Generic placeholder image

Nanoscience & Nanotechnology-Asia

Editor-in-Chief

ISSN (Print): 2210-6812
ISSN (Online): 2210-6820

Research Article

Development of Surface Modified and Aqueous Re-dispersible Nanocrystal using Pluronic F-68 and Suitable Cryoprotectant for Accelerating the Dissolution Rate of Cilnidipine

Author(s): Vijay Agarwal*, Nitin Kaushik and Surya Goel

Volume 13, Issue 5, 2023

Published on: 25 July, 2023

Article ID: e220623218147 Pages: 10

DOI: 10.2174/2210681213666230622100611

Price: $65

Abstract

Background: The research on poorly aqueous-soluble drugs of BCS class II such as Cilnidipine (CLD) demands significant improvement in their aqueous solubility and dissolution rate. Such requirements may be fulfilled by adapting the nanocrystal approach with considering the various challenges.

Objective: The prime purpose of this research work was to develop, optimize and characterize the nanocrystal of the poorly aqueous soluble drug (CLD) using the antisolvent-precipitation ultrasonication method. Such a method was followed for rapid re-dispersion of drugs in water with improving their dissolution rate.

Methods: In this study, the different nanosuspension formulations were prepared using varying concentrations of three stabilizers - Pluronic F-68, Pluronic F-127, and HPMC-15cps, as selected stabilizer candidates. The selected and optimized formulation was followed by a lyophilization process with the incorporation of two selected distinct cryoprotectants - Mannitol and Lactose. The obtained nanocrystals were evaluated for their physical appearance, aqueous re-dispersibility, and particle size. Additionally, the optimized nanoformulation was also evaluated for morphology, dissolution rate, assay, drug entrapment efficiency, and drug loading content. The in vitro dissolution of optimized drug nanocrystal was done in the phosphate buffer solution of pH 6.8 and compared with bulk CLD and a physical mixture of CLD and pluronic F-68.

Results: For optimizing drug nanosuspension, the effect of pluronic F-68 and cilnidipine concentration was investigated, and the optimal values were 0.3% w/v and 5 mg/ml, respectively. Mannitol-containing nanocrystals exhibited a white crystalline powder having a particle size of 154 nm and a good polydispersity index (0.217). Nanocrystals also demonstrated an excellent re-dispersibility in deionized water after manual shaking and no particles were observed at the bottom of the container till 15 days. Such optimized formulation also indicated an increase in dissolution rate in comparison to bulk CLD and their physical mixture with pluronic F-68. It released approximately 72.25% of the drug within 90 minutes while bulk CLD and physical mixture released only 31.24% and 30.37% of the drug, respectively at the same time. The drug assay method indicated that only 92% of the drug was present in optimized nanocrystals after the transformation of nanosuspension into nanocrystals which was less than the initial amount. In this research, the experimental work also analyzed that optimized nanocrystal has only 28.6% of drug loading content.

Conclusion: The selected method and cryoprotectant have ability to develop the aqueous re-dispersible nanocrystal for enhancing the dissolution rate and water solubility of CLD-like poorly soluble drugs.

Keywords: Nanosuspension, nanocrystals, cilnidipine, lyophilization, dissolution rate, stability.

