TY - JOUR

T1 - Development of a sustained release implant of benzathine penicillin G for secondary prophylaxis of rheumatic heart disease

AU - Barr, Renae K.

AU - Barber, Bryce W.

AU - Tait, Jessica R.

AU - Landersdorfer, Cornelia B.

AU - Salman, Sam

AU - Musk, Gabrielle C.

AU - Page-Sharp, Madhu

AU - Batty, Kevin T.

AU - Kado, Joseph

AU - Manning, Laurens

AU - Carapetis, Jonathan R.

AU - Boyd, Ben J.

N1 - Funding Information: The Telethon Kids Institute is acknowledged for funding this project. The HPLC studies were conducted at the Helen MacPherson Smith Trust laboratory and Monash University (Parkville Campus). The X-ray diffraction studies were conducted on the SAXS/WAXS beamline at the Australian Synchrotron. This work was supported by the Australian National Health and Medical Research Council (APP1173874). BB is supported by a Novo Nordisk Laureate Research Fellowship. Funding Information: The Telethon Kids Institute is acknowledged for funding this project. The HPLC studies were conducted at the Helen MacPherson Smith Trust laboratory and Monash University (Parkville Campus). The X-ray diffraction studies were conducted on the SAXS/WAXS beamline at the Australian Synchrotron. This work was supported by the Australian National Health and Medical Research Council (APP1173874). BB is supported by a Novo Nordisk Laureate Research Fellowship.

PY - 2023

Y1 - 2023

N2 - Background: Regular intramuscular (i.m.) benzathine penicillin G (BPG) injections have been the cornerstone of rheumatic heart disease (RHD) secondary prophylaxis since the 1950s. Patient adherence to IM BPG is poor, largely due to pain, the need for regular injections every 3–4 weeks and health sector delivery challenges in resource-limited settings. There is an urgent need for new approaches for secondary prophylaxis, such as an implant which could provide sustained penicillin concentrations for more than 6 months. Methods: In this study we developed and evaluated a slow release implant with potential for substantially extended treatment. The side wall of a solid drug rich core was coated with polycaprolactone which acts as an impermeable barrier. The exposed surfaces at the ends of the implant defined the release surface area, and the in vitro release rate of drug was proportional to the exposed surface area across implants of differing diameter. The in vivo pharmacokinetics and tolerability of the implants were evaluated in a sheep model over 9 weeks after subcutaneous implantation. Results: The absolute release rates obtained for the poorly water-soluble benzathine salt were dependent on the exposed surface area demonstrating the impermeability of the wall of the implant. The implants were well-tolerated after subcutaneous implantation in a sheep model, without adverse effects at the implantation site. Gross structural integrity was maintained over the course of the study, with erosion limited to the dual-exposed ends. Steady release of penicillin G was observed over the 9 weeks and resulted in approximately constant plasma concentrations close to accepted target concentrations. Conclusion: In principle, a long acting BPG implant is feasible as an alternative to i.m. injections for secondary prophylaxis of RHD. However, large implant size is currently a significant impediment to clinical utility and acceptability.

AB - Background: Regular intramuscular (i.m.) benzathine penicillin G (BPG) injections have been the cornerstone of rheumatic heart disease (RHD) secondary prophylaxis since the 1950s. Patient adherence to IM BPG is poor, largely due to pain, the need for regular injections every 3–4 weeks and health sector delivery challenges in resource-limited settings. There is an urgent need for new approaches for secondary prophylaxis, such as an implant which could provide sustained penicillin concentrations for more than 6 months. Methods: In this study we developed and evaluated a slow release implant with potential for substantially extended treatment. The side wall of a solid drug rich core was coated with polycaprolactone which acts as an impermeable barrier. The exposed surfaces at the ends of the implant defined the release surface area, and the in vitro release rate of drug was proportional to the exposed surface area across implants of differing diameter. The in vivo pharmacokinetics and tolerability of the implants were evaluated in a sheep model over 9 weeks after subcutaneous implantation. Results: The absolute release rates obtained for the poorly water-soluble benzathine salt were dependent on the exposed surface area demonstrating the impermeability of the wall of the implant. The implants were well-tolerated after subcutaneous implantation in a sheep model, without adverse effects at the implantation site. Gross structural integrity was maintained over the course of the study, with erosion limited to the dual-exposed ends. Steady release of penicillin G was observed over the 9 weeks and resulted in approximately constant plasma concentrations close to accepted target concentrations. Conclusion: In principle, a long acting BPG implant is feasible as an alternative to i.m. injections for secondary prophylaxis of RHD. However, large implant size is currently a significant impediment to clinical utility and acceptability.

KW - Benzathine penicillin G

KW - Dissolution, in vivo release

KW - Polycaprolactone

KW - Rheumatic heart disease

KW - Secondary prophylaxis, long acting implant

U2 - 10.1016/j.ejpb.2023.06.006

DO - 10.1016/j.ejpb.2023.06.006

M3 - Journal article

C2 - 37354997

AN - SCOPUS:85163929443

VL - 189

SP - 240

EP - 250

JO - European Journal of Pharmaceutics and Biopharmaceutics

JF - European Journal of Pharmaceutics and Biopharmaceutics

SN - 0939-6411

ER -