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Daptomycin Proliposomes for Oral Delivery: Formulation, Characterization, and In Vivo Pharmacokinetics

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Abstract

The aim of this study was to develop a proliposomal formulation of lipopeptide antibiotic drug daptomycin (DAP) for oral delivery. Thin film hydration was the selected method for preparation of proliposomes. Different phospholipids including soy-phosphatidylcholine (SPC), hydrogenated egg-phosphatidylcholine (HEPC), and distearoyl-phosphatidylcholine (DSPC) were evaluated in combination with cholesterol. The inclusion of surface charge modifiers in the formulation such as dicetyl phosphate (DCP) and stearylamine (SA) to enhance drug encapsulation was also evaluated. Particle size, surface charge, and encapsulation efficiency were performed on daptomycin-hydrated proliposomes as part of physical characterization. USP type II dissolution apparatus with phosphate buffer (pH 6.8) was used for in vitro drug release studies. Optimized formulation was evaluated for in vivo pharmacokinetics after oral administration to Sprague-Dawley rats. Proliposomes composed of SPC exhibited higher entrapment efficiency than those containing HEPC or DSPC. The highest entrapment efficiency was achieved by positively charged SPC-SA proliposomes, showing an encapsulation efficiency of 92% and a zeta potential of + 28 mV. In vitro drug release of optimized formulation demonstrated efficient drug retention totaling for less than 20% drug release within the first 60 min and only 42% drug release after 2 h. Pharmacokinetic parameters after single oral administration of optimized proliposomal formulation indicated a significant increase in oral bioavailability of DAP administered as SPC-SA proliposomes when compared to drug solution. Based on these results, incorporation of charge modifiers into proliposomes may increase drug loading and proliposomes an attractive carrier for oral delivery of daptomycin.

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References

  1. Singh R, Singh S, Lillard JW. Past, present, and future technologies for oral delivery of therapeutic proteins. J Pharm Sci. 2008;97(7):2497–523. https://doi.org/10.1002/jps.21183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Renukuntla J, Vadlapudi AD, Patel A, Boddu SHS, Mitra AK. Approaches for enhancing oral bioavailability of peptides and proteins. Int J Pharm. 2013;447(1–2):75–93. https://doi.org/10.1016/j.ijpharm.2013.02.030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Gupta S, Jain A, Chakraborty M, Sahni JK, Ali J, Dang S. Oral delivery of therapeutic proteins and peptides: a review on recent developments. Drug Deliv. 2013;20(6):237–46.

    Article  CAS  PubMed  Google Scholar 

  4. Ismail R, Csóka I. Novel strategies in the oral delivery of antidiabetic peptide drugs—insulin, GLP 1 and its analogs. Eur J Pharm Biopharm. 2017;115:257–67. https://doi.org/10.1016/j.ejpb.2017.03.015.

    Article  CAS  PubMed  Google Scholar 

  5. Gupta V, Hwang BH, Doshi N, Mitragotri S. A permeation enhancer for increasing transport of therapeutic macromolecules across the intestine. J Control Release. 2013;172(2):541–9. https://doi.org/10.1016/j.jconrel.2013.05.002.

    Article  CAS  PubMed  Google Scholar 

  6. Bernkop-Schnürch A. Reprint of: nanocarrier systems for oral drug delivery: do we really need them? Eur J Pharm Sci. 2013;50(1):2–7. https://doi.org/10.1016/j.ejps.2013.06.011.

    Article  PubMed  Google Scholar 

  7. Muheem A, Shakeel F, Jahangir MA, Anwar M, Mallick N, Jain GK, et al. A review on the strategies for oral delivery of proteins and peptides and their clinical perspectives. Saudi Pharm J. https://doi.org/10.1016/j.jsps.2014.06.004.

  8. Payne NI, Timmins P, Ambrose CV, Ward MD, Ridgway F. Proliposomes: a novel solution to an old problem. J Pharm Sci. 1986;75(4):325–9.

    Article  CAS  PubMed  Google Scholar 

  9. Torchilin VP. Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov. 2005;4(2):145–60.

    Article  CAS  PubMed  Google Scholar 

  10. Potluri P, Betageri GV. Mixed-micellar proliposomal systems for enhanced oral delivery of progesterone. Drug Deliv. 2006;13(3):227–32. https://doi.org/10.1080/10717540500395007.

