TRANSETHOSOMES AS BREAKTHROUGH TOOL FOR CONTROLLED TRANSDERMAL DELIVERY OF DEXKETOPROFEN TROMETAMOL: DESIGN, FABRICATION, STATISTICAL OPTIMIZATION, IN VITRO, AND EX VIVO CHARACTERIZATION

SARA M. SOLIMAN; KAREEM OMAR RASHWAN; MAHMOUD TEAIMA; BHASKARA R. JASTI; MOHAMED AHMED EL-NABARAWI; KHALED M. ABDEL-HALEEM

doi:10.22159/ijap.2022v14i6.45726

Authors

SARA M. SOLIMAN Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, October 6 University, 6th of October City, Giza https://orcid.org/0000-0003-3143-5894
KAREEM OMAR RASHWAN Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, October 6 University, 6th of October City, Giza https://orcid.org/0000-0002-4072-4949
MAHMOUD TEAIMA Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt https://orcid.org/0000-0002-7565-301X
BHASKARA R. JASTI Department of Pharmaceutics and Medicinal Chemistry, Thomas J. Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, USA https://orcid.org/0000-0002-6893-1237
MOHAMED AHMED EL-NABARAWI Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt https://orcid.org/0000-0003-0070-1969
KHALED M. ABDEL-HALEEM Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, October 6 University, 6th of October City, Giza https://orcid.org/0000-0001-7272-2676

DOI:

https://doi.org/10.22159/ijap.2022v14i6.45726

Keywords:

Transethosomes, Transdermal drug delivery, Dexketoprofen trometamol, Permeation

Abstract

Objective: Transethosomes (TEs) have introduced an emerging avenue of interest in vesicular research for transdermal delivery of drugs and can be a proper delivery system for painkillers like NSAIDS. This study aimed to formulate and characterize the potential of TE to enhance the transdermal transport of Dexketoprofen trometamol (DKT) to achieve controlled pain management compared to DKT solution.

Methods: Factorial design (2³) was adopted to appraise the influence of independent variables, namely, Lipoid S100 and surfactant concentrations and surfactant type (X₃) on the % solubilization efficiency (% SE), vesicle size (VS), and % release efficiency (% RE). Thin film hydration was the preferred approach for preparing TEs where vesicle size, zeta potential, polydispersity index, %SE and %RE were investigated. The optimized formula was nominated and subjected to several studies. For the permeation study, optimum TE was incorporated into carbapol gel base for comparison with DKT solution. Also, an accelerated stability study was assessed for optimized formula.

Results: All the prepared DKT-loaded TEs revealed acceptable VS, PDI, and ZP. The highest %SE (86.08±1.05 %) and lowest %RE (44.62±1.36 %) were observed in case of F1. The optimized formula (F1) displayed VS of 133.2±1.62 nm, PDI of 0.342±0.03 and ZP of-21.6±2.45 mV. F1 revealed enhanced skin permeation of a 2.6-fold increase compared with DKT solution. Moreover, F1 was stable upon storage and a non-significant change (P>0.05) was observed.

Conclusion: DKT was successfully incorporated into vesicle carrier and can signify an alternative option for providing this therapy, bypassing the poor bioavailability and considerable adverse consequences of using the oral route besides improved patient compliance.

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References

Albash R, Abdelbary AA, Refai H, El-Nabarawi MA. Use of transethosomes for enhancing the transdermal delivery of olmesartan medoxomil: in vitro, ex vivo, and in vivo evaluation. Int J Nanomedicine. 2019;14:1953-68. doi: 10.2147/ IJN.S196771, PMID 30936696.

Sivaraman A, Banga AK. Novel in situ forming hydrogel microneedles for transdermal drug delivery. Drug Deliv Transl Res. 2017;7(1):16-26. doi: 10.1007/s13346-016-0328-5, PMID 27562294.

