Kin Tang

Improved Human Bioavailability of Vemurafenib, a Practically Insoluble Drug, Using an Amorphous Polymer-Stabilized Solid Dispersion Prepared by a Solvent-Controlled Coprecipitation Process

The present work deals with improving the solubility of vemurafenib, a practically insoluble drug, by converting it into an amorphous-solid dispersion using a solvent-controlled precipitation process. The dispersion containing vemurafenib and hypromellose acetate succinate (HPMCAS), an enteric polymer, is termed microprecipitated bulk powder (MBP), in which the drug is uniformly dispersed within the polymeric substrate. HPMCAS was found to be the most suitable polymer for vemurafenib MBP, among a series of enteric polymers based on superior physical stability and drug-release characteristics of the MBP. The MBP provided a greater rate and extent of dissolution than crystalline drug, reaching an apparent drug concentration of 28-35 µg/mL, almost 30-fold higher than solubility of crystalline drug at 1 µg/mL. The supersaturation was also maintained for more than 4 h. Upon exposure to high temperature and humidity, the MBP was destabilized, resulting in crystallization and lower dissolution rate. The control of moisture and temperature is essential to maintain the stability of the MBP. In a relative human bioavailability study, vemurafenib MBP provided a four- to fivefold increase in exposure compared with crystalline drug. Improving solubility with an amorphous-solid dispersion is a viable strategy for the development of practically insoluble compounds.

Designing biorelevant dissolution tests for lipid formulations : Case example -Lipid suspension of RZ-50

Biorelevant dissolution test methods for lipid formulations of RZ-50, an experimental Roche compound, were developed and compared with standard compendial methods in terms of their in vivo predictability. Release of RZ-50, a poorly soluble weakly acidic drug, from lipid suspensions filled in soft gelatin capsules was studied in compendial and biorelevant media using the USP Apparatus 2 (paddle method) and the USP Apparatus 3 (Bio-Dis method). Pharmacokinetic data were obtained in dogs after oral administration of a single 2.5mg dose of RZ-50 soft gelatin capsules in the postprandial state. Level A IVIVC analysis and curve comparison of fraction drug dissolved vs. absorbed using the Weibull distribution were used to evaluate the in vitro methods in terms of their ability to fit the in vivo plasma profiles. Very low drug release was observed with the paddle method owing to poor dispersibility of the lipids in the dissolution media, whereas the Bio-Dis method hydrodynamics facilitated release of the drug by emulsifying the formulation in the medium. The best IVIVC was obtained using a dissolution medium representing fed gastric conditions in combination with the Bio-Dis method. Curve comparisons of the fraction drug absorbed and the fraction drug dissolved profiles based on Weibull distribution fits yielded similar results. The Bio-Dis/biorelevant in vitro method appears to be suitable for this type of lipid formulation.

Development of novel microprecipitated bulk powder (MBP) technology for manufacturing stable amorphous formulations of poorly soluble drugs.

A novel method was developed to manufacture amorphous formulations of poorly soluble compounds that cannot be processed with existing methods such as spray drying and melt extrusion. The manufacturing process and the characterization of the resulting amorphous dispersion are presented via examples of two research compounds. The novel process is utilized N,N-dimethylacetamide (DMA) to dissolve the drug and the selected ionic polymer. This solution is then co-precipitated into aqueous medium. The solvent is extracted out by washing and the co-precipitated material is isolated by filtration followed by drying. The dried material is referred to as microprecipitated bulk powder (MBP). The amorphous form prepared using this method not only provides excellent in vitro and in vivo performance but also showed excellent stability. The stabilization of amorphous dispersion is attributed to the high T(g), ionic nature of the polymer that help to stabilize the amorphous form by possible ionic interactions, and/or due to the insolubility of polymer in water. In addition to being an alternate technology for amorphous formulation of difficult compounds, MBP technology provides advantages with respect to stability, density and downstream processing.

Dissolution media simulating the proximal canine gastrointestinal tract in the fasted state

Human biorelevant media have been shown to be a useful tool in pharmaceutical development and to provide input for in silico prediction of pharmacokinetic profiles after oral dosing. Dogs, in particular Beagles, are often used as animal models for preclinical studies. Key differences in the composition of human and canine gastric and intestinal fluids are described in the literature and underscore the need to develop a discrete set of biorelevant media, adapted to the conditions of the proximal canine gastrointestinal (GI) tract, to improve forecast and interpretation of preclinical results using in vitro dissolution studies. Canine biorelevant media can also be used in the development of oral dosage forms for companion animals, which is a rapidly growing market. The compositions of Fasted State Simulated Gastric Fluid canine (FaSSGFc) and Fasted State Simulated Intestinal Fluid canine (FaSSIFc) are adapted to the physiological composition of the corresponding gastrointestinal fluids in terms of pH, buffer capacity, osmolality, surface tension, as well as the bile salt, phospholipid, and free fatty acid content (in terms of concentration and reported subtypes). It was demonstrated that canine Fasted State Simulated Intestinal Fluid (FaSSIFc) is superior in predicting the solubility of model compounds in Canine Intestinal Fluid (CIF) compared to the human biorelevant media (FaSSIF and FaSSIF-V2). Two different versions of FaSSGFc, composed at pH 1.5 and pH 6.5, offer the possibility to design in vitro studies which correspond to the in vivo study design, depending on whether pentagastrin is used to decrease the gastric pH in the dogs or not. Canine biorelevant media can therefore be recommended to achieve more accurate forecasting and interpretation of pharmacokinetic studies of oral drug products in dogs.

Summary Workshop Report: Facilitating Oral Product Development and Reducing Regulatory Burden Through Novel Approaches to Assess Bioavailability/ Bioequivalence

This summary workshop report highlights presentations and over-arching themes from an October 2011 workshop. Discussions focused on best practices in the application of biopharmaceutics in oral drug product development and evolving bioequivalence approaches. Best practices leverage biopharmaceutic data and other drug, formulation, and patient/disease data to identify drug development challenges in yielding a successfully performing product. Quality by design and product developability paradigms were discussed. Development tools include early development strategies to identify critical absorption factors and oral absorption modeling. An ongoing theme was the desire to comprehensively and systematically assess risk of product failure via the quality target product profile and root cause and risk analysis. However, a parallel need is reduced timelines and fewer resources. Several presentations discussed applying Biopharmaceutics Classification System (BCS) and in vitro–in vivo correlations in development and in post-development and discussed both resource savings and best scientific practices. The workshop also focused on evolving bioequivalence approaches, with emphasis on highly variable products (HVDP), as well as specialized modified-release products. In USA, two bioequivalence approaches for HVDP are the reference-scaled average bioequivalence approach and the two-stage group-sequential design. An adaptive sequential design approach is also acceptable in Canada. In European Union, two approaches for HVDP are a two-stage design and an approach to widen Cmax acceptance limits. For some specialized modified-release products, FDA now requests partial area under the curve. Rationale and limitations of such metrics were discussed (e.g., zolpidem and methylphenidate). A common theme was the benefit of the scientific and regulatory community developing, validating, and harmonizing newer bioequivalence methodologies (e.g., BCS-based waivers and HVDP trial designs).