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Tuning the release rate of rilpivirine from PLGA-based in situ forming implants

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Abstract

In situ forming implants (ISFI) based on poly(lactic-co-glycolic acid) (PLGA) are promising long-acting injectable depots for the treatment of human immunodeficiency virus-1 infection. One of the key parameters of depot formulations is the drug release rate which is critical for the development of optimal dosing regimens. The goal of this research is to investigate the most significant factors affecting the rilpivirine release rate from PLGA-based ISFI, including the influence of the polymer content and structure (i.e. molecular weights, lactide/glycolide ratios, and chemistry of the terminal group). Thus, the use of a low molecular weight PLGA reduces the burst-effect from 17.5 to 4.7% of the drug content and enables continuous release of rilpivirine over the period of 42 days. At the same time, a more hydrophobic PLGA with a lactide/glycolide ratio of 75/25 and a terminal ester group affects to a greater extent the rilpivirine release rate in the third phase of the release process, when destruction of the polymer matrix starts. The rilpivirine release profile from the implant, formed by using a 30% (w/w) solution of PLGA with a higher content of lactic acid (75:25) and a terminal ester group, is similar to the dissolution profile of rilpivirine nanocrystals (Rekambis®).

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References

  1. Flexner C (2019) Modern HIV therapy: progress and prospects. Clin Pharmacol Ther 105:61–70. https://doi.org/10.1002/cpt.1284

    Article  PubMed  Google Scholar 

  2. Williams J, Sayles HR, Meza JL et al (2013) Long-acting parenteral nanoformulated antiretroviral therapy: interest and attitudes of HIV-infected patients. Nanomedicine 8:1807–1813. https://doi.org/10.2217/nnm.12.214

    Article  CAS  PubMed  Google Scholar 

  3. Baert L, Kloostervan ’t G, Dries W et al (2009) Development of a long-acting injectable formulation with nanoparticles of rilpivirine (TMC278) for HIV treatment. Eur J Pharm Biopharm 72:502–508. https://doi.org/10.1016/j.ejpb.2009.03.006

    Article  CAS  PubMed  Google Scholar 

  4. Mordant C, Schmitt B, Pasquier E et al (2007) Synthesis of novel diarylpyrimidine analogues of TMC278 and their antiviral activity against HIV-1 wild-type and mutant strains. Eur J Med Chem 42:567–579. https://doi.org/10.1016/j.ejmech.2006.11.014

    Article  CAS  PubMed  Google Scholar 

  5. Namasivayam V, Vanangamudi M, Kramer VG et al (2019) The journey of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) from lab to clinic. J Med Chem 62:4851–4883. https://doi.org/10.1021/acs.jmedchem.8b00843

    Article  CAS  PubMed  Google Scholar 

  6. (2021) FDA Approves cabenuva and vocabria for the treatment of HIV-1 infection. In: Food and Drug Administration. https://www.fda.gov/

  7. Swindells S, Andrade-Villanueva J-F, Richmond GJ et al (2020) Long-acting cabotegravir and rilpivirine for maintenance of HIV-1 suppression. N Engl J Med 382:1112–1123. https://doi.org/10.1056/nejmoa1904398

    Article  CAS  PubMed  Google Scholar 

  8. Spreen WR, Margolis DA, Pottage JC (2013) Long-acting injectable antiretrovirals for HIV treatment and prevention. Curr Opin HIV AIDS 8:565–571. https://doi.org/10.1097/COH.0000000000000002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gunawardana M, Remedios-Chan M, Miller CS et al (2015) Pharmacokinetics of long-acting tenofovir alafenamide (GS-7340) subdermal implant for HIV prophylaxis. Antimicrob Agents Chemother 59:3913–3919. https://doi.org/10.1128/AAC.00656-15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Solorio L, Olear AM, Hamilton JI et al (2012) Noninvasive characterization of the effect of varying PLGA molecular weight blends on in situ forming implant behavior using ultrasound imaging. Theranostics 2:1064–1077. https://doi.org/10.7150/thno.4181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Karunakaran D, Simpson SM, Su JT et al (2021) Design and testing of a cabotegravir implant for HIV prevention. J Controll Release 330:658–668. https://doi.org/10.1016/j.jconrel.2020.12.024

    Article  CAS  Google Scholar 

  12. Barrett SE, Teller RS, Forster SP et al (2018) Extended-duration MK-8591-eluting implant as a candidate for HIV treatment and prevention. Antimicrob Agents Chemother 62:e01058-e1118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kempe S, Mäder K (2012) In situ forming implants—an attractive formulation principle for parenteral depot formulations. J Controll Release 161:668–679. https://doi.org/10.1016/j.jconrel.2012.04.016

    Article  CAS  Google Scholar 

  14. Chaudhary K, Patel MM, Mehta PJ (2019) Long-acting injectables: current perspectives and future promise. Crit Rev Ther Drug Carrier Syst 36:137–181. https://doi.org/10.1615/CritRevTherDrugCarrierSyst.2018025649

