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Formulation Development, Optimization, and Characterization of Entrectinib-Loaded Supersaturable Self-Nanoemulsifying Drug Delivery Systems

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Abstract

Entrectinib is a novel potent anticancer drug with poor aqueous solubility. A supersaturable self-nanoemulsifying drug delivery system of entrectinib is developed using a super saturation promoter. The components of the isotropic mixture of SNEDDS were selected based on solubility and emulsification study. The optimum composition was identified using phase diagrams and further optimized by mixture design. The supersaturated SNEDDS was prepared using HPMC K4M as precipitation inhibitor. The droplet of sSNEDDS ranges from 118.42 ± 1.26 to 128.34 ± 0.63 nm with PDI values range from 0.112 to 0.204, which is significantly smaller than that observed with plain SNEDDS. The percent transmittance of the diluted formulation was found to be 98.78 ± 0.74. The viscosity was found to be 528 ± 32 centipoises indicating the good flow ability. FTIR and DSC studies indicated the amorphization of the drug. The dissolution profile of sSNEDDS indicated the faster release of drug compared to both pure drug suspension and SNEDDS formulation. The drug release rate is directly proportional to the concentration of the drug. The drug release from the insoluble matrix is a square root of time-dependent Fickian diffusion process. The formulation was found to be stable and transparent at all pH values and the percent transmittance was more than 95%. No significant difference was observed with all the samples exposed at different storage conditions. This study demonstrated the feasibility of stabilizing and improving the in vitro performance of SNEDDS by incorporating HPMC K4M as precipitation inhibitor.

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Abbreviations

NBDDS:

nano-based drug delivery system

SNEDDS:

self-nanoemulsifying drug delivery system

sSNEDDS:

supersaturable self-nanoemulsifying drug delivery system

PDI:

polydispersity index

HPMC:

hydroxy propyl methyl cellulose

FTIR spectroscopy:

Fourier transformed infrared spectroscopy

DSC:

differential scanning calorimetry

TEM:

transmission electron microscope

FGFR:

fibroblast growth factor receptor

US FDA:

United States Food and Drug Administration

BCS:

biopharmaceutical classification systems

GRAS:

generally recognized as safe

GIT:

gastro intestinal tract

References

  1. Weinstein, I. B., & Joe, A. K. (2006). Mechanisms of disease: Oncogene addiction–A rationale for molecular targeting in cancer therapy. Nature Clinical Practice. Oncology, 3(8), 448–457. https://doi.org/10.1038/ncponc0558

    Article  Google Scholar 

  2. Frampton, J. E. (2021). Entrectinib: A review in NTRK+ solid tumours and ROS1+ NSCLC. Drugs, 81, 697–708. https://doi.org/10.1007/s40265-021-01503-3

    Article  Google Scholar 

  3. Rolfo, C., Ruiz, R., Giovannetti, E., Gil-Bazo, I., Russo, A., Passiglia, F., Giallombardo, M., Peeters, M., & Raez, L. (2015). Entrectinib: A potent new TRK, ROS1, and ALK inhibitor. Expert Opinion on Investigational Drugs, 24(11), 1493–1500. https://doi.org/10.1517/13543784.2015.1096344

    Article  Google Scholar 

  4. Delgado, J., Pean, E., Melchiorri, D., Migali, C., Josephson, F., Enzmann, H., & Pignatti, F. (2021). The European Medicines Agency review of entrectinib for the treatment of adult or paediatric patients with solid tumours who have a neurotrophic tyrosine receptor kinase gene fusions and adult patients with non-small-cell lung cancer harbouring ROS1 rearrangements. ESMO Open, 6(2), 100087. https://doi.org/10.1016/j.esmoop.2021.100087

    Article  Google Scholar 

  5. Sigal, D., Tartar, M., Xavier, M., Bao, F., Foley, P., Luo, D., Christiansen, J., Hornby, Z., Maneval, E. C., & Multani, P. (2017). Activity of entrectinib in a patient with the first reported NTRK fusion in neuroendocrine cancer. Journal of the National Comprehensive Cancer Network, 15, 1317–1322. https://doi.org/10.6004/jnccn.2017.7029

