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


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.

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Change history

  • 15 March 2018

    Jürgen B. Bulitta’s name was misspelled in the original version of the article. It is correct as reflected here. The original article has been revised.


  1. 1.

    Carapetis JR, et al. Acute rheumatic fever and rheumatic heart disease. Nat Rev Dis Prim. 2016;2:15084.

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Marijon E, Mirabel M, Celermajer DS, Jouven X. Rheumatic heart disease. Lancet. 2012;379(9819):953–64. https://doi.org/10.1016/S0140-6736(11)61171-9.

    Article  PubMed  Google Scholar 

  3. 3.

    Watkins DA, Johnson CO, Colquhoun SM, Karthikeyan G, Beaton A, Bukhman G, et al. Global, regional, and national burden of rheumatic heart disease, 1990-2015. N Engl J Med. 2017;377(8):713–22. https://doi.org/10.1056/NEJMoa1603693.

    Article  PubMed  Google Scholar 

  4. 4.

    Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden of group A streptococcal diseases. Lancet Infect Dis. 2005;5(11):685–94. https://doi.org/10.1016/S1473-3099(05)70267-X.

    Article  PubMed  Google Scholar 

  5. 5.

    Wyber R, Taubert K, Marko S, Kaplan EL. Benzathine penicillin G for the management of RHD. Glob Heart. 2013;8(3):227–34. https://doi.org/10.1016/j.gheart.2013.08.011.

    Article  PubMed  Google Scholar 

  6. 6.

    Horn DL, Zabriskie JB, Austrian R, Cleary PP, Ferretti JJ, Fischetti VA, et al. Why have group A streptococci remained susceptible to penicillin? Report on a symposium. Clin Infect Dis. 1998;26(6):1341–5. https://doi.org/10.1086/516375.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Currie B. Benzathine penicillin—down but not out. North Territ Dis Control Bull. 2006;13(2):1–3.

    Google Scholar 

  8. 8.

    Holanda e Silva K, et al. New insight about pharmaceutical dosage forms for benzathine penicillin G. Rev Ciênc Farm Básica Apl. 2006;27(1):21–6.

    CAS  Google Scholar 

  9. 9.

    Broderick MP, Hansen CJ, Russell KL, Kaplan EL, Blumer JL, Faix DJ. Serum penicillin G levels are lower than expected in adults within two weeks of administration of 1.2 million units. PLoS One. 2011;6(10):e25308. https://doi.org/10.1371/journal.pone.0025308.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Uhrich KE, Cannizzaro SM, Langer RS, Shakesheff KM. Polymeric systems for controlled drug release. Chem Rev. 1999;99(11):3181–98. https://doi.org/10.1021/cr940351u.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Wyber R, Boyd BJ, Colquhoun S, Currie BJ, Engel M, Kado J, et al. Preliminary consultation on preferred product characteristics of benzathine penicillin G for secondary prophylaxis of rheumatic fever. Drug Deliv Transl Res. 2016;6(5):572–8. https://doi.org/10.1007/s13346-016-0313-z.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Ikada Y, Tsuji H. Biodegradable polyesters for medical and ecological applications. Macromol Rapid Commun. 2000;21(3):117–32. https://doi.org/10.1002/(SICI)1521-3927(20000201)21:3<117::AID-MARC117>3.0.CO;2-X.

    CAS  Article  Google Scholar 

  13. 13.

    Makadia HK, Siegel SJ. Poly lactic-co-glycolic acid (PLGA) as biodegradable controlled drug delivery carrier. Polymers (Basel). 2011;3(3):1377–97. https://doi.org/10.3390/polym3031377.

    CAS  Article  Google Scholar 

  14. 14.

    Alexis F. Factors affecting the degradation and drug-release mechanism of poly(lactic acid) and poly[(lactic acid)-co-(glycolic acid)]. Polym Int. 2005;54(1):36–46. https://doi.org/10.1002/pi.1697.

    CAS  Article  Google Scholar 

  15. 15.

    Rabin C, Liang Y, Ehrlichman RS, Budhian A, Metzger KL, Majewski-Tiedeken C, et al. In vitro and in vivo demonstration of risperidone implants in mice. Schizophr Res. 2008;98(1–3):66–78. https://doi.org/10.1016/j.schres.2007.08.003.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Sampath SS, Garvin K, Robinson DH. Preparation and characterization of biodegradable poly(l-lactic acid) gentamicin delivery systems. Int J Pharm. 1992;78(1):165–74. https://doi.org/10.1016/0378-5173(92)90367-B.

    CAS  Article  Google Scholar 

  17. 17.

