CILNIDIPINE-LOADED TRANSDERMAL NANOEMULSION-BASED GEL: SYNTHESIS, OPTIMISATION, CHARACTERISATION, AND PHARMACOKINETIC EVALUATION

MAHESH T. GAIKWAD; RAJENDRA P. MARATHE

doi:10.22159/ijap.2025v17i1.52689

Authors

MAHESH T. GAIKWAD Govt College of Pharmacy, Opp. Govt. Polytechnic, Osmanpura, Chhatrapati Sambhajinagar-431005, Maharashtra, India https://orcid.org/0000-0003-3252-7969
RAJENDRA P. MARATHE Department of Pharmaceutical Chemistry, Govt College of Pharmacy, Opp. Govt. Polytechnic, Osmanpura, Chhatrapati Sambhajinagar-431005, Maharashtra, India

DOI:

https://doi.org/10.22159/ijap.2025v17i1.52689

Keywords:

Cilnidipine, Pseudo-ternary phase diagram, Transdermal flux, Bioavailability, Pharmacokinetics, Dermal toxicity

Abstract

Objective: The aim of the study was to enhance transdermal flux and bioavailability, thereby reforming the effectiveness of drug delivery by synthesising and characterising cilnidipine-loaded nanoemulsion-based gel.

Methods: The research was conducted with meticulous planning and execution. After preformulation studies, cilnidipine-loaded nanoemulsions were synthesised using probe sonication and optimised by a 2-factor central composite design. The optimised nanoemulsions were loaded in Carbopol 940 and HPMC K₄M gelling system. The optimised nanoemulsions were characterised for droplet size, zeta potential, viscosity, refractive index, pH and TEM, and cilnidipine-loaded nanoemulsion gels were characterised for clarity, homogeneity, consistency, spreadability, extrudability, pH, viscosity, in vitro diffusion study, dermal toxicity, and pharmacokinetic profiling. The process was accurately planned and accomplished at each step to ensure the precision and reliability of the results.

Results: The findings of this research are not just significant; they are groundbreaking. The steady-state flux values observed ranged from 35.71±1.27 µg/cm²/h to 107.7±2.04 µg/cm²/h for DOE_CiL_1 to 9 and 40.88±1.44 µg/cm²/h to 80.64±1.38 µg/cm²/h for NEn_CiL_GeL_1 to 4. These results underscore the diverse efficacy of different formulations in facilitating drug delivery through the skin. The pharmacokinetics profile of cilnidipine also showed remarkable changes. The C_max for the cilnidipine tablet was 332.3±14.2 ng/ml, whereas it significantly increased (p<0.05) to 593.00±24.8 ng/ml in the nanoemulsion gel, demonstrating a substantial enhancement in drug concentration. Additionally, the AUC_0-12 showed a significant (p<0.05) increase from 1279±34.1 ng/ml. h with the tablet to 1922.50±162.8 ng/ml. h with the nanoemulsion gel. The AUC_0-∞ also increased from 1395.5±156.7 ng/ml·h for the tablet to 1962.30±174.9 ng/ml. h for the nanoemulsion gel, further confirming the improved bioavailability of cilnidipine with the nanoemulsion gel. These significant bioavailability improvements cause excitement about the potential impact of this research, which could revolutionise transdermal drug delivery systems in the pharmaceutical business, leading to more effective and efficient drug delivery methods.

Conclusion: The results of this novel study are not only promising but also hold the potential to be transformative. The significant improvement in transdermal flux from the cilnidipine-loaded nanoemulsion gel reveals a substantial increase in the drug's bioavailability. This breakthrough could eliminate several drawbacks of cilnidipine, like first-pass fate and poor solubility, and provide a safer, more convenient delivery method for managing hypertension.

Downloads

Download data is not yet available.

References

Shete MM. Cilnidipine: next-generation calcium channel blocker. J Assoc Physicians India. 2016;64(4):95-9. PMID 27734656.

Chandra KS, Ramesh G. The fourth generation calcium channel blocker: cilnidipine. Indian Heart J. 2013 Dec;65(6):691-5. doi: 10.1016/j.ihj.2013.11.001, PMID 24407539.

Diwan R, Ravi PR, Pathare NS, Aggarwal V. Pharmacodynamic pharmacokinetic and physical characterization of cilnidipine loaded solid lipid nanoparticles for oral delivery optimized using the principles of design of experiments. Colloids Surf B Biointerfaces. 2020 Sep 1;193:111073. doi: 10.1016/j.colsurfb.2020.111073, PMID 32388122.

Renjish C, Ittiyavirah SP, Harindran J, Sudhakaran Nair CR. Preparation characterisation evaluation and DFT analysis of cilnidipine-L-phenylalanine cocrystal. Int J Appl Pharm. 2023 Nov 1;15(6):365-72.

