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. Carapetis
  • Ben J. Boyd
Original Article

Abstract

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.

Keywords

Rheumatic fever Antibiotic Sustained release Drug delivery PLGA Therapeutic implant 

Notes

Acknowledgements

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)

References

  1. 1.
    Carapetis JR, et al. Acute rheumatic fever and rheumatic heart disease. Nat Rev Dis Prim. 2016;2:15084.CrossRefPubMedPubMedCentralGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.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.CrossRefPubMedPubMedCentralGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefPubMedGoogle 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.CrossRefGoogle 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.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Malik K, et al. Atrigel: a potential parenteral controlled drug delivery system. Der Pharmacia Sinica. 2010;1(1):74–81.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.CrossRefPubMedGoogle Scholar
  20. 20.
    Dunn RL. The Atrigel drug delivery system. In: Drugs and the pharmaceutical sciences. New York: Dekker; 2003. p. 647–55.Google Scholar
  21. 21.
    Patel DB. A review on atrigel drug delivery system. J Glob Pharma Technol. 2010;2:85–90.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.
  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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefGoogle Scholar
  30. 30.
    Chapter VI. Binding of penicillin to plasma protein. Acta Radiol. 1954;41(sup118):51–4.CrossRefGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle Scholar

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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