DEVELOPMENT AND ASSESSMENT OF A SELF-NANOEMULSIFYING DRUG DELIVERY SYSTEM FOR ENHANCED SOLUBILITY OF DASATINIB

PRAGATHI DEVANAND BANGERA; EESHA SHUKLA; DIVYA DHATRI KARA; RAJESHWARI ROYCHOWDHURY; MAHESHA KEERIKKADU; VAMSHI KRISHNA TIPPAVAJHALA; MAHALAXMI RATHNANAND

doi:10.22159/ijap.2025v17i1.52404

Authors

PRAGATHI DEVANAND BANGERA Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India https://orcid.org/0009-0009-3493-4825
EESHA SHUKLA Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
DIVYA DHATRI KARA Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
RAJESHWARI ROYCHOWDHURY UCL School of Pharmacy, University College London, London, United Kingdom
MAHESHA KEERIKKADU Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India https://orcid.org/0009-0007-3599-7364
VAMSHI KRISHNA TIPPAVAJHALA Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India https://orcid.org/0000-0001-6540-9550
MAHALAXMI RATHNANAND Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India

DOI:

https://doi.org/10.22159/ijap.2025v17i1.52404

Keywords:

Self-nano emulsifying drug delivery system (SNEDDs), Dasatinib, Nano-emulsification, Oral bioavailability

Abstract

Objective: The objective of this study was to increase the water solubility of Dasatinib (DAS) by incorporating it into a Self-Nano Emulsifying Drug Delivery System (SNEDDS). Dasatinib, a Biopharmaceutics classification system (BCS) class II drug, has poor solubility in aqueous media, affecting its oral bioavailability. Various oils, surfactants, and co-surfactants were chosen based on solubility tests, with the highest solubility selected.

Methods: Various compositions of oils, surfactants and co-surfactants with Smix concentrations as 1:1, 1:2 and 2:1 and there were 9 formulations under each of these groups with Oil: Smix concentrations of 1:9, 2:8, 3:7, 4:6, 5:5, 6:4, 7:3, 8:2 and 9:1. Capmul MCM, Cremophor EL, and Tween 20 were selected as oil phase, surfactant, and co-surfactant, respectively. A pseudo-ternary phase diagram using the water titration technique optimized the nano-emulsification ratio. The optimized formulation was characterized and evaluated for thermodynamic stability, cloud point measurement, zeta potential, Poly dispersity Index (PDI), globule size, percent transmittance, robustness to dilution, and dissolution studies.

Results: Transmittance of 95% was demonstrated by the formulation, indicating transparency and stability. The zeta potential was over 30 mV, indicating strong electrical stability, and the average globule size was measured to be 85 nm. The formulation was shown to be stable at body temperature, as evidenced by the cloud point being reported above 95 °C. The formulation maintained its stability when diluted in water, 0.1N acid, and phosphate buffer. The formulation contained 85% of the dasatinib, according to the drug content study. The optimized SNEDDS formulation significantly increased drug release in in vitro drug release experiments as compared to the pure medication. The oral bioavailability of dasatinib in the SNEDDS formulation was shown to be 3.24 times higher than that of the pure medication, according to in vivo pharmacokinetic tests.

Conclusion: Consequently, the findings indicated that the formulation of dasatinib SNEDDS functions as a means of achieving increased drug loading, better dissolving profiles, and increased bioavailability for the BCS Class II drug dasatinib.

Downloads

Download data is not yet available.

References

Rinaldi I, Winston K. Chronic myeloid leukemia from pathophysiology to treatment free remission: a narrative literature review. J Blood Med. 2023 Apr;14:261-77. doi: 10.2147/JBM.S382090, PMID 37051025.

Nicholson E, Holyoake T. The chronic myeloid leukemia stem cell. Clin Lymphoma Myeloma. 2009 Dec 1;9 Suppl 4:S376-81. doi: 10.3816/CLM.2009.s.037, PMID 20007106.

Wong SF, Mirshahidi H. Use of tyrosine kinase inhibitors for chronic myeloid leukemia: management of patients and practical applications for pharmacy practitioners. Ann Pharmacother. 2011 Jun;45(6):787-97. doi: 10.1345/aph.1P784, PMID 21672900.

Garcia Gutierrez V, Hernandez Boluda JC. Tyrosine kinase inhibitors available for chronic myeloid leukemia: efficacy and safety. Front Oncol. 2019 Jul 3;9:603. doi: 10.3389/fonc.2019.00603, PMID 31334123.