    Gad HA, El-Nabarawi MA, Abd El-Hady SS. Formulation and evaluation of PLA and PLGA in situ implants containing secnidazole and/or doxycycline for treatment of periodontitis. AAPS PharmSciTech. 2008;9(3):878–84. https://doi.org/10.1208/s12249-008-9126-9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Malik K, et al. Atrigel: a potential parenteral controlled drug delivery system. Der Pharmacia Sinica. 2010;1(1):74–81.

    CAS  Google Scholar 

  19. 19.

    Sun H, Mei L, Song C, Cui X, Wang P. The in vivo degradation, absorption and excretion of PCL-based implant. Biomaterials. 2006;27(9):1735–40. https://doi.org/10.1016/j.biomaterials.2005.09.019.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Dunn RL. The Atrigel drug delivery system. In: Drugs and the pharmaceutical sciences. New York: Dekker; 2003. p. 647–55.

  21. 21.

    Patel DB. A review on atrigel drug delivery system. J Glob Pharma Technol. 2010;2:85–90.

    CAS  Google Scholar 

  22. 22.

    Eligard® Full prescribing information sheet. Tolmar Pharmaceuticals. 04/08/2014]; http://www.eligard.com/Docs/Pdf/TOLMAR%20Pharmaceuticals_Web_PI_05-07-14.pdf].

  23. 23.

    Atridox® Full prescribing information sheet. Tolmar Pharmaceuticals. 04/08/2014]; http://www.carepathways.com/DictionaryFDA2.cfm?RetDoc=http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/050751s015lbl.pdf&drugname=ATRIDOX&ActiveIngredient=DOXYCYCLINEHYCLATE&type=Label].

  24. 24.

    Periti P, Mazzei T, Mini E. Clinical pharmacokinetics of depot leuprorelin. Clin Pharmacokinet. 2002;41(7):485–504. https://doi.org/10.2165/00003088-200241070-00003.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Zhang Y, Wischke C, Mittal S, Mitra A, Schwendeman SP. Design of controlled release PLGA microspheres for hydrophobic fenretinide. Mol Pharm. 2016;13(8):2622–30. https://doi.org/10.1021/acs.molpharmaceut.5b00961.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Kempe S, Mader K. In situ forming implants—an attractive formulation principle for parenteral depot formulations. J Control Release. 2012;161(2):668–79. https://doi.org/10.1016/j.jconrel.2012.04.016.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Manoharan C, Singh J. Insulin loaded PLGA microspheres: effect of zinc salts on encapsulation, release, and stability. J Pharm Sci. 2009;98(2):529–42. https://doi.org/10.1002/jps.21445.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Navarro PG, Blázquez IH, Osso BQ, Martı́nez de las Parras PJ, Puentedura MIM, Garcı́a AAM. Penicillin degradation catalysed by Zn(II) ions in methanol. Int J Biol Macromol. 2003;33(4–5):159–66. https://doi.org/10.1016/S0141-8130(03)00081-3.

    Article  PubMed  Google Scholar 

  29. 29.

    Wischke C, Schwendeman SP. Degradable polymeric carriers for parenteral controlled drug delivery. In: Siepmann J, Siegel RA, Rathbone MJ, editors. Fundamentals and applications of controlled release drug delivery. Boston: Springer US; 2012. p. 171–228. https://doi.org/10.1007/978-1-4614-0881-9_8.

    Google Scholar 

  30. 30.

    Chapter VI. Binding of penicillin to plasma protein. Acta Radiol. 1954;41(sup118):51–4.

    Article  Google Scholar 

  31. 31.

    Ebert SC, Leggett J, Vogelman B, Craig WA. Evidence for a slow elimination phase for penicillin G. J Infect Dis. 1988;158(1):200–2. https://doi.org/10.1093/infdis/158.1.200.

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Kaplan EL, Berrios X, Speth J, Siefferman T, Guzman B, Quesny F. Pharmacokinetics of benzathine penicillin G: serum levels during the 28 days after intramuscular injection of 1,200,000 units. J Pediatr. 1989;115(1):146–50. https://doi.org/10.1016/S0022-3476(89)80352-X.

    CAS  Article  PubMed  Google Scholar 

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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.


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).

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Correspondence to Jonathan R. Carapetis or Ben J. Boyd.

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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.

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The original version of this article was revised: Jürgen B. Bulitta’s name was misspelled in the original version of the article.

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Montagnat, O.D., Webster, G.R., Bulitta, J.B. et al. Lessons learned in the development of sustained release penicillin drug delivery systems for the prophylactic treatment of rheumatic heart disease (RHD). Drug Deliv. and Transl. Res. 8, 729–739 (2018). https://doi.org/10.1007/s13346-018-0482-z

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  • Rheumatic fever
  • Antibiotic
  • Sustained release
  • Drug delivery
  • PLGA
  • Therapeutic implant