Skip to main content
SpringerLink
Log in

Development of a long-acting tablet with ticagrelor high-loaded nanostructured lipid carriers

  • Original Article
  • Published:
Drug Delivery and Translational Research Aims and scope Submit manuscript

Abstract

Ticagrelor (TCG), an antiplatelet agent, has low solubility and permeability; thus, there are many trials to apply the pharmaceutical technology for the enhancement of TCG solubility and permeability. Herein, we have developed the TCG high-loaded nanostructured lipid carrier (HL-NLC) and solidified the HL-NLC to develop the oral tablet. The HL-NLC was successfully fabricated and optimized with a particle size of 164.5 nm, a PDI of 0.199, an encapsulation efficiency of 98.5%, and a drug loading of 16.4%. For the solidification of HL-NLC (S-HL-NLC), the adsorbent was determined based on the physical properties of the S-HL-NLC, such as bulk density, tap density, angle of repose, Hausner ratio, Carr’s index, and drug content. Florite R was chosen because of its excellent adsorption capacity, excellent physical properties, and solubility of the powder after manufacturing. Using an S-HL-NLC, the S-HL-NLC tablet with HPMC 4 K was prepared, which is showed a released extent of more than 90% at 24 h. Thus, we have developed the sustained release tablet containing the TCG-loaded HL-NLC. Moreover, the formulations have exhibited no cytotoxicity against Caco-2 cells and improved the cellular uptake of TCG. In pharmacokinetic study, compared with raw TCG, the bioavailability of HL-NLC and S-HL-NLC was increased by 293% and 323%, respectively. In conclusion, we successfully developed the TCG high-loaded NLC tablet, that exhibited a sustained release profile and enhanced oral bioavailability.

Graphical abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Data availability

Data sharing is not applicable to this article because no datasets were generated or analyzed during the current study.

References

  1. Siller-Matula JM, Jilma B. Ticagrelor: from discovery to Phase III clinical trial. Future Cardiol. 2010;6:753–64.

    Article  CAS  PubMed  Google Scholar 

  2. Goto S, Huang C-H, Park S-J, Emanuelsson H, Kimura T. Ticagrelor vs. clopidogrel in Japanese, Korean and Taiwanese patients with acute coronary syndrome–randomized, double-blind, phase III PHILO study–. Circ J. 2015;79:2452–60.

    Article  PubMed  Google Scholar 

  3. Gao C-Z, Ma Q-Q, Wu J, Liu R, Wang F, Bai J, et al. Comparison of the effects of ticagrelor and clopidogrel on inflammatory factors, vascular endothelium functions and short-term prognosis in patients with acute ST-Segment Elevation Myocardial Infarction Undergoing Emergency Percutaneous Coronary Intervention: a pilot study. Cell Physiol Biochem. 2018;48:385–96.

    Article  CAS  PubMed  Google Scholar 

  4. Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med. 2015;372:1791–800.

    Article  PubMed  Google Scholar 

  5. Liu S, Wang Z, Hou L, Tian X, Zhang X, Cai W. Predicting the effect of tea polyphenols on ticagrelor by incorporating transporter-enzyme interplay mechanism. Chem Biol Interact. 2020;330:109228.

    Article  CAS  PubMed  Google Scholar 

  6. Huang J, Wang Q, Li T, Xia N, Xia Q. Nanostructured lipid carrier (NLC) as a strategy for encapsulation of quercetin and linseed oil: preparation and in vitro characterization studies. J Food Eng. 2017;215:1–12.

    Article  CAS  Google Scholar 

  7. Shah NV, Seth AK, Balaraman R, Aundhia CJ, Maheshwari RA, Parmar GR. Nanostructured lipid carriers for oral bioavailability enhancement of raloxifene: Design and in vivo study. J Adv Res. 2016;7:423–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Tran TH, Ramasamy T, Truong DH, Choi H-G, Yong CS, Kim JO. Preparation and characterization of fenofibrate-loaded nanostructured lipid carriers for oral bioavailability enhancement. AAPS PharmSciTech. 2014;15:1509–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tamjidi F, Shahedi M, Varshosaz J, Nasirpour AJ. Nanostructured lipid carriers (NLC): a potential delivery system for bioactive food molecules. Innov Food Sci Emerg Technol. 2013;19:29–43.

    Article  CAS  Google Scholar 

  10. Liu D, Li J, Pan H, He F, Liu Z, Wu Q, et al. Potential advantages of a novel chitosan-N-acetylcysteine surface modified nanostructured lipid carrier on the performance of ophthalmic delivery of curcumin. Sci Rep. 2016;6:1–14.

