Understanding TIM Technology

Dissolution is one of the most established testing methodologies in the pharmaceutical field. Traditionally, it has played a key role in quality control (QC). However, over the years there has been a push toward developing novel in vitro and in silico dissolution approaches within formulation development to predict clinical exposure outcomes with a strong imperative to move away from unethical animal testing. While a standardized array of pharmacopeial equipment exists, this equipment is fundamentally lacking in relevance to the human body and is instead designed with simplicity and reproducibility in mind. Being able to study the interplay of oral formulations with the dynamically changing environment of the gastrointestinal tract, demands the utilization of in vitro models that are designed based on in vivo observations and data.

TIM Technology

There are a range of non-compendial dissolution tools available. However, industry is often cautious to adopt these systems due to a lack of standardization and validation. To date, TIM Systems are the most validated advanced intestinal models available with over 30 years of use in pharmaceutical research.

TIM-1 - Stomach and Small Intestine

The TIM-1 is a four-compartmental model of the upper GI tract, representing the stomach, duodenum, jejunum and ileum, connected by peristaltic valve pumps. The lumen of each compartment is represented by a flexible, cylindrical silicone tube. A software-controlled system communicates with in-line probes to control mixing, transit of the contents, dynamic secretions of simulated gastric and intestinal fluids. Input settings can be modified to represent a range of GI conditions, including fasted and fed states, the latter using FDA standard or customised meals. Intestinal secretions introduced include electrolytes, bile, pancreatin and sodium bicarbonate. Gastric acid and sodium bicarbonate control pH following a predetermined curve or according to feedback from pH probes, mimicking human buffer systems. Absorption of water-soluble digestion products (up to 10 kDa) is mimicked by dialysis membranes connected to the jejunal and ileal compartments. Lipophilic products are removed through a 50 nm filter that enables passage of micelles but retains fat droplets (Minekus, et al. 2015).

tiny-TIMsg

The tiny-TIMsg, is also an upper GI model designed to increase throughput and specialized for formulations that do not rely on multicompartmental models for the intestine. It has an advanced gastric compartment, the TIM-agc, which further improves biorelevance of the simulated stomach by incorporating human gastric architecture. Further, gastric motility is controlled in a more physiologically relevant manner, mimicking pressure & shear forces, the housekeeper wave and phase-specific gastric emptying

TIM-2 - Colon Model

The TIM-2 is the most advanced in vitro model of the human colon to date, photographed above. The extensively validated model includes fermentation, dynamic secretions and absorption phenomena and a lumen with a flexible wall to mimic the contractile motility of the colon. Moreover, TIM-2 has four individual units that can operate in parallel over a period of one week, boosting research throughput. The model can be inoculated with microbiota from individuals of different age ranges (infants, adults, elderly), disease states (healthy, irritable bowel disease, Crohn’s Disease, etc.), geographical populations, and so on. Following inoculation, a short adaptation period is required which permits development of a dense, diverse and active bacterial population.

TIM-2 can simulate conditions of each region of the colon to study how drug release from a formulation is influenced by intracolonic environments and the effects of drug release on resident bacterial population. The dialysis system absorbs drug molecules, water and microbial metabolites as is the case in vivo. The TIM-2 is suitable for testing modified release formulations that are designed to reach the colon before achieving full drug release.

Core Applications

Any type of oral formulations and delivery systems can be tested in TIM

The performance of each formulation will be affected by the interplay between the drug substance, the excipients and or formulation vehicle, and the dynamically changing environment of the GI lumen. The TIM Systems reproduce this interplay and, therefore, predict the behavior of oral formulations. This allows the comparison between different formulations, such as different dosage forms including powders, liquids, tablets and capsules, or release kinetics (immediate vs. controlled release), changes in excipient composition, variability between different manufacturers and batch quality control, among other variables.

Furthermore, the effects of different conditions on the rate of release, solubility and bioaccessibility of an API can also be investigated. For instance, food effect studies may be performed by administating the FDA-recommended high fat meal (or others), or postprandial conditions, such as increased bile secretion, compared to fasted state conditions. Other conditions include: proton-pump inhibitor coadministration (by elevating the gastric pH), variation in gastric emptying or motility, reduced secretion of pancreatic fluids or enzymes, age-specific parameters, different species, extreme parameter values that may present in different states and so on. Other performance criteria may include pH effect, precipitation risk, metabolite formation and survival of live biotherapeutic products.

How is this tested?

Formulation efficacy is typically assessed by the bioaccessible fraction. This data corresponds to the fraction that would be available for absorption through the gut wall in vivo, i.e., the amount of API dissolved in the lumen of the small or large intestine.

Bioaccessibility can be reported as:

• a percentage of the amount of API recovered from the TIM experiment (% of recovery)
• a percentage of the label-claimed dose (% of dose) at specific GI segments or following complete transit.
• area under the curve (AUC), which corresponds to the area defined by the bioaccessibility of a compound measured over time. This follows the typical format of results obtained from in vivo studies, allowing for a direct comparison using simple techniques such as prediction error or absolute average fold error (AAFE), for example.

Measuring Absorption Potential

As a biorelevant in vitro screening tool used to differentiate candidate formulations, TIM has been validated in applications across stages of development, such as: the development and optimization of formulations, selection process in drug substance modifications (different salts or solid forms) and/or formulations, bridging formulations during clinical trial programs or commercial manufacturing, predicting food effect, PPI co-administration, and dose linearity in exposure because of solubility limitations.

A TIM experiment produces the following data:

• Tmax and Cmax
• Luminal API concentrations (total and dissolved) at different time points and different GI sites
• API/biologics stability in the lumen of the GI tract
• Visualization of formulation behaviour (disintegration, swelling, erosion, release)
• Amount of API delivered into the colon
• API / excipient and colonic microbiome interactions
• Inputs for in silico modelling (PBBM) software platforms

The TIM Company is a CRO based in the Netherlands, utilizing its novel in vitro technology to perofm studies for predicting oral formulation behavior in vivo. As the most advanced intestinal models, TIM simulates different GI conditions in healthy adults, disease conditions, pediatric populations, fasted and fed states, PPI drug co-administration and more.