Drug Delivery and Translational Research

, Volume 8, Issue 3, pp 729–739 | Cite as

Lessons learned in the development of sustained release penicillin drug delivery systems for the prophylactic treatment of rheumatic heart disease (RHD)

  • Oliver D. Montagnat
  • Graham R. Webster
  • Jürgen B. Bulitta
  • Cornelia Landersdorfer
  • Rosemary Wyber
  • Meru Sheel
  • Jonathan R. CarapetisEmail author
  • Ben J. BoydEmail author
Original Article


The current prophylactic treatment to prevent rheumatic heart disease requires four-weekly intramuscular injection of a suspension of the poorly soluble benzathine salt form of penicillin G (BPG) often for more than 10 years. In seeking to reduce the frequency of administration to improve adherence, biodegradable polymer matrices have been investigated. Poly(lactide-co-glycolide) (PLGA)-based in situ forming precursor systems containing N-methyl-2-pyrrolidone as solvent and PLGA-based monolithic implants for surgical implantation containing BPG were developed. Long-term release studies indicated low and plateaued release of penicillin G, but continual favourable release profiles for the benzathine counterion, indicating degradation of the polymer and generation of acidic microenvironment being detrimental to penicillin stability. In order to avoid the issue of the acidic product, poly(caprolactone)(PCL) implants were also investigated, with favourable penicillin G release behaviour being achieved, and slow release over 180 days. However, when taking into account the mass of polymer, and the total dose of drug calculated from literature pharmacokinetic parameters for penicillin G, we concluded that an implant size of over 7 g would still be required. This may preclude clinical deployment of a polymer matrix type delivery system for this indication in children and adolescents. Therefore, we have learned that biodegradable PLGA-type systems are not suitable for development of sustained release BPG treatments and that although the PCL system provides favourable release behaviour, the total size of the implant may still present a hurdle for future development.


Rheumatic fever Antibiotic Sustained release Drug delivery PLGA Therapeutic implant 



The authors wish to thank Charlotte Mulder, Errol Malta and Mark Sullivan from Medicines Development Ltd. (MDL) for their helpful discussions on this work. The authors would also like to thank Corbion Purac for providing samples of PLA/PLGA copolymers free of charge.

Funding information

Jonathan Carapetis and Ben Boyd have received funding from the Telethon New Children’s Hospital Research Fund to explore new formulations of benzathine penicillin G (Grant number: F55541).

Compliance with ethical standards

Conflict of interest

Jonathan Carapetis and Meru Sheel are investigators on a BPG projected funded by Novartis Institutes for BioMedical Research. Rosemary Wyber has provided technical advice to Pfizer on BPG but has not received funding.

Supplementary material

13346_2018_482_MOESM1_ESM.pdf (241 kb)
ESM 1 (PDF 240 kb)


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Copyright information

© Controlled Release Society 2018
corrected publication [March 2018]

Authors and Affiliations

  1. 1.Drug Delivery Disposition and Dynamics—Monash Institute of Pharmaceutical SciencesMonash University (Parkville Campus)ParkvilleAustralia
  2. 2.Telethon Kids InstituteThe University of Western AustraliaSubiacoAustralia
  3. 3.Princess Margaret Hospital for ChildrenPerthAustralia
  4. 4.ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical SciencesMonash University (Parkville Campus)ParkvilleAustralia

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