Song H, Wen J, Li H, Meng Y, Zhang Y, Zhang N. Enhanced transdermal permeability and drug deposition of rheumatoid arthritis via sinomenine hydrochloride-loaded antioxidant surface transethosome. Int J Nanomedicine. 2019;14:3177-88. doi: 10.2147/IJN.S188842, PMID 31118630.

Song CK, Balakrishnan P, Shim CK, Chung SJ, Chong S, Kim DD. A novel vesicular carrier, transethosome, for enhanced skin delivery of voriconazole: characterization and in vitro/in vivo evaluation. Colloids Surf B Biointerfaces. 2012;92:299-304. doi: 10.1016/j.colsurfb.2011.12.004, PMID 22205066.

Öztürk AA, Kıyan HT. Treatment of oxidative stress-induced pain and inflammation with dexketoprofen trometamol loaded different molecular weight chitosan nanoparticles: formulation, characterization and anti-inflammatory activity by using in vivo HET-CAM assay. Microvasc Res. 2020;128:103961. doi: 10.1016/j.mvr.2019.103961, PMID 31758946.

Meng S, Chen Z, Yang L, Zhang W, Liu D, Guo J. Enhanced transdermal bioavailability of testosterone propionate via surfactant-modified ethosomes. Int J Nanomedicine. 2013;8:3051-60. doi: 10.2147/IJN.S46748, PMID 23990718.

Chen ZX, Li B, Liu T, Wang X, Zhu Y, Wang L. Evaluation of paeonol-loaded transethosomes as transdermal delivery carriers. Eur J Pharm Sci. 2017;99:240-5. doi: 10.1016/j.ejps.2016.12.026, PMID 28039091.

Azizah N, Sagita E, Iskandarsyah I. In vitro penetration tests of transethosome gel preparations containing capsaicin. Int J App Pharm. 2017;9:116. doi: 10.22159/ijap.2017.v9s1.68_75.

Mishra KK. Withdrawal notice: development of itraconazole-loaded transethosomes for improved transdermal delivery. Recent Pat Nanotechnol. 2021. doi: 10.2174/ 1872210515666211129115811, PMID 34844550.

Al Shuwaili AH, Rasool BK, Abdulrasool AA. Optimization of elastic transfersomes formulations for transdermal delivery of pentoxifylline. Eur J Pharm Biopharm. 2016;102:101-14. doi: 10.1016/j.ejpb.2016.02.013, PMID 26925505.

Ma M, Wang J, Guo F, Lei M, Tan F, Li N. Development of nanovesicular systems for dermal imiquimod delivery: physicochemical characterization and in vitro/in vivo evaluation. J Mater Sci Mater Med. 2015;26(6):191. doi: 10.1007/s10856-015-5524-1, PMID 25989936.

Castillo Henriquez L, Sanabria Espinoza P, Murillo Castillo B, Montes de Oca-Vasquez G, Batista Menezes D, Calvo Guzman B. Topical chitosan-based thermo-responsive scaffold provides dexketoprofen trometamol controlled release for 24 h use. Pharmaceutics. 2021;13(12). doi: 10.3390/pharmaceutics13122100, PMID 34959381.

Ferrara F, Benedusi M, Sguizzato M, Cortesi R, Baldisserotto A, Buzzi R. Ethosomes and transethosomes as cutaneous delivery systems for quercetin: A preliminary study on melanoma cells. Pharmaceutics. 2022;14(5). doi: 10.3390/ pharmaceutics14051038.

Rodriguez Luna A, Talero E, Avila Roman J, Romero AMF, Rabasco AM, Motilva V. Preparation and in vivo evaluation of rosmarinic acid-loaded transethosomes after percutaneous application on a psoriasis animal model. AAPS PharmSciTech. 2021;22(3):103. doi: 10.1208/s12249-021-01966-3, PMID 33712964.