    Article  CAS  PubMed  Google Scholar 

  11. Nekkanti V, Venkatesan N, Betageri G. Proliposomes for oral delivery: progress and challenges. Curr Pharm Biotechnol. 2015;16:303–12.

    Article  CAS  PubMed  Google Scholar 

  12. Wang JP, Maitani Y, Takayama K, Pharmacokinetics NT. Antitumor effect of doxorubicin carried by stealth and remote loading proliposome. Pharm Res. 2000;17(7):782–7. https://doi.org/10.1023/a:1007543805947.

    Article  CAS  PubMed  Google Scholar 

  13. Song KH, Chung SJ, Shim CK. Preparation and evaluation of proliposomes containing salmon calcitonin. J Controll Release: Off J Controll Release Soc. 2002;84(1–2):27–37.

    Article  CAS  Google Scholar 

  14. Murata M, Yonamine T, Tanaka S, Tahara K, Tozuka Y, Takeuchi H. Surface modification of liposomes using polymer–wheat germ agglutinin conjugates to improve the absorption of peptide drugs by pulmonary administration. J Pharm Sci. 2013;102(4):1281–9. https://doi.org/10.1002/jps.23463.

    Article  CAS  PubMed  Google Scholar 

  15. Colletier J-P, Chaize B, Winterhalter M, Fournier D. Protein encapsulation in liposomes: efficiency depends on interactions between protein and phospholipid bilayer. BMC Biotechnol. 2002;2(1):9. https://doi.org/10.1186/1472-6750-2-9.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Veerapu G, Gangadharappa HV, Nagashubha B, Balamuralidhara V. Review on novel carrier system: liposomes and proliposomes. Drug Deliv Lett. 2014;4(2):96–109.

    Article  CAS  Google Scholar 

  17. Tantisripreecha C, Jaturanpinyo M, Panyarachun B, Sarisuta N. Development of delayed-release proliposomes tablets for oral protein drug delivery. Drug Dev Ind Pharm. 2012;38(6):718–27. https://doi.org/10.3109/03639045.2011.623168.

    Article  CAS  PubMed  Google Scholar 

  18. Dvorchik BH, Brazier D, DeBruin MF, Arbeit RD. Daptomycin pharmacokinetics and safety following administration of escalating doses once daily to healthy subjects. Antimicrob Agents Chemother. 2003;47(4):1318–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zaffiri L, Gardner J, Toledo-Pereyra LH. History of antibiotics: from fluoroquinolones to daptomycin (part 2). J Investig Surg. 2013;26(4):167–79. https://doi.org/10.3109/08941939.2013.808461.

    Article  Google Scholar 

  20. Zupančič O, Partenhauser A, Lam HT, Rohrer J, Bernkop-Schnürch A. Development and in vitro characterisation of an oral self-emulsifying delivery system for daptomycin. Eur J Pharm Sci. 2016;81:129–36. https://doi.org/10.1016/j.ejps.2015.10.005.

    Article  PubMed  Google Scholar 

  21. Hiremath PS, Soppimath KS, Betageri GV. Proliposomes of exemestane for improved oral delivery: formulation and in vitro evaluation using PAMPA, Caco-2 and rat intestine. Int J Pharm. 2009;380(1–2):96–104. https://doi.org/10.1016/j.ijpharm.2009.07.008.

    Article  CAS  PubMed  Google Scholar 

  22. Yanamandra S, Venkatesan N, Kadajji VG, Wang Z, Issar M, Betageri GV. Proliposomes as a drug delivery system to decrease the hepatic first-pass metabolism: case study using a model drug. Eur J Pharm Sci. 2014;64:26–36. https://doi.org/10.1016/j.ejps.2014.08.008.

    Article  CAS  PubMed  Google Scholar 

  23. Tobin CM, Darville JM, Lovering AM, MacGowan AP. An HPLC assay for daptomycin in serum. J Antimicrob Chemother. 2008;62(6):1462–3. https://doi.org/10.1093/jac/dkn414.

