Development, optimization and characterization of zaltoprofen-loaded bilosomes using response surface methodology

Aymen Al-Shaybani; Fatima J Jawad

doi:10.12991/jrespharm.1796232

Development, optimization and characterization of zaltoprofen-loaded bilosomes using response surface methodology

Abstract

This study aims to generate and optimize Zaltoprofen-loaded bilosomes for improved transdermal delivery, utilizing a Box-Behnken design to evaluate the influence of formulation factors on bilosome characteristics. Bilosomes were produced utilizing a blend of Span 60 and various amounts of Tween 60., Cholesterol, and Sodium Deoxycholate. The impact of these formulation variables was assessed on entrapment efficiency, vesicle size, polydispersity index, and zeta potential. The morphology and surface characteristics of the bilosomes were analyzed using Transmission Electron Microscopy and Scanning Electron Microscopy. The improved formulations underwent invitro drug release and permeation experiments to evaluate their efficacy. The results of the present study showed that the optimized bilosomal formulation (F3) demonstrated an entrapment efficiency of 89.38%, a vesicle size of 227.252 nm, polydispersity index of 0.2714, and zeta potential of -29.841 mV. The values of the formulation variables for F3 were 15 mg Sodium Deoxycholate, 37.5 mg Cholesterol, and 100 mg tween 60. Transmission Electron Microscopy and Scanning Electron Microscopy analyses confirmed the spherical shape and uniform surface morphology of the bilosomes. In-vitro drug release studies showed sustained release over 480 minutes, with a maximum release of 96.63%. In-vitro permeation studies indicated a 43.924-fold increase in permeation compared to the Zaltoprofen dispersion. In conclusion, the findings of this study demonstrate that Zaltoprofen-loaded bilosomes significantly enhance drug permeation and stability compared to Zaltoprofen dispersions. The optimized formulation exhibited improved drug stability, enhanced permeation, and sustained release, offering a viable alternative to conventional oral and injectable drug administration routes.

Keywords

References

[1] Yoo S, Kim J, Jeong ET, Hwang SJ, Kang NG, Lee J. Penetration rates into the stratum corneum layer: A novel quantitative indicator for assessing skin barrier function. Skin Res Technol. 2024;30(3):e13655. https://doi.org/10.1111/srt.13655.
[2] Salih OS, Al-Akkam EJ. Preparation, In vitro, and Ex vivo Evaluation of Ondansetron Loaded Invasomes for Transdermal Delivery. Iraqi J Pharm Sci. 2023;32:71–84. https://doi.org/10.31351/vol32iss3pp71-84.
[3] Jaiswal D, Jain DrP. Recent Updates and Advancement of Transdermal Drug Delivery System. Int J Sci Res Sci Eng Technol. 2023:634–642. https://doi.org/10.32628/ijsrset23103176.
[4] Abdulbaqi MR, Rajab NA. Preparation, characterization and ex vivo permeability study of transdermal apixaban O/W nanoemulsion based gel. Iraqi J Pharm Sci. 2021;29:214–222. https://doi.org/10.31351/vol29iss2pp214-222.
[5] Guy RH. Transdermal drug delivery. Handb Exp Pharmacol. 2010;197:399–410. https://doi.org/10.1007/978-3-642-00477-3_13.
[6] Limongi T, Susa F, Marini M, Allione M, Torre B, Pisano R, di Fabrizio E. Lipid-Based Nanovesicular Drug Delivery Systems. Nanomaterials (Basel). 2021;11(12):3391. https://doi.org/10.3390/nano11123391.
[7] Akhtar N, Singh V, Yusuf M, Khan RA. Non-invasive drug delivery technology: development and current status of transdermal drug delivery devices, techniques and biomedical applications. Biomed Tech (Berl). 2020;65(3):243-272. https://doi.org/10.1515/bmt-2019-0019.
[8] Alhasso B, Ghori MU, Conway BR. Systematic Review on the Effectiveness of Essential and Carrier Oils as Skin Penetration Enhancers in Pharmaceutical Formulations. Sci Pharm. 2022;90(1):14. https://doi.org/10.3390/scipharm90010014.