Chen M, Liu X, Fahr A. Skin penetration and deposition of carboxyfluorescein and temoporfin from different lipid vesicular systems: in vitro study with finite and infinite dosage application. Int J Pharm. 2011;408(1-2):223-34. doi: 10.1016/j.ijpharm.2011.02.006, PMID 21316430.

Abd El-Halim SM, Abdelbary GA, Amin MM, Zakaria MY, Shamsel-Din HA, Ibrahim AB. Stabilized oral nanostructured lipid carriers of adefovir dipivoxil as a potential liver targeting: estimation of liver function panel and uptake following intravenous injection of radioiodinated indicator. Daru. 2020;28(2):517-32. doi: 10.1007/s40199-020-00355-8, PMID 32564282.

Das S, Chaudhury A. Recent advances in lipid nanoparticle formulations with solid matrix for oral drug delivery. AAPS PharmSciTech. 2011;12(1):62-76. doi: 10.1208/s12249-010-9563-0, PMID 21174180.

Verma S, Bhardwaj A, Vij M, Bajpai P, Goutam N, Kumar L. Oleic acid vesicles: a new approach for topical delivery of antifungal agent. Artif Cells Nanomed Biotechnol. 2014;42(2):95-101. doi: 10.3109/21691401.2013.794351, PMID 23656670.

Sudhakar K, Mishra V, Jain S, Rompicherla NC, Malviya N, Tambuwala MM. Development and evaluation of the effect of ethanol and surfactant in vesicular carriers on lamivudine permeation through the skin. Int J Pharm. 2021;610:121226. doi: 10.1016/j.ijpharm.2021.121226, PMID 34710540.

Farooq M, Usman F, Zaib S, Shah HS, Jamil QA, Akbar Sheikh F. Fabrication and evaluation of voriconazole loaded Transethosomal gel for enhanced antifungal and antileishmanial activity. Molecules. 2022;27(10). doi: 10.3390/molecules27103347, PMID 35630825.

Garg V, Singh H, Bhatia A, Raza K, Singh SK, Singh B. Systematic development of Transethosomal gel system of piroxicam: formulation optimization, in vitro evaluation, and ex vivo assessment. AAPS PharmSciTech. 2017;18(1):58-71. doi: 10.1208/s12249-016-0489-z, PMID 26868380.

Abdellatif MM, Khalil IA, Khalil MAF. Sertaconazole nitrate loaded nanovesicular systems for targeting skin fungal infection: in vitro, ex-vivo and in vivo evaluation. Int J Pharm. 2017;527(1-2):1-11. doi: 10.1016/j.ijpharm.2017.05.029, PMID 28522423.

ElMeshad AN, Abdel Haleem KM, Abdel Gawad NA, El-Nabarawi MA, Sheta NM. Core in cup ethylmorphine hydrochloride tablet for dual fast and sustained pain relief: formulation, characterization, and pharmacokinetic study. AAPS PharmSciTech. 2020;21(7):244. doi: 10.1208/s12249-020-01759-0, PMID 32856114.

Sheta NM, Boshra SA, Mamdouh MA, Abdel-Haleem KM. Design and optimization of silymarin loaded in lyophilized fast melt tablets to attenuate lung toxicity induced via HgCl2 in rats. Drug Deliv. 2022;29(1):1299-311. doi: 10.1080/10717544.2022.2068696, PMID 35470762.

Teaima HM, Abdel Haleem KM, Osama M, El-Nabarawi MA, M Fayez S. Bi-laminated oral disintegrating film for dual delivery of pitavastatin calcium and lornoxicam: fabrication, characterization and pharmacokinetic study. Int J App Pharm. 2022;14(2):53-60.

Ascenso A, Raposo S, Batista C, Cardoso P, Mendes T, Praça FG. Development, characterization, and skin delivery studies of related ultra deformable vesicles: transfersomes, ethosomes, and transethosomes. Int J Nanomedicine. 2015;10:5837-51. doi: 10.2147/IJN.S86186, PMID 26425085.

