Cilnidipine nanocrystals; Formulation, characterization and bioavailability study

Year 2024, Volume: 28 Issue: 6, 2057 - 2067, 28.06.2025

Suray A. Hazzaa Nawal A. Rajab

https://izlik.org/JA42ZA25AA

Abstract

Cilnidipine a fourth generation calcium channel blockers, it was utilized to reduce cardiovascular events. Since cilnidipine is a material classified as Biopharmaceutics Classification System (BCS) Class-II, which is extremely poorly soluble and has a high permeability in turn low bioavailability. Thus, by employing solvent anti-solvent technology, cilnidipine (CLD) can be produced as nanocrystals (NCs). Getting beyond those obstacles could boost the material's solubility and bioavailability. A pair of distinct stabilizers (Soluplus® and Tween20) in a ratio of CLD: Soluplus : Tween20 (1:0.25:0.5) were used to prepare cilnidipine nanocrystals (CLD NCs). Rats were used to evaluate and assess the pharmacokinetics in vivo parameters of CLD and CLD NCs. The optimal formula that was created revealed 62.1 nm with 0.18, which represent particle size and polydispersity index (PDI), respectively. At 6 minutes, 99% of CLD NCs were released in phosphate buffer 6.8. It is evident that CLD NCs had a higher relative bioavailability by around 3.17 times and that their area under the concentration time curve (AUC) and CPmax were greater than those of bulk CLD. Additionally, the CLD NCs' Tmax was lower than that of the CLD pure medication. Accordingly, it was evident from the observed pharmacokinetic parameters (AUC, CPmax, and Tmax) that the CLD NCs enhanced the the oral bioavailability of CLD in rats.