[9] Ali SK, Al-Akkam EJ. Bilosomes as Soft Nanovesicular Carriers for Ropinirole Hydrochloride: Preparation and In- vitro Characterization. Iraqi J Pharm Sci. 2023:32:177–187. https://doi.org/10.31351/vol32issSuppl.pp177-187.
[10] Conacher M, Alexander J, Brewer JM. Oral immunisation with peptide and protein antigens by formulation in lipid vesicles incorporating bile salts (bilosomes). Vaccine. 2001;19(20-22):2965-2974.
[11] Al-Mahallawi AM, Abdelbary AA, Aburahma MH. Investigating the potential of employing bilosomes as a novel vesicular carrier for transdermal delivery of tenoxicam. Int J Pharm. 2015;485:329–340. https://doi.org/10.1016/j.ijpharm.2015.03.033.
[12] Sohail R, Mathew M, Patel KK, Reddy SA, Haider Z, Naria M, Habib A, Abdin ZU, Razzaq Chaudhry W, Akbar A. Effects of Non-steroidal Anti-inflammatory Drugs (NSAIDs) and Gastroprotective NSAIDs on the Gastrointestinal Tract: A Narrative Review. Cureus. 2023;15(4):e37080. https://doi.org/10.7759/cureus.37080
[13] Vonkeman HE, van de Laar MA. Nonsteroidal anti-inflammatory drugs: adverse effects and their prevention. Semin Arthritis Rheum. 2010;39(4):294-312. https://doi.org/10.1016/j.semarthrit.2008.08.001.
[14] Vane JR. Inhibition of Prostaglandin Synthesis as a Mechanism of Action for Aspirin-like Drugs. Nat New Biol. 1971;231:232–235. https://doi.org/10.1038/newbio231232a0.
[15] Chaiamnuay S, Allison JJ, Curtis JR. Risks versus benefits of cyclooxygenase-2-selective nonsteroidal antiinflammatory drugs. Am J Health Syst Pharm. 2006;63(19):1837-1851. https://doi.org/10.2146/ajhp050519.
[16] Hirate K, Uchida A, Ogawa Y, Arai T, Yoda K. Zaltoprofen, a non-steroidal anti-inflammatory drug, inhibits bradykinin-induced pain responses without blocking bradykinin receptors. Neurosci Res. 2006;54:288–294. https://doi.org/10.1016/j.neures.2005.12.016.
[17] Bindu S, Mazumder S, Bandyopadhyay U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective. Biochem Pharmacol. 2020;180:114147. https://doi.org/10.1016/j.bcp.2020.114147.
[18] Simon LS. Role and regulation of cyclooxygenase-2 during inflammation. Am J Med. 1999;106(5B):37S-42S. https://doi.org/10.1016/s0002-9343(99)00115-1
[19] Liu B, Linley JE, Du X, Zhang X, Ooi L, Zhang H, Gamper N. The acute nociceptive signals induced by bradykinin in rat sensory neurons are mediated by inhibition of M-type K+ channels and activation of Ca2+-activated Cl- channels. J Clin Invest. 2010;120:1240–1252. https://doi.org/10.1172/JCI41084.
[20] Pham TMA, Lee DH, Na YG, Jin M, Jung M, Kim HE, Yoo H, Won JH, Lee JY, Baek JS, Han SC, Lee HK, Cho CW. Enhancement of S(+)-zaltoprofen oral bioavailability using nanostructured lipid carrier system. Arch Pharm Res. 2022;45:822–835. https://doi.org/10.1007/s12272-022-01413-2.
[21] Muruganantham S, Krishnaswami V, Kandasamy R, Alagarsamy S. Potentiating the solubility of BCS class II drug zaltoprofen using nanodispersion technology. J Dispers Sci Technol. 2024;45:632–641. https://doi.org/10.1080/01932691.2023.2173224.
[22] Padihar B, Biswal B. Design, development and evaluation of zaltoprofen sustained release tablet. J Chem Pharm Res 2013;5(11):464–473.
[23] Mishra R, Prabhavalkar KS, Bhatt LK. Preparation, optimization, and evaluation of Zaltoprofen-loaded microemulsion and microemulsion-based gel for transdermal delivery. J Liposome Res. 2016;26:297–306. https://doi.org/10.3109/08982104.2015.1120746.
[24] Baek JS, Lim JH, Kang JS, Shin SC, Jung SH, Cho CW. Enhanced transdermal drug delivery of zaltoprofen using a novel formulation. Int J Pharm. 2013;453:358–362. https://doi.org/10.1016/j.ijpharm.2013.05.059.
[25] Alam P, Siddiqui NA, Rehman MT, Hussain A, Akhtar A, Mir SR, Alajmi MF. Box-Behnken Design (BBD)-Based Optimization of Microwave-Assisted Extraction of Parthenolide from the Stems of Tarconanthus camphoratus and Cytotoxic Analysis. Molecules. 2021;26(7):1876. https://doi.org/10.3390/molecules26071876.
[26] Naji GH, Al Gawhari FJ. Evaluation of types and concentration of bile salts impact on physical properties of nisoldipine-loaded bilosomes. Pharmacia. 2024;71:1–7. https://doi.org/10.3897/pharmacia.71.e116917.
[27] Hadi H, Hussein A. Effect of Addition a Sodium Deoxycholate as an Edge Activator -for Preparation of Ondansetron HCl Tansfersomal Dispersion. Al Mustansiriyah J Pharm Sci. 2023;23:429–442. https://doi.org/10.32947/ajps.v23i4.1097.
[28] Ismail A, Teiama M, Magdy B, Sakran W. Development of a Novel Bilosomal System for Improved Oral Bioavailability of Sertraline Hydrochloride: Formulation Design, In Vitro Characterization, and Ex Vivo and In Vivo Studies. AAPS PharmSciTech. 2022;23(6):188. https://doi.org/10.1208/s12249-022-02339-0.
