Preclinical Bioavailability Strategy for Decisions on Clinical Drug Formulation Development: An In Depth Analysis.

The aim of the presented retrospective analysis was to verify whether a previously proposed Janssen Biopharmaceutical Classification System (BCS)-like decision tree, based on preclinical bioavailability data of a solution and suspension formulation, would facilitate informed decision making on the clinical formulation development strategy. In addition, the predictive value of (in vitro) selection criteria, such as solubility, human permeability, and/or a clinical dose number (Do), were evaluated, potentially reducing additional supporting formulation bioavailability studies in animals. The absolute ( F) and relative ( F) bioavailability of an oral solution and suspension, respectively, in rat or dog and the anticipated BCS classification were analyzed for 89 Janssen compounds with 28 of these having F and F in both rat and dog at doses around 10 and 5 mg/kg, respectively.

Evaluation of Three Amorphous Drug Delivery Technologies to Improve the Oral Absorption of Flubendazole.

This study investigates 3 amorphous technologies to improve the dissolution rate and oral bioavailability of flubendazole (FLU). The selected approaches are (1) a standard spray-dried dispersion with hydroxypropylmethylcellulose (HPMC) E5 or polyvinylpyrrolidone-vinyl acetate 64, both with Vitamin E d-α-tocopheryl polyethylene glycol succinate; (2) a modified process spray-dried dispersion (MPSDD) with either HPMC E3 or hydroxypropylmethylcellulose acetate succinate (HPMCAS-M); and (3) confining FLU in ordered mesoporous silica (OMS). The physicochemical stability and in vitro release of optimized formulations were evaluated following 2 weeks of open conditions at 25°C/60% relative humidity (RH) and 40°C/75% RH.

High speed electrospinning for scaled-up production of amorphous solid dispersion of itraconazole.

High speed electrospinning (HSES), compatible with pharmaceutical industry, was used to demonstrate the viability of the preparation of drug-loaded polymer nanofibers with radically higher productivity than the known single-needle electrospinning (SNES) setup. Poorly water-soluble itraconazole (ITRA) was formulated with PVPVA64 matrix polymer using four different solvent-based methods such as HSES, SNES, spray drying (SD) and film casting (FC). The formulations were assessed in terms of improvement in the dissolution rate of ITRA (using a "tapped basket" dissolution configuration) and analysed by SEM, DSC and XRPD.

Summary report of PQRI Workshop on Nanomaterial in Drug Products: current experience and management of potential risks.

At the Product Quality Research Institute (PQRI) Workshop held last January 14-15, 2014, participants from academia, industry, and governmental agencies involved in the development and regulation of nanomedicines discussed the current state of characterization, formulation development, manufacturing, and nonclinical safety evaluation of nanomaterial-containing drug products for human use. The workshop discussions identified areas where additional understanding of material attributes, absorption, biodistribution, cellular and tissue uptake, and disposition of nanosized particles would continue to inform their safe use in drug products. Analytical techniques and methods used for in vitro characterization and stability testing of formulations containing nanomaterials were discussed, along with their advantages and limitations.

Nanosuspension for the delivery of a poorly soluble anti-cancer kinase inhibitor.

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.

In vivo methods for drug absorption - comparative physiologies, model selection, correlations with in vitro methods (IVIVC), and applications for formulation/API/excipient characterization including food effects.

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 today's 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.

Collaborative development of 2-hydroxypropyl-β-cyclodextrin for the treatment of Niemann-Pick type C1 disease.

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-β-cyclodextrin (HP-β-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).

Early pharmaceutical profiling to predict oral drug absorption: current status and unmet needs.

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.

In vitro models for the prediction of in vivo performance of oral dosage forms.

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.

Evaluation of gastrointestinal drug supersaturation and precipitation: strategies and issues.

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.

Cyclodextrins as functional excipients: methods to enhance complexation efficiency.