    Article  Google Scholar 

  6. Meneses-Lorente, G., Bentley, D., Guerini, E., Kowalski, K., Chow-Maneval, E., Yu, L., Brink, A., Djebli, N., Mercier, F., Buchheit, V., & Phipps, A. B. (2021). Characterization of the pharmacokinetics of entrectinib and its active M5 metabolite in healthy volunteers and patients with solid tumors. Investigational New Drugs, 39(3), 803–811. https://doi.org/10.1007/s10637-020-01047-5

    Article  Google Scholar 

  7. Al-Salama, Z. T., & Keam, S. J. (2019). Entrectinib: First global approval. Drugs, 79(13), 1477–1483. https://doi.org/10.1007/s40265-019-01177-y

    Article  Google Scholar 

  8. Parrott, N., Stillhart, C., Lindenberg, M., Wagner, B., Kowalski, K., Guerini, E., Djebli, N., & Meneses-Lorente, G. (2020). Physiologically based absorption modelling to explore the impact of food and gastric pH changes on the pharmacokinetics of entrectinib. The AAPS Journal, 22(4), 78. https://doi.org/10.1208/s12248-020-00463-y

    Article  Google Scholar 

  9. Sharma, M., Sharma, R., & Jain, D. K. (2016). Nanotechnology based approaches for enhancing oral bioavailability of poorly water soluble antihypertensive drugs. Scientifica. https://doi.org/10.1155/2016/8525679

  10. Morakul, B. (2020). Self-nanoemulsifying drug delivery systems (SNEDDS): An advancement technology for oral drug delivery. Pharm Sci Asia, 47(3), 205–220. https://doi.org/10.1208/s12249-020-01765-2

    Article  Google Scholar 

  11. Salawi, A. (2022). Self-emulsifying drug delivery systems: A novel approach to deliver drugs. Drug Delivery, 29(1), 1811–1823. https://doi.org/10.1080/10717544.2022.2083724

    Article  Google Scholar 

  12. Mishra, D. K., Shandilya, R., & Mishra, P. K. (2018). Lipid based nanocarriers: A translational perspective. Nanomedicine: Nanotechnology, Biology and Medicine, 14(7), 2023–2050. https://doi.org/10.1016/j.nano.2018.05.021

    Article  Google Scholar 

  13. Shrestha, H., Bala, R., & Arora, S. (2014). Lipid-based drug delivery systems. Journal of Pharmaceutics. https://doi.org/10.1155/2014/801820

  14. Krstić, M., Medarević, Đ., Đuriš, J., & Ibrić, S. (2018). Self-nanoemulsifying drug delivery systems (SNEDDS) and self-microemulsifying drug delivery systems (SMEDDS) as lipid nanocarriers for improving dissolution rate and bioavailability of poorly soluble drugs. In M. G. Alexandru (Ed.), Lipid nanocarriers for drug targeting (pp. 473–508). William Andrew Publishing. https://doi.org/10.1016/B978-0-12-813687-4.00012-8

    Chapter  Google Scholar 

  15. Wang, C. Y., Yen, C. C., Hsu, M. C., & Wu, Y. T. (2020). Self-nanoemulsifying drug delivery systems for enhancing solubility, permeability, and bioavailability of sesamin. Molecules, 25(14), 3119. https://doi.org/10.3390/molecules25143119

    Article  Google Scholar 

  16. Patel, J., Patel, A., Raval, M., & Sheth, N. (2011). Formulation and development of a self-nanoemulsifying drug delivery system of irbesartan. Journal of Advanced Pharmaceutical Technology & Research, 2(1), 9–16 https://www.japtr.org/text.asp?2011/2/1/9/79799

    Article  Google Scholar 

  17. Anuar, N., Sabri, A. H., Effendi, T. J. B., & Hamid, K. A. (2020). Development and characterisation of ibuprofen-loaded nanoemulsion with enhanced oral bioavailability. Heliyon, 6(7), e04570. https://doi.org/10.1016/j.heliyon.2020.e04570