[29] Nasr M, Mansour S, Mortada ND, Elshamy AA. Vesicular aceclofenac systems: A comparative study between liposomes and niosomes. J Microencapsul. 2008;25:499–512. https://doi.org/10.1080/02652040802055411.
[30] Junyaprasert VB, Singhsa P, Suksiriworapong J, Chantasart D. Physicochemical properties and skin permeation of Span 60/Tween 60 niosomes of ellagic acid. Int J Pharm. 2012;423:303–311. https://doi.org/10.1016/j.ijpharm.2011.11.032.
[31] Opatha SAT, Titapiwatanakun V, Chutoprapat R. Transfersomes: A promising nanoencapsulation technique for transdermal drug delivery. Pharmaceutics. 2020;12:1–23. https://doi.org/10.3390/pharmaceutics12090855.
[32] Choi S, Kang B, Yang E, Kim K, Kwak MK, Chang PS, Jung HS. Precise control of liposome size using characteristic time depends on solvent type and membrane properties. Sci Rep. 2023;13(1):4728. https://doi.org/10.1038/s41598-023-31895-z.
[33] Al-Edhari GH, Al Gawhari FJ. Study the Effect of Formulation Variables on Preparation of Nisoldipine Loaded Nano Bilosomes. Iraqi J Pharm Sci. 2023;32:271–282. https://doi.org/10.31351/vol32issSuppl.pp271-282.
[34] Jovanović AA, Balanč BD, Ota A, Ahlin Grabnar P, Djordjević VB, Šavikin KP, Bugarski BM, Nedović VA, Poklar Ulrih N. Comparative Effects of Cholesterol and β-Sitosterol on the Liposome Membrane Characteristics. Eur J Lipid Sci Technol. 2018;120:201800039. https://doi.org/10.1002/ejlt.201800039.
[35] Khan I, Needham R, Yousaf S, Houacine C, Islam Y, Bnyan R, Sadozai SK, Elrayess MA, Elhissi A. Impact of phospholipids, surfactants and cholesterol selection on the performance of transfersomes vesicles using medical nebulizers for pulmonary drug delivery. J Drug Deliv Sci Technol. 2021;66:102822. https://doi.org/10.1016/j.jddst.2021.102822.
[36] Rizwanullah ZS, Rizwanullah M, Mir SR, Amin S. Bilosomes nanocarriers for improved oral bioavailability of acyclovir: A complete characterization through in vitro, ex-vivo and in vivo assessment. J Drug Deliv Sci Technol. 2020;57. https://doi.org/10.1016/j.jddst.2020.101634.
[37] Ahmed S, Kassem MA, Sayed S. Bilosomes as promising nanovesicular carriers for improved transdermal delivery: Construction, in vitro optimization, ex vivo permeation and in vivo evaluation. Int J Nanomedicine. 2020;15:9783–9798. https://doi.org/10.2147/IJN.S278688.
[38] Ali SK, Al-Akkam EJ. Effects of Different Types of Bile Salts on the Physical Properties of Ropinirole-Loaded Bilosomes. Al-Rafidain J Med Sci. 2023;5:134–142. https://doi.org/10.54133/ajms.v5i.176.
[39] Derringer G, Suich R. Simultaneous Optimization of Several Response Variables. J Qual Technol. 1980;12:214–219. https://doi.org/10.1080/00224065.1980.11980968.
[40] Zafar A, Alruwaili NK, Imam SS, Alsaidan OA, Yasir M, Ghoneim MM, Alshehri S, Anwer MK, Almurshedi AS, Alanazi AS. Development and evaluation of luteolin loaded pegylated bilosome: optimization, in vitro characterization, and cytotoxicity study. Drug Deliv. 2021;28:2562–2573. https://doi.org/10.1080/10717544.2021.2008055.
[41] Enright EF, Griffin BT, Gahan CGM, Joyce SA. Microbiome-mediated bile acid modification: Role in intestinal drug absorption and metabolism. Pharmacol Res. 2018;133:170–186. https://doi.org/10.1016/j.phrs.2018.04.009.
[42] Elebyary TT, Sultan A, El-Sayed Abu-Risha S, El Maghraby G. Effect of formulation variables on drug release from bilosomes; effect of cholesterol concentration. J Adv Med Pharm. 2024;0:56–59. https://doi.org/10.21608/jampr.2024.290747.1073.
[43] Akartas I, Ates A. Design of Azithromycin Loaded Eudragit Rl 100 Nanoparticles With Extended Antibacterial Effect. Farmacia. 2023;71:345–358. https://doi.org/10.31925/farmacia.2023.2.15.
[44] Pasquali RC, Taurozzi MP, Bregni C. Some considerations about the hydrophilic-lipophilic balance system. Int J Pharm. 2008;356:44–51. https://doi.org/10.1016/j.ijpharm.2007.12.034.
[45] Noor AD, Rajab NA. Formulation and characterization of niosomes for controlled delivery of tolmetin. J Pharm Negat Results. 2022;13:159–169. https://doi.org/10.47750/pnr.2022.13.04.021.
[46] Al-Sarraf MA, Hussein AA, Al-Kinani KK. Formulation, Characterization, and Optimization of Zaltoprofen Nanostructured Lipid Carriers (NLCs). Int J Drug Deliv Technol. 2021;11:434–442. https://doi.org/10.25258/ijddt.11.2.35.
[47] Rao MT, Rao YS, Vijaya Ratna J, Kamala Kumari P V. Characterization and Ex vivo Studies of Nanoparticle Incorporated Transdermal Patch of Itraconazole. Indian J Pharm Sci. 2020;82:809–818. https://doi.org/10.36468/PHARMACEUTICAL-SCIENCES.708.

