PREPARATION AND CHARACTERIZATION OF KETOPROFEN MENTHOSOME GEL AS A TOPI-CAL DELIVERY NANOCARRIER: EX VIVO ASSESSMENT
DOI:
https://doi.org/10.22159/ijap.2026v18i2.57045Keywords:
Cholesterol, Ethanol injection, Franz cell, Lipid-based nanocarrier, MentholAbstract
Objective: This study aimed to enhance the transdermal permeation of ketoprofen (KTP) by formulating a menthosomal gel as a vesicular nanocarrier.
Methods: KTP-loaded menthosomes were produced using the ethanol injection-probe sonication method. A mixed-level factorial design was employed to statistically investigate the effects of menthol (X1), Span60® (X2), and soybean lecithin (SL) (X3) as independent variables at different actual levels on the dependent responses, including particle size (PS), polydispersity index (PDI), and entrapment efficiency (%EE). These independent variables generated fifteen experimental runs. Fourier Transform Infrared Spectroscopy (FTIR) analysis confirmed the compatibility between KTP and the excipients. The surface morphology of the menthosome was examined using Field Emission Scanning Electron Microscopy (FESEM). The selected formula was incorporated into a Carbopol 934 gel. Viscosity, pH, drug content (DC), and ex vivo permeation were used to characterize the KTP menthosomal gel.
Results: Among the formulations, K11 showed a PS of 218.4±12 nm, a PDI of 0.14±0.04, a zeta potential (ZP) of −35±2 mV, indicating high stability of the formulation, an EE% of 89.3±1.3%, and a percentage of release of 95.7±0.9% within 6 h. The FESEM images demonstrated that the KTP-loaded menthosomes exhibited a spherical morphology with a uniform distribution. KTP-excipient compatibility was confirmed by FTIR analysis. The best formula was incorporated into a gel based on Carbopol 934, which demonstrated a pH of 6±0.2, meeting the benchmark pH for skin application, and a DC of 98.7±0.8%, which is crucial for ensuring therapeutic efficacy, and an ex vivo permeation rate of 81.2±3.1% over 14 h.
Conclusion: The findings suggest that KTP-loaded menthosomes could be a promising carrier for the transdermal delivery of the hydrophobic drug; by facilitating deeper penetration and sustained delivery, these improvements can be attributed to the synergistic action of menthol with lipid-based nanocarriers. This lipoidal vesicular system effectively enhances therapeutic performance.
References
1. Alkilani AZ, McCrudden MT, Donnelly RF. Transdermal drug delivery: innovative pharmaceutical developments based on disruption of the barrier properties of the stratum corneum. Pharmaceutics. 2015 Oct;7(4):438-70. doi: 10.3390/pharmaceutics7040438, PMID 26506371.
2. Miller MA, Pisani E. The cost of unsafe injections. Bull World Health Organ. 1999;77(10):808-11. PMID 10593028.
3. Callaghan TM, Wilhelm KP. A review of ageing and an examina-tion of clinical methods in the assessment of ageing skin. Part 2: clinical perspectives and clinical methods in the evaluation of ageing skin. Int J Cosmet Sci. 2008 Oct;30(5):323-32. doi: 10.1111/j.1468-2494.2008.00455.x, PMID 18822037.
4. Ahmed IS, Nafadi MM, Fatahalla FA. Formulation of a fast-dissolving ketoprofen tablet using freeze-drying in blisters technique. Drug Dev Ind Pharm. 2006 Apr;32(4):437-42. doi: 10.1080/03639040500528913, PMID 16638681.
5. Abd-Elrahman AA, El Nabarawi MA, Hassan DH, Taha AA. Keto-profen mesoporous silica nanoparticles SBA-15 hard gelatin capsules: preparation and in vitro/in vivo characterization. Drug Deliv. 2016 Nov;23(9):3387-98. doi: 10.1080/10717544.2016.1186251, PMID 27167529.