    Google Scholar 

  11. Della Rocca J, Liu D, Lin WJN. Are high drug loading nanoparticles the next step forward for chemotherapy? Nanomedicine. 2012;7:303–5.

    Article  CAS  PubMed  Google Scholar 

  12. Jia L-J, Zhang D-R, Li Z-Y, Feng F-F, Wang Y-C, Dai W-T, et al. Preparation and characterization of silybin-loaded nanostructured lipid carriers. Drug Deliv. 2010;17:11–8.

    Article  CAS  PubMed  Google Scholar 

  13. Son G-H, Na Y-G, Huh HW, Wang M, Kim M-K, Han M-G, et al. Systemic design and evaluation of ticagrelor-loaded nanostructured lipid carriers for enhancing bioavailability and antiplatelet activity. Pharmaceutics. 2019;11:222.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Beloqui A, Solinís MÁ, Gascón AR, del Pozo-Rodríguez A, des Rieux A, Préat V. Mechanism of transport of saquinavir-loaded nanostructured lipid carriers across the intestinal barrier. J Control Rel. 2013;16:115–23.

    Article  Google Scholar 

  15. Hu F-Q, Jiang S-P, Du Y-Z, Yuan H, Ye Y-Q, Zeng S. Preparation and characteristics of monostearin nanostructured lipid carriers. Int J Pharm. 2006;314:83–9.

    Article  CAS  PubMed  Google Scholar 

  16. Sun B, Luo C, Li L, Wang M, Du Y, Di D, et al. Core-matched encapsulation of an oleate prodrug into nanostructured lipid carriers with high drug loading capability to facilitate the oral delivery of docetaxel. Colloids Surf B Biointerfaces. 2016;143:47–55.

    Article  CAS  PubMed  Google Scholar 

  17. Battaglia L, Gallarate M. Lipid nanoparticles: state of the art, new preparation methods and challenges in drug delivery. Expert Opin Drug Deliv. 2012;9:497–508.

    Article  CAS  PubMed  Google Scholar 

  18. Iqbal MA, Md S, Sahni JK, Baboota S, Dang S, Ali J. Nanostructured lipid carriers system: recent advances in drug delivery. J Drug Target. 2012;20:813–30.

    Article  CAS  PubMed  Google Scholar 

  19. Kobierski S, Ofori-Kwakye K, Müller RH, Keck CM. Resveratrol nanosuspensions: Interaction of preservatives with nanocrystal production. Pharmazie. 2011;66:942–7.

    CAS  PubMed  Google Scholar 

  20. Xia D, Shrestha N, van de Streek J, Mu H, Yang M. Spray drying of fenofibrate loaded nanostructured lipid carriers. Asian J Pharm Sci. 2016;11:507–15.

    Article  Google Scholar 

  21. Tian Z, Yi Y, Yuan H, Han J, Zhang X, Xie Y, et al. Solidification of nanostructured lipid carriers (NLCs) onto pellets by fluid-bed coating: preparation, in vitro characterization and bioavailability in dogs. Powder Technol. 2013;247:120–7.

    Article  CAS  Google Scholar 

  22. Souto E, Mehnert W, Müller R. Polymorphic behaviour of Compritol® 888 ATO as bulk lipid and as SLN and NLC. J Microencapsul. 2006;23:417–33.

    Article  CAS  PubMed  Google Scholar 

  23. Shete H, Patravale V. Long chain lipid based tamoxifen NLC. Part I: preformulation studies, formulation development and physicochemical characterization. Int J Pharm. 2013;454:573–83.

    Article  CAS  PubMed  Google Scholar 

  24. Salminen H, Helgason T, Aulbach S, Kristinsson B, Kristbergsson K, Weiss J, et al. Influence of co-surfactants on crystallization and stability of solid lipid nanoparticles. J Colloid Interface Sci. 2014;426:256–63.

    Article  CAS  PubMed  Google Scholar 

  25. Lopes MA, Abrahim-Vieira B, Oliveira C, Fonte P, Souza AM, Lira T, et al. Probing insulin bioactivity in oral nanoparticles produced by ultrasonication-assisted emulsification/internal gelation. Int J Nanomedicine. 2015;10:5865.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Müller RH, Jacobs C. Buparvaquone mucoadhesive nanosuspension: preparation, optimisation and long-term stability. Int J Pharm. 2002;237:151–61.

    Article  PubMed  Google Scholar 

  27. Shevalkar G, Vavia P. Solidified nanostructured lipid carrier (S-NLC) for enhancing the oral bioavailability of ezetimibe. J Drug Deliv Sci Technol. 2019;53:101211.

