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Design and Characterization of HY-038 Solid Dispersions via Spray Drying Technology: In Vitro and In Vivo Evaluations

  • Research Article
  • Theme: Advancements in Amorphous Solid Dispersions to Improve Bioavailability
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Abstract

The aim of this study was to prepare HY-038 solid dispersions (SDs) with single carrier at high drug loading and then forming a tablet to enhance solubility, dissolution, and bioavailability via spray drying technology. At the same time, we hope to develop a more convenient in vitro method to predict the absorption behavior of different formulations in vivo. Different solid dispersions, varying in drug/polymer ratios, were prepared. Infrared spectroscopy, differential scanning calorimetry, scanning electron microscope, and X-ray diffraction were used to perform solid-state characterizations of the pure drug and SDs. Contact angle of water, dissolution in pH = 6.8 phosphate buffer, and in vivo absorption in dogs were studied. As a result, solid-state characterization demonstrated the transformation of the crystalline HY-038 to an amorphous state in the solid dispersions, and the in vivo exposure followed with the trend of the dissolution curve combined with contact angle. Compared with the prototype formulation, the Cmax and AUC0–∞ of optimized formulation SD2 (HY-038-HPMCAS 3:1) increased by about 5 ~ 9 times at the same dose. More importantly, the SD2 formulation showed approximately linear increases in Cmax and AUC0–∞ as the dose increased from 50 to 100 mg, while the prototype formulation reached absorption saturation at 50 mg. SD2 (HY-038-HPMCAS 3:1) was selected as the best formulation for the downstream development.

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References

  1. Nkansah P, Antipas A, Lu Y, Varma M, Rotter C, Rago B, et al. Development and evaluation of novel solid nanodispersion system for oral delivery of poorly water-soluble drugs. J Control Release. 2013;169(1–2):150–61. https://doi.org/10.1016/j.jconrel.2013.03.032.

    Article  CAS  PubMed  Google Scholar 

  2. Adeoye O, Conceicao J, Serra PA, Bento DSA, 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. https://doi.org/10.1016/j.carbpol.2019.115287.

    Article  CAS  PubMed  Google Scholar 

  3. James K. Bioorganic and Medicinal Chemistry Letters. Nature (London). 1992;359(6394):458. https://doi.org/10.1016/j.bmcl.2017.09.041.

    Article  CAS  Google Scholar 

  4. Tahir M, Khalid U, Ijaz M, Shah GM, Naeem MA, Shahid M, et al. Combined application of bio-organic phosphate and phosphorus solubilizing bacteria (Bacillus strain MWT 14) improve the performance of bread wheat with low fertilizer input under an arid climate. Braz J Microbiol. 2018;49(S1):15–24. https://doi.org/10.1016/j.bjm.2017.11.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Jansook P, Ogawa N, Loftsson T. Cyclodextrins: structure, physicochemical properties and pharmaceutical applications. Int J Pharmaceut. 2018;535(1–2):272–84. https://doi.org/10.1016/j.ijpharm.2017.11.018.

    Article  CAS  Google Scholar 

  6. Xu J, Huang L, Chen C, Wang J, Long X. Effective lead immobilization by phosphate rock solubilization mediated by phosphate rock amendment and phosphate solubilizing bacteria. Chemosphere (Oxford). 2019;237:124540. https://doi.org/10.1016/j.chemosphere.2019.124540.

    Article  CAS  Google Scholar 

  7. Gala U, Miller D, Williams RO. Improved dissolution and pharmacokinetics of abiraterone through KinetiSol® enabled amorphous solid dispersions. Pharmaceutics. 2020;12(4):357. https://doi.org/10.3390/pharmaceutics12040357.

    Article  CAS  PubMed Central  Google Scholar 

  8. Laitinen R, Lobmann K, Grohganz H, Priemel P, Strachan CJ, Rades T. Supersaturating drug delivery systems: the potential of co-amorphous drug formulations. Int J Pharm. 2017;532(1):1–12. https://doi.org/10.1016/j.ijpharm.2017.08.123.

    Article  CAS  PubMed  Google Scholar 

  9. Monschke M, Wagner KG. Impact of HPMCAS on the dissolution performance of polyvinyl alcohol celecoxib amorphous solid dispersions. Pharmaceutics. 2020;12(6):541. https://doi.org/10.3390/pharmaceutics12060541.

