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In Vitro and In Vivo testing of 3D-Printed Amorphous Lopinavir Printlets by Selective Laser Sinitering: Improved Bioavailability of a Poorly Soluble Drug

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Abstract

The aim of this paper was to investigate the effects of formulation parameters on the physicochemical and pharmacokinetic (PK) behavior of amorphous printlets of lopinavir (LPV) manufactured by selective laser sintering 3D printing method (SLS). The formulation variables investigated were disintegrants (magnesium aluminum silicate at 5–10%, microcrystalline cellulose at 10–20%) and the polymer (Kollicoat® IR at 42–57%), while keeping printing parameters constant. Differential scanning calorimetry, X-ray powder diffraction, and Fourier-transform infrared analysis confirmed the transformation of the crystalline drug into an amorphous form. A direct correlation was found between the disintegrant concentration and dissolution. The dissolved drug ranged from 71.1 ± 5.7% to 99.3 ± 2.7% within 120 min. A comparative PK study in rabbits showed significant differences in the rate and extent of absorption between printlets and compressed tablets. The values for Tmax, Cmax, and AUC were 4 times faster, and 2.5 and 1.7 times higher in the printlets compared to the compressed tablets, respectively. In conclusion, the SLS printing method can be used to create an amorphous delivery system through a single continuous process.

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References

  1. Wu C-j, You J-z, Wang X-j. Thermal decomposition mechanism of tenofovir disoproxil fumarate. J Therm Anal Calorim. 2018;132(1):471–82. https://doi.org/10.1007/s10973-017-6910-3.

    Article  CAS  Google Scholar 

  2. Kesisoglou F, Wu Y. Understanding the effect of API properties on bioavailability through absorption modeling. Aaps j. 2008;10(4):516–25. https://doi.org/10.1208/s12248-008-9061-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Savjani KT, Gajjar AK, Savjani JK. Drug solubility: importance and enhancement techniques. ISRN Pharm. 2012;2012: 195727. https://doi.org/10.5402/2012/195727.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hughes JP, Rees S, Kalindjian SB, Philpott KL. Principles of early drug discovery. Br J Pharmacol. 2011;162(6):1239–49. https://doi.org/10.1111/j.1476-5381.2010.01127.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Jain S, Patel N, Lin S. Solubility and dissolution enhancement strategies: current understanding and recent trends. Drug Dev Ind Pharm. 2015;41(6):875–87. https://doi.org/10.3109/03639045.2014.971027.

    Article  CAS  PubMed  Google Scholar 

  6. Sareen S, Mathew G, Joseph L. Improvement in solubility of poor water-soluble drugs by solid dispersion. Int J Pharm Investig. 2012;2(1):12–7. https://doi.org/10.4103/2230-973x.96921.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zhou Y, Du J, Wang L, Wang Y. Nanocrystals technology for improving bioavailability of poorly soluble drugs: a mini-review. J Nanosci Nanotechnol. 2017;17(1):18–28. https://doi.org/10.1166/jnn.2017.13108.

    Article  CAS  PubMed  Google Scholar 

  8. Chogale MM, Ghodake VN, Patravale VB. Performance parameters and characterizations of nanocrystals: a brief review. Pharmaceutics. 2016;8(3). https://doi.org/10.3390/pharmaceutics8030026.

  9. Hamideh A, Rahman Z, Dharani S, Khuroo T, Mohamed EM, Nutan MTH, et al. Preparation and characterization of dicarboxylic acids salt of aripiprazole with enhanced physicochemical properties. Pharm Dev Technol. 2021;26(4):455–63. https://doi.org/10.1080/10837450.2021.1888978.

    Article  CAS  PubMed  Google Scholar 

  10. Afrooz H, Mohamed EM, Barakh Ali SF, Dharani S, Nutan MTH, Khan MA, et al. Salt engineering of aripiprazole with polycarboxylic acids to improve physicochemical properties. AAPS PharmSciTech. 2021;22(1):31. https://doi.org/10.1208/s12249-020-01875-x.

    Article  CAS  PubMed  Google Scholar 

  11. Gupta D, Bhatia D, Dave V, Sutariya V, Varghese Gupta S. Salts of therapeutic agents: chemical, physicochemical, and biological considerations. Molecules. 2018;23(7). https://doi.org/10.3390/molecules23071719.

