ORBITO

Oral administration is the most common route for medication, which can come in the form of solid tablets, capsules, or chewable tablets, or as drinkable liquids. Solid medications, such as tablets and capsules, deliver the active ingredient to the patient after they dissolve in the gastrointestinal (GI) tract and are then absorbed into the bloodstream.

However, the seemingly simple task of swallowing a pill hides a complex process which is influenced by the drug, the formulation, and GI factors like food and liquid consumption, gastric pH (acidity), and the absorptive capabilities of the digestive tract. To be able to design successful  simulation tools fundamental for the efficient development of new oral pharmaceutical dosage forms, scientists need a thorough knowledge of key aspects of GI physiology and their impact on formulation performance and subsequent drug release behaviour.

The main purpose of the OrBiTo project was to develop and optimise new lab-based and computational tools which could predict the performance of oral drug formulations in patients with greater accuracy than previously available tools.

Aiming to reduce and replace drug absorption studies in animals and humans currently required throughout all phases of drug development, with predictive in vitro and in silico tools, OrBiTo scientists set out to develop a framework for optimal use of tools able to predict the influence of drug form and formulation on oral drug absorption.

Tap or gas

The project’s main achievement is a novel understanding of the oral absorption process based on about 20 mechanistic in vivo studies that resulted in better knowledge of GI fluids and conditions, intestinal wall permeability, and drug concentrations in the GI tract, all of which form the basis for the improvement of in vitro and in silico predictive tools.

By further increasing our understanding of the oral drug absorption process, creating new and refined in vivo predictive tools, validating and standardising key existing tools, as well as developing a guidance for the rational use of an array of different tools, the project’s ultimate goal was to reduce the need for exposing laboratory animals and healthy volunteers to developmental drugs.

An illustrative and interesting discovery of OrBiTo was the impact of sparkling water on the absorption of the painkiller paracetamol when taking a standard tablet. Scientists at KU Leuven investigated the time it takes for paracetamol to reach the small intestine, from where it can be absorbed into the bloodstream. They found that a paracetamol tablet dissolves faster with sparkling water – on average, it took only 10 minutes for the drug to reach the small intestine, compared with half an hour when taken with tap water. Reaching maximum levels of paracetamol in the bloodstream took, on average, 30 minutes with sparkling water, but more than 90 minutes with tap water.

The study proved the important role of the stomach in oral drug absorption, since pressure events in the stomach, which occurred more frequently after intake of sparkling water, can determine the rate of drug dissolution and transfer to the small intestine. It further revealed the challenge of developing drug formulations that can withstand these real-life fluctuations in gastric physiology.

By magnetic resonance imaging (MRI) measurements of gastric volumes, OrBiTo researchers at Greifswald University  discovered that taking oral medicine with food, as commonly recommended, results in a slower rate of drug absorption since it follows the average six-hour long food route to the intestines. More importantly, since water empties from the stomach more rapidly than food, future medicines could be designed to follow the water, and this will result in faster drug absorption.

Other achievements:

• 15 new or refined in vitro predictive tools;
• significant standardisation and validation of in vitro predictive tools;
• decision tools and best practice guidance for the rational use of this array of predictive methods;
• ring studies with EFPIA partners to determine the inter-laboratory reproducibility of biorelevant dissolution testing;
• a new database format for the storage of biopharmaceutics and in vivo data populated with historical data from EFPIA;
• about 170 papers published in leading international pharmaceutics journals;
• more than 60 examples of the implementation of OrBiTo tools, methods and best practice guides at industrial partners.

By taking a new approach to investigating and validating novel and existing biopharmaceutics tools, and by using active pharmaceutical ingredients, formulations and supporting data from industry partners, OrBiTo scientists were able to capture the full complexity of the GI drug absorption process. They focused on an improved insight into GI physiology and drug absorption, the development of physicochemical and in vitro tools, and  the integration of all data through the application of in silico models of drug absorption.

OrBiTo results will contribute to:

1. reducing the time and money needed for drug development (a clinical absorption study takes at least six months and a failed late-stage study could lead to delayed drug launch);
2. lower manufacturing costs through in vivo relevant quality tests, and
3. the development of better products for patients with improved efficacy/safety properties through improved product designs.

The OrBiTo project brought together more than 150 scientists from 13 industrial and 14 academic, regulatory and technology partners, each contributing with unique expertise and best practice. That provided the opportunity for developing novel and, at the same time, practically useful solutions. The results of the project influenced similar ones outside the EU, such as Cobito, a similar type of consortium started in Japan. The OrBiTo database will be maintained and enriched by a new consortium formed of past members of OrBiTo, and with funding primarily from EFPIA. In addition, two more EU initiatives in the oral biopharmaceutics area – PEARLL and UNGAP, both with the participation of industry and academia, are to follow OrBiTo.