Double Act

Pharmaceutical formulations are becoming ever more complex in order to meet the challenges of delivering new compounds that have difficult properties such as poor solubility, permeability or potency. There is also a push towards achieving tailored therapeutic approaches and enhancing the clinical performance of currently used compounds as part of their lifecycle management. With this drive toward increasingly complex dosage form design comes the need to validate robust clinical performance in the highly variable and challenging environment of the gastrointestinal (GI) tract.

A tablet designed to deliver a constant (zero order) rate of drug release throughout the gut will have to maintain this performance in the face of changing local pH; the grinding action of the antrum in the stomach; the physical presence of food; gradually reducing water availability; and digestive secretions, among others. Despite the range of very useful biorelevant in vitro tests that are available, the ultimate challenge for the formulation scientist remains the variability of the human gut. Pharmacokinetic (PK) profiling gives a reasonable indication of performance, but how do you ensure that the formulation behaves in vivo as designed?

Gamma Scintigraphic Imaging

Gamma scintigraphy is a technique whereby a gamma emitting radioisotope is used to ‘tag’ the carrier formulation, allowing its progress to be monitored in vivo following administration to a patient or volunteer. Typical gamma emitters used are technetium-99m (99mTc) and indium-111 (111In), commonly complexed with agents such as diethylene triamine pentaacetic acid to ensure there is no absorption of the radioisotope into the systemic circulation. Alternatively, a radiolabelled ion exchange resin can be incorporated into the dose, with a particle size in a range which ensures absorption from the gut cannot occur.

As it is gamma radiation that is detected, the data obtained from such studies are quantitative as well as qualitative, allowing calculation of the amount of a dosage form remaining in a particular area – for example, the percentage emptied from the stomach to the absorptive regions of the intestine – and the kinetics of processes such as tablet disintegration, distribution and clearance in the eye.

The method of incorporating the radiolabel into the formulation will vary, depending on how it is expected to behave in vivo, and which part of its performance the investigator wishes to monitor. For example, to evaluate the erosion or disintegration of a polymer matrix, it is essential to ensure that the radiolabel is distributed homogenously throughout the tablet. It is also critical that the radiolabel is only released in response to the physical erosion process, rather than diffusing out through the polymer matrix. In this case, the radiolabel should be included in an insoluble form, and incorporated into the formulation during the manufacturing process – during blending or granulation, for example.

In one particular case, a very small amount (<2 per cent) of 99mTc-labelled activated charcoal was incorporated into a tablet blend for the investigation of erosion rates and robustness of hydroxypropylmethyl cellulose (HPMC) matrix formulations (1). Scintigraphic imaging showed that at concentrations above the percolation threshold of the polymer (Tablet B), erosion rates were largely independent of location in the gut, whereas below the percolation threshold (Tablet A), performance was not robust (see Figure 1).

Dosage Performance

On the other hand, if it is the GI transit of a non-disintegrating core that is of interest, it may be possible to incorporate the radiolabel into an intact pre-manufactured tablet by carefully drilling a small hole and adding a radiolabel to the core. It is also feasible to incorporate two different radiolabels of different energies into the same formulation, and visualise them both simultaneously in vivo. For example, this could be used to monitor the behaviour of a modified release bilayer tablet.

A key point is that while it is often useful to radiolabel the active drug to understand the absorption, distribution, metabolism and elimination of a compound, gamma scintigraphic studies to validate dosage form performance are designed so that the behaviour of the actual delivery device is being monitored (1,2). In fact, this type of study commonly employs well-characterised pharmaceutical compounds as a marker used as proof of concept for a platform technology, or where enhanced clinical benefits of an ‘old’ compound are sought by providing more targeted and appropriate release behaviour.

When used in combination with PK blood sampling – a technique known as pharmacoscintigraphy – a detailed understanding of in vivo dosage form performance can be attained.