    Article  Google Scholar 

  18. Ahmed, O. A., Badr-Eldin, S. M., Tawfik, M. K., Ahmed, T. A., Khalid, M., & Badr, J. M. (2014). Design and optimization of self-nanoemulsifying delivery system to enhance quercetin hepatoprotective activity in paracetamol-induced hepatotoxicity. Journal of Pharmaceutical Sciences, 103(2), 602–612. https://doi.org/10.1002/jps.23834

    Article  Google Scholar 

  19. Zhang, J., Wen, X., Dai, Y., & Xia, Y. (2019). Mechanistic studies on the absorption enhancement of a self-nanoemulsifying drug delivery system loaded with norisoboldine-phospholipid complex. International Journal of Nanomedicine, 14, 7095–7106. https://doi.org/10.2147/IJN.S211905

    Article  Google Scholar 

  20. Buya, A. B., Beloqui, A., Memvanga, P. B., & Préat, V. (2020). Self-nano-emulsifying drug-delivery systems: From the development to the current applications and challenges in oral drug delivery. Pharmaceutics, 12(12), 1194. https://doi.org/10.3390/pharmaceutics12121194

    Article  Google Scholar 

  21. Thomas, N., Müllertz, A., Graf, A., & Rades, T. (2012). Influence of lipid composition and drug load on the in vitro performance of self-nanoemulsifying drug delivery systems. Journal of Pharmaceutical Sciences, 101(5), 1721–1731. https://doi.org/10.1002/jps.23054

    Article  Google Scholar 

  22. Bandyopadhyay, S., Katare, O. P., & Singh, B. (2014). Development of optimized supersaturable self-nanoemulsifying systems of ezetimibe: Effect of polymers and efflux transporters. Expert Opinion on Drug Delivery, 11(4), 479–492. https://doi.org/10.1517/17425247.2014.877885

    Article  Google Scholar 

  23. Nazlı, H., Mesut, B., & Özsoy, Y. (2021). In vitro evaluation of a solid supersaturated self nanoemulsifying drug delivery system (Super-SNEDDS) of aprepitant for enhanced solubility. Pharmaceuticals, 14(11), 1089. https://doi.org/10.3390/ph14111089

    Article  Google Scholar 

  24. Thomas, N., Holm, R., Müllertz, A., & Rades, T. (2012). In vitro and in vivo performance of novel supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS). Journal of Controlled Release, 160(1), 25–32. https://doi.org/10.1016/j.jconrel.2012.02.027

    Article  Google Scholar 

  25. Nair, A. B., Singh, B., Shah, J., Jacob, S., Aldhubiab, B., Sreeharsha, N., Morsy, M. A., Venugopala, K. N., Attimarad, M., & Shinu, P. (2022). Formulation and evaluation of self-nanoemulsifying drug delivery system derived tablet containing sertraline. Pharmaceutics, 14(2), 336. https://doi.org/10.3390/pharmaceutics14020336

    Article  Google Scholar 

  26. Nasr, A., Gardouh, A., & Ghorab, M. (2016). Novel solid self-nanoemulsifying drug delivery system (S-SNEDDS) for oral delivery of olmesartan medoxomil: Design, formulation, pharmacokinetic and bioavailability evaluation. Pharmaceutics, 8(3), 20. https://doi.org/10.3390/pharmaceutics8030020

    Article  Google Scholar 

  27. Shastri, P. N., Ubale, R. V., & D’Souza, M. J. (2013). Implementation of mixture design for formulation of albumin containing enteric-coated spray-dried microparticles. Drug Development and Industrial Pharmacy, 39(2), 164–175. https://doi.org/10.3109/03639045.2012.664148

    Article  Google Scholar 

  28. Patel, M., Shaikh, F., & Surti, N. (2021). Optimization of glipizide floating matrix tablet using simplex lattice design. Indian Journal of Pharmaceutical Sciences, 83(2), 297–306. https://doi.org/10.36468/pharmaceutical-sciences.776

