In this interview, Karl Box shows how particle drift analysis with flux techniques enhances oral drug absorption in pharmaceutical research.
Can you tell us about Pion’s Rainbow Dynamic Dissolution Monitor?
Pion’s flagship product is the Rainbow Dynamic Dissolution Monitor, a fiber optic UV spectrometer that is designed to work with a variety of dissolution and permeation equipment from Pion and other manufacturers.
It has up to eight fiber optic probes that can be put into measuring vessels. This allows us to measure drug dissolution, solubilization, and permeation of drugs directly in the vessels.
Eliminating the need to separate samples for offline analysis yields real-time insights. The system usually collects data every 30 seconds, providing precise information about a sample’s behavior.
How does the Rainbow Dynamic Dissolution Monitor integrate with Pion’s Dissolution-Absorption tools for assessing drug performance?
The Rainbow Dynamic Dissolution Monitor may be smoothly integrated into a variety of Pion’s dissolution and absorption tools.
For example, in early development, the MicroFLUX™system measures drug permeability across a membrane dividing donor and acceptor compartments using Rainbow probes. As we get to clinical development, tools such as the MiniFLUX, BioFLUX™, and MacroFLUX™ come into play.
These devices have a donor chamber separated from an acceptor chamber by a biomimetic membrane.
The Rainbow UV probes monitor concentrations in both the donor vessel and the acceptor absorption chamber, assessing Flux performance and providing a comprehensive picture of drug behavior at various phases of development.
Can you explain the concept of particle drift and its impact on drug absorption?
Numerous studies have shown that when an Active Pharmaceutical Ingredient (API) dose surpasses the intestinal solubility limitations, oral absorption might be higher than expected.
This shows that undissolved particles can have a major impact on the absorption process in vivo, even when solubility is limited.
Particle drift is the phenomenon in which undissolved nanoparticles in a drug formulation diffuse into the solution’s unstirred water layer near the membrane surface and dissolve there. This can increase medication permeability, allowing for more effective absorption.
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Could you share details about the piroxicam case study demonstrating the particle drifting effect and its findings?
The MicroFLUX™ equipment was used to investigate the flux behavior of untreated piroxicam and its nanosubstances. This was a partnership with Nanoform in Finland, and the results were initially presented at the Controlled Release Society’s annual meeting in 2023.
Experiments were carried out in pH 5 acetate buffer with varying drug loadings on the donor side. Flux was measured across Pion’s gastrointestinal tract membrane into the acceptor sink buffer in the receiver. In all tests, the donor vessel loadings surpassed the piroxicam solubility limit.
The findings revealed a clear impact of particle size on flux. The piroxicam nanosuspension had a significantly higher Flux than the bulk suspension. In addition, we determined the upper limit of flux improvement, which happens when the unstirred water layer reaches solubility saturation.
We evaluated how particle drift affected overall in vitro flux, which has broader implications for the creation of enabling formulations.
The study shows that lowering particle size not only improves dissolving rates but also increases drug permeability, especially for drugs whose unstirred water layer permeability inhibits absorption.
This is especially significant for drugs that have high membrane permeability and require large dosages. In these circumstances, particle size reduction can help enhance total medication absorption.
What are the implications of these findings for biopharmaceutical modeling and in vivo absorption?
The findings have important implications for biopharmaceutical modeling and in vivo absorption. Drug absorption relies heavily on the large surface area of the human intestine, which is dominated by the intestine wall’s circular folds and villi.
When scaling in vitro Flux results to in vivo conditions, we must account for the variation in membrane surface area and scale the results to reflect the three-dimensional nature of the folds and villi structures.
For example, a two-fold increase in in vitro Flux could result in a tenfold increase in in vivo absorption due to the surface area given by the villi structures.
The particle drift effect permits nanoparticles to penetrate the unstirred water layer, increasing the amount of medication available for absorption. This is a game changer since properly constructed in vitro Flux experiments enable scientists to quantify the relative improvement in in vivo absorption due to nanoscale reduction.
How does Pion’s Predictor™ software help translate in vitro results to in vivo-relevant data?