Details

Primary Language

English

Subjects

Pharmacology and Pharmaceutical Sciences (Other)

Journal Section

Research Article

Authors

Aymen Al-Shaybani
0009-0007-3214-5422
Iraq

Fatima J Jawad ^* This is me
0000-0002-4906-6241
Iraq

Publication Date

November 2, 2025

Submission Date

October 9, 2024

Acceptance Date

November 23, 2024

Published in Issue

Year 2025 Volume: 29 Number: 6

DOI

https://doi.org/10.12991/jrespharm.1796232

IZ

https://izlik.org/JA56LM67KY

Cite

RIS / Bibtex

APA

Al-Shaybani, A., & J Jawad, F. (2025). Development, optimization and characterization of zaltoprofen-loaded bilosomes using response surface methodology. Journal of Research in Pharmacy, 29(6), 2253-2266. https://doi.org/10.12991/jrespharm.1796232

AMA

1.Al-Shaybani A, J Jawad F. Development, optimization and characterization of zaltoprofen-loaded bilosomes using response surface methodology. J. Res. Pharm. 2025;29(6):2253-2266. doi:10.12991/jrespharm.1796232

Chicago

Al-Shaybani, Aymen, and Fatima J Jawad. 2025. “Development, Optimization and Characterization of Zaltoprofen-Loaded Bilosomes Using Response Surface Methodology”. Journal of Research in Pharmacy 29 (6): 2253-66. https://doi.org/10.12991/jrespharm.1796232.

EndNote

Al-Shaybani A, J Jawad F (November 1, 2025) Development, optimization and characterization of zaltoprofen-loaded bilosomes using response surface methodology. Journal of Research in Pharmacy 29 6 2253–2266.

IEEE

[1]A. Al-Shaybani and F. J Jawad, “Development, optimization and characterization of zaltoprofen-loaded bilosomes using response surface methodology”, J. Res. Pharm., vol. 29, no. 6, pp. 2253–2266, Nov. 2025, doi: 10.12991/jrespharm.1796232.

ISNAD

Al-Shaybani, Aymen - J Jawad, Fatima. “Development, Optimization and Characterization of Zaltoprofen-Loaded Bilosomes Using Response Surface Methodology”. Journal of Research in Pharmacy 29/6 (November 1, 2025): 2253-2266. https://doi.org/10.12991/jrespharm.1796232.

JAMA

1.Al-Shaybani A, J Jawad F. Development, optimization and characterization of zaltoprofen-loaded bilosomes using response surface methodology. J. Res. Pharm. 2025;29:2253–2266.

MLA

Al-Shaybani, Aymen, and Fatima J Jawad. “Development, Optimization and Characterization of Zaltoprofen-Loaded Bilosomes Using Response Surface Methodology”. Journal of Research in Pharmacy, vol. 29, no. 6, Nov. 2025, pp. 2253-66, doi:10.12991/jrespharm.1796232.

Vancouver

1.Aymen Al-Shaybani, Fatima J Jawad. Development, optimization and characterization of zaltoprofen-loaded bilosomes using response surface methodology. J. Res. Pharm. 2025 Nov. 1;29(6):2253-66. doi:10.12991/jrespharm.1796232