  12. Rahman Z, Dharani S, Barakh Ali SF, Afrooz H, Reddy IK, Khan MA. Effect of processing parameters and controlled environment storage on the disproportionation and dissolution of extended-release capsule of phenytoin sodium. Int J Pharm. 2018;550(1–2):290–9. https://doi.org/10.1016/j.ijpharm.2018.07.042.

    Article  CAS  PubMed  Google Scholar 

  13. Dharani S, Rahman Z, Barakh Ali SF, Afrooz H, Khan MA. Quantitative estimation of phenytoin sodium disproportionation in the formulations using vibration spectroscopies and multivariate methodologies. Int J Pharm. 2018;539(1–2):65–74. https://doi.org/10.1016/j.ijpharm.2018.01.005.

    Article  CAS  PubMed  Google Scholar 

  14. Hamed R, Mohamed EM, Sediri K, Khan MA, Rahman Z. Development of stable amorphous solid dispersion and quantification of crystalline fraction of lopinavir by spectroscopic-chemometric methods. Int J Pharm. 2021;602: 120657. https://doi.org/10.1016/j.ijpharm.2021.120657.

    Article  CAS  PubMed  Google Scholar 

  15. Bhujbal SV, Mitra B, Jain U, Gong Y, Agrawal A, Karki S, et al. Pharmaceutical amorphous solid dispersion: a review of manufacturing strategies. Acta Pharmaceutica Sinica B. 2021;11(8):2505–36. https://doi.org/10.1016/j.apsb.2021.05.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zidan AS, Rahman Z, Sayeed V, Raw A, Yu L, Khan MA. Crystallinity evaluation of tacrolimus solid dispersions by chemometric analysis. Int J Pharm. 2012;423(2):341–50. https://doi.org/10.1016/j.ijpharm.2011.11.003.

    Article  CAS  PubMed  Google Scholar 

  17. Chivate A, Garkal A, Dhas N, Mehta T. Hot-melt extrusion: an emerging technique for solubility enhancement of poorly water-soluble drugs. PDA J Pharm Sci Technol. 2021;75(4):357–73. https://doi.org/10.5731/pdajpst.2019.011403.

    Article  CAS  PubMed  Google Scholar 

  18. Baumann JM, Adam MS, Wood JD. Engineering advances in spray drying for pharmaceuticals. Annu Rev Chem Biomol Eng. 2021;12:217–40. https://doi.org/10.1146/annurev-chembioeng-091720-034106.

    Article  CAS  PubMed  Google Scholar 

  19. Hamed R, Mohamed EM, Rahman Z, Khan MA. 3D-printing of lopinavir printlets by selective laser sintering and quantification of crystalline fraction by XRPD-chemometric models. Int J Pharm. 2021;592: 120059. https://doi.org/10.1016/j.ijpharm.2020.120059.

    Article  CAS  PubMed  Google Scholar 

  20. Sham HL, Kempf DJ, Molla A, Marsh KC, Kumar GN, Chen C-M, et al. ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease. Antimicrob Agents Chemother. 1998;42(12):3218–24. https://doi.org/10.1128/AAC.42.12.3218.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mangum EM, Graham KK. Lopinavir-ritonavir: a new protease inhibitor. Pharmacotherapy. 2001;21(11):1352–63. https://doi.org/10.1592/phco.21.17.1352.34419.

    Article  CAS  PubMed  Google Scholar 

  22. Jamróz W, Kurek M, Łyszczarz E, Szafraniec J, Knapik-Kowalczuk J, Syrek K, et al. 3D printed orodispersible films with Aripiprazole. Int J Pharm. 2017;533(2):413–20. https://doi.org/10.1016/j.ijpharm.2017.05.052.

    Article  CAS  PubMed  Google Scholar 

  23. Awad A, Fina F, Trenfield SJ, Patel P, Goyanes A, Gaisford S, et al. 3D printed pellets (miniprintlets): a novel, multi-drug, controlled release platform technology. Pharmaceutics. 2019;11(4). https://doi.org/10.3390/pharmaceutics11040148.

  24. Mohamed EM, Barakh Ali SF, Rahman Z, Dharani S, Ozkan T, Kuttolamadom MA, et al. Formulation optimization of selective laser sintering 3D-printed tablets of clindamycin palmitate hydrochloride by response surface methodology. AAPS PharmSciTech. 2020;21(6):232. https://doi.org/10.1208/s12249-020-01775-0.

