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Development of Spray-Dried Cyclodextrin-Based Pediatric Anti-HIV Formulations

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Abstract

The human immunodeficiency virus (HIV) impacts up to 37 million people globally, of which 1.8 million are children. To date, there is no cure for HIV, although treatment options such as antiretroviral therapy (ART) are available. ART, which involves a patient taking a combination of antiretrovirals, is being used to treat HIV clinically. Despite the effectiveness of ART, there is currently no palatable pediatric formulation to treat HIV in children, which has hindered patient compliance and overall treatment efficacy. In addition, anti-HIV therapeutics are often poorly water-soluble, and hence have poor bioavailability. In the present study, we developed a pediatric-friendly formulation for anti-HIV therapeutics with improved dissolution characteristics of the therapeutic agents. Lopinavir (LPV) and ritonavir (RTV), available as FDA-approved fixed-dose combination products, were chosen as model ART drugs, and the formulation and processing parameters of spray-dried cyclodextrin (CD)-based LPV and RTV complexes were studied. Results showed that the spray-dried complexes exhibited enhanced dissolution profiles in comparison to pure drugs, particularly spray-dried β-CD complexes, which showed the most favorable dissolution profiles. This current formulation with enhanced dissolution and taste-masking ability through the use of cyclodextrin has the potential to address the unmet need for the development of suitable pediatric formulations.

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References

  1. Nelson AG, Zhang X, Ganapathi U, Szekely Z, Charles W, Owen A, et al. HHS Public Access. J Control Release. 2016;219:669–80.

    Article  Google Scholar 

  2. Mallipeddi R, Rohan LC. Progress in antiretroviral drug delivery using nanotechnology. Int J Nanomedicine. 2010;5:533–47.

    Article  CAS  Google Scholar 

  3. Bhatti AB, Usman M, Kandi V. Current scenario of HIV/AIDS, treatment options, and major challenges with compliance to antiretroviral therapy. Cureus. 2016;8:1–12.

    Google Scholar 

  4. Pham K, Li D, Guo S, Penzak S, Dong X. Development and in vivo evaluation of child-friendly lopinavir/ritonavir pediatric granules utilizing novel in situ self-assembly nanoparticles. J Control Release. 2016;226:88–97.

    Article  CAS  Google Scholar 

  5. Schlatter AF, Deathe AR, Vreeman RC. The need for pediatric formulations to treat children with HIV. AIDS Research and Treatment. 2016;2016:1654938.

    Article  Google Scholar 

  6. Ivanovska V, Rademaker CMA, Van Dijk L, Mantel-Teeuwisse AK. Pediatric drug formulations: a review of challenges and progress. Pediatrics. 2014;134:361–72.

    Article  Google Scholar 

  7. Chandwani A. Shuter J (2008) Lopinavir / ritonavir in the treatment of HIV-1 infection: a review. Ther Clin Risk Manag. 2008;4:1023–33.

    Article  CAS  Google Scholar 

  8. Best Pharmaceutical’s for Children Act (BPCA). https://www.nichd.nih.gov/research/supported/bpca

  9. Pittman DW, Brantly AM, Drobonick AL, King HT, Mesta DC, Richards CG, et al. The palatability of lopinavir and ritonavir delivered by an innovative freeze-dried fast-dissolving tablet formulation. AIDS Research and Treatment. 2018;5908167.

  10. Saokham P, Muankaew C, Jansook P, Loftsson T. Solubility of cyclodextrins and drug/cyclodextrin complexes. Molecules. 2018;23:1–15.

    Article  Google Scholar 

  11. Chay SK, Keating AV, James C, Aliev AE, Haider S, Craig DQM. Evaluation of the taste-masking effects of (2-hydroxypropyl)-β-cyclodextrin on ranitidine hydrochloride: a combined biosensor, spectroscopic and molecular modelling assessment. RSC Adv. 2018;8:3564–73.

    Article  CAS  Google Scholar 

  12. Loftsson T, Hreinsdóttir D, Másson M. The complexation efficiency. J Incl Phenom Macrocycl Chem. 2007;57:545–52.

    Article  CAS  Google Scholar 

  13. Brynn Hibbert D, Thordarson P. The death of the Job plot, transparency, open science and online tools, uncertainty estimation methods and other developments in supramolecular chemistry data analysis. Chem Commun. 2016;52:12792–805.

    Article  CAS  Google Scholar 

  14. Thordarson P. Determining association constants from titration experiments in supramolecular chemistry. Chem Soc Rev. 2011;40:1305–23.

    Article  CAS  Google Scholar 

  15. Molecular Operating Environment (MOE), 2019.01; Chemical Computing Group ULC, 1010 Sherbooke St. West, Suite #910, Montreal, QC, Canada, H3A 2R7, 2021

  16. Goyal G, Vavia PR. Complexation approach for fixed dose tablet formulation of lopinavir and ritonavir: an anomalous relationship between stability constant, dissolution rate and saturation solubility. J Incl Phenom Macrocycl Chem. 2011;73:75–85.

