(T1230-07-44) Leveraging Protein as a Local Buffering Agent to Safeguard Probiotics in Alginate Encapsulates during Gastric Transit

Purpose:  Antisense oligonucleotide (ASO) therapy has proven effective in treating a wide range of diseases. Current delivery routes include intravenous infusions and intrathecal and subcutaneous injections. These routes require frequent administration or high doses to achieve a lasting therapeutic effect at the intended site of action. Polymeric Implant mediated ASO delivery offers sustained release and overcomes the challenges associated with frequent ASO delivery. This study investigates the sustained release of an antisense oligonucleotide from VitalDose® ethylene-vinyl acetate (EVA) polymeric implants.

Methods:  VitalDose® EVA was cryogenically ground and hot-melt extruded with a 20-oligo gapmer, 2-MOE modified, fully phosphorothioated antisense oligonucleotide (ASO) to yield monolithic core implant samples (n = 6). EVA Implants were loaded with 60% or 70% w/w of ASO. Functional membranes of EVA and mannitol were applied on extruded implant to tune release kinetics. Membrane modified implant samples were incubated in Tris-EDTA buffer at 100 RPM and maintained at 37°C to analyze drug stability and release kinetics. All samples were analyzed via HPLC-UV using an anion exchange column.

Results:  Hot-melt extrusion of ASO implants was carried out at a mild processing temperature of 65 °C. HPLC data indicated that ASO released from implant cores remained stable after-hot melt extrusion and during drug release for 16 months (see Fig. 1). Additionally, membrane modified implants demonstrated ability to reduce the release rate as compared to non-membrane implant cores. Overall, three different membrane configurations were analyzed and drug release from the linear phase of the curve extending from day 14 to day 43 showed a drug release rate from 0.3 to 0.45 mg/day (see Fig. 2). This is in contrast to implant cores that demonstrated a 2 mg/day release rate during the first week (linear phase of the curve). The drug release at day 43 of membrane implants was 40 % to 70 %. The drug release from non-membrane implant cores was ~ 84% at this timepoint.

Conclusion:  Mild processing conditions can yield long-acting ASO-eluting implants. Non membrane implant cores demonstrated stability for over a year and achieved near complete drug release. Multilayer configurations were established by applying functional membranes and tunability of release was achieved. This opens a new frontier for ASO delivery for chronic conditions.

Acknowledgements: No conflict of interest is to be disclosed for the publication of the data presented in this poster.


Non membrane implants show ASO Stability Over 16 Months


12-month multilayer ASO release