The TIM technology is used to get consistent and reliable scientific data about the behavior of your oral drug products during transit through the stomach, the small intestine and large intestine.
Twenty years of experience with dynamic gastrointestinal simulation and performance of evaluation studies in comparison with clinical studies guarantees the predictive quality of the results for a broad range of TIM research applications.
The TIM-1 and tiny-TIM systems simulate the successive dynamic conditions in the stomach and small intestine, TIM-2 in the large intestine.
TIM studies quickly and cost-efficiently provide reliable information about the gastrointestinal release, stability, and bioaccessibility of your drug compounds.
Studies can be performed under simulated human conditions and animal conditions related to different types of drinks and meals, age, health status, and according to different dosage forms and co-medication. This information enables better informed decisions to be made, minimizing the number of subsequent animal experiments and clinical studies.
The multi-compartmental, computer-controlled TIM-1 system accurately simulates the successive dynamic human conditions or animal conditions in the stomach and the three parts of the small intestine: duodenum, jejunum and ileum. These conditions are responsible for the digestion of food and the release and dissolution of nutrients, bioactive compounds and pharmaceutical ingredients. Dissolved low molecular weight compounds are dialyzed or filtrated from the jejunum and ileum compartments. Samples collected during the experiments are analyzed for the respective compounds. These data give an accurate insight in the total and time-related availability for absorption of nutrients and drugs.
The TIM-2 system simulates the large intestine (colon). This includes high-density, metabolic active microbiota of human (e.g. adult or children, healthy or diseased) or animal origin under strict anaerobic conditions. The composition of the microbiota in TIM-2 is stable over a long term, as measured with DNA technologies. This is realized by accurate simulation of the colon conditions, such as temperature, pH control, peristalsis, the supply of non-digested food compounds as substrates for the microbiota and continuous filtration of the microbial metabolites and water that are produced. This enables the effect of a test product (e.g. prebiotics or a colon-targeted drug) on the microbiome and vice versa to be measured. Besides measurements of the microbiome using DNA technologies metabolites produced by the microbiome are also measured using TNO Triskelion’s analytical platforms. At least three experiments (for example, a duplicate experiment with the test product and one blank experiment) are performed in parallel. This enables a direct and reliable analysis of the effect of the test product on the microbiome compared to the blank experiment with identical start compositions of the microbiome. The throughput performance is relatively high in contrast to other in vitro dynamic colon systems.
Application for pharmaceutics
The TIM-1, tiny-TIM and TIM-2 systems have been used for more than 15 years for testing single or combined active pharmaceutical ingredients (APIs) and different types of oral dosage forms under simulated fasted or fed state human and/or animal GI conditions.
The main applications of the TIM systems in drug or formulation development processes are:
- Comparison of newly developed formulations with a reference formulation on the (regional) bioaccessibility of the API to select the most promising candidate for in vivo bioavailability or bioequivalence studies.
- Comparison of the bioaccessibility of an API from different formulations tested under fasted and fed state conditions to gain insight into the expected clinical food effect and/or to select the optimum test conditions for the in vivo clinical bioavailability studies.
The TIM systems simulating the human upper GI tract (TIM-1 and tiny-TIM) are part of the European IMI OrBiTo project (for more information: http://www.imi.europa.eu/content/orbito). This project (2012-2017), with a long list of participating pharmaceutical industrial and research partners, aims to develop a framework for the optimum use of predictive tools and preclinical models.
APIs and formulations
The physical-chemical properties of the API and the structure of the molecules (e.g. micro- versus nano-particles) determine the dissolution and bioaccessibility of the API. For their bioaccessibility especially low-soluble APIs (BCS class II and IV) depend on the formulation and the dissolution under the successive GI conditions after oral dosing. A broad range of oral dosage forms, from liquids to enteric coated single or multiple (mini) tablets, can be investigated in TIM under fasted and fed GI conditions. This may include fixed-dose formulations or a combination of an immediate-release and modified-release formulation. For extended or colon-targeted release formulations we measure the release and bioaccessibility of the APIs in the upper and lower GI tract by combining TIM-1 or tiny-TIM with the TIM-2 system.
Effect of food and co-medication
The TIM systems are also often applied to investigate the food effect on the bioaccessibility of the API during passage through the GI tract simulating fed state conditions as compared with the simulated fasted conditions. These differences in GI conditions include gastric pH, transit time and enzyme and bile concentrations. Not only liquid meals but also realistic solid meals (e.g. the high-fat meal often applied in clinical studies) can be tested in combination with the test product in the TIM system enabling the food effect in clinical studies to be predicted.
In addition, the effect of co-medication on the bioaccessibility of an API can be investigated in TIM. This can be a direct drug-drug interaction effect, e.g. influencing the release and/or solubility, or an indirect interaction by altered GI conditions after oral dose co-medication, such as a higher gastric pH by co-dosing with a proton-pump inhibitor (PPI) or delayed gastric emptying by morphine.
Pediatrics and Geriatrics
Age-related human GI conditions can be simulated for neonates and infants as well as the elderly to investigate the (off-label) use of (multiple) drugs after intake with age-related food matrices (e.g. formula milk, apple sauce).