    Article  PubMed  Google Scholar 

  15. Maturavongsadit P, Shrivastava R, Sykes C et al (2021) Biodegradable polymeric solid implants for ultra-long-acting delivery of single or multiple antiretroviral drugs. Int J Pharm 605:120844. https://doi.org/10.1016/j.ijpharm.2021.120844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Benhabbour SR, Kovarova M, Jones C et al (2019) Ultra-long-acting tunable biodegradable and removable controlled release implants for drug delivery. Nat Commun 10:4324. https://doi.org/10.1038/s41467-019-12141-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. (2020) Assessment report. Rekambys

  18. Thakur RRS, McMillan HL, Jones DS (2014) Solvent induced phase inversion-based in situ forming controlled release drug delivery implants. J Control Release 176:8–23. https://doi.org/10.1016/j.jconrel.2013.12.020

    Article  CAS  PubMed  Google Scholar 

  19. Zare M, Mobedi H, Barzin J et al (2008) Effect of additives on release profile of leuprolide acetate in an in situ forming controlled-release system. in vitro study. J Appl Polym Sci 107:3781–3787. https://doi.org/10.1002/app.27520

    Article  CAS  Google Scholar 

  20. Ahmed TA, Ibrahim HM, Ibrahim F et al (2012) Development of biodegradable in situ implant and microparticle injectable formulations for sustained delivery of haloperidol. J Pharm Sci 101:3753–3762. https://doi.org/10.1002/jps.23250

    Article  CAS  PubMed  Google Scholar 

  21. Ibrahim TM, El-Megrab NA, El-Nahas HM (2020) Optimization of injectable PLGA in-situ forming implants of anti-psychotic risperidone via Box-Behnken design. J Drug Deliv Sci Technol 58:101803. https://doi.org/10.1016/j.jddst.2020.101803

    Article  CAS  Google Scholar 

  22. Kanwar N, Sinha VR (2019) In situ forming depot as sustained-release drug delivery systems. Crit Rev Ther Drug Carrier Syst 36:93–136. https://doi.org/10.1615/CritRevTherDrugCarrierSyst.2018025013

    Article  PubMed  Google Scholar 

  23. Wang X, Burgess DJ (2021) Drug release from in situ forming implants and advances in release testing. Adv Drug Deliv Rev. https://doi.org/10.1016/j.addr.2021.113912

    Article  PubMed  PubMed Central  Google Scholar 

  24. Luan X, Bodmeier R (2006) Influence of the poly(lactide-co-glycolide) type on the leuprolide release from in situ forming microparticle systems. J Controll Release 110:266–272. https://doi.org/10.1016/j.jconrel.2005.10.005

    Article  CAS  Google Scholar 

  25. Chhabra S, Sachdeva V, Singh S (2007) Influence of end groups on in vitro release and biological activity of lysozyme from a phase-sensitive smart polymer-based in situ gel forming controlled release drug delivery system. Int J Pharm 342:72–77. https://doi.org/10.1016/j.ijpharm.2007.04.034

    Article  CAS  PubMed  Google Scholar 

  26. Patel V, Akbari B, Deshmukh A et al (2015) A review on PLGA based solvent induced in-situ forming implant. Res J Pharm Dos Technol 8:127

    Google Scholar 

  27. Romero GB, Keck CM, Müller RH (2016) Simple low-cost miniaturization approach for pharmaceutical nanocrystals production. Int J Pharm 501:236–244. https://doi.org/10.1016/j.ijpharm.2015.11.047

    Article  CAS  PubMed  Google Scholar 

  28. Ermolenko Y, Nazarova N, Belov A et al (2022) Potential of the capillary electrophoresis method for PLGA analysis in nano-sized drug formulations. J Drug Deliv Sci Technol 70:103220. https://doi.org/10.1016/j.jddst.2022.103220

    Article  CAS  Google Scholar 

  29. Hatefi A, Amsden B (2002) Biodegradable injectable in situ forming drug delivery systems. J Control Release 80:9–28. https://doi.org/10.1016/S0168-3659(02)00008-1

    Article  CAS  PubMed  Google Scholar 

  30. Parent M, Nouvel C, Koerber M et al (2013) PLGA in situ implants formed by phase inversion: critical physicochemical parameters to modulate drug release. J Control Release 172:292–304. https://doi.org/10.1016/j.jconrel.2013.08.024

    Article  CAS  PubMed  Google Scholar 

  31. Williams PE, Crauwels HM, Basstanie ED (2015) Formulation and pharmacology of long-acting rilpivirine. Curr Opin HIV AIDS 10:233–238. https://doi.org/10.1097/COH.0000000000000164

    Article  CAS  PubMed  Google Scholar 

  32. Stokbroekx SCM (2010) Crystalline form of 4–4–4-(2-cyanoethenyl)-2,6-dimethylphenyl-amino-2-pyrimidinylaminobenzonitrile