McCormack PL, Keam SJ. Dasatinib: a review of its use in the treatment of chronic myeloid leukaemia and Philadelphia chromosome positive acute lymphoblastic leukaemia. Drugs. 2011 Sep 1;71(13):1771-95. doi: 10.2165/11207580-000000000-00000, PMID 21902298.

Kamath AV, Wang J, Lee FY, Marathe PH. Preclinical pharmacokinetics and in vitro metabolism of dasatinib (BMS-354825): a potent oral multi targeted kinase inhibitor against SRC and BCR-ABL. Cancer Chemother Pharmacol. 2008 Mar 1;61(3):365-76. doi: 10.1007/s00280-007-0478-8, PMID 17429625.

Budha NR, Frymoyer A, Smelick GS, Jin JY, Yago MR, Dresser MJ. Drug absorption interactions between oral targeted anticancer agents and PPIs: is pH-dependent solubility the achilles heel of targeted therapy? Clin Pharmacol Ther. 2012 Aug;92(2):203-13. doi: 10.1038/clpt.2012.73, PMID 22739140.

Christopher LJ, Cui D, WU C, Luo R, Manning JA, Bonacorsi SJ. Metabolism and disposition of dasatinib after oral administration to humans. Drug Metab Dispos. 2008;36(7):1357-64. doi: 10.1124/dmd.107.018267, PMID 18420784.

Baloch J, Sohail MF, Sarwar HS, Kiani MH, Khan GM, Jahan S. Self nanoemulsifying drug delivery system (SNEDDS) for improved oral bioavailability of chlorpromazine: in vitro and in vivo evaluation. Medicina (Kaunas). 2019 May;55(5):210. doi: 10.3390/medicina55050210, PMID 31137751.

Hassan S, Prakash G, Ozturk A, Saghazadeh S, Sohail MF, Seo J. Evolution and clinical translation of drug delivery nanomaterials. Nano Today. 2017 Aug 1;15:91-106. doi: 10.1016/j.nantod.2017.06.008, PMID 29225665.

Gupta S, Chavhan S, Sawant KK. Self nanoemulsifying drug delivery system for adefovir dipivoxil: design characterization in vitro and ex vivo evaluation. Colloids Surf A Physicochem Eng Aspects. 2011 Dec 5;392(1):145-55. doi: 10.1016/j.colsurfa.2011.09.048.

Elgart A, Cherniakov I, Aldouby Y, Domb AJ, Hoffman A. Improved oral bioavailability of BCS class 2 compounds by self nano emulsifying drug delivery systems (SNEDDS): the underlying mechanisms for amiodarone and talinolol. Pharm Res. 2013 Dec 1;30(12):3029-44. doi: 10.1007/s11095-013-1063-y, PMID 23686373.

Galatage ST, Trivedi R, Bhagwat DA. Oral self emulsifying nanoemulsion systems for enhancing dissolution bioavailability and anticancer effects of camptothecin. J Drug Deliv Sci Technol. 2022 Dec 1;78:103929. doi: 10.1016/j.jddst.2022.103929.

Kumar R, Kumar R, Khurana N, Singh SK, Khurana S, Verma S. Enhanced oral bioavailability and neuroprotective effect of fisetin through its SNEDDS against rotenone induced parkinson’s disease rat model. Food Chem Toxicol. 2020 Oct 1;144:111590. doi: 10.1016/j.fct.2020.111590, PMID 32710995.

Detholia K, Mohandas A, Varia U, Jadeja M, Katariya H. Development and optimization of ropinirole loaded self nanoemulsifying tablets. Futur J Pharm Sci. 2023 Aug 9;9(1):66. doi: 10.1186/s43094-023-00516-x.

Rathore C, Hemrajani C, Sharma AK, Gupta PK, Jha NK, Aljabali AA. Self-nanoemulsifying drug delivery system (SNEDDS) mediated improved oral bioavailability of thymoquinone: optimization characterization pharmacokinetic and hepatotoxicity studies. Drug Deliv Transl Res. 2023 Jan 1;13(1):292-307. doi: 10.1007/s13346-022-01193-8, PMID 35831776.

Akhtar N, Mohammed SA, Khan RA, Yusuf M, Singh V, Mohammed HA. Self-generating nano emulsification techniques for alternatively routed bioavailability enhanced delivery especially for anti-cancers anti-diabetics and miscellaneous drugs of natural and synthetic origins. J Drug Deliv Sci Technol. 2020 Aug 1;58:101808. doi: 10.1016/j.jddst.2020.101808.