Cyclodextrins have gained currency as useful solubilizing excipients with an ever increasing list of beneficial properties and functionalities. Although their use in liquid dosage forms including oral and parenteral solutions is straightforward, their application to solids can be confounded by the added bulk that is contributed to the formulation. This factor has limited the use of cyclodextrin in tablets and relates systems mainly to potent drug substances.

Supersaturating drug delivery systems: fast is not necessarily good enough.

An emerging technology subtype that has been adopted by formulators to address low-solubility issues is the supersaturating drug delivery system; this system is based on the "spring" and "parachute" design elements, which have been applied to lipid-based formulations, S(M)EDDS, solid dispersions, nano-based systems, and many others. This broad formulation approach attempts to delicately balance the need of creating intraluminal drug concentrations in excess of its thermodynamic solubility while at the same time providing for sufficient solution stability to allow for useful drug absorption. The conundrum created is that the higher the extent of supersaturation, the lower the physical stability of the metastable solution based on an increased tendency for a solubilized drug to precipitate.

Self-assembly of cyclodextrin complexes: effect of temperature, agitation and media composition on aggregation.

Recently it has been shown that aggregation of drug/cyclodextrin inclusion complexes is strongly influenced by the drug molecule in addition to self-assembling tendencies of the cyclodextrin itself in aqueous media. Whereas the mechanistic basis of cyclodextrin self-assembly is known, the driving forces for complex aggregation are still unknown. In the present study, the influence of temperature on hydrocortisone/2-hydroxypropyl-β-cyclodextrin complex aggregation is investigated as are influences associated with the addition of ethanol or water soluble polymers to the aqueous systems.

Pharmaceutical applications of cyclodextrins: effects on drug permeation through biological membranes.

Objectives: Cyclodextrins are useful solubilizing excipients that have gained currency in the formulator's armamentarium based on their ability to temporarily camouflage undesirable physicochemical properties. In this context cyclodextrins can increase oral bioavailability, stabilize compounds to chemical and enzymatic degradation and can affect permeability through biological membranes under certain circumstances. This latter property is examined herein as a function of the published literature as well as work completed in our laboratories.

Self-assembly of cyclodextrins: the effect of the guest molecule.

The principle action by which cyclodextrins solubilize compounds is via inclusion complex formation. However, data suggest that cyclodextrins and their complexes also aggregate in solution and this aggregation contributes to their ability to solubilize poorly water-soluble materials. The current effort aims at better understanding the role of guest molecule nature (i.

Self-assembly of cyclodextrin complexes: aggregation of hydrocortisone/cyclodextrin complexes.

Cyclodextrins (CDs) are well known functional excipients for solubilization and stabilization of drugs in aqueous formulations as well as enabling adjuncts for increasing the oral bioavailability of solid dosage forms. More recently a number of the valuable properties of these CDs have been ascribed to nanoparticulate aggregation in addition to its ability to form molecular inclusion complexes. The purpose of this study is to identify and characterize the aggregation of CD inclusion complexes with a model drug, hydrocortisone, in saturated solutions which are more relevant to drug formulation than highly dilute systems.

Pharmaceutical applications of cyclodextrins: basic science and product development.

Objectives: Drug pipelines are becoming increasingly difficult to formulate. This is punctuated by both retrospective and prospective analyses that show that while 40% of currently marketed drugs are poorly soluble based on the definition of the biopharmaceutical classification system (BCS), about 90% of drugs in development can be characterized as poorly soluble. Although a number of techniques have been suggested for increasing oral bioavailability and for enabling parenteral formulations, cyclodextrins have emerged as a productive approach.

Application of PAMPA-models to predict BBB permeability including efflux ratio, plasma protein binding and physicochemical parameters.

This study examines whether algorithms to predict brain penetration of 88 drug candidates could benefit from inclusion of PAMPA data such as P(eff), flux and membrane retention. Specifically the ability to fit experimentally derived LogBB data with PAMPA information and compound related physicochemical and structural parameters was assessed. Collected data were analyzed by partial least square analysis and various regression models for LogBB.

