(T1230-05-29) Finding the Alternative Path: Formulation Strategies for Sustained Release of Challenging Small Molecule Compounds

Purpose: Developing early-stage chemical matters with diverse properties to fulfill the target goals could be very costly and challenging. Some of the challenges for these pharmaceutical compounds can be lower oral bio-availability and high toxicity finding, such as body weight loss, at an undesired coverage. To mitigate this challenging problem of having low bioavailability but high tox, a few strategies could be considered. To bypass the first-path effect without going through oral (PO) route, drug administered via Intravenous (IV) infusion, and subcutaneous (SC) could enter the systemic circulation directly without passing through the liver first. These routes can result in higher levels of active drug in the bloodstream. Each of these routes of administration has its own advantages and disadvantages, and the choice of which route to use will depend on a variety of factors. One of the factors is the formulation which can alter the PK profile and ultimately achieve longer coverage of the target concentration. The goal of this work was to evaluate two model compounds GNE-1 and GNE-2, which have different physio-chemical properties using different formulation strategies to improve and alter their systemic pharmacokinetic (PK) profiles. The in-vivo results would provide insight of potential formulation performance to enable further understanding of the biological pathway to optimize chemical matter with improved properties.

Methods: Two compounds GNE-1 and GNE-2 were selected to compare different formulation strategies to improve and to optimize the systemic PK profiles in rodent mouse studies. The methods used to conducted different in-vivo studies were through PO, IP, IV infusion, and SC routes. Compound GNE-1 was dosed via PO, IP, IV infusion, and SC at different dose level with desired target IC50 coverage maintained at 1.4 µM. Compound GNE-2 was dosed via IV infusion and SC with desired target IC50 coverage maintained at 0.56 µM. The formulations developed for these in-vivo studies were evaluated and screened by the discovery formulation group. The vehicle selected for the SC study was approved by the safety working group to support the PK study. The vehicle selected for the IV infusion study is compatible with the iPRECIO pump system and demonstrated its safety and stability to use for conducting long-term PK study.

Results: The alternative formulation strategies demonstrated the target exposure with desired systemic coverage is achievable. For model compound GNE-1, which has relative moderate kinetic solubility and moderate permeability with high potency, oil formulation via SC depot maintained great exposure above IC50 at 24 hours in comparison with iPRECIO pump IV infusion. For model compound GNE-2, which has low kinetic solubility and high permeability with moderate potency, the IV infusion via iPRECIO pump formulation can maintain exposure at target IC50 for over 100 hours. Both iPRECIO pump IV infusion and subcutaneous injection are promising strategies for early development stage molecules. SC route administration is a less invasive option than iPRECIO pump IV infusion. On the other hand, iPRECIO pump IV infusion could provide much longer exposure for longer term studies.

Conclusion: The iPRECIO pump IV infusion and SC strategies can alter the PK profile resulting in a longer acting sustained release compared to PO and IP. The physiochemical properties of compounds and potency are important factors when considering the strategy. Evaluating subcutaneous relevant dissolution model to compare the two compounds subcutaneous formulations helps to have a better understand of the drug-release profile. The next step is to evaluate more compounds with diverse physiochemical properties to optimize the formulation strategic approaches.

References: 1. Ramadon, D. et. al. (2021) DOI:10.1007/s13346-021-00909-6
2. Iprecio pump https://www.iprecio.com/products/tabid/190/Default.aspx
3. https://www.optimale.co.uk/articles/subcutaneous-testosterone-injection/
4. https://drug-dev.com/formulation-forum-rational-design-development-of-long-acting-injectable-dosage-forms/
5. Leung, D. et al. (2017) DOI: 10.1208/s12249-016-0698-5, AAPS PharmSciTech

Acknowledgements: Jie Pang, Vijay Sethuraman, Dennis Leung, Karthik Nagapudi, Jason Zbeig, Anwesha Dey, Tom De Bruyn, Miaoran Ning.

Figure 1: Parenteral strategy to generate a sustained release profile via iPRECIO implantable infusion pump and subcutaneous depot.

Figure 2: GNE-1 dosed (A) PO and (B) IP with limited target coverage time. (C) Implantable infusion pump, iPRECIO pump, sustained release achieved but below target systemic concentration. (D) Oil subcutaneous depot, sustained release and improved systemic concentration coverage time.

Figure 3: GNE-2 dosed to improve systemic concentration coverage time with a sustained release strategy (A) subcutaneous oil depot sustained release did not achieve target concentration (B) implantable infusion iPRECIO pump resulted in sustained release above the target coverage concentration for 100 hours.