Previous studies have shown that the formulation of an active pharmaceutical ingredient (API) entrapped in the Pheroid® (Pheroid for simplification) delivery system enhances absorption of the API, suppresses its metabolism, and may contribute to an increase in the quantity of the API present at the site of action. Higher drug levels at the active site should particularly increase the effectiveness of a drug with a narrow therapeutic index and reduce the incidence of the resistance that may otherwise arise if the sub-therapeutic levels of the API are in contact with the site of interest. Two approaches were followed in this study. First, the radioactive tracer molecule 99mTechnetium methylene diphosphonate (99mTc MDP) was used. Intravenously injected 99mTc MDP is an extremely effective bone-seeking radiopharmaceutical used in the diagnosis of bone disorders such as bone metastases in patients. However, if entrapped inside a Pheroid vesicle, it will locate to that site, usually an organ, where the Pheroid vesicles may tend to accumulate. Experiments conducted with 99mTc MDP alone or with Pheroid will therefore establish how efficiently Pheroid vesicles localize and will also indicate the preferred site of localization inside a body. The process would involve the oral administration of 99mTc MDP either alone or with Pheroid, involving an animal model. It would also involve tracking localization to particular organs, blood or other sites. The second approach requires the use of chloroquine (CQ) labeled with carbon-14 (14C-CQ,) to compare absorption of the drug both with and without the Pheroid system. The intention was to compare oral absorption and bio-distribution of 14C-CQ administered either alone or entrapped in the Pheroid system. It was also possible to establish whether the Pheroid affects the biological half-lives of the CQ and residence times of CQ in the different organs of the body. Absorption of free 99mTc MDP (orally adminsistered) through the intestinal tract is negligible but it was anticipated that increased absorption will be observed when 99mTc MDP was entrapped in the Pheroid system. In the 99mTc MDP study, different routes of administration of 99mTc MDP, as well as 99mTc MDP entrapped and not entrapped in the Pheroid system, were investigated. The Sprague Dawley rat was used as animal model. Rats were divided into three groups of four rats each for the first part of the study. In the first group, only 99mTc MDP was injected intravenously in order to establish natural distribution of the 99mTc MDP. For the second group, 99mTc MDP was administered orally in order to establish whether there was any absorption through the intestinal tract. In the third group, the 99mTc MDP was entrapped in Pheroid vesicles and this formulation was administered orally in order to establish whether the Pheroid system enhanced oral absorption. The animals were sacrificed four hours after administration and organs were harvested and were counted for radioactivity to determine the percentage of injected/administrated dose in each organ. After oral administration, the Pheroid system was found to have facilitated absorption of 99mTc MDP through the intestinal tract into the blood. 99mTc MDP concentrations in the femur, although lower, were still comparable with that observed after intravenous administration of 99mTc MDP in the absence of Pheroid. Thus, overall, excellent absorption of the Pheroid entrapped 99mTc MDP through the intestinal tract was seen in contrast to little or zero absorption of the compound in the reference formulations. The half-life of the radio-labelled compound in the blood was prolonged after oral administration owing to the Pheroid. To investigate the bio-distribution of radioactive chloroquine (14C-CQ) Sprague Dawley rats were divided into two groups of four rats each. In the first group, 14C-CQ in deionised (DI) water was administered orally, and in the second group 14C-CQ entrapped in Pheroid vesicles was administered, also orally. The animals were sacrificed one, two and four hours after administration and subjected to comprehensive macroscopic inspection. All the organs were harvested and radioactivity was determined with liquid scintillation after applicable sample preparation. The Pheroid system produced much higher organ and blood concentrations of 14C-CQ and enhanced residence times within the organs and blood in comparison with that of 14C-CQ administered alone. Commercial applications of these results are possible, as a number of radiopharmaceutical products can presently be administered only intravenously. The added potential of these new Pheroid formulations could be of significance in the treatment of malaria, as chloroquine is inexpensive and widely available. Another point of interest is that the use of these formulations may enable micromolar drug concentrations to be achieved using drug dosage regimes that usually produce only nanomolar levels. However, safety aspects would have to be carefully monitored. / PhD (Pharmaceutics), North-West University, Potchefstroom Campus, 2015

