[Show abstract][Hide abstract] ABSTRACT: We hypothesized that nanosuspensions could be promising for the delivery of the poorly water soluble anti-cancer multi-targeted kinase inhibitor, MTKi-327. Hence, the aims of this work were (i) to evaluate the MTKi-327 nanosuspension for parenteral and oral administrations and (ii) to compare this nanosuspension with other nanocarriers in terms of anti-cancer efficacy and pharmacokinetics. Therefore, four formulations of MTKi-327 were studied: (i) PEGylated PLGA-based nanoparticles, (ii) self-assembling PEG750-p-(CL-co-TMC) polymeric micelles, (iii) nanosuspensions of MTKi-327; and (iv) Captisol solution (pH=3.5). All the nano-formulations presented a size below 200 nm. Injections of the highest possible dose of the three nano-formulations did not induce any side effects in mice. In contrast, the maximum tolerated dose of the control Captisol solution was 20-fold lower than its highest possible dose. The highest regrowth delay of A-431-tumor-bearing nude mice was obtained with MTKi-327 nanosuspension, administered intravenously, at a dose of 650 mg/kg. After intravenous and oral administration, the AUC0-∞ of MTKi-327 nanosuspension was 2.4-fold greater than that of the Captisol solution. Nanosuspension may be considered as an effective anti-cancer MTKi-327 delivery method due to (i) the higher MTKi-327 maximum tolerated dose, (ii) the possible intravenous injection of MTKi-327, (iii) its ability to enhance the administered dose and (iv) its higher efficacy.
Full-text · Article · May 2014 · European Journal of Pharmaceutics and Biopharmaceutics
[Show abstract][Hide abstract] ABSTRACT: This review summarizes the current knowledge on anatomy and physiology of the human gastrointestinal tract in comparison with that of common laboratory animals (dog, pig, rat and mouse) with emphasis on in vivo methods for testing and prediction of oral dosage form performance. A wide range of factors and methods are considered in addition, such as imaging methods, perfusion models, models for predicting segmental/regional absorption, in vitro in vivo correlations as well as models to investigate the effects of excipients and the role of food on drug absorption. One goal of the authors was to clearly identify the gaps in todays knowledge in order to stimulate further work on refining the existing in vivo models and demonstrate their usefulness in drug formulation and product performance testing.
No preview · Article · Mar 2014 · European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences
[Show abstract][Hide abstract] ABSTRACT: In 2010, the National Institutes of Health (NIH) established the Therapeutics for Rare and Neglected Diseases (TRND) program within the National Center for Advancing Translational Sciences (NCATS), which was created to stimulate drug discovery and development for rare and neglected tropical diseases through a collaborative model between the NIH, academic scientists, nonprofit organizations, and pharmaceutical and biotechnology companies. This paper describes one of the first TRND programs, the development of 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) for the treatment of Niemann-Pick disease type C1 (NPC1). NPC is a neurodegenerative, autosomal recessive rare disease caused by a mutation in either the NPC1 (about 95% of cases) or the NPC2 gene (about 5% of cases). These mutations affect the intracellular trafficking of cholesterol and other lipids, which leads to a progressive accumulation of unesterified cholesterol and glycosphingolipids in the CNS and visceral organs. Affected individuals typically exhibit ataxia, swallowing problems, seizures, and progressive impairment of motor and intellectual function in early childhood, and usually die in adolescence. There is no disease modifying therapy currently approved for NPC1 in the US. A collaborative drug development program has been established between TRND, public and private partners that has completed the pre-clinical development of HP-beta-CD through IND filing for the current Phase I clinical trial that is underway. Here we discuss how this collaborative effort helped to overcome scientific, clinical and financial challenges facing the development of new drug treatments for rare and neglected diseases, and how it will incentivize the commercialization of HP-beta-CD for the benefit of the NPC patient community.
Full-text · Article · Feb 2014 · Current Topics in Medicinal Chemistry
[Show abstract][Hide abstract] ABSTRACT: Preformulation measurements are used to estimate the fraction absorbed in vivo for orally administered compounds and thereby allow an early evaluation of the need for enabling formulations. As part of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary of the pharmaceutical profiling methods available, with focus on in silico and in vitro models typically used to forecast active pharmaceutical ingredient's (APIs) in vivo performance after oral administration. An overview of the composition of human, animal and simulated gastrointestinal (GI) fluids is provided and state-of-the art methodologies to study API properties impacting on oral absorption are reviewed. Assays performed during early development, i.e. physicochemical characterization, dissolution profiles under physiological conditions, permeability assays and the impact of excipients on these properties are discussed in detail and future demands on pharmaceutical profiling are identified. It is expected that innovative computational and experimental methods that better describe molecular processes involved in vivo during dissolution and absorption of APIs will be developed in the OrBiTo. These methods will when successful provide early insights into successful pathways (medicinal chemistry or formulation strategy) and are anticipated to increase the number of new APIs with good oral absorption being discovered.