Graphical Abstract
[1]
Pawar, V.K.; Singh, Y.; Mehar, J.G. Engineered monocrystal technology: In vivo fate, targeting and applications in drug delivery. Acta Pharm. Sin. B, 2016, 6, 106-113.
[2]
Junghanns, J.U.A.H.; Müller, R.H. Nanocrystal technology, drug delivery and clinical applications. Int. J. Nanomedicine, 2008, 3(3), 295-309.
[PMID: 18990939]
[3]
Keck, C.; Müller, R. Drug nanocrystals of poorly soluble drugs produced by high pressure homogenisation. Eur. J. Pharm. Biopharm., 2006, 62(1), 3-16.
[http://dx.doi.org/10.1016/j.ejpb.2005.05.009] [PMID: 16129588]
[4]
Sun, L.; Hu, Y.; Zhang, L. Recent trends in nanocrystals for pharmaceutical applications. Curr. Pharm. Des., 2018, 24(21), 2394-2402.
[http://dx.doi.org/10.2174/1381612824666180524103341] [PMID: 29792137]
[5]
Onoue, S.; Yamada, S.; Chan, K. Nanodrugs: Pharmacokinetics and safety. Int. J. Nanomedicine, 2014, 9, 1025-1037.
[http://dx.doi.org/10.2147/IJN.S38378] [PMID: 24591825]
[6]
Junyaprasert, V.B.; Morakul, B. Nanocrystals for enhancement of oral bioavailability of water-poorly soluble drugs. Asian J Pharmaceut Sci, 2015, 10(1), 13-23.
[http://dx.doi.org/10.1016/j.ajps.2014.08.005]
[7]
Gulsun, T.; Gursory, R.N.; Oner, L. Nanocrystal technology for oral delivery of poorly water-soluble drugs. Fabad. J. Pharm. Sci., 2009, 34, 55-65.
[8]
Zhang, D.; Tan, T.; Gao, L.; Zhao, W.; Wang, P. Preparation of azithromycin nanosuspensions by high pressure homogenization and its physicochemical characteristics studies. Drug Dev. Ind. Pharm., 2007, 33(5), 569-575.
[http://dx.doi.org/10.1080/03639040600975147] [PMID: 17520449]
[9]
Chingunpitak, J.; Puttipipatkhachorn, S.; Chavalitshewinkoon-Petmitr, P.; Tozuka, Y.; Moribe, K.; Yamamoto, K. Formation, physical stability and iIn vitro antimalarial activity of dihydroartemisinin nanosuspensions obtained by co-grinding method. Drug Dev. Ind. Pharm., 2008, 34(3), 314-322.
[http://dx.doi.org/10.1080/03639040701662388] [PMID: 18363147]
[10]
Xiong, R.; Lu, W.; Li, J.; Wang, P.; Xu, R.; Chen, T. Preparation and characterization of intravenously injectable nimodipine nanosuspension. Int. J. Pharm., 2008, 350(1-2), 338-343.
[http://dx.doi.org/10.1016/j.ijpharm.2007.08.036] [PMID: 17920794]
[11]
Müller, R.H.; Peters, K. Nanosuspensions for the formulation of poorly soluble drugs. Int. J. Pharm., 1998, 160(2), 229-237.
[http://dx.doi.org/10.1016/S0378-5173(97)00311-6]
[12]
Van Eerdenbrugh, B.; Van den Mooter, G.; Augustijns, P. Top-down production of drug nanocrystals: Nanosuspension stabilization, miniaturization and transformation into solid products. Int. J. Pharm., 2008, 364(1), 64-75.
[http://dx.doi.org/10.1016/j.ijpharm.2008.07.023] [PMID: 18721869]
[13]
Krause, K.P.; Kayser, O.; Mäder, K.; Gust, R.; Müller, R.H. Heavy metal contamination of nanosuspensions produced by high-pressure homogenisation. Int. J. Pharm., 2000, 196(2), 169-172.
[http://dx.doi.org/10.1016/S0378-5173(99)00414-7] [PMID: 10699711]
[14]
Verma, S.; Gokhale, R.; Burgess, D.J. A comparative study of top-down and bottom-up approaches for the preparation of micro/nanosuspensions. Int. J. Pharm., 2009, 380(1-2), 216-222.
[http://dx.doi.org/10.1016/j.ijpharm.2009.07.005] [PMID: 19596059]
[15]
Kamiya, S.; Kurita, T.; Miyagishima, A.; Arakawa, M. Preparation of griseofulvin nanoparticle suspension by high-pressure homogenization and preservation of the suspension with saccharides and sugar alcohols. Drug Dev. Ind. Pharm., 2009, 35(8), 1022-1028.