6. Ferreira LM, Cervi VF, Gehrcke M, Da Silveira EF, Azambuja JH, Braganhol E. Ketoprofen-loaded pomegranate seed oil nanoe-mulsion stabilized by pullulan: selective antiglioma formulation for intravenous administration. Colloids Surf B Biointerfaces. 2015 Jun;130:272-7. doi: 10.1016/j.colsurfb.2015.04.023, PMID 25935266.
7. Bhatia A, Singh B, Raza K, Wadhwa S, Katare OP. Tamoxifen-loaded lecithin organogel (LO) for topical application: develop-ment optimization and characterization. Int J Pharm. 2013 Feb;444(1-2):47-59. doi: 10.1016/j.ijpharm.2013.01.029, PMID 23353077.
8. Solanki AB, Parikh JR, Parikh RH. Formulation and optimization of piroxicam proniosomes by 3-factor, 3-level box-behnken de-sign. AAPS PharmSciTech. 2007;8(4):E86. doi: 10.1208/pt0804086, PMID 18181547.
9. El Zaafarany GM, Awad GA, Holayel SM, Mortada ND. Role of edge activators and surface charge in developing ultradeform-able vesicles with enhanced skin delivery. Int J Pharm. 2010 Sep;397(1-2):164-72. doi: 10.1016/j.ijpharm.2010.06.034, PMID 20599487.
10. Song CK, Balakrishnan P, Shim CK, Chung SJ, Chong S, Kim DD. A novel vesicular carrier transethosome for enhanced skin deliv-ery of voriconazole: characterization and in vitro/in vivo evaluation. Colloids Surf B Biointerfaces. 2012 Apr;92:299-304. doi: 10.1016/j.colsurfb.2011.12.004, PMID 22205066.
11. Nayak D, Tippavajhala VK. A comprehensive review on preparation, evaluation and applications of deformable liposomes. Iran J Pharm Res. 2021;20(1):186-205. doi: 10.22037/ijpr.2020.112878.13997, PMID 34400952.
12. Mitrovic D, Zaklan D, Danic M, Stanimirov B, Stankov K, Al-Salami H. The pharmaceutical and pharmacological potential applications of bilosomes as nanocarriers for drug delivery. Molecules. 2025 Mar;30(5):1181. doi: 10.3390/molecules30051181, PMID 40076403.
13. Shanta Taher SS, Sadeq ZA, Al-Kinani KK, Alwan ZS. Solid lipid nanoparticles as a promising approach for delivery of anticancer agents: review article. Mil Med Sci Lett. 2022;91(3):197-207. doi: 10.31482/mmsl.2021.042.
14. Sforzi J, Palagi L, Aime S. Liposome-based bioassays. Biology (Basel). 2020;9(8):202. doi: 10.3390/biology9080202, PMID 32752243.
15. Al-Sawaf OFB, Jalal F. Novel probe sonication method for the preparation of meloxicam bilosomes for transdermal delivery: part one. J Res Med Dent Sci. 2023;11(6):5–12.
16. Khalifa NE, Nur AO, Osman ZA. Artemether-loaded ethylcellu-lose nanosuspensions: effects of formulation variables, physical stability and drug release profile. Int J Pharm Pharm Sci. 2017 Jun;9(6):90. doi: 10.22159/ijpps.2017v9i6.18321.
17. Gupta V, Joshi NK. Formulation development and evaluation of ketoprofen-loaded transethosomes gel. J Drug Deliv Ther. 2022 Jan;12(1):86-90. doi: 10.22270/jddt.v12i1.5177.
18. De Spiegeleer B, Wattyn E, Slegers G, Van Der Meeren P, Vlaminck K, Van Vooren L. The importance of the cosolvent propylene glycol on the antimicrobial preservative efficacy of a pharmaceutical formulation by DOE-ruggedness testing. Pharm Dev Technol. 2006 Jan;11(3):275-84. doi: 10.1080/10837450600767342, PMID 16895838.