Full-text · Article · Nov 2013 · European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences
[Show abstract][Hide abstract] ABSTRACT: OrBiTo is a new European project within the IMI programme in the area of oral biopharmaceutics tools that includes world leading scientists from nine European universities, one regulatory agency, one non-profit research organisation, four SMEs together with scientists from twelve pharmaceutical companies. The OrBiTo project will address key gaps in our knowledge of gastrointestinal (GI) drug absorption and deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery and. This will be achieved through novel prospective investigations to define new methodologies as well as refinement of existing tools. Extensive validation of novel and existing biopharmaceutics tools will be performed using API, formulations and supporting datasets from industry partners. A combination of high quality in vitro or in silico characterizations of API and formulations will be integrated into physiologically based in silico biopharmaceutics models capturing the full complexity of GI drug absorption. This approach gives an unparalleled opportunity to initiate a transformational change in industrial research and development to achieve model-based pharmaceutical product development in accordance with the Quality by Design concept. Benefits include an accelerated and more efficient drug candidate selection, formulation development process, particularly for challenging projects such as low solubility molecules (BCS II and IV), enhanced and) and modified-release formulations, as well as allowing optimisation of clinical product performance for patient benefit. In addition, the tools emerging from OrBiTo is expected to significantly reduce demand for animal experiments in the future as well as reducing the number of human bioequivalence studies required to bridge formulations after manufacturing or composition changes.
No preview · Article · Nov 2013 · European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences
[Show abstract][Hide abstract] ABSTRACT: Accurate prediction of the in vivo biopharmaceutical performance of oral drug formulations is critical to efficient drug development. Traditionally, in vitro evaluation of oral drug formulations has focused on disintegration and dissolution testing for quality control (QC) purposes. The connection with in vivo biopharmaceutical performance has often been ignored. More recently, the switch to assessing drug products in a more biorelevant and mechanistic manner has advanced the understanding of drug formulation behavior. Notwithstanding this evolution, predicting the in vivo biopharmaceutical performance of formulations that rely on complex intraluminal processes (e.g. solubilization, supersaturation, precipitation…) remains extremely challenging. Concomitantly, the increasing demand for complex formulations to overcome low drug solubility or to control drug release rates urges the development of new in vitro tools. Development and optimizing innovative, predictive Oral Biopharmaceutical Tools is the main target of the OrBiTo project within the Innovative Medicines Initiative (IMI) framework. A combination of physico-chemical measurements, in vitro tests, in vivo methods, and physiology-based pharmacokinetic modeling is expected to create a unique knowledge platform, enabling the bottlenecks in drug development to be removed and the whole process of drug development to become more efficient.
No preview · Article · Aug 2013 · European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences
[Show abstract][Hide abstract] ABSTRACT: Cyclodextrins are value-adding functions excipients which have garnered significant interest and are widely used in pharmaceutical and nutraceutical products. These materials can contribute to the optimal biopharmaceutical performance of a medicine and in some cases are enabling, meaning that the drug product would not be possible without the technology. It has been estimated that products enabled by chemically modified cyclodextrins account for sales of almost US$2 billion (2008 figures). While all compounds will not necessarily benefit from the application of cyclodextrins, the approach is simple to test. Based on this simplicity as well as the low toxicological potential of these materials, cyclodextrins are often used in early drug screening and early clinical assessments and figure highly in formulation decision trees. While solubilization is, to date, the most often cited reason for using cyclodextrins, their ability to influence stability as well as other aspects of a drug suggests a significant potential for the derivatives in the future. Thus, assessments of cyclodextrin complexation and aggregation point to the possibility of increased delivery through biological membranes as well as drug products with improved shelf-lives. Cyclodextrins have also gained interest as components of siRNA delivery vectors as well as in numerous industrial applications.
[Show abstract][Hide abstract] ABSTRACT: Supersaturating Drug Delivery Systems (SDDS) hold the promise of enabling intestinal absorption for difficult-to-formulate, poorly soluble drug candidates based on a design approach that includes (1) converting the drug into a high energy or rapidly dissolving system which presents a supersaturated solution to the gastrointestinal environment and (2) dosage form components that act to stabilize the formed metastable drug solution through nucleation and/or crystal growth inhibition. The appropriate development and study of SDDS require that useful and biorelevant supersaturation and precipitation assays are available. This review summarizes different methodological aspects of currently available in vitro assays, including the generation of supersaturation (solvent shift, pH shift or formulation-induced), the quantification of supersaturation and the detection of precipitation. Also down-scaled approaches, including 96-well plate setups, are described and situated in the pharmaceutical development cycle based on their consumption of API as well as time requirements. Subsequently, the ability to extrapolate in vitro supersaturation assessment to the in vivo situation is discussed as are direct and indirect clinical tools that can shed light on SDDS. By emphasizing multiple variables that affect the predictive power of in vitro assays (e.g. the nature of the test media, hydrodynamics, temperature and sink versus non-sink conditions), this review finally highlights the need for further harmonization and biorelevance improvement of currently available in vitro procedures for supersaturation and precipitation evaluation.
No preview · Article · Nov 2012 · International Journal of Pharmaceutics