    Article  Google Scholar 

  29. Sanka, K., Suda, D., & Bakshi, V. (2016). Optimization of solid-self nanoemulsifying drug delivery system for solubility and release profile of clonazepam using simplex lattice design. Journal of Drug Delivery Science and Technology, 33, 114–124. https://doi.org/10.1016/j.jddst.2016.04.003

    Article  Google Scholar 

  30. Indrati, O., Martien, R., Rohman, A., & Nugroho, A. K. (2020). Application of simplex lattice design on the optimization of andrographolide self-nanoemulsifying drug delivery system (SNEDDS). Indones J Pharm, 31(2), 124–130. https://doi.org/10.14499/indonesianjpharm31iss2pp124

    Article  Google Scholar 

  31. Rangaraj, N., Shah, S., Maruthi, A. J., Pailla, S. R., Cheruvu, H. S., Sujatha, D., & Sampathi, S. (2019). Quality by design approach for the development of self-emulsifying systems for oral delivery of febuxostat: Pharmacokinetic and pharmacodynamic evaluation. AAPS PharmSciTech, 20(7), 1–16. https://doi.org/10.1208/s12249-019-1476-y

    Article  Google Scholar 

  32. Czajkowska-Kośnik, A., Szekalska, M., Amelian, A., Szymańska, E., & Winnicka, K. (2015). Development and evaluation of liquid and solid self-emulsifying drug delivery systems for atorvastatin. Molecules, 20(12), 21010–21022. https://doi.org/10.3390/molecules201219745

    Article  Google Scholar 

  33. Wu, L., Qiao, Y., Wang, L., Guo, J., Wang, G., He, W., Yin, L., & Zhao, J. (2015). A self-microemulsifying drug delivery system (SMEDDS) for a novel medicative compound against depression: A preparation and bioavailability study in rats. AAPS PharmSciTech, 16(5), 1051–1058. https://doi.org/10.1208/s12249-014-0280-y

    Article  Google Scholar 

  34. Kazi, M., Al-Swairi, M., Ahmad, A., Raish, M., Alanazi, F. K., Badran, M. M., Khan, A. A., Alanazi, A. M., & Hussain, M. D. (2019). Evaluation of self-nanoemulsifying drug delivery systems (SNEDDS) for poorly water-soluble talinolol: Preparation, in vitro and in vivo assessment. Frontiers in Pharmacology, 10, 459. https://doi.org/10.3389/fphar.2019.00459

    Article  Google Scholar 

  35. Beg, S., Katare, O. P., & Singh, B. (2017). Formulation by design approach for development of ultrafine self-nanoemulsifying systems of rosuvastatin calcium containing long-chain lipophiles for hyperlipidemia management. Colloids and Surfaces. B, Biointerfaces, 159, 869–879. https://doi.org/10.1016/j.colsurfb.2017.08.050

    Article  Google Scholar 

  36. Weerapol, Y., Limmatvapirat, S., Nunthanid, J., & Sriamornsak, P. (2014). Self-nanoemulsifying drug delivery system of nifedipine: Impact of hydrophilic–lipophilic balance and molecular structure of mixed surfactants. AAPS PharmSciTech, 15(2), 456–464. https://doi.org/10.1208/s12249-014-0078-y

    Article  Google Scholar 

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  1. GITAM School of Pharmacy, GITAM Deemed to be University, Hyderabad, Telangana, 502329, India

    Muthadi Radhika Reddy & Kumar Shiva Gubbiyappa

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  1. Muthadi Radhika Reddy
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MRR carried out the entire research and prepared the manuscript. KSG guided the work and reviewed the manuscript.

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Correspondence to Muthadi Radhika Reddy.

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Reddy, M.R., Gubbiyappa, K.S. Formulation Development, Optimization, and Characterization of Entrectinib-Loaded Supersaturable Self-Nanoemulsifying Drug Delivery Systems. BioNanoSci. 13, 521–540 (2023). https://doi.org/10.1007/s12668-023-01094-1

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