Formulation and evaluation of niosomal gel containing apremilast: optimization, in-vitro release and skin permeation studies
DOI:
https://doi.org/10.1590/s2175-97902026e24681Keywords:
Apremilast, Niosomes, Box-Behnken Design, Topical drug delivery, Skin permeationAbstract
The objective of this study was to develop, optimize and evaluate Apremilast niosomes integrated into a topical gel for improved skin permeation. Niosomes were prepared by thin film hydration technique using cholesterol and Poloxamer 188. Niosomes optimization was employed using Box-Behnken Design wherein three variables cholesterol concentration, Poloxamer 188 concentration and stirring speeds were studied on responses entrapment efficiency, particle size, drug release, and release kinetics. The optimized niosomes were further evaluated for zeta potential and surface characterization by transmission electron microscopy. The selected niosomes were loaded into Carbopol based gel and evaluated for appearance, pH, rheology, in vitro drug release and ex vivo skin permeation studies on excised rat dorsal skin. The niosomal formulations by BBD design exhibited entrapment efficiencies ranging from 53.43% to 76.36% and particle sizes from 204 nm to 282 nm. Sustained drug release profiles were observed, with drug release percentages between 60.01% and 99.11% after 10h. Based on the opted design space and experimentation, optimization of niosomes by thin film hydration using BBD was achieved. The optimized niosomes were assessed for particle size (274.7 nm), zeta potential (37.6 mV), entrapment efficiency (68.29%), drug release (88.36% after 10h), transmission electron microscopy (uniform distribution with spherical shape) and drug release kinetics showing Korsmeyer-Peppas (non-fickian) model as best fit for drug release. The niosomal gel was formulated with acceptable characteristics for appearance (uniform gel, without phase separation), pH (6.91), viscosity (1498.7 Pa.s) and drug content (96.5%). Similarly, conventional Apremilast gel was also prepared for drug release and skin permeation comparison. The in vitro release experiments indicated consistent and sustained drug release for 6h with 83.5% drug release compared to conventional gel which showed 3h with 97.1% of drug release. Skin permeation studies showed improved deposition of Apremilast with niosomal gel in the skin (1750µg) compared to the conventional gel formulation (731µg), indicating improved skin permeation and deposition of Apremilast in the skin by niosomal drug delivery. The results emphasize the potential of niosomal gel formulations for enhancing topical delivery of Apremilast. The optimized niosomes loaded into topical gel system improved skin permeation and drug deposition with the layers of the skin. These attributes show the potential to improve drug delivery across the skin for poorly permeable drugs. Future research shall focus on in vivo studies to establish efficacy and safety for therapeutic applications.
Downloads
References
Agarwal K, Das A, Das S, De A. Impact of psoriasis on quality of life. Indian J Dermatol. 2022;67(4):387-91. doi: 10.4103/ijd.ijd_572_22
Alnaim AS, Shah H, Nair AB, Mewada V, Patel S, Jacob S, et al. Qbd-based approach to optimize niosomal gel of levosulpiride for transdermal drug delivery. Gels. 2023;9(3):213. doi:10.3390/gels9030213.
Anwer MK, Mohammad M, Ezzeldin E, Fatima F, Alalaiwe A, Iqbal M. Preparation of sustained release apremilast-loaded PLGA nanoparticles: in vitro characterization and in vivo pharmacokinetic study in rats. Int J Nanomed. 2019;14:1587-95. doi:10.2147/IJN.S195048.
Bhardwaj P, Tripathi P, Gupta R, Pandey S. Niosomes: A review on niosomal research in the last decade. J Drug Deliv Technol. 2020;56:101581. doi: 10.1016/j.jddst.2020.101581.
Bhardwaj P, Tripathi P, Pandey S, Gupta R, Ramchandra Patil P. Cyclosporine and Pentoxifylline laden tailored niosomes for the effective management of psoriasis: In-vitro optimization, Ex-vivo and animal study. Int J Pharm. 2022;626:122143. doi: 10.1016/j.ijpharm.2022.122143.
El-Say KM, Abd-Allah FI, Lila AE, Hassan Ael-S, Kassem AE. Diacerein niosomal gel for topical delivery: development, in vitro and in vivo assessment. J Liposome Res. 2016;26(1):57-68. doi: 10.3109/08982104.2015.1029495.