Pion’s new Predictor™ software tool is designed to take data from the Rainbow instrument and translate in vitro results into in vivo forecasts.
These include correcting for in vivo absorption barrier properties like unstirred water layer thickness, scaling the results based on drug permeability and available intestinal surface area, accounting for dose clearance differences between in vitro and in vivo systems, and adjusting for intestinal transit time.
The total mass absorbed in vivo is calculated, resulting in the maximum absorbable dose. The oral fraction absorbed is then calculated by dividing the total mass absorbed by the supplied dose and converted to a percentage.
Pion Predictor™ software uses the GUT framework to help model drug absorption. How can in vitro Flux be used within this framework?
The Gastrointestinal Unified Theoretical (GUT) framework, described in Kiyohiko Sugano’s book “Biopharmaceutical Modelling and Simulations: Theory, Practice, Method and Applications” published by Wiley in 2012, is a system of equations that model key processes such as dissolution, precipitation, and absorption.
To create reliable predictions, this system requires input parameters such as measured physicochemical qualities and constants. These factors quantify dissolution and precipitation rates, as well as drug permeability, which leads to estimates of oral absorption.
While the equations may sound difficult, one intriguing component of this model is that in vitro Flux can act as a substitute for many of the dissolution and permeation processes involved. Using Pion’s Flux assay results, many of the equations driving dissolution and permeation in the GUT framework can be replaced.
This allows you to calculate the amount of a material permeating the intestinal wall using simply the Flux value, as long as it is supported by the solubility and dissolution behavior observed in the donor vessel. The accuracy of these predictions is dependent on how well the experimental assay mimics intestinal conditions.
Another case study was conducted in collaboration with researchers at Ritsumeikan University. How do the Celecox Flux assays’ results demonstrate the impact of particle drift on oral drug absorption prediction?
Another study was conducted with Shiori Ishida and Kiyo Sugano from Ritsumeikan University in Japan. The primary purpose was to investigate the effect of particle drift on the in vitro Flux of Celecoxib formulations and utilize the results to predict in vivo human oral absorption.
Celecox, the commercial formulation, comprises a significant concentration of nanosized particles, which may affect its pharmacokinetics. Our study, which was first presented at the AAPS annual meeting in 2023, investigated how these nanosized particles affect drug absorption.
The Celecox Flux assay results show that incorporating the particle drift effect in predictive models greatly enhances the accuracy of oral fraction absorbed estimates.
When utilizing the Predictor software without accounting for particle drift, the largest fraction absorbed is observed at the lowest administered dose, while the lowest fraction absorbed occurs at the highest dose.
This result is mostly due to the drug’s substantial solubility and unstirred water layer permeability. The anticipated oral absorption for the highest dose remains below 10 % throughout the intestinal transit time.
When the particle drift impact is included in the model, the proportion of Flux caused by particle drift is adjusted based on villi access, resulting in a significant improvement in forecasting the total oral drug fraction absorbed across all dose levels. This change brings predictions closer to published human oral fraction absorbed data.
The comparison of anticipated fraction absorbed values demonstrates that disregarding particle drift leads to more erroneous estimates at higher dosages. Accounting for the particle drifting effect improves the in vitro predictions’ alignment with the expected in vivo results.
This study shows how Flux data may be utilized to estimate the absolute in vivo proportion of drug absorbed, calculate the contribution of particle drift to the total Flux value, and account for its impact when scaling to in vivo settings.
Pion Flux assays aid in the creation of enabling formulations by detecting particle drift effects, analyzing bioavailability improvements due to improved surface access, and fine-tuning drug absorption predictions in clinical trials.
About Karl Box
Karl Box was appointed Chief Scientific Officer (Europe) at Pion (UK) in 2020. He is responsible for scientific and chemistry-related responsibilities within the organization, as well as assisting commercial activities and business development.
His expertise is in physicochemical measurements, and he has built a successful career developing innovative apparatus and tests to aid in drug discovery and development.
This information has been sourced, reviewed and adapted from materials provided by Pion Inc.
For more information on this source, please visit Pion Inc.
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