Keywords

Cilnidipine , Soluplus , Nanocrystals , Tween20 , solvent anti-solvent

References

• [1] Al-lami MS, Oudah MH, Rahi FA. Preparation and characterization of domperidone nanoparticles for dissolution improvement. Iraqi J Pharm Sci. 2018;27(1):39-52. https://doi.org/10.31351/vol27iss1pp39-52
• [2] Shukr MH, Ismail S, Ahmed SM. Development and optimization of ezetimibe nanoparticles with improved antihyperlipidemic activity. J Drug Deliv Sci Technol. 2019;49:383-395. http://dx.doi.org/10.1016/j.jddst.2018.12.001
• [3] Arora D, Khurana B, Rath G, Nanda S, Goyal AK. Recent advances in nanosuspension technology for drug delivery. Curr Pharm Des. 2018;24(21):2403-2415. https://doi.org/10.2174/1381612824666180522100251
• [4] Rashid AM, Abd-Alhammid SN. Formulation and characterization of itraconazole as nanosuspension dosage form for enhancement of solubility. Iraqi J Pharm Sci. 2019;28(2):124-133. https://doi.org/10.31351/vol28iss2pp124-133
• [5] Azimullah S, Sudhakar C, Kumar P, Patil A, Usman MRM, Usman MZS, Jain BV. Nanosuspensions as a promising approach to enhance bioavailability of poorly soluble drugs: An update. J drug deliv Ther. 2019;9(2):574-582. https://doi.org/10.22270/jddt.v9i2.2436
• [6] Rathore SK, Pathak BK. Formulation and evaluation of aceclofenac-loaded nanoparticles by solvent evaporation method. Res J Pharm Dosage Forms and Tech. 2020;12(4):237-244. https://doi.org/10.5958/0975-4377.2020.00039.7
• [7] Alhagiesa AW, Ghareeb MM. The Formulation and characterization of nimodipine nanoparticles for the enhancement of solubility and dissolution rate. Iraqi J Pharm Sci. 2021;30(2):143-152. https://doi.org/10.31351/vol30iss2pp143-152
• [8] Thapa RK, Kim JO. Nanomedicine-based commercial formulations: Current developments and future prospects. J Pharm Investig. 2023;53(1):19-33. https://doi.org/10.1007%2Fs40005-022-00607-6
• [9] Hussien RM, Ghareeb MM. Formulation and characterization of isradipine nanoparticle for dissolution enhancement. Iraqi J Pharm Sci. 2021;30(1):218-225. https://doi.org/10.31351/vol30iss1pp218-225
• [10] 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;193:111073. https://doi.org/10.1016/j.colsurfb.2020.111073
• [11] Rao MRP, Kulkarni S, Sonawane A, Sugaonkar S. Self-nanoemulsifying drug delivery system of cilnidipine. Indian J Pharm Educ Res. 2021;55(3):664-676. http//doi.org/10.5530/ijper.55.3.138
• [12] Chakraborty RN, Langade D, More S, Revandkar V, Birla A. Efficacy of cilnidipine (L/N-type Calcium Channel Blocker) in treatment of hypertension: A meta-analysis of randomized and non-randomized controlled trials. Cureus. 2021;13(11):e19822. https://doi.org/10.7759/cureus.19822
• [13] Hu Q, Fu X, Su Y, Wang Y, Gao S, Wang X, Xu Y, Yu C. Enhanced oral bioavailability of koumine by complexation with hydroxypropyl-β-cyclodextrin: Preparation, optimization, ex vivo and in vivo characterization. Drug Deliv. 2021;28(1):2415-2426. https://doi.org/10.1080/10717544.2021.1998248
• [14] Khan FU, Nasir F, Iqbal Z, Neau S, Khan I, Hassan M, Iqbal M, Ullah A, Khan SI, Sakhi M. Improved ocular bioavailability of moxifloxacin HCl using PLGA nanoparticles: Fabrication, characterization, in-vitro and in-vivo evaluation. Iran J Pharm Res. 2021;20(3):592. https://doi.org/10.22037%2Fijpr.2021.114478.15054
• [15] Shaker MA, Elbadawy HM, Al Thagfan SS, Shaker MA. Enhancement of atorvastatin oral bioavailability via encapsulation in polymeric nanoparticles. Int J Pharm. 2021;592:120077. https://doi.org/10.1016/j.ijpharm.2020.120077
• [16] Gigliobianco MR, Casadidio C, Censi R, Di Martino P. Nanocrystals of poorly soluble drugs: drug bioavailability and physicochemical stability. Pharmaceutics. 2018;10(3):134. https://doi.org/10.3390/pharmaceutics10030134
• [17] Kadhim ZJ, Rajab NA. Formulation and characterization of glibenclamide nanoparticles as an oral film. Int J Drug Deliv Technol. 2022;12(1):387-394. http://dx.doi.org/10.25258/ijddt.12.1.70
• [18] Abbas IK, Rajab NA, Hussein AA. Formulation and in-vitro evaluation of darifenacin hydrobromide as buccal films. Iraqi J Pharm Sci. 2019;28(2):83-94. https://doi.org/10.31351/vol28iss2pp83-94
• [19] Liu Q, Mai Y, Gu X, Zhao Y, Di X, Ma X, Yang J. A wet-milling method for the preparation of cilnidipine nanosuspension with enhanced dissolution and oral bioavailability. J Drug Deliv Sci Technol. 2020;55:101371. https://doi.org/10.1016/j.jddst.2019.101371