Gao S, Sui Z, Jiang Q, Jiang Y. Functional evaluation of niosomes utilizing surfactants in nanomedicine applications. Int J Nanomed. 2024;19:10283-305. doi: 10.2147/IJN.S480639.
Gouda R, Baishya H, Qing Z. Application of mathematical models in drug release kinetics of carbidopa and levodopa ER tablets. J Develop Drugs. 2017;6(2):1-8. doi:10.4172/2329-6631.1000171.
Goyal G, Garg T, Malik B, Chauhan G, Rath G, Goyal AK. Development and characterization of niosomal gel for topical delivery of benzoyl peroxide. Drug Deliv. 2015 Dec;22(8):1027-42. doi: 10.3109/10717544.2013.855277.
Gudjonsson JE, Johnston A, Sigmundsdottir H, Valdimarsson H. Immunopathogenic mechanisms in psoriasis. Clin Exp Immunol. 2004;135(1):1-8. doi: 10.1111/j.1365-2249.2004.02310.x.
Keating GM. Apremilast: A review in psoriasis and psoriatic arthritis. Drugs. 2017;77(4):459-72. doi: 10.1007/s40265-017-0709-1.
Kim MH, Kim KT, Sohn SY, Lee JY, Lee CH, Yang H, et al. Formulation and evaluation of Nanostructured Lipid Carriers (NLCs) of 20(S)-Protopanaxadiol (PPD) by Box-Behnken Design. Int J Nanomed. 2019;14:8509-20. doi: 10.2147/IJN.S215835.
Kolahdooz H, Khori V, Erfani-Moghadam V, Livani F, Mohammadi S, Memarian A. in Skin lesions of psoriatic patients: A pilot randomized controlled trial. Life. 2023;13:1076. doi: 10.3390/life13051076.
Krishnaiah YS, Xu X, Rahman Z, Yang Y, Katragadda U, Lionberger R, et al. Development of performance matrix for generic product equivalence of acyclovir topical creams. Int J Pharm. 2014;475(1-2):110-22. doi: 10.1016/j.ijpharm.2014.07.034.
Label of Apremilast Tablet (Otezla®). Available at: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f6b1f516-4972-4d82-bced-113e47b41cc5.
Lebwohl M. The role of salicylic acid in the treatment of psoriasis. Int J Dermatol. 1999;38(1):16-24. doi: 10.1046/j.1365-4362.1999.00500.x.
Madan JR, Khobaragade S, Dua K, Awasthi R. Formulation, optimization, and in vitro evaluation of nanostructured lipid carriers for topical delivery of Apremilast. Dermatol Ther. 2020;33(3):e13370. doi: 10.1111/dth.13370.
Obeid MA, Khadra I, Aljabali AAA, Amawi H, Ferro VA. Characterisation of niosome nanoparticles prepared by microfluidic mixing for drug delivery. Int J Pharm X. 2022;4:100137. doi: 10.1016/j.ijpx.2022.100137.
Pandey SS, Shah KM, Maulvi FA, Desai DT, Gupta AR, Joshi SV, et al. Topical delivery of cyclosporine loaded tailored niosomal nanocarriers for improved skin penetration and deposition in psoriasis: Optimization, ex vivo and animal studies. J Drug Deliv Sci Technol. 2021;63: 102441. doi: 10.1016/j.jddst.2021.102441.
Parmar PK, Bansal AK. Novel nanocrystal-based formulations of apremilast for improved topical delivery. Drug Deliv Transl Res. 2021;11:966–83. doi: 10.1007/s13346-020-00809-1.
Qiu F, Xi L, Chen S, Zhao Y, Wang Z, Zheng Y. Celastrol Niosome Hydrogel Has Anti-Inflammatory Effect on Skin Keratinocytes and Circulation without Systemic Drug Exposure in Psoriasis Mice. Int J Nanomed. 2021;16:6171-82. doi: 10.2147/IJN.S323208.
Rad ME, Egil AC, Ince GO, Yuce M, Zarrabi A. Optimization of curcumin loaded niosomes for drug delivery applications. Coll Surfaces A. 2022;654:129921. doi: 10.1016/J.COLSURFA.2022.129921.