Mendes AC, Gorzelanny C, Halter N, Schneider SW, Chronakis IS. Hybrid electrospun chitosan-phospholipids nanofibers for transdermal drug delivery. Int J Pharm. 2016;510(1):48-56. doi: 10.1016/j.ijpharm.2016.06.016, PMID 27286632.

Moolakkadath T, Aqil M, Ahad A, Imam SS, Iqbal B, Sultana Y. Development of transethosomes formulation for dermal fisetin delivery: Box-Behnken design, optimization, in vitro skin penetration, vesicles-skin interaction and dermatokinetic studies. Artif Cells Nanomed Biotechnol. 2018;46(Suppl):755-65. doi: 10.1080/21691401.2018.1469025, PMID 29730964.

Shah H, Nair AB, Shah J, Bharadia P, Al-Dhubiab BE. Proniosomal gel for transdermal delivery of lornoxicam: optimization using factorial design and in vivo evaluation in rats. Daru. 2019;27(1):59-70. doi: 10.1007/s40199-019-00242-x, PMID 30701460.

Teaima M, Abdelmonem R, Adel YA, El-Nabarawi MA, El-Nawawy TM. Transdermal delivery of telmisartan: formulation, in vitro, ex vivo, iontophoretic permeation enhancement and comparative pharmacokinetic study in rats. Drug Des Devel Ther. 2021;15:4603-14. doi: 10.2147/DDDT.S327860, PMID 34785889.

Aboud HM, Ali AA, El-Menshawe SF, Elbary AA. Nanotransfersomes of carvedilol for intranasal delivery: formulation, characterization and in vivo evaluation. Drug Deliv. 2016;23(7):2471-81. doi: 10.3109/10717544. 2015.1013587, PMID 25715807.

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(1-2):329-40. doi: 10.1016/j.ijpharm.2015.03.033, PMID 25796122.

Abdulbaqi IM, Darwis Y, Assi RA, Khan NAK. Transethosomal gels as carriers for the transdermal delivery of colchicine: statistical optimization, characterization, and ex vivo evaluation. Drug Des Devel Ther. 2018;12:795-813. doi: 10.2147/DDDT.S158018, PMID 29670336.

Alhakamy NA, Aldawsari HM, Ali J, Gupta DK, Warsi MH, Bilgrami AL. Brucine-loaded transliposomes nanogel for topical delivery in skin cancer: statistical optimization, in vitro and dermatokinetic evaluation. 3 Biotech. 2021;11(6):288. doi: 10.1007/s13205-021-02841-5, PMID 34109091.

Chen Y, Qiao F, Fan Y, Han Y, Wang Y. Interactions of cationic/anionic mixed surfactant aggregates with phospholipid vesicles and their skin penetration ability. Langmuir. 2017;33(11):2760-9. doi: 10.1021/acs.langmuir. 6b04093, PMID 28013540.

Yeo LK, Olusanya TOB, Chaw CS, Elkordy AA. Brief effect of a small hydrophobic drug (cinnarizine) on the physicochemical characterisation of niosomes produced by thin-film hydration and microfluidic methods. Pharmaceutics. 2018;10(4). doi: 10.3390/pharmaceutics10040185, PMID 30322124.

Miyazawa T, Itaya M, Burdeos GC, Nakagawa K, Miyazawa T. A critical review of the use of surfactant-coated nanoparticles in nanomedicine and food nanotechnology. Int J Nanomedicine. 2021;16:3937-99. doi: 10.2147/IJN.S298606, PMID 34140768.

Bragagni M, Mennini N, Maestrelli F, Cirri M, Mura P. Comparative study of liposomes, transfersomes and ethosomes as carriers for improving topical delivery of celecoxib. Drug Deliv. 2012;19(7):354-61. doi: 10.3109/ 10717544.2012. 724472, PMID 23043648.