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 BPGwere 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.

[1]  Andrea Beaton,et al.  Global, Regional, and National Burden of Rheumatic Heart Disease, 1990–2015 , 2017, The New England journal of medicine.

[2]  G. Karthikeyan,et al.  Preliminary consultation on preferred product characteristics of benzathine penicillin G for secondary prophylaxis of rheumatic fever , 2016, Drug Delivery and Translational Research.

[3]  C. Wischke,et al.  Design of Controlled Release PLGA Microspheres for Hydrophobic Fenretinide. , 2016, Molecular pharmaceutics.

[4]  G. Karthikeyan,et al.  Acute rheumatic fever and rheumatic heart disease , 2015, Nature Reviews Disease Primers.

[5]  E. Kaplan,et al.  Benzathine Penicillin G for the Management of RHD: Concerns About Quality and Access, and Opportunities for Intervention and Improvement. , 2013, Global heart.

[6]  Sabine Kempe,et al.  In situ forming implants - an attractive formulation principle for parenteral depot formulations. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[7]  E. Kaplan,et al.  Serum Penicillin G Levels Are Lower Than Expected in Adults within Two Weeks of Administration of 1.2 Million Units , 2011, PloS one.

[8]  Hirenkumar K. Makadia,et al.  Poly Lactic-co-Glycolic Acid ( PLGA ) as Biodegradable Controlled Drug Delivery Carrier , 2011 .

[9]  D. Patel A REVIEW ON ATRIGEL DRUG DELIVERY SYSTEM , 2010 .

[10]  Jagdish Singh,et al.  Insulin loaded PLGA microspheres: effect of zinc salts on encapsulation, release, and stability. , 2009, Journal of pharmaceutical sciences.

[11]  Heba A. Gad,et al.  Formulation and Evaluation of PLA and PLGA In Situ Implants Containing Secnidazole and/or Doxycycline for Treatment of Periodontitis , 2008, AAPS PharmSciTech.

[12]  S. Siegel,et al.  In vitro and in vivo demonstration of risperidone implants in mice , 2008, Schizophrenia Research.

[13]  I. B. Araújo,et al.  A new insight about pharmaceutical dosage forms for benzathine penicillin G , 2006 .

[14]  Cunxian Song,et al.  The in vivo degradation, absorption and excretion of PCL-based implant. , 2006, Biomaterials.

[15]  J. Carapetis,et al.  The global burden of group A streptococcal diseases. , 2005, The Lancet. Infectious diseases.

[16]  Pilar Gutiérrez Navarro,et al.  Penicillin degradation catalysed by Zn(II) ions in methanol. , 2003, International journal of biological macromolecules.

[17]  Y. Ikada,et al.  Biodegradable polyesters for medical and ecological applications , 2000 .

[18]  K. Shakesheff,et al.  Polymeric systems for controlled drug release. , 1999, Chemical reviews.

[19]  E L Kaplan,et al.  Why have group A streptococci remained susceptible to penicillin? Report on a symposium. , 1998, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[20]  E. Kaplan,et al.  Pharmacokinetics of benzathine penicillin G: serum levels during the 28 days after intramuscular injection of 1,200,000 units. , 1989, The Journal of pediatrics.

[21]  W. Craig,et al.  Evidence for a slow elimination phase for penicillin G. , 1988, The Journal of infectious diseases.

[22]  P. Soulié,et al.  RHEUMATIC HEART DISEASE , 1954, La semaine des hopitaux : organe fonde par l'Association d'enseignement medical des hopitaux de Paris.

[23]  C. Wischke,et al.  Degradable Polymeric Carriers for Parenteral Controlled Drug Delivery , 2012 .

[24]  I. Singh,et al.  Atrigel: A potential parenteral controlled drug delivery system , 2010 .

[25]  B. Currie Benzathine penicillin - down but not out , 2006 .

[26]  F. Alexis Factors affecting the degradation and drug-release mechanism of poly(lactic acid) and poly[(lactic acid)-co-(glycolic acid)] , 2005 .

[27]  E. Mini,et al.  Clinical Pharmacokinetics of Depot Leuprorelin , 2002, Clinical pharmacokinetics.

[28]  K. Garvin,et al.  Preparation and characterization of biodegradable poly(l-lactic acid) gentamicin delivery systems , 1992 .