Application of PAMPA-models to predict BBB permeability including efflux ratio, plasma protein binding and physicochemical parameters.

This study examines whether algorithms to predict brain penetration of 88 drug candidates could benefit from inclusion of PAMPA data such as Peff, flux and membrane retention. Specifically the ability to fit experimentally derived LogBB data with PAMPA information and compound related physicochemical and structural parameters was assessed. Collected data were analyzed by partial least square analysis and various regression models for LogBB.

Physicochemical properties of the amorphous drug, cast films, and spray dried powders to predict formulation probability of success for solid dispersions: etravirine.

Solid dispersion technology represents an enabling approach to formulate poorly water-soluble drugs. While providing for a potentially increased oral bioavailability secondary to an increased drug dissolution rate, amorphous dispersions can be limited by their physical stability. The ability to assess formulation risk in this regard early in development programs can not only help in guiding development strategies but can also point to critical design elements in the configuration of the dosage form.

Prediction of blood-brain barrier penetration of poorly soluble drug candidates using surface activity profiling.

The aim of this study was to determine whether transepithelial transport across the blood-brain barrier (BBB) [expressed as the logarithm of blood/brain partitioning coefficient (logbb)] could be correlated to surface tension properties for a series of new chemical entities (NCEs) having extremely low solubility in aqueous media. Surface tension data were generated by the "Du Nouy maximum pull force method" using an automated, small volume Kibron Delta 8 Multi-channel tensiometer. Using the surface pressure/concentration profiles, parameters such as the maximum surface pressure, cross-sectional area and the air-water partitioning coefficient were calculated for the individual compounds and correlated with their in vivo logbb values.

Active and passive tumor targeting of a novel poorly soluble cyclin dependent kinase inhibitor, JNJ-7706621.

The anti-cancer cyclin dependent kinase (CDK) inhibitors are poorly soluble drugs. The aims of this work were (i) to formulate a novel CDK inhibitor, JNJ-7706621, in polymeric micelles and nanoparticles, (ii) to compare passive and active targeting on tumor growth and (iii) to evaluate the potential synergy of JNJ-7706621 with Paclitaxel. Therefore, JNJ-7706621 was encapsulated in self-assembling diblock copolymers made up of epsilon-caprolactone (CL) and trimethylene carbonate (TMC) (PEG-p-(CL-co-TMC)) polymeric micelles and in (poly(lactide-co-glycolide)) (PLGA)-based PEGylated nanoparticles (passive targeting) as well as in RGD-grafted nanoparticles (active targeting).

Evaluation of various PAMPA models to identify the most discriminating method for the prediction of BBB permeability.

The Parallel Artificial Membrane Permeability Assay (PAMPA) has been successfully introduced into the pharmaceutical industry to allow useful predictions of passive oral absorption. Over the last 5 years, researchers have modified the PAMPA such that it can also evaluate passive blood-brain barrier (BBB) permeability. This paper compares the permeability of 19 structurally diverse, commercially available drugs assessed in four different PAMPA models: (1) a PAMPA-BLM (black lipid membrane) model, (2) a PAMPA-DS (Double Sink) model, (3) a PAMPA-BBB model and (4) a PAMPA-BBB-UWL (unstirred water layer) model in order to find the most discriminating method for the prediction of BBB permeability.

Novel self-assembling PEG-p-(CL-co-TMC) polymeric micelles as safe and effective delivery system for paclitaxel.

Paclitaxel (PTX) is an effective anti-cancer drug currently used to treat a wide variety of cancers. Unfortunately, nonaqueous vehicle containing Cremophor EL is associated with serious clinical side effects. This work aimed to evaluate the ability of polymeric micelles to (i) solubilize PTX without Cremophor EL and to be used as a (ii) safe and (iii) effective delivery system for PTX.