Rahangdale M, Pandey P. Development and Characterization of Apremilast Transethosomal Gel for Transdermal Delivery. Int J Pharm Sci Nanotechnol. 2021;14(3):5508-1. doi: 10.37285/ijpsn.2021.14.3.8.
Rapalli VK, Sharma S, Roy A, Singhvi G. Design and dermatokinetic evaluation of Apremilast loaded nanostructured lipid carriers embedded gel for topical delivery: A potential approach for improved permeation and prolong skin deposition. Colloids Surf B Biointerfaces. 2021;206:111945. doi: 10.1016/j.colsurfb.2021.111945.
Rapalli VK, Singhvi G, Dubey SK, Gupta G, Chellappan DK, Dua K. Emerging landscape in psoriasis management: From topical application to targeting biomolecules. Biomed Pharmacother. 2018;106:707-13. doi: 10.1016/j.biopha.2018.06.136.
Riccardi D, Baldino L, Reverchon E. Liposomes, transfersomes and niosomes: production methods and their applications in the vaccinal field. J Transl Med. 2024;22:339. doi: 10.1186/s12967-024-05160-4.
Salem HF, Kharshoum RM, Abou-Taleb HA, Farouk HO, Zaki RM. Fabrication and appraisal of simvastatin via tailored niosomal nanovesicles for transdermal delivery enhancement: In vitro and in vivo assessment. Pharmaceutics. 2021 Jan 21;13(2):138. doi: 10.3390/pharmaceutics13020138.
Sambhakar S, Paliwal S, Sharma S, Singh B. Formulation of risperidone loaded proniosomes for effective transdermal delivery: an in-vitro and in-vivo study. Bull Fac Pharm Cairo Univ. 2017;55(2):239–47. doi:10.1016/j.bfopcu.2017.09.003.
Sandeep G, Reddy VD, Devireddy SR. Formulation and evaluation of fluconazole pro-niosomal gel for topical Administration. J Appl Pharm Sci. 2014;4(7): 098-104. doi: 10.7324/JAPS.2014.40717.
Schafer P. Apremilast mechanism of action and application to psoriasis and psoriatic arthritis. Biochem Pharmacol. 2012;83(12):1583-90. doi: 10.1016/j.bcp.2012.01.001.
Shah A, Boldhane S, Pawar A, Bothiraja C. Advanced development of a non-ionic surfactant and cholesterol material based niosomal gel formulation for the topical delivery of anti-acne drugs. Mater Adv. 2020;1(6):1763-74. doi:10.1039/d0ma00298d.
Shah P, Goodyear B, Dholaria N, Puri V, Michniak-Kohn B. Nanostructured Non-Ionic Surfactant Carrier-Based Gel for Topical Delivery of Desoximetasone. Int J Mol Sci. 2021;22(4):1535. doi: 10.3390/ijms22041535.
Shetty K, Sherje AP. Nano intervention in topical delivery of corticosteroid for psoriasis and atopic dermatitis-a systematic review. J Mater Sci Mater Med. 2021;32(8):88. doi: 10.1007/s10856-021-06558-y.
Soni S, Baghel K, Soni ML, Kashaw SK, Soni V. Size-dependent effects of niosomes on the penetration of methotrexate in skin layers. Futur J Pharm Sci. 2024;10(48):1-18. doi: 10.1186/s43094-024-00624-2.
Zaid Alkilani A, Hamed R, Abdo H, Swellmeen L, Basheer HA, Wahdan W, Abu Kwiak AD. Formulation and evaluation of azithromycin-loaded niosomal gel: Optimization, in vitro studies, rheological characterization, and cytotoxicity study. ACS Omega. 2022;7(44):39782-93. doi: 10.1021/acsomega.2c03762.
Downloads
Published
Data Availability Statement
All data is available within the article or its supplementary materials.
Issue
Section
License
Copyright (c) 2026 Brazilian Journal of Pharmaceutical Sciences
This work is licensed under a Creative Commons Attribution 4.0 International License.
All content of the journal, except where identified, is licensed under a Creative Commons attribution-type BY.
The on-line journal has open and free access.