A formulation designed to release drugs in the colon may rely on a functional coating that only dissolves in response to the pH changes in the lower gut, or in the presence of the bacterial enzymes in the colon. However, with PKs alone it may be difficult to elucidate whether this coating functioned appropriately, or whether any blood plasma levels of drug observed resulted from absorption in upper regions of the small intestine if the coating did not perform as expected. Pharmacoscintigraphy enables direct visualisation and correlation of location and PK profile, providing a much more detailed confirmation of successful performance.

In Vivo Visualisation

This type of data is invaluable for demonstrating robustness of performance in vivo. Novel pulsatile release oral formulations have been developed to enhance therapy in clinical indications (such as sleep maintenance insomnia, cardiovascular disease and rheumatoid arthritis), by tailoring the time of release to coincide with the known exacerbation of symptoms of these conditions according to circadian rhythms (3,4).

The formulations are prepared using press coating technology, where a gradually eroding barrier layer is compressed around a drug containing core tablet. This may be an immediate release or sustained release core. However, in either case, the action of the core tablet cannot begin until the inert barrier layer has eroded away at a pre-defined rate, enabling the release around the time at which peak plasma levels are required. This type of strategy is particularly useful for clinical conditions which tend to fl are up overnight, or just before waking – for example, the high blood pressure and heart rate that is associated with an increase in cardiovascular events, such as heart attacks, which are observed in the first few hours after waking.

By incorporating a delay before drug release, it means that the patient will be able to take the tablet at a convenient hour, and will not be exposed to unnecessarily high blood plasma levels when it is not therapeutically necessary. As the timing of drug release is based entirely on the time following ingestion, it is essential to establish that lag time performance is independent of dosage form location in the gut. By radiolabelling the core tablet, clinical pharmacoscintigraphic studies have validated the in vivo performance of the time delayed technology (5,6).

Figure 2 shows typical scintigraphic images obtained following administration of a formulation designed for sleep maintenance insomnia. During in vitro validation studies, radiolabel release from the core was observed to begin at 95 minutes, with complete release at 171.7 ± 15 minutes. Figure 2 also shows good in vivo correlation with this data, with clear evidence of the onset of dispersion of the radiolabel from the core tablet in the image acquired 97.5 (mean 98 ± 10) minutes post-dose, and complete radiolabel release at 157.5 minutes (mean 153 ± 8).

Formulation Strategies

Combining scintigraphy with other clinical techniques can be used to further understand and demonstrate the potential therapeutic benefi ts of advanced formulation strategies for existing compounds. Alendronate (EX101) is a bisphosphonate used in the treatment of osteoporosis and, when taken in tablet form, has been associated with dyspepsia, dysphagia and oesophageal ulcers (7). A novel buffered solution formulation of EX101, designed to minimise the risk of oesophageal damage by the dual action of removing the likelihood of solid dose oesophageal adhesion and buffering the local pH to a level at which it is less harmful to the gastric mucosa, was compared with a commercially available tablet formulation – Fosamax™ –using gamma scintigraphy with simultaneous gastric pH monitoring (8). Scintigraphic imaging was used to monitor and compare the gastric emptying rate of the two formulations (for example, the time the formulation remained in the region where it may be refluxed), and pH monitoring was used to demonstrate that the buffered solution typically maintained the gastric pH above three (see Figure 3).

Gamma scintigraphy also has applications in the evaluation of non-oral dosage forms, provided that an appropriate method of radiolabelling the formulation can be found. For example, the technique was used to evaluate the performance of a nasal insert formulation designed to prolong drug residence in the nasal cavity, where the clearance half-life is typically around 15 minutes (9,10). These prototype gelling formulations were radiolabelled with 111In, and the kinetics of the spread and residence time in the nasal cavity was evaluated. The scintigraphic data obtained clearly demonstrated the requirement for a balance between polymer concentration and over/under hydration of the formulation to optimise nasal residence time (see Figure 4).

Valuable Insight

Gamma scintigraphy and pharmacoscintigraphy are firmly established as clinical techniques for evaluating, visualising and understanding dosage form performance in vivo. Valuable insight into the robustness of formulation performance in the variable environment of the GI tract can help identify potential problems before a full-scale clinical trial is initiated, and provide the confidence needed to move forward into larger studies.