Cherukkoth R, Ittiyavirah SP, Harindran J, Nair CR. Characterization evaluation and density functional analysis of cilnidipine otinamide cocrystals developed by liquid assisted grinding technique: a sustainable approach for enhanced solubility. Int J Appl Pharm. 2024 Mar 1;16(2):132-8.

PN R, ND. Formulation development and characterisation of cilnidipine loaded solid lipid nanoparticles. Asian J Pharm Clin Res. 2018 Sep 1;11(9):120-5. doi: 10.22159/ajpcr.2018.v11i9.24666.

Bhalerao A, Chaudhari PP. Formulation of solid lipid nanoparticles of cilnidipine for the treatment of hypertension. J Drug Delivery Ther. 2019 May 15;9(3):212-21. doi: 10.22270/jddt.v9i3.2849.

Mankar SD, Tupe A. Solubility enhancement and evaluation of cilnidipine using solid dispersion techniques. Int J Exp Res Rev. 2023;32:347-57. doi: 10.52756/ijerr.2023.v32.030.

Karemore MN, Bali NR. Gellan gum-based gastroretentive tablets for bioavailability enhancement of cilnidipine in human volunteers. Int J Biol Macromol. 2021 Mar 31;174:424-39. doi: 10.1016/j.ijbiomac.2021.01.199, PMID 33539955.

Anand K, Karmakar S, Mandal P, Shaharyar MA, Bhowmik R, Mondal A. Formulation development optimization and characterization of cilnidipine loaded self microemulsifying drug delivery system. Asian Pac J health Sci; 2021.

Khatoon K, Rizwanullah M, Amin S, Mir SR, Akhter S. Cilnidipine loaded transfersomes for transdermal application: formulation optimization in vitro and in vivo study. J Drug Deliv Sci Technol. 2019 Dec 1;54:101303. doi: 10.1016/j.jddst.2019.101303.

Mishra R, Mir SR, Amin S. Polymeric nanoparticles for improved bioavailability of cilnidipine. Int J Pharm Pharm Sci. 2017 Feb 27;9(4):129. doi: 10.22159/ijpps.2017v9i4.15786.

Kumar Sharma A, Singh Naruka P, Soni S, Sarangdevot YS, Khandelwal M, Aman S. Development and evaluation cilnidipine fast dissolving tablet by using isapghula husk as natural superdisintegrant. Int J Current Pharm Rev Res. 2019;11(1):1-11.

Shaikh F, Patel M, Patel V, Patel A, Shinde G, Shelke S. Formulation and optimization of cilnidipine loaded nanosuspension for the enhancement of solubility dissolution and bioavailability. J Drug Deliv Sci Technol. 2022 Mar;69:103066. doi: 10.1016/j.jddst.2021.103066.

Liu Q, Mai Y, GU X, Zhao Y, DI X, MA X. A wet milling method for the preparation of cilnidipine nanosuspension with enhanced dissolution and oral bioavailability. J Drug Deliv Sci Technol. 2020 Feb 1;55:101371. doi: 10.1016/j.jddst.2019.101371.

A Alzalzalee R, Kassab HJ. Cilnidipine nanoparticles oral film: preparation and evaluation. JRP. 2024;28(1):191-6. doi: 10.29228/jrp.687.

Tandel H, Raval K, Nayani A, Upadhay M. Preparation and evaluation of cilnidipine microemulsion. J Pharm Bioallied Sci. 2012;4 Suppl 1:S114-5. doi: 10.4103/0975-7406.94162, PMID 23066184.

Sharma A, Singh AP, Harikumar SL. Development and optimization of nanoemulsion-based gel for enhanced transdermal delivery of nitrendipine using box behnken statistical design. Drug Dev Ind Pharm. 2020;46(2):329-42. doi: 10.1080/03639045.2020.1721527, PMID 31976777.

Chapter GA. 21-nanoemulsions. Nanoparticles for biomedical applications. In: Chung EJ, Leon L, Rinaldi C, editors. Micro and Nano Technologies; 2020. p. 371-84. Available from: https://www.sciencedirect.com/science/article/pii/B9780128166628000217elsevier. [Last accessed on 20 Nov 2024].

Gheorghe I, Saviuc C, Ciubuca B, Lazar V, Chifiriuc MC. Nanodrug delivery systems for transdermal drug delivery. Grumezescu AM, editor. Chapter 8 nanomater drug delivery ther. William Andrew Publishing; 2019. p. 225-44. Available from: https://www.sciencedirect.com/science/article/pii/B9780128165058000102. [Last accessed on 20 Nov 2024].

MC Clements DJ, Jafari SM. General aspects of nanoemulsions and their formulation. Jafari SM, McClements DJ, editors. Chapter 1. Nanoemulsions. In: Academic Press; 2018. p. 3-20. Available from: https://www.sciencedirect.com/science/article/pii/B9780128118382000011. [Last accessed on 20 Nov 2024].