[http://dx.doi.org/10.1080/03639040802698786] [PMID: 19466885]
[16]
Li, X.S.; Wang, J.X.; Shen, Z.G.; Zhang, P.Y.; Chen, J.F.; Yun, J. Preparation of uniform prednisolone microcrystals by a controlled microprecipitation method. Int. J. Pharm., 2007, 342(1-2), 26-32.
[http://dx.doi.org/10.1016/j.ijpharm.2007.04.025] [PMID: 17566675]
[17]
Zhang, X.; Xia, Q.; Gu, N. Preparation of all-trans retinoic acid nanosuspensions using a modified precipitation method. Drug Dev. Ind. Pharm., 2006, 32(7), 857-863.
[http://dx.doi.org/10.1080/03639040500534184] [PMID: 16908423]
[18]
Kocbek, P.; Baumgartner, S.; Kristl, J. Preparation and evaluation of nanosuspensions for enhancing the dissolution of poorly soluble drugs. Int. J. Pharm., 2006, 312(1-2), 179-186.
[http://dx.doi.org/10.1016/j.ijpharm.2006.01.008] [PMID: 16469459]
[19]
Tandel, H.; Raval, K.; Nayani, A.; Upadhay, M. Preparation and evaluation of cilnidipine microemulsion. J. Pharm. Bioallied Sci., 2012, 4(5), 114-115.
[http://dx.doi.org/10.4103/0975-7406.94162]
[20]
Chen, C.; Xie, X.; Li, Y.; Zhou, C.; Song, Y.; Yan, Z.; Yang, X. Influence of different polymers on crystallization tendency and dissolution behavior of cilnidipine in solid dispersions. Drug Dev. Ind. Pharm., 2014, 40(4), 441-451.
[http://dx.doi.org/10.3109/03639045.2013.767825] [PMID: 23614831]
[21]
Nagar, S.K.; Soniwala, M.M. Optimization of cilnidipine nanosuspension using a centre composite design. Int. J. Pharm. Sci. Drug Res., 2017, 9(4), 149-159.
[http://dx.doi.org/10.25004/IJPSDR.2017.090401]
[22]
Bakhle, S.S.; Avari, J.G. Development and characterization of solid self-emulsifying drug delivery system of cilnidipine. Chem. Pharm. Bull. (Tokyo), 2015, 63(6), 408-417.
[http://dx.doi.org/10.1248/cpb.c14-00326] [PMID: 26027464]
[23]
Hu, L.; Zhang, H.; Song, W.; Gu, D.; Hu, Q. Investigation of inclusion complex of cilnidipine with hydroxypropyl-β-cyclodextrin. Carbohydr. Polym., 2012, 90(4), 1719-1724.
[http://dx.doi.org/10.1016/j.carbpol.2012.07.057] [PMID: 22944438]
[24]
Agarwal, V.; Bajpai, M. Investigation of formulation and process parameters for the production of esomeprazole nanosuspension by anti solventprecipitation ultrasonication technique. Curr. Nanosci., 2013, 9(6), 773-779.
[http://dx.doi.org/10.2174/15734137113099990079]
[25]
Agarwal, V.; Bajpai, M. Preparation and optimization of esomeprazole nanosuspension using evaporative precipitation-ultrasonication. Trop. J. Pharm. Res., 2014, 13(4), 497-503.
[http://dx.doi.org/10.4314/tjpr.v13i4.2]
[26]
Agarwal, V.; Bajpai, M. Design, fabrication and characterization of esomeprazole nanocrystals for enhancing the dissolution rate and stability. Recent Pat. Nanotechnol., 2021, 15(2), 165-179.
[http://dx.doi.org/10.2174/1872210514666201016150915] [PMID: 33069204]
[27]
Shen, S.; Wu, Y.; Liu, Y.; Wu, D. High drug-loading nanomedicines: Progress, current status, and prospects. Int. J. Nanomedicine, 2017, 12(12), 4085-4109.
[http://dx.doi.org/10.2147/IJN.S132780] [PMID: 28615938]
[28]
Liu, Y.; Yang, G.; Jin, S.; Xu, L.; Zhao, C.X. Development of high‐drug‐loading nanoparticles. ChemPlusChem, 2020, 85(9), 2143-2157.
[http://dx.doi.org/10.1002/cplu.202000496] [PMID: 32864902]

Rights & Permissions Print Export Cite as
© 2024 Bentham Science Publishers | Privacy Policy