Parvataneni DM, Devraj R, Mangamoori LN. Micelles entrapped microparticles technology: a novel approach to resolve dissolution and bioavailability problems of poorly water soluble drugs. J Microencapsul. 2020;37(3):254-69. doi: 10.1080/02652048.2020.1729883, PMID 32052664.

Khan BH, Sandhya P. Formulation and in vivo evaluation of dasatinib loaded solid lipid nanoparticles. Int J Pharm Sci Drug Res. 2022 Nov;14(6):824-32. doi: 10.25004/IJPSDR.2022.140621.

Aguilera DG, Tsimberidou AM. Dasatinib in chronic myeloid leukemia: a review. Ther Clin Risk Manag. 2009 Mar;5(2):281-9. doi: 10.2147/tcrm.s3425, PMID 19536317.

Chen BA, Chen R. The role of dasatinib in the management of andnbsp; chronic myeloid leukemia. DDDT. 2015 Feb 9;773-9.

Date AA, Desai N, Dixit R, Nagarsenker M. Self nanoemulsifying drug delivery systems: formulation insights applications and advances. Nanomedicine (Lond). 2010 Dec;5(10):1595-616. doi: 10.2217/nnm.10.126, PMID 21143036.

Ramachandra B, Naidu NV, Sekhar CK. Validation of RP-HPLC method for estimation of dasatinib in bulk and its pharmaceutical dosage forms. Int J Pharm Biol Sci. 2014;4(1):61-8.

Nataraj KS, Sivalingachari P, Naveen SS, Alekhya K. Method development and validation for the estimation of dasatinib monohydrate tablets by RP-HPLC. Asian J Res Chem. 2013;6(9):859-62.

Shakeel F, Iqbal M, Ezzeldin E. Bioavailability enhancement and pharmacokinetic profile of an anticancer drug ibrutinib by self nanoemulsifying drug delivery system. J Pharm Pharmacol. 2016;68(6):772-80. doi: 10.1111/jphp.12550, PMID 27018771.

Azeem A, Rizwan M, Ahmad FJ, Iqbal Z, Khar RK, Aqil M. Nanoemulsion components screening and selection: a technical note. AAPS Pharm Sci Tech. 2009 Mar 1;10(1):69-76. doi: 10.1208/s12249-008-9178-x, PMID 19148761.

Patel A, Shelat P, Lalwani A. Development and optimization of solid self nanoemulsifying drug delivery system (S-SNEDDS) using scheffe’s design for improvement of oral bioavailability of nelfinavir mesylate. Drug Deliv Transl Res. 2014 Apr 1;4(2):171-86. doi: 10.1007/s13346-014-0191-1, PMID 25786731.

Sanka K, Suda D, Bakshi V. Optimization of solid self nanoemulsifying drug delivery system for solubility and release profile of clonazepam using simplex lattice design. J Drug Deliv Sci Technol. 2016 Jun 1;33:114-24. doi: 10.1016/j.jddst.2016.04.003.

Patel J, Dhingani A, Garala K, Raval M, Sheth N. Quality by design approach for oral bioavailability enhancement of irbesartan by self nanoemulsifying tablets. Drug Deliv. 2014 Sep;21(6):412-35. doi: 10.3109/10717544.2013.853709, PMID 24215334.

Teaima M, Hababeh S, Khanfar M, Alanazi F, Alshora D, El-Nabrawi M. Design and optimization of pioglitazone hydrochloride self nanoemulsifying drug delivery system (SNEDDS) incorporated into an orally disintegrating tablet. Pharmaceutics. 2022;14(2):425. doi: 10.3390/pharmaceutics14020425, PMID 35214157.

Mohd AB, Sanka K, Bandi S, Diwan PV, Shastri N. Solid self nanoemulsifying drug delivery system (S-SNEDDS) for oral delivery of glimepiride: development and antidiabetic activity in albino rabbits. Drug Deliv. 2015 May 19;22(4):499-508. doi: 10.3109/10717544.2013.879753, PMID 24471856.

Nazlı H, Mesut B, Ozsoy Y. In vitro evaluation of a solid supersaturated self nanoemulsifying drug delivery system (Super-SNEDDS) of aprepitant for enhanced solubility. Pharmaceuticals (Basel). 2021;14(11):1089. doi: 10.3390/ph14111089, PMID 34832871.