    Article  Google Scholar 

  17. Adeoye O, Conceição J, Serra PA, Bento da Silva A, Duarte N, Guedes RC, et al. Cyclodextrin solubilization and complexation of antiretroviral drug lopinavir: in silico prediction: effects of derivatization, molar ratio and preparation method. Carbohydr Polym. 2020;227:115287.

    Article  CAS  Google Scholar 

  18. Del Valle EMM. Cyclodextrins and their uses: a review. Process Biochem. 2003;39:1033–46.

    Article  Google Scholar 

  19. Baykal A, Bozkurt A, Jeremy R, Asiri SMM, Lima-Tenório MK, Kaewsaneha C, et al. Multistimuli-responsive magnetic assemblies. Advanced Nanocarriers for Therapeutics. 2019;2:155–93.

    CAS  Google Scholar 

  20. Rajbanshi B, Saha S, Das K, Barman BK, Sengupta S, Bhattacharjee A, et al. Study to probe subsistence of host-guest inclusion complexes of α and β-cyclodextrins with biologically potent drugs for safety regulatory dischargement. Sci Rep. 2018;8:1–20.

    Article  CAS  Google Scholar 

  21. Wang CL, Zhou L, Zhang L, Xiang JF, Rambo BM, Sessler JL, et al. Discrete 1 : 1 complexes and higher order assemblies formed from aminobenzene sulphonate anions and a tetraimidazolium “molecular box.”. Chem Commun. 2017;53:3669–72.

    Article  CAS  Google Scholar 

  22. Gryczke A, Langley N, Alshahrani SM, Park J-B, Alsulays BB, Majumdar S, et al. Stability-enhanced hot-melt extruded amorphous solid dispersions via combinations of Soluplus® and HPMCAS-HF. AAPS PharmSciTech. 2015;16:824–34.

    Article  Google Scholar 

  23. Thakral NK, Zanon RL, Kelly RC, Thakral S. Applications of powder X-ray diffraction in small molecule pharmaceuticals: achievements and aspirations. J Pharm Sci. 2018;107:2969–82.

    Article  CAS  Google Scholar 

  24. Sakuma S, Matsumoto S, Ishizuka N, Mohri K, Fukushima M, Ohba C, et al. Enhanced boosting of oral absorption of lopinavir through electrospray coencapsulation with ritonavir. J Pharm Sci. 2015;104:2977–85.

    Article  CAS  Google Scholar 

  25. Gallicano K. Antiretroviral-drug concentrations in semen. Antimicrob Agents Chemother. 2000;44:1117–8.

    Article  CAS  Google Scholar 

  26. Alopaeus JF, Hagesæther E, Tho I. Micellisation mechanism and behaviour of soluplus®–furosemide micelles: preformulation studies of an oral nanocarrier-based system. Pharmaceuticals. 2019;12:1–23.

    Article  Google Scholar 

  27. Karagianni A, Kachrimanis K, Nikolakakis I. Co-amorphous solid dispersions for solubility and absorption improvement of drugs: composition, preparation, characterization and formulations for oral delivery. Pharmaceutics. 2018;10:98.

    Article  CAS  Google Scholar 

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Funding

This work was supported in part by the IPEC-Americas Foundation Emerging Researcher Award and the Institutional Development Award (IDeA) Network for Biomedical Research Excellence from the National Institute of General Medical Sciences of the National Institutes of Health under the grant number P20GM103430. The SEM and XRD data was acquired at the RI Consortium for Nanoscience and Nanotechnology, a URI College of Engineering core facility partially funded by the National Science Foundation EPSCoR, Cooperative Agreement #OIA-1655221.

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Authors and Affiliations

  1. Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, 7 Greenhouse Road, Kingston, Rhode Island, 02881, USA

    Ryan Ivone, Samantha A. Meenach & Jie Shen

  2. Department of Chemistry, University of Rhode Island, Kingston, Rhode Island, USA

    Ashvin Fernando & Brenton DeBoef

  3. Department of Chemical Engineering, University of Rhode Island, Kingston, Rhode Island, USA

    Samantha A. Meenach & Jie Shen

Authors
  1. Ryan Ivone
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  2. Ashvin Fernando
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  3. Brenton DeBoef
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  4. Samantha A. Meenach
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  5. Jie Shen
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Contributions

Ryan Ivone (first author): (1) the conception and design of the study; (2) acquisition of data; (3) analysis and interpretation of data; (4) drafting the article; (5) revising it critically for important intellectual content.

Ashvin Fernando: (1) acquisition of data; (2) analysis and interpretation of data; (3) final approval of the version to be submitted.

Brenton DeBoef: (1) analysis and interpretation of data; (2) final approval of the version to be submitted.

Samantha Meenach (corresponding author): (1) the conception and design of the study; (2) revising it critically for important intellectual content; (3) final approval of the version to be submitted.

Jie Shen (corresponding author): (1) the conception and design of the study; (2) revising it critically for important intellectual content; (3) final approval of the version to be submitted.

Corresponding authors

Correspondence to Samantha A. Meenach or Jie Shen.

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Ivone, R., Fernando, A., DeBoef, B. et al. Development of Spray-Dried Cyclodextrin-Based Pediatric Anti-HIV Formulations. AAPS PharmSciTech 22, 193 (2021). https://doi.org/10.1208/s12249-021-02068-w

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