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

    Article  CAS  Google Scholar 

  34. Thackaberry EA, Wang X, Schweiger M et al (2014) Solvent-based formulations for intravenous mouse pharmacokinetic studies: tolerability and recommended solvent dose limits. Xenobiotica 44:235–241. https://doi.org/10.3109/00498254.2013.845706

    Article  CAS  PubMed  Google Scholar 

  35. Schwendeman SP, Shah RB, Bailey BA, Schwendeman AS (2014) Injectable controlled release depots for large molecules. J Controll Release 190:240–253. https://doi.org/10.1016/j.jconrel.2014.05.057

    Article  CAS  Google Scholar 

  36. Bradshaw J, White S (2018) Combining human needs with high viscosity formulations. ONdrugDelivery Magazine 16–21

  37. von Burkersroda F, Schedl L, Göpferich A (2002) Why degradable polymers undergo surface erosion or bulk erosion. Biomaterials 23:4221–4231. https://doi.org/10.1016/S0142-9612(02)00170-9

    Article  Google Scholar 

  38. Wischke C, Zhang Y, Mittal S, Schwendeman SP (2010) Development of PLGA-based injectable delivery systems for hydrophobic fenretinide. Pharm Res 27:2063–2074. https://doi.org/10.1007/s11095-010-0202-y

    Article  CAS  PubMed  Google Scholar 

  39. Ermolenko YV, Semyonkin AS, Ulianova YV et al (2020) Role of hydrolytic degradation of polylactide drug carriers in developing micro- and nanoscale polylactide-based drug dosage forms. Russ Chem Bull 69:1416–1427. https://doi.org/10.1007/s11172-020-2918-0

    Article  CAS  Google Scholar 

  40. Astaneh R, Erfan M, Moghimi H, Mobedi H (2009) Changes in morphology of in situ forming PLGA implant prepared by different polymer molecular weight and its effect on release behavior. J Pharm Sci 98:135–145. https://doi.org/10.1002/jps.21415

    Article  CAS  PubMed  Google Scholar 

  41. Hopkins KA, Vike N, Li X et al (2019) Noninvasive characterization of in situ forming implant diffusivity using diffusion-weighted MRI. J Controll Release 309:289–301. https://doi.org/10.1016/j.jconrel.2019.07.019

    Article  CAS  Google Scholar 

  42. Patel RB, Solorio L, Wu H et al (2010) Effect of injection site on in situ implant formation and drug release in vivo. J Controll Release 147:350–358. https://doi.org/10.1016/j.jconrel.2010.08.020

    Article  CAS  Google Scholar 

  43. Graham PD, Brodbeck KJ, McHugh AJ (1999) Phase inversion dynamics of PLGA solutions related to drug delivery. J Controll Release 58:233–245. https://doi.org/10.1016/S0168-3659(98)00158-8

    Article  CAS  Google Scholar 

  44. Solorio L, Babin BM, Patel RB et al (2010) Noninvasive characterization of in situ forming implants using diagnostic ultrasound. J Control Release 143:183–190. https://doi.org/10.1016/j.jconrel.2010.01.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Joiner JB, Prasher A, Young IC et al (2022) Effects of drug physicochemical properties on in-situ forming implant polymer degradation and drug release kinetics. Pharmaceutics 14:1188. https://doi.org/10.3390/pharmaceutics14061188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The study was carried out with the financial support of the Russian Foundation for Basic Research within the framework of the scientific project No. 20-315-90104.The authors would like to thank Purac Biochem bv., Netherlands, for providing samples of Purasorb® PDLG 5004 and Purasorb® PDLG 5004A polymers. The authors are grateful to Dr. Alexander Kurkin (M.V. Lomonosov Moscow State University) for a generous gift of rilpivirine substance.

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Authors and Affiliations

  1. Scientific and Educational Laboratory of Drug Delivery Systems, D. I. Mendeleev University of Chemical Technology of Russia, Miusskaya Square, 9, Moscow, Russia, 125047

    Yulia Ulianova, Yulia Ermolenko, Sergey Tkachenko & Svetlana Gelperina

  2. Department of Chemistry and Technology of Biomedical Preparations, D. I. Mendeleev University of Chemical Technology of Russia, Miusskaya Square, 9, Moscow, Russia, 125047

    Yulia Ulianova, Yulia Ermolenko, Sergey Tkachenko & Svetlana Gelperina

  3. Institute for Translational Medicine and Biotechnology, I. M. Sechenov First Moscow State Medical University, 8-2 Trubetskaya Str., Moscow, Russia, 119991

    Vladimir Trukhan

  4. Center for Collective Use. D. I. Mendeleev, D. I. Mendeleev University of Chemical Technology of Russia, Miusskaya Square, 9, Moscow, Russia, 125047

    Alexander Morozov

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  1. Yulia Ulianova
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Ulianova, Y., Ermolenko, Y., Tkachenko, S. et al. Tuning the release rate of rilpivirine from PLGA-based in situ forming implants. Polym. Bull. 80, 11401–11420 (2023). https://doi.org/10.1007/s00289-022-04623-2

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