19. Oudah SA, Al-Khedairy EB. Development and characterization of bilastine nanosuspension for enhanced dissolution in orodis-persible films. Open Nano. 2025;21:100230. doi: 10.1016/j.onano.2024.100230.
20. Salih OS, Al-Akkam EJ. Preparation in-vitro and ex-vivo evalua-tion of ondansetron-loaded invasomes for transdermal delivery. IJPS. 2023;32(3):71-84. doi: 10.31351/vol32iss3pp71-84.
21. Modi C, Bharadia P. In vitro and ex-vivo evaluation of transfer-somal gel of methotrexate. Braz J Pharm Sci. 2023;59:e22643. doi: 10.1590/s2175-97902023e22643.
22. Abbas HK, Wais FMH, Abood AN. Preparation and evaluation of ketoprofen nanosuspension using solvent evaporation tech-nique. Iraqi J Pharm Sci. 2017;26(2):41-55. doi: 10.31351/vol26iss2pp41-55.
23. Wannas AN, Abdul-Hasan MT, Mohammed Jawad KKM, Razzaq IF. Preparation and in vitro evaluation of self-nanoemulsifying drug delivery systems of ketoprofen. Int J Appl Pharm. 2023 May;15(3):71-9. doi: 10.22159/ijap.2023v15i3.46892.
24. Oudah MH. Formulation and characterization of ketoprofen nanoparticles as hydrogel dosage form. Kufa J Pharm Sci. 2025;2(1):14-22.
25. Al-Mahmood S, Rajab NA. Effect of unsaturated fatty acids on the topical delivery of caspofungin ufasomes: in vitro/ ex vivo evaluation and anti-fungal study against Candida albicans. OpenNano. 2025 Jul;24:100250. doi: 10.1016/j.onano.2025.100250.
26. Tous S, Fathy MF, Fetih G, Gad SF. Preparation and evaluation of ketoprofen-loaded calcium alginate beads. Int J PharmTech Res. 2014;6(3):1100–12.
27. Silalahi AA, Ramlan Sinaga K, Sumaiyah S. Formulation and evaluation of ketoprofen transdermal matrix patch containing different polymer components. Asian J Pharm Clin Res. 2018 Nov;11(11):316. doi: 10.22159/ajpcr.2018.v11i11.27282.
28. Kadam RD, Gunesh N, Dhembre, Umesh T, Jadhao, Sandip T, Thoke, Dharamraj A, Rathod, Venkatesh, R Kauthekar. Formula-tion and evaluation of a sustained-release matrix tablet of keto-profen. World J Bio Pharm Health Sci. 2024;20(2):295-304. doi: 10.30574/wjbphs.2024.20.2.0875.
29. Rozas R, Ortiz AC, Penaloza S, Lizama S, Flores ME, Morales J. Kinetic and methodological insights into hydrophilic drug re-lease from mesoporous silica nanocarriers. Pharmaceutics. 2025 May;17(6):694. doi: 10.3390/pharmaceutics17060694, PMID 40574007.
30. Muhammed SA, Al-Kinani KK. Formulation and in vitro evalua-tion of meloxicam as a self-microemulsifying drug delivery sys-tem. F1000Res. 2023 May;12:315. doi: 10.12688/f1000research.130749.2, PMID 37359788.
31. Khudhair AS, Sabri LA. Preparation and evaluation of topical hydrogel containing ketoconazole-loaded bilosomes. Acta Pharm Sci. 2024;62(4):762. doi: 10.23893/1307-2080.APS6250.
32. Ali SK, Al-Akkam EJ. Oral nanobilosomes of ropinirole: prepara-tion compatibility and ex-vivo intestinal absorption study. J Adv Pharm Educ Res. 2023;13(4):8-15. doi: 10.51847/B7uaDLOWfq.