Shah MR, Imran M, Ullah S. Nanoemulsions. Chapter 4. Lipid based nanocarriers for drug delivery and diagnosis. Shah MR, Imran M, Ullah S, editors. In: William Andrew Publishing; 2017. p. 111-37. Available from: https://www.sciencedirect.com/science/article/pii/B9780323527293000044. [Last accessed on 20 Nov 2024].

Tirnaksiz F, Akkus S, Celebi N. 9-nanoemulsions as drug delivery systems. In: Monzer F, editor. Colloids in drug delivery. CRC Press, Taylor & Francis Group; 2010. p. 221-44. doi: 10.1201/9781439818268-c9.

Aparna C, Srinivas P, Rao Patnaik KS. Enhanced transdermal permeability of telmisartan by a novel nanoemulsion gel. Int J Pharm Pharm Sci. 2015;7(4):335-42.

Bali V, Ali M, Ali J. Study of surfactant combinations and development of a novel nanoemulsion for minimising variations in bioavailability of ezetimibe. Colloids Surf B Biointerfaces. 2010 Apr 1;76(2):410-20. doi: 10.1016/j.colsurfb.2009.11.021, PMID 20042320.

Borhade V, Pathak S, Sharma S, Patravale V. Clotrimazole nanoemulsion for malaria chemotherapy. Part I: Preformulation studies formulation design and physicochemical evaluation. Int J Pharm. 2012 Jul 15;431(1-2):138-48. doi: 10.1016/j.ijpharm.2011.12.040, PMID 22227344.

Chadha R, Bhandari S. Drug excipient compatibility screening role of thermoanalytical and spectroscopic techniques. J Pharm Biomed Anal. 2014 Jan 18;87:82-97. doi: 10.1016/j.jpba.2013.06.016, PMID 23845418.

Secilmis Canbay H, Polat M, Doganturk M. Study of stability and drug excipient compatibility of estriol. Bilge Int J Sci Technol Res. 2019 Sep 30;3(2):102-7. doi: 10.30516/bilgesci.582054.

Hamza MY, Abd El Aziz ZR, Aly Kassem M, El Nabarawi MA. Loxoprofen nanosponges: formulation characterization and ex vivo study. Int J App Pharm. 2022 Mar 1;14(2):233-41. doi: 10.22159/ijap.2022v14i2.43670.

Lakavath SK, Ahad HA. Construction of ternary phase diagram for three component system (oil water surfactant) as a preliminary step before formulating a nanoemulsion. Eur Chem Bull. 2023;12(10):10669-79.

Jayapal N, Vamshi Vishnu Y. Formulation and in vivo evaluation of self-nanoemulsifying drug delivery system of ramipril in wistar rats. Asian J Pharm Clin Res. 2021;14(7):126-36. doi: 10.22159/ajpcr.2021.v14i7.42003.

Modarres Gheisari SM, Gavagsaz Ghoachani R, Malaki M, Safarpour P, Zandi M. Ultrasonic nano emulsification a review. Ultrason Sonochem. 2019 Apr;52:88-105. doi: 10.1016/j.ultsonch.2018.11.005, PMID 30482437.

Mohamadi Saani S, Abdolalizadeh J, Zeinali Heris S. Ultrasonic/sonochemical synthesis and evaluation of nanostructured oil in water emulsions for topical delivery of protein drugs. Ultrason Sonochem. 2019 Jul 1;55:86-95. doi: 10.1016/j.ultsonch.2019.03.018, PMID 31084795.

Rahma H, Suciati T. Formulation of sodium ascorbyl phosphate (SAP) in to O/W nanoemulsion. Int J App Pharm. 2023 May 1;15(3):242-6. doi: 10.22159/ijap.2023v15i3.46643.

Saraswathi TS, Roshini R, Damodharan N, Mothilal M, Janani SK. Development of lipid based vesicles of terbinafine gel for skin delivery by 32full factorial design. Int J App Pharm. 2024 Jul 7;16(4):231-43. doi: 10.22159/ijap.2024v16i4.50460.

Deka T, Das MK, Das S, Das P, Singha LR. Box behnken design approach to develop nano vesicular herbal gel for the management of skin cancer in experimental animal model. Int J App Pharm. 2022 Nov 1;14(6):148-66. doi: 10.22159/ijap.2022v14i6.45867.

Jyothi JB. Design of gastroretentive polymeric low density microballoons of mebendazole using response surface. Methodology. 2022;15(7):149-5. doi: 10.22159/ajpcr.2022v15i7.44090.

Elmataeeshy ME, Sokar MS, Bahey El Din M, Shaker DS. Enhanced transdermal permeability of terbinafine through novel nanoemulgel formulation; development in vitro and in vivo characterization. Future Journal of Pharmaceutical Sciences. 2018 Jun;4(1):18-28. doi: 10.1016/j.fjps.2017.07.003.

