forms of amorphous solid dispersions (ASDs) have rarely been assessed for their crushability, although it might possibly be a more frequent practice than thought to facilitate oral administration in several clinical conditions (e.g. dysphagia) when no oral liquids of the same drug are available. Nevertheless, there are concerns that contraindicate these formulations' modification by grinding. For example, amorphous-amorphous phase separation, induction of crystallization, decreasing particle sizes, etc. might occur during grinding without knowing the implications on bioavailability. Hence, in this study, Sporanox® (itraconazole), Intelence® (etravirine), Noxafil® (posaconazole) and Norvir® (ritonavir), were selected as "model" enabling formulations (based on ASD) to evaluate if this concern was justified. Their assessment in simple and biorelevant media by two-stage in-vitro drug-release testing was performed which resulted in strong suspicion that pulverization is contradicted for some of these formulations. Despite differences were observed, uncertainty remains on the clinical relevance of these data as by golden standard it should still be confirmed by bioequivalence trials.status: publishe

New perspectives for fixed dose combinations of poorly water soluble compounds: a case study with ezetimibe and lovastatin

PURPOSE: Aiming to improve the dissolution rate of ezetimibe (EZE) and lovastatin (LOV) in a fixed dose combination (FDC), co-amorphous systems and ternary solid dispersions were prepared by quench cooling and spray drying, respectively. METHODS: Formulations were characterized through X-ray diffraction, modulated differential scanning calorimetry, infrared spectroscopy, scanning electron microscopy and laser diffraction, and evaluated by 'in vitro' dissolution. Stability studies were conducted at different conditions during 30 days with the ternary solid dispersion composed of 75% of Soluplus® (ELS 1:1 75%). RESULTS: Single phase co-amorphous systems made up of the pure drugs were not able to increase the dissolution rate of EZE and LOV. However, ternary solid dispersions achieved high dissolution for both compounds, especially when Soluplus® was used as carrier. The dissolution efficiency increased up to 18 (EZE) and 6 (LOV) times in ternary solid dispersions, compared to the crystalline drugs. ELS 1:1 75% preserved its amorphous state during 30 days, in different stability conditions. CONCLUSIONS: A spray dried ternary solid dispersion able to enhance the dissolution rate of two poorly soluble, therapeutically complementary drugs, is reported for the first time. These promising results open new perspectives for the development of more advanced FDCs.status: publishe

Influence of formulation composition and process on the characteristics and in vitro release from PLGA-based sustained release injectables

Understanding and controlling the in vitro release behavior of a formulation is a first step toward rationalized selection of a solubility enhancing formulation strategy with a desired release profile in vivo. Therefore six model formulations, representing three different formulation strategies, were physicochemically analyzed and their in vitro release was determined. Solid dispersions based on a PLGA/PVP matrix were compared to solid dispersions in a pure PLGA matrix. Additionally these solid dispersion strategies were compared to the strategy of particle size reduction by means of an API microsuspension. Depending on composition and manufacturing method, formulations varied in particle size, porosity, phase behavior, surface coverage and physical state of the API. This resulted in observed differences in their in vitro release profile. For the various formulation strategies tested both a porous PLGA-based formulation and PLGA/PVP-based formulations, resulted in vitro in sustained release of the poorly soluble API with over 50% of drug released after 24h. For PLGA-based formulations the porosity was identified as a critical parameter influencing in vitro drug release. For the PLGA/PVP-based formulations the release rate can be tailored by the amount of PLGA present. Particle size reduction resulted in immediate total drug release.publisher: Elsevier articletitle: Influence of formulation composition and process on the characteristics and in vitro release from PLGA-based sustained release injectables journaltitle: European Journal of Pharmaceutics and Biopharmaceutics articlelink: http://dx.doi.org/10.1016/j.ejpb.2014.11.009 content_type: article copyright: Copyright © 2014 Elsevier B.V. All rights reserved.status: publishe

Development and characterization of a solid dispersion film for the vaginal application of the anti-HIV microbicide UAMC01398