    Article  CAS  PubMed Central  Google Scholar 

  10. Chaudhary S, Nair AB, Shah J, Gorain B, Jacob S, Shah H, et al. Enhanced solubility and bioavailability of dolutegravir by solid dispersion method: in vitro and in vivo evaluation—a potential approach for HIV therapy. AAPS Pharmscitech. 2021. https://doi.org/10.1208/s12249-021-01995-y.

    Article  PubMed  Google Scholar 

  11. Aldosari BN, Almurshedi AS, Alfagih IM, AlQuadeib BT, Altamimi MA, Imam SS, et al. Formulation of Gelucire®-based solid dispersions of atorvastatin calcium: in vitro dissolution and in vivo bioavailability study. AAPS Pharmscitech. 2021. https://doi.org/10.1208/s12249-021-02019-5.

    Article  PubMed  Google Scholar 

  12. Pezzoli R, Lyons JG, Gately N, Higginbotham CL. Stability studies of hot-melt extruded ternary solid dispersions of poorly-water soluble indomethacin with poly(vinyl pyrrolidone-co-vinyl acetate) and polyethylene oxide. J DRUG DELIV SCI TEC. 2019;52:248–54. doi:https://doi.org/10.1016/j.jddst.2019.04.023.

  13. Jelić D, Liavitskaya T, Vyazovkin S. Thermal stability of indomethacin increases with the amount of polyvinylpyrrolidone in solid dispersion. Thermochim Acta. 2019;676:172–6. https://doi.org/10.1016/j.tca.2019.04.011.

    Article  CAS  Google Scholar 

  14. Yeo S, An J, Park C, Kim D, Lee J. Design and characterization of phosphatidylcholine-based solid dispersions of aprepitant for enhanced solubility and dissolution. Pharmaceutics. 2020;12(5):407. https://doi.org/10.3390/pharmaceutics12050407.

    Article  CAS  PubMed Central  Google Scholar 

  15. Pawar BM, Rahman SNR, Pawde DM, Goswami A, Shunmugaperumal T. Orally administered drug solubility-enhancing formulations: lesson learnt from optimum solubility-permeability balance. AAPS Pharmscitech. 2021. https://doi.org/10.1208/s12249-021-01936-9.

    Article  PubMed  Google Scholar 

  16. Bertoni S, Albertini B, Ferraro L, Beggiato S, Dalpiaz A, Passerini N. Exploring the use of spray congealing to produce solid dispersions with enhanced indomethacin bioavailability: in vitro characterization and in vivo study. Eur J Pharm Biopharm. 2019;139:132–41. https://doi.org/10.1016/j.ejpb.2019.03.020.

    Article  CAS  PubMed  Google Scholar 

  17. Shi NQ, Wang SR, Zhang Y, Huo JS, Wang LN, Cai JH, et al. Hot melt extrusion technology for improved dissolution, solubility and “spring-parachute” processes of amorphous self-micellizing solid dispersions containing BCS II drugs indomethacin and fenofibrate: profiles and mechanisms. Eur J Pharm Sci. 2019;130:78–90. https://doi.org/10.1016/j.ejps.2019.01.019.

    Article  CAS  PubMed  Google Scholar 

  18. Lim C, Kang JK, Jung CE, Sim T, Her J, Kang K, et al. Preparation and characterization of a lutein solid dispersion to improve its solubility and stability. AAPS Pharmscitech. 2021. https://doi.org/10.1208/s12249-021-02036-4.

    Article  PubMed  Google Scholar 

  19. Colombo M, de Lima Melchiades G, Michels LR, Figueiró F, Bassani VL, Teixeira HF, et al. Solid dispersion of kaempferol: formulation development, characterization, and oral bioavailability assessment. AAPS Pharmscitech. 2019. https://doi.org/10.1208/s12249-019-1318-y.

    Article  PubMed  Google Scholar 

  20. Sahoo A, Kumar NSK, Suryanarayanan R. Crosslinking: an avenue to develop stable amorphous solid dispersion with high drug loading and tailored physical stability. J Control Release. 2019;311–312:212–24. https://doi.org/10.1016/j.jconrel.2019.09.007.