    Article  CAS  Google Scholar 

  28. Emami J, Mohiti H, Hamishehkar H, Varshosaz J. Formulation and optimization of solid lipid nanoparticle formulation for pulmonary delivery of budesonide using Taguchi and Box-Behnken design. Res Pharm Sci. 2015;10:17.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Okolie JA, Epelle EI, Nanda S, Castello D, Dalai AK, Kozinski JA. Modeling and process optimization of hydrothermal gasification for hydrogen production: a comprehensive review. J Supercrit Fluids. 2021;173:105199.

    Article  CAS  Google Scholar 

  30. Sweed NM, Fayez AM, El-Emam SZ, Dawoud MHS. Response surface optimization of self nano-emulsifying drug delivery system of rosuvastatin calcium for hepatocellular carcinoma. J Pharm Investig. 2021;51:85–101.

    Article  CAS  Google Scholar 

  31. Rohmah M, Raharjo S, Hidayat C, Martien R. Application of response surface methodology for the optimization of β-carotene-loaded nanostructured lipid carrier from mixtures of palm stearin and palm olein. J Am Oil Chem Soc. 2020;97:213–23.

    Article  CAS  Google Scholar 

  32. Anwar W, Dawaba HM, Afouna MI, Samy AM, Rashed MH, Abdelaziz AE. Enhancing the oral bioavailability of candesartan cilexetil loaded nanostructured lipid carriers: In vitro characterization and absorption in rats after oral administration. Pharmaceutics. 2020;12:1047.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kan S, Lu J, Liu J, Wang J, Zhao Y. A quality by design (QbD) case study on enteric-coated pellets: Screening of critical variables and establishment of design space at laboratory scale. Asian J Pharm Sci. 2014;9:268–78.

    Article  Google Scholar 

  34. Soni G, Yadav KS, Gupta MK. QbD based approach for formulation development of spray dried microparticles of erlotinib hydrochloride for sustained release. J Drug Deliv Sci Technol. 2020;57:101684.

    Article  CAS  Google Scholar 

  35. Waghule T, Rapalli VK, Singhvi G, Manchanda P, Hans N, Dubey SK, et al. Voriconazole loaded nanostructured lipid carriers based topical delivery system: QbD based designing, characterization, in-vitro and ex-vivo evaluation. J Drug Deliv Sci Technol. 2019;52:303–15.

    Article  CAS  Google Scholar 

  36. Nayak AP, Tiyaboonchai W, Patankar S, Madhusudhan B, Souto EB. Curcuminoids-loaded lipid nanoparticles: novel approach towards malaria treatment. Colloids Surf B Biointerfaces. 2010;81:263–73.

    Article  CAS  PubMed  Google Scholar 

  37. Suriyanon N, Punyapalakul P, Ngamcharussrivichai C. Mechanistic study of diclofenac and carbamazepine adsorption on functionalized silica-based porous materials. Chem Eng J. 2013;214:208–18.

    Article  CAS  Google Scholar 

  38. Saker A, Cares-Pacheco M-G, Marchal P, Falk V. Powders flowability assessment in granular compaction: what about the consistency of Hausner ratio? Powder Technol. 2019;354:52–63.

    Article  CAS  Google Scholar 

  39. Patel MM, Patel RJ. Linagliptin loaded solid-SMEEDS for enhanced solubility and dissolution: formulation development and optimization by D-optimal design. J Drug Deliv Ther. 2019;9:47–56.

    Article  CAS  Google Scholar 

  40. Qi S, McAuley WJ, Yang Z, Tipduangta P. Physical stabilization of low-molecular-weight amorphous drugs in the solid state: a material science approach. Ther Deliv. 2014;5:817–41.

    Article  CAS  PubMed  Google Scholar 

  41. Park J-B, Choi B-K, Kang C-Y. Effects of absorbent materials on a self-emulsifying drug delivery system for a poorly water soluble drug. J Pharm Investig. 2015;45:529–39.

    Article  CAS  Google Scholar 

  42. Khatri P, Katikaneni P, Desai D, Minko T. Evaluation of Affinisol® HPMC polymers for direct compression process applications. J Drug Deliv Sci Technol. 2018;47:461–7.

    Article  CAS  Google Scholar 

  43. Ghori MU, Ginting G, Smith AM, Conway BR. Simultaneous quantification of drug release and erosion from hypromellose hydrophilic matrices. Int J Pharm. 2014;465:405–12.

    Article  CAS  PubMed  Google Scholar 

  44. Vrbanac H, Krese A. The influence of different mechanical stress on the release properties of HPMC matrix tablets in sucrose-NaCl media. J Drug Deliv Sci Technol. 2019;54:101246.