Previous studies have shown that the formulation of an active pharmaceutical ingredient (API) entrapped in the Pheroid® (Pheroid for simplification) delivery system enhances absorption of the API, suppresses its metabolism, and may contribute to an increase in the quantity of the API present at the site of action. Higher drug levels at the active site should particularly increase the effectiveness of a drug with a narrow therapeutic index and reduce the incidence of the resistance that may otherwise arise if the sub-therapeutic levels of the API are in contact with the site of interest. Two approaches were followed in this study. First, the radioactive tracer molecule 99mTechnetium methylene diphosphonate (99mTc MDP) was used. Intravenously injected 99mTc MDP is an extremely effective bone-seeking radiopharmaceutical used in the diagnosis of bone disorders such as bone metastases in patients. However, if entrapped inside a Pheroid vesicle, it will locate to that site, usually an organ, where the Pheroid vesicles may tend to accumulate. Experiments conducted with 99mTc MDP alone or with Pheroid will therefore establish how efficiently Pheroid vesicles localize and will also indicate the preferred site of localization inside a body. The process would involve the oral administration of 99mTc MDP either alone or with Pheroid, involving an animal model. It would also involve tracking localization to particular organs, blood or other sites. The second approach requires the use of chloroquine (CQ) labeled with carbon-14 (14C-CQ,) to compare absorption of the drug both with and without the Pheroid system. The intention was to compare oral absorption and bio-distribution of 14C-CQ administered either alone or entrapped in the Pheroid system. It was also possible to establish whether the Pheroid affects the biological half-lives of the CQ and residence times of CQ in the different organs of the body. Absorption of free 99mTc MDP (orally adminsistered) through the intestinal tract is negligible but it was anticipated that increased absorption will be observed when 99mTc MDP was entrapped in the Pheroid system. In the 99mTc MDP study, different routes of administration of 99mTc MDP, as well as 99mTc MDP entrapped and not entrapped in the Pheroid system, were investigated. The Sprague Dawley rat was used as animal model. Rats were divided into three groups of four rats each for the first part of the study. In the first group, only 99mTc MDP was injected intravenously in order to establish natural distribution of the 99mTc MDP. For the second group, 99mTc MDP was administered orally in order to establish whether there was any absorption through the intestinal tract. In the third group, the 99mTc MDP was entrapped in Pheroid vesicles and this formulation was administered orally in order to establish whether the Pheroid system enhanced oral absorption. The animals were sacrificed four hours after administration and organs were harvested and were counted for radioactivity to determine the percentage of injected/administrated dose in each organ. After oral administration, the Pheroid system was found to have facilitated absorption of 99mTc MDP through the intestinal tract into the blood. 99mTc MDP concentrations in the femur, although lower, were still comparable with that observed after intravenous administration of 99mTc MDP in the absence of Pheroid. Thus, overall, excellent absorption of the Pheroid entrapped 99mTc MDP through the intestinal tract was seen in contrast to little or zero absorption of the compound in the reference formulations. The half-life of the radio-labelled compound in the blood was prolonged after oral administration owing to the Pheroid. To investigate the bio-distribution of radioactive chloroquine (14C-CQ) Sprague Dawley rats were divided into two groups of four rats each. In the first group, 14C-CQ in deionised (DI) water was administered orally, and in the second group 14C-CQ entrapped in Pheroid vesicles was administered, also orally. The animals were sacrificed one, two and four hours after administration and subjected to comprehensive macroscopic inspection. All the organs were harvested and radioactivity was determined with liquid scintillation after applicable sample preparation. The Pheroid system produced much higher organ and blood concentrations of 14C-CQ and enhanced residence times within the organs and blood in comparison with that of 14C-CQ administered alone. Commercial applications of these results are possible, as a number of radiopharmaceutical products can presently be administered only intravenously. The added potential of these new Pheroid formulations could be of significance in the treatment of malaria, as chloroquine is inexpensive and widely available. Another point of interest is that the use of these formulations may enable micromolar drug concentrations to be achieved using drug dosage regimes that usually produce only nanomolar levels. However, safety aspects would have to be carefully monitored. / PhD (Pharmaceutics), North-West University, Potchefstroom Campus, 2015