    Article  CAS  PubMed  Google Scholar 

  21. Balani PN, Wong SY, Ng WK, Widjaja E, Tan RB, Chan SY. Influence of polymer content on stabilizing milled amorphous salbutamol sulphate. Int J Pharm. 2010;391(1–2):125–36. https://doi.org/10.1016/j.ijpharm.2010.02.029.

    Article  CAS  PubMed  Google Scholar 

  22. Gurunath S, Pradeep Kumar S, Basavaraj NK, Patil PA. Amorphous solid dispersion method for improving oral bioavailability of poorly water-soluble drugs. J Pharm Res. 2013;6(4):476–80. https://doi.org/10.1016/j.jopr.2013.04.008.

    Article  CAS  Google Scholar 

  23. Nowak P, Krupa A, Kubat K, Węgrzyn A, Harańczyk H, Ciułkowska A, et al. Water vapour sorption in tadalafil-Soluplus co-milled amorphous solid dispersions. Powder Technol. 2019;346:373–84. https://doi.org/10.1016/j.powtec.2019.02.010.

    Article  CAS  Google Scholar 

  24. Ramos L. Use of new tailored and engineered materials for matrix solid-phase dispersion. TrAC Trends Anal Chem. 2019;118:751–8. https://doi.org/10.1016/j.trac.2019.07.006.

    Article  CAS  Google Scholar 

  25. Cheng X, Gao J, Li J, Cheng G, Zou M, Piao H. In vitro-in vivo correlation for solid dispersion of a poorly water-soluble drug efonidipine hydrochloride. AAPS Pharmscitech. 2020. https://doi.org/10.1208/s12249-020-01685-1.

    Article  PubMed  Google Scholar 

  26. Ziaee A, Albadarin AB, Padrela L, Femmer T, O’Reilly E, Walker G. Spray drying of pharmaceuticals and biopharmaceuticals: critical parameters and experimental process optimization approaches. Eur J Pharm Sci. 2019;127:300–18. https://doi.org/10.1016/j.ejps.2018.10.026.

    Article  CAS  PubMed  Google Scholar 

  27. Torrado-Salmerón C, Guarnizo-Herrero V, Gallego-Arranz T, Del Val-Sabugo Y, Torrado G, Morales J, et al. Improvement in the oral bioavailability and efficacy of new ezetimibe formulations—comparative study of a solid dispersion and different micellar systems. Pharmaceutics. 2020;12(7):617. https://doi.org/10.3390/pharmaceutics12070617.

    Article  CAS  PubMed Central  Google Scholar 

  28. Xiong X, Zhang M, Hou Q, Tang P, Suo Z, Zhu Y, et al. Solid dispersions of telaprevir with improved solubility prepared by co-milling: formulation, physicochemical characterization, and cytotoxicity evaluation. Mater Sci Eng C. 2019;105:110012. https://doi.org/10.1016/j.msec.2019.110012.

    Article  CAS  Google Scholar 

  29. Monschke M, Kayser K, Wagner KG. Processing of polyvinyl acetate phthalate in hot-melt extrusion—preparation of amorphous solid dispersions. Pharmaceutics. 2020;12(4):337. https://doi.org/10.3390/pharmaceutics12040337.

    Article  CAS  PubMed Central  Google Scholar 

  30. Monschke M, Wagner KG. Amorphous solid dispersions of weak bases with pH-dependent soluble polymers to overcome limited bioavailability due to gastric pH variability—an in-vitro approach. Int J Pharm. 2019;564:162–70. https://doi.org/10.1016/j.ijpharm.2019.04.034.

    Article  CAS  PubMed  Google Scholar 

  31. Zhang Q, Zhao Y, Zhao Y, Ding Z, Fan Z, Zhang H, et al. Effect of HPMCAS on recrystallization inhibition of nimodipine solid dispersions prepared by hot-melt extrusion and dissolution enhancement of nimodipine tablets. Colloids Surf B Biointerfaces. 2018;172:118–26. https://doi.org/10.1016/j.colsurfb.2018.08.030.

    Article  CAS  PubMed  Google Scholar 

  32. Guo S, Zhou F, Chen X, Zhao J, Huang D et al. 4,6,7-trisubstituted 1,2-dihydropyrrolo[3,4-c]pyridin/pyrimidin-3-one derivatives and uses thereof. 2020. US20200223846A1.