33. Kmkm AM, Ghareeb MM. Natural oil nanoemulsion-based gel vehicle for enhancing antifungal effect of topical luliconazole. J Fac Med Baghdad. 2023 Apr;65(1):65-73. doi: 10.32007/jfacmedbagdad.6512058.
34. Kasparaviciene G, Maslii Y, Herbina N, Kazlauskiene D, Marksa M, Bernatoniene J. Development and evaluation of two-phase gel formulations for enhanced delivery of active ingredients: sodium diclofenac and camphor. Pharmaceutics. 2024 Mar;16(3):366. doi: 10.3390/pharmaceutics16030366, PMID 38543261.
35. Ahmed MM, Fatima F, Anwer MK, Ibnouf EO, Kalam MA, Alshamsan A. Formulation and in vitro evaluation of topical nanosponge-based gel containing butenafine for the treatment of fungal skin infection. Saudi Pharm J. 2021 May;29(5):467-77. doi: 10.1016/j.jsps.2021.04.010, PMID 34135673.
36. Gavat CC. Ultraviolet (UV) spectrophotometric analysis of ketoprofen in tablets–statistical validation of proposed method. In: The 4th International Online Conference on Nanomaterials, Basel Switzerland: MDPI; 2023. p. 60. doi: 10.3390/IOCN2023-14442.
37. Hassan M, Sabri LA. Development and evaluation of aceclofenac-loaded nanosponge hydrogel for enhanced topical anti-inflammatory delivery. Int J Appl Pharm. 2025 Mar;17(2):104-14. doi: 10.22159/ijap.2025v17i2.53014.
38. Kar K, Sudheer P. Formulation and evaluation of niosomal drug delivery system of ketoprofen. RGUHS J PharmSci. 2016 Jan;5(4):173-80. doi: 10.5530/rjps.2015.4.7.
39. K Chandur V, TK T, Shabaraya A R. Comparative characterization of gel-loaded ketoprofen nanosponges for topical delivery. Int J Health Sci Res. 2023 Jan;13(1):44-58. doi: 10.52403/ijhsr.20230108.
40. Lombardo D, Kiselev MA. Methods of liposomes preparation: formation and control factors of versatile nanocarriers for bio-medical and nanomedicine application. Pharmaceutics. 2022 Feb;14(3):543. doi: 10.3390/pharmaceutics14030543, PMID 35335920.
41. Nayak D, Shetty MM, Halagali P, Rathnanand M, Gopinathan A, John J. Formulation optimization and evaluation of ibuprofen-loaded menthosomes for transdermal delivery. Int J Pharm. 2024 Nov;665:124671. doi: 10.1016/j.ijpharm.2024.124671, PMID 39245088.
42. Manjushree H, Nayak D, Halagali P, Rathnanand M, Tawale R, Ananthmurthy K. Menthol-based novel ultra-deformable vesicle: formulation optimization and evaluation of an antifungal drug. AAPS PharmSciTech. Jan. 2025;26(1):23. doi: 10.1208/s12249-024-03021-3, PMID 39779535.
43. Gaur PK, Bajpai M, Mishra S, Verma A. Development of ibuprofen nanoliposome for transdermal delivery: physical characterization in vitro/in vivo studies and anti-inflammatory activity. Artif Cells Nanomed Biotechnol. 2016 Jan;44(1):370-5. doi: 10.3109/21691401.2014.953631, PMID 25211229.
44. Kar K, Sudheer P. Formulation and evaluation of niosomal drug delivery system of ketoprofen. RGUHS J PharmSci. 2016 Jan;5(4):173-80. doi: 10.5530/rjps.2015.4.7.
45. Ghanbarzadeh S, Arami S. Enhanced transdermal delivery of diclofenac sodium via conventional liposomes, ethosomes and transfersomes. BioMed Res Int. 2013;2013:616810. doi: 10.1155/2013/616810, PMID 23936825.