    Article  CAS  PubMed  Google Scholar 

  25. Trenfield SJ, Goyanes A, Telford R, Wilsdon D, Rowland M, Gaisford S, et al. 3D printed drug products: non-destructive dose verification using a rapid point-and-shoot approach. Int J Pharm. 2018;549(1–2):283–92. https://doi.org/10.1016/j.ijpharm.2018.08.002.

    Article  CAS  PubMed  Google Scholar 

  26. Kayalar C, Rahman Z, Mohamed EM, Dharani S, Khuroo T, Helal N, Kuttolamadom MA, Khan MA, et al. Preparation and characterization of 3D-printed dose-flexible printlets of tenofovir disoproxil fumarate. AAPS PharmSciTech. 2023;24(6):171. https://doi.org/10.1208/s12249-023-02623-7.

    Article  CAS  PubMed  Google Scholar 

  27. Barakh Ali SF, Mohamed EM, Ozkan T, Kuttolamadom MA, Khan MA, Asadi A, et al. Understanding the effects of formulation and process variables on the printlets quality manufactured by selective laser sintering 3D printing. Int J Pharm. 2019;570: 118651. https://doi.org/10.1016/j.ijpharm.2019.118651.

    Article  CAS  PubMed  Google Scholar 

  28. FDA: Guidance for industry – Bioanalytical method validation. https://www.fda.gov/files/drugs/published/Bioanalytical-Method-Validation-Guidance-for-Industry.pdf (2018). Accessed Oct 22 2022.

  29. Zhang Y, Huo M, Zhou J, Shaofei X. PKSolver: An add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Computer methods and programs in biomedicine. 2010;1;99(3):306–14. https://doi.org/10.1016/j.cmpb.2010.01.007

  30. Wagner JG. Application of the Wagner-Nelson absorption method to the two-compartment open model. J Pharmacokinet Biopharm. 1974;2(6):469–86.

    Article  CAS  PubMed  Google Scholar 

  31. Baghel S, Cathcart H, O’Reilly NJ. Polymeric amorphous solid dispersions: a review of amorphization, crystallization, stabilization, solid-state characterization, and aqueous solubilization of biopharmaceutical classification system class II drugs. J Pharm Sci. 2016;105(9):2527–44. https://doi.org/10.1016/j.xphs.2015.10.008.

    Article  CAS  PubMed  Google Scholar 

  32. Browne E, Worku ZA, Healy AM. Physicochemical properties of poly-vinyl polymers and their influence on ketoprofen amorphous solid dispersion performance: a polymer selection case study. Pharmaceutics. 2020;12(5). https://doi.org/10.3390/pharmaceutics12050433.

  33. Fina F, Goyanes A, Gaisford S, Basit AW. Selective laser sintering (SLS) 3D printing of medicines. Int J Pharm. 2017;529(1–2):285–93. https://doi.org/10.1016/j.ijpharm.2017.06.082.

    Article  CAS  PubMed  Google Scholar 

  34. Dharani S, Barakh Ali SF, Afrooz H, Mohamed EM, Cook P, Khan MA, et al. Development of methamphetamine abuse-deterrent formulations using sucrose acetate isobutyrate. J Pharm Sci. 2020;109(3):1338–46. https://doi.org/10.1016/j.xphs.2019.12.003.

    Article  CAS  PubMed  Google Scholar 

  35. Machado J, Baleanu D, Al-Zhrani AA, Alhamed YA, Zahid AH, Youssef TE. On similarities in infrared spectra of complex drugs. Romanian reports in Physics. 2014:382–93.

  36. Patel G, Shelat P, Lalwani A. Statistical modeling, optimization and characterization of solid self-nanoemulsifying drug delivery system of lopinavir using design of experiment. Drug Deliv. 2016;23(8):3027–42. https://doi.org/10.3109/10717544.2016.1141260.

    Article  CAS  PubMed  Google Scholar 

  37. Du S, Li WS, Wu YR, Fu Y, Yang C, Wang J. Comparison of the physical and thermodynamic stability of amorphous azelnidipine and its coamorphous phase with piperazine. RSC Adv. 2018;8(57):32756–64. https://doi.org/10.1039/C8RA05535A.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  38. Reddy BP, Reddy KR, Reddy RR, Reddy DM, Reddy KSC. Polymorphs of lopinavir. Google Patents. 2013.