• [20] Mohana M, Vijayalakshmi S. Development and characterization of solid dispersion-based orodispersible tablets of cilnidipine. Beni-Suef Univ J Basic Appl Sci. 2022;11(1):83. https://doi.org/10.1186/s43088-022-00259-3
• [21] Salih OS, Al-Akkam EJ. Pharmacokinetic parameters of ondansetron in rats after oral solution and transdermal invasomes gel: A comparison study. J Adv Pharm Educ Res. 2023;13(1):117. https://doi.org/10.51847/HS5a27EI6o
• [22] Kachave RN, Yelmame SS, Mundhe AG. Quantitative estimation of cilnidipine and valsartan in rat plasma by RP HPLC: its pharmacokinetic application. Futur J Pharm Sci. 2021;7:1-7. https://doi.org/10.1186/s43094-020-00153-8
• [23] Shekhawat P, Pokharkar V. Risk assessment and QbD based optimization of an eprosartan mesylate nanosuspension: In-vitro characterization, PAMPA and in-vivo assessment. Int J Pharm. 2019;567:118415. https://doi.org/10.1016/j.ijpharm.2019.06.006
• [24] Shariare MH, Altamimi MA, Marzan AL, Tabassum R, Jahan B, Reza HM, Rahman M, Ahsan GU, Kazi M. In vitro dissolution and bioavailability study of furosemide nanosuspension prepared using design of experiment (DoE). Saudi Pharm J. 2019;27(1):96-105. https://doi.org/10.1016/j.jsps.2018.09.002
• [25] Guo X, Guo Y, Zhang M, Yang B, Liu H, Yin T, Zhang Y, He H, Wang Y, Liu D, Gou J, Tang X. A comparative study on in vitro and in vivo characteristics of enzalutamide nanocrystals versus amorphous solid dispersions and a better prediction for bioavailability based on “spring-parachute” model. Int J Pharm. 2022;628:122333. https://doi.org/10.1016/j.ijpharm.2022.122333
• [26] Shinkar DM, Jadhav SS, Pingale PL, Boraste SS, VishvnathAmrutkar S. Formulation, evaluation, and optimization of glimepiride nanosuspension by using antisolvent evaporation technique. Pharmacophore. 2022;13(4):49-58. https://doi.org/10.51847/1yGT4slm1W
• [27] Rajab NA , Jawad MS. Preparation and evaluation of rizatriptan benzoate loaded nanostructured lipid carrier using different surfactant/co-surfactant systems. Int J Drug Deliv Technol. 2023;13(1):120-126. http://dx.doi.org/10.25258/ijddt.13.1.18
• [28] Mohammady M, Yousefi G. Freeze-drying of pharmaceutical and nutraceutical nanoparticles: The effects of formulation and technique parameters on nanoparticles characteristics. J Pharm Sci. 2020;109(11):3235-3247. https://doi.org/10.1016/j.xphs.2020.07.015
• [29] Al Hazzaa SA, Rajab NA. Cilnidipine nanocrystals, formulation and evaluation for optimization of solubility and dissolution rate. Iraqi J Pharm Sci. 2023;32(Suppl.):127-135. https://doi.org/10.31351/vol32issSuppl.pp127-135
• [30] Muhesen RA, Rajab NA. Formulation and characterization of olmesartan medoxomil as a nanoparticle. Res J Pharm Technol. 2023;16(7):3314-3320. https://doi.org/10.52711/0974-360X.2023.00547
• [31] Mhetre RL, Hol VB, Chanshetti RR, Dhole SN. Optimisation of cilnidipine nanoparticles using box-behnken design: In-vitro, toxicity and bioavailability oral assessment. Mater Technol. 2022;37(11):1796-1807. http://dx.doi.org/10.1080/10667857.2021.1988038
• [32] Abdulqader AA, Rajab NA. Bioavailability study of posaconazole in rats after oral poloxamer P188 nano-micelles and posaconazole pure drug. J Adv Pharm Educ Res. 2023;13(2):141. http://dx.doi.org/10.31351/vol32issSuppl.pp26-32
• [33] Arslan A, Yet B, Nemutlu E, Akdağ Çaylı Y, Eroğlu H, Öner L. Celecoxib nanoformulations with enhanced solubility, dissolution rate, and oral bioavailability: Experimental approaches over in vitro/in vivo evaluation. Pharmaceutics. 2023;15(2):363. https://doi.org/10.3390/pharmaceutics15020363
• [34] Alotaibi BS, Pervaiz F, Buabeid M, Ashames A, Fahelelbom KM, Siddique S, Shoukat H , Rehman S , Noreen S, Murtaza G. Nanostructured lipid carriers based suppository for enhanced rectal absorption of ondansetron: In vitro and in vivo evaluations. Arab J Chem. 2021;14(12):103426. https://doi.org/10.1016/j.arabjc.2021.103426
• [35] Hazzaa SA, Rajab NA. A comparison study of in-vivo pharmacokinetic parameters after oral cilnidipine nanocrystals administration https://doi.org/10.51847/TY2pMYm8ew in rats. J Adv Pharm Educ Res. 2023;13(4):52-56.