The purpose of this work was to design and evaluate a vaginal film delivery system for UAMC01398, a novel non-nucleoside reverse transcriptase inhibitor currently under investigation for use as an anti-HIV microbicide. UAMC01398 (1mg) films consisting of hydroxypropylmethylcellulose (HPMC) and polyethylene glycol 400 (PEG400) in different ratios were prepared by solvent evaporation. Based on its flexibility, softness and translucent appearance, the 30% PEG400 and 70% HPMC containing film was selected for further assessment. The vaginal film formulation was fast-dissolving (<10 min in 1 mL of vaginal fluid simulant), stable up to at least one month and safe toward epithelial cells and lactobacilli. Furthermore, formulating UAMC01398 into the film dosage form did not influence its antiviral activity. Powder X-ray diffraction revealed the amorphous nature of the UAMC01398 film, resulting in enhanced compound permeation across the epithelial HEC-1A cell layer, presumably owing to the induction of supersaturation. The in vivo vaginal tissue uptake of UAMC01398 in rabbits, as measured by systemic concentrations, was increased compared to the previously established non-solubilizing gel (significant difference) and sulfobutyl ether-β-cyclodextrin (5%) containing gel. To conclude, we identified a film formulation suitable for the vaginal delivery of UAMC01398.publisher: Elsevier articletitle: Development and characterization of a solid dispersion film for the vaginal application of the anti-HIV microbicide UAMC01398 journaltitle: International Journal of Pharmaceutics articlelink: http://dx.doi.org/10.1016/j.ijpharm.2014.08.054 content_type: article copyright: Copyright © 2014 Elsevier B.V. All rights reserved.status: publishe

Combined 19F MRI and CT imaging for the visualization of delayed release of compounds using pH-sensitive polymers coated capsules in vitro and in a hamster animal model

status: publishe

Visualization of delayed release of compounds from pH-sensitive capsules in vitro and in vivo in a hamster model

Delayed controlled release is an innovative strategy to locally administer therapeutic compounds (e.g. chemotherapeutics, antibodies etc.). This would improve efficiency and reduce side effects compared with systemic administration. To enable the evaluation of the efficacy of controlled release strategies both in vitro and in vivo, we investigated the release of contrast agents ((19)F-FDG and BaSO4) to the intestinal tract from capsules coated with pH-sensitive polymers (EUDRAGIT L-100) by using two complementary techniques, i.e. (19)F magnetic resonance imaging (MRI) and computed tomography (CT). Using in vitro (19)F-MRI, we were able to non-destructively and dynamically establish a time window of 2 h during which the capsules are resistant to low pH. With (19)F-MRI, we could establish the exact time point when the capsules became water permeable, before physical degradation of the capsule. This was complemented by CT imaging, which provided longitudinal information on physical degradation of the capsule at low pH that was only seen after 230 min. After oral administration to hamsters, (19)F-MRI visualized the early event whereby the capsule becomes water permeable after 2 h. Additionally, using CT, the integrity and location (stomach and small intestines) of the capsule after administration could be monitored. In conclusion, we propose combined (19)F-MRI and CT to non-invasively visualize the different temporal and spatial events regarding the release of compounds, both in an in vitro setting and in the gastrointestinal tract of small animal models. This multimodal imaging approach will enable the in vitro and in vivo evaluation of further technical improvements to controlled release strategies.status: publishe

Establishing the Foundation for the Global Observing System for Marine Life

Maintaining healthy, productive ecosystems in the face of pervasive and accelerating human impacts including climate change requires globally coordinated and sustained observations of marine biodiversity. Global coordination is predicated on an understanding of the scope and capacity of existing monitoring programs, and the extent to which they use standardized, interoperable practices for data management. Global coordination also requires identification of gaps in spatial and ecosystem coverage, and how these gaps correspond to management priorities and information needs. We undertook such an assessment by conducting an audit and gap analysis from global databases and structured surveys of experts. Of 371 survey respondents, 203 active, long-term (>5 years) observing programs systematically sampled marine life. These programs spanned about 7% of the ocean surface area, mostly concentrated in coastal regions of the United States, Canada, Europe, and Australia. Seagrasses, mangroves, hard corals, and macroalgae were sampled in 6% of the entire global coastal zone. Two-thirds of all observing programs offered accessible data, but methods and conditions for access were highly variable. Our assessment indicates that the global observing system is largely uncoordinated which results in a failure to deliver critical information required for informed decision-making such as, status and trends, for the conservation and sustainability of marine ecosystems and provision of ecosystem services. Based on our study, we suggest four key steps that can increase the sustainability, connectivity and spatial coverage of biological Essential Ocean Variables in the global ocean: (1) sustaining existing observing programs and encouraging coordination among these; (2) continuing to strive for data strategies that follow FAIR principles (findable, accessible, interoperable, and reusable); (3) utilizing existing ocean observing platforms and enhancing support to expand observing along coasts of developing countries, in deep ocean basins, and near the poles; and (4) targeting capacity building efforts. Following these suggestions could help create a coordinated marine biodiversity observing system enabling ecological forecasting and better planning for a sustainable use of ocean resources