  39. El-Badry M, Alanazi FK, Mahrous GM, Alsarra IA. Effects of Kollicoat IR® and hydroxypropyl-β-cyclodextrin on the dissolution rate of omeprazole from its microparticles and enteric-coated capsules. Pharm Dev Technol. 2010;15(5):500–10. https://doi.org/10.3109/10837450903300171.

    Article  CAS  PubMed  Google Scholar 

  40. Das K, Ray D, Bandyopadhyay N, Sengupta S. Study of the properties of microcrystalline cellulose particles from different renewable resources by XRD, FTIR, nanoindentation, TGA and SEM. J Polym Environ. 2010;18(3):355–63.

    Article  CAS  Google Scholar 

  41. Ramírez B. Microcrystalline cellulose (MCC) analysis and quantitative phase analysis of ciprofloxacin/MCC mixtures by Rietveld XRD refinement with physically based background. Cellulose. 2018;v. 25(no. 5):pp. 2795–815–018 v.25 no.5. https://doi.org/10.1007/s10570-018-1761-z.

  42. USP43-NF38: lopinavir and ritonavir tablet monograph. Accessed 2022.

  43. FDA: Kaletra (lopinavir/ritonavir) for oral use https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021251s058,021906s053lbl.pdf. Accessed Oct 22 2022.

  44. Donato EM, Martins LA, Fröehlich PE, Bergold AM. Development and validation of dissolution test for lopinavir, a poorly water-soluble drug, in soft gel capsules, based on in vivo data. J Pharm Biomed Anal. 2008;47(3):547–52.

    Article  CAS  PubMed  Google Scholar 

  45. Madgulkar AR, Bhalekar MR, Kadam AA. Improvement of oral bioavailability of lopinavir without co-administration of ritonavir using microspheres of thiolated xyloglucan. AAPS PharmSciTech. 2018;19(1):293–302. https://doi.org/10.1208/s12249-017-0834-x.

    Article  CAS  PubMed  Google Scholar 

  46. Saigal N, Baboota S, Ahuja A, Ali J. Microcrystalline cellulose as a versatile excipient in drug research. J Young Pharmacists. 2009. p. 6.

  47. Bhargava H, Shah D, Anaebonam A, Oza B. An evaluation of Smecta as a tablet disintegrant and dissolution aid. Drug Dev Ind Pharm. 1991;17(15):2093–102.

    Article  CAS  Google Scholar 

  48. FDA: Guidance document- bioequivalence studies with pharmacokinetic endpoints for drugs submitted under an ANDA Guidance for industry. (2021). Accessed May 31 2022.

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Acknowledgements

We acknowledge the TAMU Materials Characterization Facility for allowing us to use SEM.

Funding

This work was partially supported by the National Institute of Health R56 grant #1R56HD106612 and 1R01HD112077.

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Authors and Affiliations

  1. Irma Lerma Rangel School of Pharmacy, Texas A&M Health Science Center, Texas A&M University, Reynolds Medical Sciences Building, Suite 159, College Station, TX, 77843-1114, United States of America

    Canberk Kayalar, Nada Helal, Eman M. Mohamed, Sathish Dharani, Tahir Khuroo, Ziyaur Rahman & Mansoor A. Khan

  2. Dept. of Engineering Technology & Industrial Distribution, College of Engineering, Texas A&M University, College Station, TX, 77843, United States of America

    Mathew A. Kuttolamadom

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  1. Canberk Kayalar
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  2. Nada Helal
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Contributions

Canberk Kayalar: validation, investigation, formal analysis; Nada Helal: validation, investigation; Eman M. Mohamed: investigation; Sathish Dharani: investigation; Tahir Khuroo: investigation; Mathew A. Kuttolamadom: formal analysis; writing—review and editing; Supervision; Ziyaur Rahman: conceptualization; formal analysis; writing—review and editing; supervision; project administration; Mansoor A. Khan: conceptualization; formal analysis; writing—review and editing; supervision; project administration.

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Correspondence to Mansoor A. Khan.

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Kayalar, C., Helal, N., Mohamed, E.M. et al. In Vitro and In Vivo testing of 3D-Printed Amorphous Lopinavir Printlets by Selective Laser Sinitering: Improved Bioavailability of a Poorly Soluble Drug. AAPS PharmSciTech 25, 20 (2024). https://doi.org/10.1208/s12249-023-02729-y

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