46. Das J, Debbarma A, Lalhlenmawia H. Formulation and in vitro evaluation of poly-(D, L-Lactide-CO-Glycolide) (PLGA) nanoparticles of ellagic acid and its effect on human breast cancer MCF-7 cell line. Int J Curr Pharm Sci. 2021;13(5):56-62. doi: 10.22159/ijcpr.2021v13i5.1887.
47. Egla M, Rajab NA. Sericin-based paclitaxel nanoparticles: prepa-ration and physicochemical evaluation. Iraqi J Pharm Sci. 2025 Feb;33((4SI)):169-78. doi: 10.31351/vol33iss(4SI)pp169-178.
48. Elkomy MH, Eid HM, Elmowafy M, Shalaby K, Zafar A, Abdelga-wad MA. Bilosomes as a promising nanoplatform for oral deliv-ery of an alkaloid nutraceutical: improved pharmacokinetic profile and snowballed hypoglycemic effect in diabetic rats. Drug Deliv. 2022 Dec;29(1):2694-704. doi: 10.1080/10717544.2022.2110997, PMID 35975320.
49. Duche G, Sanderson JM. The chemical reactivity of membrane lipids. Chem Rev. 2024;124(6):3284-330. doi: 10.1021/acs.chemrev.3c00608, PMID 38498932.
50. Abdulbaqi IM, Darwis Y, Khan NA, Assi RA, Khan AA. Ethosomal nanocarriers: the impact of constituents and formulation tech-niques on ethosomal properties in vivo studies and clinical trials. Int J Nanomedicine. 2016;11:2279-304. doi: 10.2147/IJN.S105016, PMID 27307730.
51. Park H, Sut TN, Yoon BK, Zhdanov VP, Cho NJ, Jackman JA. Un-raveling how cholesterol affects multivalency-induced mem-brane deformation of sub-100 nm lipid vesicles. Langmuir. 2022 Dec;38(51):15950-9. doi: 10.1021/acs.langmuir.2c02252, PMID 36515977.
52. Mohammed Ali MHM. Preparation and in vitro evaluation of transferosome-based gel of meloxicam. Hilla Univ Coll J Med Sci. 2025 May;3(1):28-35. doi: 10.62445/2958-4515.1047.
53. Budai L, Budai M, Fulopne Papay ZE, Vilimi Z, Antal I. Rheologi-cal considerations of pharmaceutical formulations: focus on viscoelasticity. Gels. 2023 Jun;9(6):469. doi: 10.3390/gels9060469, PMID 37367140.
54. Malik B, Bekir E. Formulation and in vitro /in vivo evaluation of silymarin solid dispersion-based topical gel for wound healing. Iraqi J Pharm Sci. 2023;32 Suppl:42-53. doi: 10.31351/vol32issSuppl.pp42-53.
55. Sarhan F, El Gogary R, Yassin M, Soliman M. Penetration enhan-cer containing vesicles for dermal and transdermal drug deliv-ery a review. Arch Pharm Sci Ain Shams Univ. 2023;7(2):348-75. doi: 10.21608/aps.2023.246357.1141.
56. Watanabe H, Obata Y, Onuki Y, Ishida K, Takayama K. Different effects of l-and d-menthol on the microstructure of ceramide 5/cholesterol/palmitic acid bilayers. Int J Pharm. Dec. 2010;402(1-2):146-52. doi: 10.1016/j.ijpharm.2010.09.038.
57. Chen L, Ma L, Yang S, Wu X, Dai X, Wang S. A multiscale study of the penetration-enhancing mechanism of menthol. J Tradit Chin Med Sci. 2019 Oct;6(4):347-54. doi: 10.1016/j.jtcms.2019.10.001.
Published
How to Cite
Issue
Section
Copyright (c) 2026 SAMARA MOHAMMED JASIM, ABEER H. KHASRAGHI
This work is licensed under a Creative Commons Attribution 4.0 International License.