    Article  CAS  Google Scholar 

  45. Maincent J, Williams R. Sustained-release amorphous solid dispersions. Drug Deliv Transl Res. 2018;8:1714–25.

    Article  CAS  PubMed  Google Scholar 

  46. Jain AK, Söderlind E, Viridén A, Schug B, Abrahamsson B, Knopke C, et al. The influence of hydroxypropyl methylcellulose (HPMC) molecular weight, concentration and effect of food on in vivo erosion behavior of HPMC matrix tablets. J Control Release. 2014;187:50–8.

    Article  CAS  PubMed  Google Scholar 

  47. Tahara K, Yamamoto K, Nishihata T. Overall mechanism behind matrix sustained release (SR) tablets prepared with hydroxypropyl methylcellulose 2910. J Control Release. 1995;35:59–66.

    Article  CAS  Google Scholar 

  48. Na Y-G, Pham TMA, Byeon J-J, Kim M-K, Han M-G, Baek J-S, et al. Development and evaluation of TPGS/PVA-based nanosuspension for enhancing dissolution and oral bioavailability of ticagrelor. Int J Pharm. 2020;581:119287.

    Article  CAS  PubMed  Google Scholar 

  49. Kim S-J, Lee H-K, Na Y-G, Bang K-H, Lee H-J, Wang M, et al. A novel composition of ticagrelor by solid dispersion technique for increasing solubility and intestinal permeability. Int J Pharm. 2019;555:11–8.

    Article  CAS  PubMed  Google Scholar 

  50. Na Y-G, Byeon J-J, Wang M, Huh HW, Kim M-K, Bang K-H, et al. Statistical approach for solidifying ticagrelor loaded self-microemulsifying drug delivery system with enhanced dissolution and oral bioavailability. Mater Sci Eng C. 2019;104:109980.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Technology Development Program of Small and Medium Enterprises (S3119289) through the Korea Technology & Information Promotion Agency for SMEs. Also, this work was supported by the National Research Council of Science & Technology (NST) grant by the Korea government (MSIT) (grant no. CRC21021).

Funding

This work was supported by the Technology Development Program of Small and Medium Enterprises (S3119289) through the Korea Technology & Information Promotion Agency for SMEs. Also, this work was supported by the National Research Council of Science & Technology (NST) grant by the Korea government (MSIT) (grant no. CRC21021).

Author information

Authors and Affiliations

  1. College of Pharmacy, Chungnam National University, 99, Daehak-ro, Daejeon, 34134, South Korea

    Minwoo Jung, Minki Jin, Woo-Jin Jeon, HaeSoo Lee, Haeun Kim, Jong-Hee Won, Hyelim Yoo & Cheong-Weon Cho

  2. Center for Companion Animal New Drug Development, Jeonbuk Branch, Institute of Toxicology (KIT), Jeollabuk-do, Jeongeup, 53212, South Korea

    Hyoung-Woo Bai, Su-Cheol Han & Hong-Ki Lee

  3. Radiation Biotechnology and Applied Radioisotope Science, University of Science and Technology (UST), Daejeon, 34113, South Korea

    Hyoung-Woo Bai

  4. Postera Health Science Inc, Han River Misa 1st at Hyundai Knowledge Industry Center 550, Misa-daero, Hanam-si, 1005, Gyeonggi-do, South Korea

    Hearan Suh & Kyoung Un Kang

Authors
  1. Minwoo Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Minki Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Woo-Jin Jeon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. HaeSoo Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Haeun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jong-Hee Won
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hyelim Yoo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hyoung-Woo Bai
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Su-Cheol Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hearan Suh
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kyoung Un Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hong-Ki Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Cheong-Weon Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization and methodology, M Jung, M Jin; formal analysis, W-J Jeon, HS Lee; software, H Kim; validation, J-H Won; visualization, H Yoo, H-W Bai; data curation, S-C Han; Resources and methodology, H Suh, KU Kang; conceptualization and writing—original draft preparation, H–K Lee; writing—review, editing and supervision, Cheong-Weon Cho.

Corresponding authors

Correspondence to Hong-Ki Lee or Cheong-Weon Cho.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 1492 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jung, M., Jin, M., Jeon, WJ. et al. Development of a long-acting tablet with ticagrelor high-loaded nanostructured lipid carriers. Drug Deliv. and Transl. Res. 13, 1212–1227 (2023). https://doi.org/10.1007/s13346-022-01205-7

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13346-022-01205-7

Keywords

Search

Navigation