The overall goal of the proposed research is to develop and validate predictive degradation models for select pharmaceutical preparations contained in the International Space Station (ISS) medical kits. A related objective of our research is to examine whether or not integrity and performance of degraded formulations is compromised as indicated by bioequivalence in ground-based animal model. The following specific aims will be pursued to accomplish our research goal: 1) Establish a validated HPLC-MS/MS assay method that can be used for the identification and quantification of active pharmaceutical ingredient (API) and degradation products of the selected formulations. 2) Characterize degradation profiles and API content of medications received from ISS and compare with existing data from ISS payload and irradiation studies. 3) Conduct ground-based accelerated stability studies with matching set of medications selected for the above aims to develop predictive degradation models. 4) Estimate bioequivalence between Earth-based control and Space X returned formulations in a small animal model (rat) to examine integrity and performance of medications stored on board the ISS.

In the stability study, a rapid, sensitive and specific UPLC-MS/MS method was developed for the simultaneous determination of ibuprofen tablets and promethazine in tablets and injection solutions stored on board the ISS and on ground. Another rapid, sensitive, and specific UPLC-MS/MS method was developed for the identification and quantification of azithromycin tablets stored on board the ISS and on ground. With the LC-MS/MS approaches, the API of formulations was quantified. The three pharmaceuticals returned from ISS contain less API contents than their respective ground controls. Ibuprofen tablet has 14-17% less APT content than their ground controls; promethazine tablet has 14-23% less API content, while promethazine injection solution has 15-18% less API content, and azithromycin tablet has17-27% less API content. Results of this study provide important information for future identification of degradation profiles for ibuprofen and promethazine. These data will be also useful in understanding whether the degradation patterns of medications onboard space missions is the same or different from those on the ground.

In the bioequivalence study, 24 Healthy Sprague-Dawley (SD) rats in 6 group were used for the estimation of bioequivalence of Ibuprofen (IBU) tablets, promethazine in tablets, and promethazine injection solution between Space X returned formulations and the Earth-based controls. After PK (pharmokinetics) study of IBU in rats, the results showed that IBU from ISS groups were not bioequivalent to the reference control in SD rats, based on systemic exposure of AUC and maximum observed concentration (Cmax). The drug exposure was decreased since the degradation of API of ibuprofen stored in ISS. The similar pharmacokinetic studies on promethazine products; however, did not demonstrate such bio-inequivalency. It warrants further investigation with a larger sample size. On the other hand, the study might indicate that the losses of drug content might or might not lead to the non-bioequivalence. The results from this study could identify the formulations that were sensitive and degraded in the space environment. The selection of future medications should take this observation into consideration, and the storage condition requires additional measure to protect, if it is still selected.

The environmental factors of space missions may cause accelerated physical-chemical degradation or alterations in the integrity of formulations stored on board space missions for extended periods such as on the International Space Station (ISS) and exploration missions. The degradation of the active pharmaceutical ingredient (API) and adjuvants in addition to alterations of the chemical matrix of the formulation can decrease potency and bioavailability, and increase the risk of toxicity of degraded medications. Therefore, characterizing degradation profiles and developing predictive models of degradation using results from ground-based accelerated stability, bioavailability, and toxicity studies is important to ensure safe and effective pharmacotherapeutics for astronauts during extended duration space missions. This research project addresses pharmacotherapeutics risks and gaps described in the Human Research Program (HRP) road map (ExMC 17, PHA 02), and related specific task of “Stability Analysis of ISS Medications.”

The overall goal of the proposed research is to develop and validate predictive degradation models for select pharmaceutical preparations contained in the ISS medical kits. A related objective of our research is to examine whether or not integrity and performance of degraded formulations is compromised as indicated by bioequivalence in ground-based animal model. The following specific aims will be pursued to accomplish our research goal:

1) Establish a validated HPLC-MS/MS assay method that can be used for the identification and quantification of API and degradation products of the selected formulations.

2) Characterize degradation profiles and API content of medications received from ISS and compare with existing data from ISS payload and irradiation studies.

3) Conduct ground-based accelerated stability studies with matching set of medications selected for the above aims to develop predictive degradation models.

4) Estimate bioequivalence between Earth-based control and Space X returned formulations in a small animal model (rat) to examine integrity and performance of medications stored on board the ISS.