Chauhan SB, Naved T, Parvez N. Formulation and development of transdermal drug delivery system of ethinylestradiol and testosterone: in vitro evaluation. Int J App Pharm. 2019 Jan 1;11(1):55-60. doi: 10.22159/ijap.2019v11i1.28564.

Nikumbh KV, Sevankar SG, Patil MP. Formulation development in vitro and in vivo evaluation of microemulsion based gel loaded with ketoprofen. Drug Deliv. 2015 Jun 1;22(4):509-15. doi: 10.3109/10717544.2013.859186, PMID 24266589.

Shraddha M, Anuradha S. Formulation and evaluation of emulgel containing coriandrum sativum seeds oil for anti-inflammatory activity. J Drug Delivery Ther. 2019 Jun 15;9(3-s):124-30. doi: 10.22270/jddt.v9i3-s.2808.

Ali EM, Mahmood S, Sengupta P, Doolaanea AA, Chatterjee B. Sunflower oil based nanoemulsion loaded into carbopol gel: semisolid state characterization and ex vivo skin permeation. Indian J Pharm Sci. 2023 Mar 21;85(2):388-420. doi: 10.36468/pharmaceutical-sciences.1104.

NS, Chandrakala V, Srinivasan S. Review on: effect of oil surfactant and cosurfactant on microemulsion. Int J Curr Pharm Sci. 2022;14(4)23-7. doi: 10.22159/ijcpr.2022v14i4.2011.

Gaber DA, Alsubaiyel AM, Alabdulrahim AK, Alharbi HZ, Aldubaikhy RM, Alharbi RS. Nano emulsion based gel for topical delivery of an anti-inflammatory drug: in vitro and in vivo evaluation. Drug Des Devel Ther. 2023;17:1435-51. doi: 10.2147/DDDT.S407475, PMID 37216175.

OECD/OCDE. OECD Guideline for the testing of chemicals. Acute dermal toxicity: fixed dose procedure; 2017. p. 402. Available from: http://www.oecd.org/termsandconditions/. [Last accessed on 20 Nov 2024].

Banerjee S, Chattopadhyay P, Ghosh A, Pathak MP, Singh S, Veer V. Acute dermal irritation sensitization and acute toxicity studies of a transdermal patch for prophylaxis against ({+/-}) anatoxin a poisoning. Int J Toxicol. 2013 Jul;32(4):308-13. doi: 10.1177/1091581813489996, PMID 23696561.

Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. 2016;7(2):27-31. doi: 10.4103/0976-0105.177703, PMID 27057123.

Pathan IB, Jaware BP, Shelke S, Ambekar W. Curcumin loaded ethosomes for transdermal application: formulation optimization in vitro and in vivo study. J Drug Deliv Sci Technol. 2018 Apr 1;44:49-57. doi: 10.1016/j.jddst.2017.11.005.

Khani S, Keyhanfar F, Amani A. Design and evaluation of oral nanoemulsion drug delivery system of mebudipine. Drug Deliv. 2016 Jul 23;23(6):2035-43. doi: 10.3109/10717544.2015.1088597, PMID 26406153.

Smail SS, Ghareeb MM, Omer HK, Al Kinani AA, Alany RG. Studies on surfactants cosurfactants and oils for prospective use in formulation of ketorolac tromethamine ophthalmic nanoemulsions. Pharmaceutics. 2021 Apr 1;13(4):1-13. doi: 10.3390/pharmaceutics13040467, PMID 33808316.

Jadhav CM. Investigating application of non aqueous microemulsion for drug delivery: a review. AJBPS. 2014;4(29):1-9. doi: 10.15272/ajbps.v4i29.460.

Mehmood T, Ahmed A, Ahmad A, Ahmad MS, Sandhu MA. Optimization of mixed surfactants based β-carotene nanoemulsions using response surface methodology: an ultrasonic homogenization approach. Food Chem. 2018 Jul 1;253:179-84. doi: 10.1016/j.foodchem.2018.01.136, PMID 29502819.

Mou D, Chen H, DU D, Mao C, Wan J, XU H. Hydrogel thickened nanoemulsion system for topical delivery of lipophilic drugs. Int J Pharm. 2008 Apr 2;353(1-2):270-6. doi: 10.1016/j.ijpharm.2007.11.051, PMID 18215479.

Yusuf NA, Abdassah M, Sopyan I, Mauludin R, Joni IM, Chaerunisaa AY. Improved characteristics of glibenclamide as transethosome vesicular system: physicochemical solubility and in vitro permeation study. Int J App Pharm. 2024 Jan 1;16(1):172-85. doi: 10.22159/ijap.2024v16i1.49245.