Ujilestari T, Martien R, Ariyadi B, Dono ND. Self nanoemulsifying drug delivery system (SNEDDS) of amomum compactum essential oil: design formulation and characterization. J App Pharm Sci. 2018;8(6):14-21. doi: 10.7324/JAPS.2018.8603.

KE Z, Hou X, Jia X. Design and optimization of self nanoemulsifying drug delivery systems for improved bioavailability of cyclovirobuxine D. Drug Des Devel Ther. 2016 Jun 28;10:2049-60. doi: 10.2147/DDDT.S106356.

Beg S, Kaur R, Khurana RK, Rana V, Sharma T, Singh B. QBD based development of cationic self nanoemulsifying drug delivery systems of paclitaxel with improved biopharmaceutical attributes. AAPS Pharm Sci Tech. 2019 Feb 21;20(3):118. doi: 10.1208/s12249-019-1319-x, PMID 30790136.

Dalal L, Allaf AW, El Zein H. Formulation and in vitro evaluation of self nanoemulsifying liquisolid tablets of furosemide. Sci Rep. 2021 Jan 14;11(1):1315. doi: 10.1038/s41598-020-79940-5, PMID 33446749.

Nazari Vanani R, Azarpira N, Heli H, Karimian K, Sattarahmady N. A novel self nanoemulsifying formulation for sunitinib: evaluation of anticancer efficacy. Colloids Surf B Biointerfaces. 2017 Dec 1;160:65-72. doi: 10.1016/j.colsurfb.2017.09.008, PMID 28917151.

Heshmati N, Cheng X, Eisenbrand G, Fricker G. Enhancement of oral bioavailability of E804 by self nanoemulsifying drug delivery system (SNEDDS) in rats. J Pharm Sci. 2013;102(10):3792-9. doi: 10.1002/jps.23696, PMID 23934779.

Vincent M, Simon L, Brabet P, Legrand P, Dorandeu C, Him JL. Formulation and evaluation of SNEDDS loaded with original lipophenol for the oral route to prevent dry AMD and Stragardts disease. Pharmaceutics. 2022 May;14(5):1029. doi: 10.3390/pharmaceutics14051029, PMID 35631617.

Dabhi R, D Limbani M, R Sheth N. Preparation and in vivo evaluation of self nanoemulsifying drug delivery system (SNEDDS) containing ezetimibe. Curr Nanosci. 2011;7(4):616-27. doi: 10.2174/157341311796196853.

Jeevana JB, Sreelakshmi K. Design and evaluation of self nanoemulsifying drug delivery system of flutamide. J Young Pharm. 2011 Jan;3(1):4-8. doi: 10.4103/0975-1483.76413, PMID 21607048.

Shakeel F, Haq N, Al Dhfyan A, Alanazi FK, Alsarra IA. Double w/o/w nanoemulsion of 5-fluorouracil for self nanoemulsifying drug delivery system. J Mol Liq. 2014 Dec 1;200:183-90. doi: 10.1016/j.molliq.2014.10.013.

Parmar K, Patel J, Sheth N. Self nano emulsifying drug delivery system for embelin: design characterization and in vitro studies. Asian J Pharm Sci. 2015 Oct 1;10(5):396-404. doi: 10.1016/j.ajps.2015.04.006.

Reddy MR, Gubbiyappa KS. Formulation development optimization and characterization of pemigatinib loaded supersaturable self nanoemulsifying drug delivery systems. Futur J Pharm Sci. 2022 Nov 12;8(1):45. doi: 10.1186/s43094-022-00434-4.

Shahba AA, Mohsin K, Alanazi FK. Novel self nanoemulsifying drug delivery systems (SNEDDS) for oral delivery of cinnarizine: design optimization and in vitro assessment. AAPS Pharm Sci Tech. 2012 Sep 1;13(3):967-77. doi: 10.1208/s12249-012-9821-4, PMID 22760454.

Zeng L, Zhang Y. Development optimization and in vitro evaluation of norcantharidin loadedself nanoemulsifying drug delivery systems (NCTD-SNEDDS). Pharm Dev Technol. 2017 Apr 3;22(3):399-408. doi: 10.1080/10837450.2016.1219915, PMID 27487261.

Reddy KT, Gandla K, Babu PV, Chakravarthy MV, Chandrasekhar P, Sagapola R. A critical review on bioanalytical method development and validation of few oncology drugs by using LC-MS-MS. J Pharm Neg Results. 2022:16-27.