    Article  CAS  PubMed  Google Scholar 

  24. Nekkanti V, Venkatesan N, Wang Z, Betageri GV. Improved oral bioavailability of valsartan using proliposomes: design, characterization and in vivo pharmacokinetics. Drug Dev Ind Pharm. 2015;41(12):2077–88. https://doi.org/10.3109/03639045.2015.1075026.

    Article  CAS  PubMed  Google Scholar 

  25. Nekkanti V, Rueda J, Wang Z, Betageri GV. Comparative evaluation of proliposomes and self micro-emulsifying drug delivery system for improved oral bioavailability of nisoldipine. Int J Pharm. 2016;505(1–2):79–88. https://doi.org/10.1016/j.ijpharm.2016.03.065.

    Article  CAS  PubMed  Google Scholar 

  26. Betageri GV. Liposomal encapsulation and stability of dideoxyinosine triphosphate. Drug Dev Ind Pharm. 1993;19(5):531–9. https://doi.org/10.3109/03639049309062965.

    Article  CAS  Google Scholar 

  27. El-Samaligy MS, Afifi NN, Mahmoud EA. Increasing bioavailability of silymarin using a buccal liposomal delivery system: preparation and experimental design investigation. Int J Pharm. 2006;308(1–2):140–8. https://doi.org/10.1016/j.ijpharm.2005.11.006.

    Article  CAS  PubMed  Google Scholar 

  28. Zschörnig O, Arnold K, Richter W, Ohki S. Dextran sulfate-dependent fusion of liposomes containing cationic stearylamine. Chem Phys Lipids. 1992;63(1):15–22. https://doi.org/10.1016/0009-3084(92)90016-I.

    Article  PubMed  Google Scholar 

  29. Sułkowski WW, Pentak D, Nowak K, Sułkowska A. The influence of temperature, cholesterol content and pH on liposome stability. J Mol Struct. 2005;744–747:737–47. https://doi.org/10.1016/j.molstruc.2004.11.075.

    Article  Google Scholar 

  30. Khoo SM, Shackleford DM, Porter CJH, Edwards GA, Charman WN. Intestinal lymphatic transport of halofantrine occurs after oral administration of a unit-dose lipid-based formulation to fasted dogs. 2003.

  31. Kulkarni S, Betageri G, Singh M. Factors affecting microencapsulation of drugs in liposomes. J Microencapsul. 1995;12(3):229–46.

    Article  CAS  PubMed  Google Scholar 

  32. Singh B, Khurana L, Bandyopadhyay S, Kapil R, Katare OO. Development of optimized self-nano-emulsifying drug delivery systems (SNEDDS) of carvedilol with enhanced bioavailability potential. Drug Deliv. 2011;18(8):599–612. https://doi.org/10.3109/10717544.2011.604686.

    Article  CAS  PubMed  Google Scholar 

  33. Grit M, Crommelin DJA. Chemical stability of liposomes: implications for their physical stability. Chem Phys Lipids. 1993;64(1):3–18. https://doi.org/10.1016/0009-3084(93)90053-6.

    Article  CAS  PubMed  Google Scholar 

  34. Sakoulas G, Eliopoulos GM, Alder J, Eliopoulos CT. Efficacy of daptomycin in experimental endocarditis due to methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2003;47(5):1714–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors express their sincere gratitude to Western University of Health Sciences, Pomona, California for providing the facilities.

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Author notes

  1. Javier Rueda Arregui and Surya Prakasarao Kovvasu contributed equally to this work.

Authors and Affiliations

  1. Western University of Health Sciences, College of Pharmacy, 309 E. Second St., Pomona, California, 91766, USA

    Javier Rueda Arregui, Surya Prakasarao Kovvasu & Guru V. Betageri

  2. Western University of Health Sciences, Graduate College of Biomedical Sciences, Pomona, California, USA

    Guru V. Betageri

Authors
  1. Javier Rueda Arregui
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  2. Surya Prakasarao Kovvasu
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  3. Guru V. Betageri
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Correspondence to Guru V. Betageri.

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Arregui, J.R., Kovvasu, S.P. & Betageri, G.V. Daptomycin Proliposomes for Oral Delivery: Formulation, Characterization, and In Vivo Pharmacokinetics. AAPS PharmSciTech 19, 1802–1809 (2018). https://doi.org/10.1208/s12249-018-0989-0

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