  33. Huhtamäki T, Tian X, Korhonen JT, Ras RHA. Surface-wetting characterization using contact-angle measurements. Nat Protoc. 2018;13(7):1521–38. https://doi.org/10.1038/s41596-018-0003-z.

    Article  CAS  PubMed  Google Scholar 

  34. Smeets A, Koekoekx R, Clasen C, Van den Mooter G. Amorphous solid dispersions of darunavir: comparison between spray drying and electrospraying. Eur J Pharm Biopharm. 2018;130:96–107. https://doi.org/10.1016/j.ejpb.2018.06.021.

    Article  CAS  PubMed  Google Scholar 

  35. Medarević D, Cvijić S, Dobričić V, Mitrić M, Djuriš J, Ibrić S. Assessing the potential of solid dispersions to improve dissolution rate and bioavailability of valsartan: in vitro-in silico approach. Eur J Pharm Sci. 2018;124:188–98. https://doi.org/10.1016/j.ejps.2018.08.026.

    Article  CAS  PubMed  Google Scholar 

  36. Ekdahl A, Mudie D, Malewski D, Amidon G, Goodwin A. Effect of spray-dried particle morphology on mechanical and flow properties of felodipine in PVP VA amorphous solid dispersions. J Pharm Sci-US. 2019;108(11):3657–66. https://doi.org/10.1016/j.xphs.2019.08.008.

    Article  CAS  Google Scholar 

  37. Li J, Fan N, Wang X, Li C, Sun M, Wang J, et al. Interfacial interaction track of amorphous solid dispersions established by water-soluble polymer and indometacin. Eur J Pharm Sci. 2017;106:244–53. https://doi.org/10.1016/j.ejps.2017.05.067.

    Article  CAS  PubMed  Google Scholar 

  38. Tran TTD, Tran PHL. Molecular interactions in solid dispersions of poorly water-soluble drugs. Pharmaceutics. 2020;12(8):745. https://doi.org/10.3390/pharmaceutics12080745.

    Article  CAS  PubMed Central  Google Scholar 

  39. Kambayashi A, Kiyota T, Fujiwara M, Dressman JB. PBPK modeling coupled with biorelevant dissolution to forecast the oral performance of amorphous solid dispersion formulations. Eur J Pharm Sci. 2019;135:83–90. https://doi.org/10.1016/j.ejps.2019.05.013.

    Article  CAS  PubMed  Google Scholar 

  40. Browne E, Charifou R, Worku ZA, Babu RP, Healy AM. Amorphous solid dispersions of ketoprofen and poly-vinyl polymers prepared via electrospraying and spray drying: a comparison of particle characteristics and performance. Int J Pharmaceut. 2019;566:173–84. https://doi.org/10.1016/j.ijpharm.2019.05.062.

    Article  CAS  Google Scholar 

  41. Sun Z, Zhang H, He H, Sun L, Zhang X, Wang Q, et al. Cooperative effect of polyvinylpyrrolidone and HPMC E5 on dissolution and bioavailability of nimodipine solid dispersions and tablets. Asian J Pharm Sci. 2018. https://doi.org/10.1016/j.ajps.2018.08.005.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Davis M, Walker G. Recent strategies in spray drying for the enhanced bioavailability of poorly water-soluble drugs. J Control Release. 2018;269:110–27. https://doi.org/10.1016/j.jconrel.2017.11.005.

    Article  CAS  PubMed  Google Scholar 

  43. McFall H, Sarabu S, Shankar V, Bandari S, Murthy SN, Kolter K, et al. Formulation of aripiprazole-loaded pH-modulated solid dispersions via hot-melt extrusion technology: in vitro and in vivo studies. Int J Pharmaceut. 2019;554:302–11. https://doi.org/10.1016/j.ijpharm.2018.11.005.

    Article  CAS  Google Scholar 

  44. Saboo S, Mugheirbi NA, Zemlyanov DY, Kestur US, Taylor LS. Congruent release of drug and polymer: a “sweet spot” in the dissolution of amorphous solid dispersions. J Control Release. 2019;298:68–82. https://doi.org/10.1016/j.jconrel.2019.01.039.

    Article  CAS  PubMed  Google Scholar 

  45. Baghel S, Cathcart H, O’Reilly NJ. Understanding the generation and maintenance of supersaturation during the dissolution of amorphous solid dispersions using modulated DSC and 1H NMR. Int J Pharmaceut. 2018;536(1):414–25. https://doi.org/10.1016/j.ijpharm.2017.11.056.