Yang S, Zhang X, Wang Y, Wen C, Wang C, Zhou Z. Development of UPLC-MS/MS method for studying the pharmacokinetic interaction between dasatinib and posaconazole in rats. Drug Des Devel Ther. 2021 May;15:2171-8. doi: 10.2147/DDDT.S301241, PMID 34079220.

Kazi M, Alhajri A, Alshehri SM, Elzayat EM, Al Meanazel OT, Shakeel F. Enhancing oral bioavailability of apigenin using a bioactive self nano emulsifying drug delivery system (Bio-SNEDDS): in vitro-in vivo and stability evaluations. Pharmaceutics. 2020;12(8):749. doi: 10.3390/pharmaceutics12080749, PMID 32785007.

Rajinikanth C, Kathiresan K. Development and optimization of super saturable SELF-NANO emulsifying drug delivery system for dasatinib by design of experiment. Int J App Pharm. 2024 May 7;16(3):195-205. doi: 10.22159/ijap.2024v16i3.50434.

Reddy Adena SK, Matte KV, Kosuru R. Formulation optimization and in vitro characterization of dasatinib loaded polymeric nanocarriers to extend the release of the model drug. Int J App Pharm. 2021 Sep 7;13(5):318-30. doi: 10.22159/ijap.2021v13i5.41995.

Zhang N, Zhang F, XU S, Yun K, WU W, Pan W. Formulation and evaluation of luteolin supersaturatable self nanoemulsifying drug delivery system (S-SNEDDS) for enhanced oral bioavailability. J Drug Deliv Sci Technol. 2020 Aug 1;58:101783. doi: 10.1016/j.jddst.2020.101783.

Ahmad S, Hafeez A. Formulation and development of curcumin piperineloaded S-SNEDDS for the treatment of alzheimers disease. Mol Neurobiol. 2023 Feb 1;60(2):1067-82. doi: 10.1007/s12035-022-03089-7, PMID 36414909.

Nottingham E, Sekar V, Mondal A, Safe S, Rishi AK, Singh M. The role of self nanoemulsifying drug delivery systems of CDODA-me in sensitizing erlotinib-resistant non small cell lung cancer. J Pharm Sci. 2020 Jun;109(6):1867-82. doi: 10.1016/j.xphs.2020.01.010, PMID 31954111.

Bodke V, Kumbhar P, Belwalkar S, Mali AS, Waghmare K. Design and development of nanoemulsion of smilax china for anti-psoriasis activity. Int J Pharm Pharm Sci. 2024 May 1;16(5):54-66. doi: 10.22159/ijpps.2024v16i5.50327.

Usta DY, Timur B, Teksin ZS. Formulation development optimization by box-behnken design characterization in vitro ex-vivo and in vivo evaluation of bosentan loaded self nanoemulsifying drug delivery system: a novel alternative dosage form for pulmonary arterial hypertension treatment. Eur J Pharm Sci. 2022 Jul 1;174:106-59. doi: 10.1016/j.ejps.2022.106159, PMID 35263632.

Mohd Ateeq MA, Mahajan S, Saren BN, Aalhate M, Singh H, Chatterjee E. Solid self nano emulsifying drug delivery system of dasatinib: optimization in vitro ex-vivo and in vivo assessment. Ther Deliv. 2024 Sep 17;15(10):749-68. doi: 10.1080/20415990.2024.2397330, PMID 39287183.

Chaudhuri A, Shrivastava N, Kumar S, Singh AK, Ali J, Baboota S. Designing and development of omega-3 fatty acid based self nanoemulsifying drug delivery system (SNEDDS) of docetaxel with enhanced biopharmaceutical attributes for management of breast cancer. J Drug Deliv Sci Technol. 2022 Feb 1;68:103117. doi: 10.1016/j.jddst.2022.103117.

Sumirtapura YC, Pamudji JS, Mudhakir D, Suhery WN. Development and characterization of self nanoemulsifying drug delivery system (SNEDDS) formulation for enhancing dissolution of fenofibric acid. JRP. 2020;24(5):738-47. doi: 10.35333/jrp.2020.227.

Kassem AA, Mohsen AM, Ahmed RS, Essam TM. Self nanoemulsifying drug delivery system (SNEDDS) with enhanced solubilization of nystatin for treatment of oral candidiasis: design optimization in vitro and in vivo evaluation. J Mol Liq. 2016 Jun 1;218:219-32. doi: 10.1016/j.molliq.2016.02.081.