Choice of radiolabel

Aqueous phases can be followed using technetium-99m labelled diethylenetriaminepentaacetic acid (DTPA). It is absorbed from the lungs with a half time of about 1 h and rapidly cleared from the body via the kidneys. If prolonged imaging is needed, then a label that clears more slowly from the lung such as 99mTc-labelled albumin should be used. Materials such as 99mTc stannous phytate show better alveolar deposition than pertechnetate or 111In-DTPA with a slow clearance20. It has been hypothesized that phytate bears a strong structural resemblance to triphosphoinositide, a component of the lung surfactant material, and that it binds to alveolar wall receptors competing for inositol receptors. 99mTc Hexakis (t-butyl isonitrile) TBIN has been used to label the lipid phase of an aerosol21.

Some attempts have been made to label the drug itself. A bronchodilator, the anticholinergic compound ipratropium bromide, has been labelled using a cyclotron-produced radionuclide 77Br. This radionuclide has a half-life of 58 hours with peak gamma-ray energies, 239 and 521 KeV which are not ideal but are usable for scintigraphic studies. The powder produced was incorporated into pressurized canisters and it was shown that upon actuation, radioactivity was lost from the canisters at a rate equal to that of the drug22.

Labeling inhalation formulations

Significant effort has been expended in attempts to radiolabel particles in aerosol formulations. All have significant problems and require validation prior to use, since it is possible that the label may not become associated with the drug particle.

1. In many early studies, the label in solution was added to the dry canister, and the solvent evaporated prior to adding the MDI propellants and solids. Some workers extract the 99mTc into butanone prior to adding it to the canister23. The whole is then sonicated in an attempt to redistribute the label. This is one of the least satisfactory methods, since it normally uses a water-soluble label such as 99mTc-DTPA. This forms a dry film on evaporation, which is later broken up into an ill-defined population of particles in the water-immiscible propellant. It has been suggested that the label associates with the surfactant layer around the particles, but since some of the surfactant will be present in solution, the validity of this ill-characterized technique seems unclear.

2. The drug is labelled by co-crystallizing or co-precipitating with added label prior to micronizing and formulation. This is extremely difficult since the levels of activity required to label a micronizable batch of drug (1-10 g minimum) are extremely high if a useful activity (e.g. 1 MBq in 100 pg) is to be obtained in the final doses. Extensive radiation protection is required and the apparatus requires a significant decay time. In addition there may be no guarantee of success since the label may crystallize or precipitate separately from the drug and form its own population of particles.

3. Addition of labelled particles (e.g. Teflon) to the formulation. These can be made to specific sizes, e.g. by spinning disc generator. The main problem here is that is difficult to ensure that the size distribution of the test particles is representative of that of the drug, and thus it becomes extremely difficult to ensure that the labelled particles behave in vivo in the same way as the drug particles. In addition the preparation of very small labeled model particles is problematic.

4. Addition of a propellant-soluble label such as 99mTc hexamethylpropyleneamine oxidase (HMPAO) to the pMDI. This label then evaporates down on to the surface of the drug particle when the pMDI is actuated. This is probably the most interesting technique but makes a number of assumptions; firstly that propellant evaporation is complete by the time the plume enters the upper airways (which is widely contested), and secondly that each propellant droplet contains at least one drug particle. Droplets which contain no drug particles will evaporate down to a very small size which is determined by the concentration of label and soluble components (surfactants and lubricants) and may thus suggest a deposition pattern which does not match that of the drug.

5. Spray-drying of the label on to the particle surface prior to formulation24. This method can be used for powders intended for both MDI and DPI administration. It has the advantage that the label is specifically associated with the particle, but validation is required in the case of MDI formulations to ensure that the label does not redissolve into the propellant.

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