Pharmacoscintigraphic Studies

The science of imaging has been useful for gaining insights into the mechanisms of formulations and for troubleshooting difficult drug delivery problems.

In one project [14], a matrix formulation of poorly water soluble API was orally administered to dogs. A few milligrams of samarium oxide (152Sm2O3) were incorporated in the formulation, which was compressed into tablets with standard equipment and then sent out to a research reactor for neutron activation. Activation changed the stable samarium 152 isotope to the gamma emitting radioactive samarium 153 isotope (»47 h half life). The gamma-labeled formulations were then shipped back to the study facility and were orally administered to dogs in a pharmacokinetic study. Following administration, images were collected to determine dosage form location in the GIT. The purpose of the study was to determine whether the in vivo release of the API from the matrix tablet was at the rate designed from in vitro dissolution experiments. This was determined using the deconvolution method of calculation [104]. The gamma scintigraphy imaging provided a visual confirmation of GI tract location during the study. Findings indicated that, while the formulation was in the small intestine, in vivo and in vitro release closely correlated. Implicit in this study design is the assumption that liberated API would rapidly wet, dissolve, and be absorbed. Therefore, the lag between release and appearance in the systemic circulation could be ignored.

In another study [80], the API did not rapidly wet and dissolve, leading to a lag in both absorption, and appearance in the systemic circulation. In this case, the poorly soluble (but otherwise well absorbed) API was formulated as a single CR unit. Although the API was delivered from the osmotic-driven formulation, the purpose of the study was to determine whether a solubility-enhancing formulation provided sustained supersaturation of the API, with subsequent absorption in the colon. A pharmacoscintigraphic dog study again provided some insight into in vivo performance. Taking into account the point at which the dosage form entered the colon (arrows, Fig. 4.3), it was observed that the bioavailability of the API from the solubility-enhanced formulation was at best only about 20% better than the traditional formulation. A subsequent clinical pharmacoscintigraphic study in humans revealed that colonic absorption of the solubility-enhanced formulation was also similar to that from the traditional formulation ("cap," in Fig. 4.4). The authors concluded that the pharmacoscintigraphic studies provided critical additional information to allow for a better prediction of the in vivo performance of the formulation in humans.

With the power of imaging studies comes the confidence to cull "outliers" based on artifacts of GI physiology. In the pharmacoscintigraphic study discussed earlier where 6 or 18 h diffusion-controlled matrix tablets were administered to fed beagle dogs, erosion of some tablets was accelerated in the stomach [16]. In dogs where tablet erosion was not excessive before gastric emptying, the in vivo performance predicted performance in humans. In another project, the in vivo release of sertra-line HCl from a matrix tablet was highly variable in dogs [14]. Since sertraline is

Fig. 4.3 Plasma concentrations in individual dogs administered an osmotic formulation in a phar-macoscintigraphic study. Arrow heads indicate the time at which each tablet entered the colon [80]

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Fig. 4.4 Plasma concentrations in individual subjects administered traditional ("cap") and "solubility enhanced" osmotic formulations in a pharmacoscintigraphic study. Vertical lines indicate the time at which the formulation entered the colon [80]

poorly water soluble, its release in the colon resulted in low blood levels, contrasting with release in the small intestine which resulted in high blood levels. Therefore, when the location of the eroding formulation was matched with the deconvolution analysis, there was a satisfactory in vivo-in vitro correlation (IVIVC).

These examples emphasized the value of pharmacoscintigraphic studies during the preclinical development of CR formulations.

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