    Article  CAS  Google Scholar 

  46. Zhao T, Jiang L. Contact angle measurement of natural materials. Colloids Surf B: Biointerfaces. 2018;161:324–30. https://doi.org/10.1016/j.colsurfb.2017.10.056.

    Article  CAS  PubMed  Google Scholar 

  47. Zhu C, Gao Y, Li H, Meng S, Li L, Francisco JS, et al. Characterizing hydrophobicity of amino acid side chains in a protein environment via measuring contact angle of a water nanodroplet on planar peptide network. Proc Natl Acad Sci. 2016;113(46):12946–51. https://doi.org/10.1073/pnas.1616138113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wilson V, Lou X, Osterling DJ, Stolarik DF, Jenkins G, Gao W, et al. Relationship between amorphous solid dispersion in vivo absorption and in vitro dissolution: phase behavior during dissolution, speciation, and membrane mass transport. J Control Release. 2018;292:172–82. https://doi.org/10.1016/j.jconrel.2018.11.003.

    Article  CAS  PubMed  Google Scholar 

  49. Pestieau A, Lebrun S, Cahay B, Brouwers A, Streel B, Cardot J, et al. Evaluation of different in vitro dissolution tests based on level a in vitro–in vivo correlations for fenofibrate self-emulsifying lipid-based formulations. Eur J Pharm Biopharm. 2017;112:18–29. https://doi.org/10.1016/j.ejpb.2016.10.030.

    Article  CAS  PubMed  Google Scholar 

  50. Mercuri A, Fares R, Bresciani M, Fotaki N. An in vitro–in vivo correlation study for nifedipine immediate release capsules administered with water, alcoholic and non-alcoholic beverages: impact of in vitro dissolution media and hydrodynamics. Int J Pharmaceut. 2016;499(1–2):330–42. https://doi.org/10.1016/j.ijpharm.2015.12.047.

    Article  CAS  Google Scholar 

  51. Nguyen MA, Flanagan T, Brewster M, Kesisoglou F, Beato S, Biewenga J, et al. A survey on IVIVC/IVIVR development in the pharmaceutical industry—Past experience and current perspectives. Eur J Pharm Sci. 2017;102:1–13. https://doi.org/10.1016/j.ejps.2017.02.029.

    Article  CAS  PubMed  Google Scholar 

  52. Wendelboe J, Knopp MM, Khan F, Chourak N, Rades T, Holm R. Importance of in vitro dissolution conditions for the in vivo predictability of an amorphous solid dispersion containing a pH-sensitive carrier. Int J Pharmaceut. 2017;531(1):324–31. https://doi.org/10.1016/j.ijpharm.2017.08.078.

    Article  CAS  Google Scholar 

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Acknowledgements

The authors thank Maudie Carey at New York University for her help in language correcting and polishing.

Funding

This work was supported by Grants from the National Natural Science Foundation of China (81773201), Development Project of Shanghai Peak Disciplines-Integrative Medicine (20180101), and the Flexible Talent Program in Xinjiang province.

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  1. Taotao Jiang and Limei Han have contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai, 201203, People’s Republic of China

    Taotao Jiang, Limei Han, Enhao Lu, Wenxiu He & Xianyi Sha

  2. Yangtze River Pharmaceutical Group, Shanghai Haiyan Pharmaceutical Technology Co. Ltd., No. 8, 67 Libing Road, Shanghai, 201203, China

    Taotao Jiang

  3. Department of Emergency Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People’s Republic of China

    Shilin Du

  4. The Institutes of Integrative Medicine of Fudan University, 120 Urumqi Middle Road, Shanghai, 200040, People’s Republic of China

    Xianyi Sha

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Conceptualization and design of the work: XYS and TTJ; investigation and drafting: TTJ, LMH, and EHL; Final approval of the version to be published: SLD and WXH. All authors have read and agreed to the published version of the manuscript.

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Jiang, T., Han, L., Lu, E. et al. Design and Characterization of HY-038 Solid Dispersions via Spray Drying Technology: In Vitro and In Vivo Evaluations. AAPS PharmSciTech 22, 267 (2021). https://doi.org/10.1208/s12249-021-02135-2

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