Design and characterisation of colloidal nanocarriers for enhanced skin delivery of etodolac

Abstract

The aim of this work was to develop colloidal nanocarriers for skin delivery of etodolac (ETD), which is a non-steroidal anti-inflammatory drug orally used for the management of acute pain and inflammation, but leads to unfavourable effects on the stomach. The oleic acid and blend of Labrasol/Trancutol P were used as oil phase and surfactant/co-surfactant mixture in the microemulsion formulations, respectively. ETD loaded microemulsions selecting the microemulsion region of pseudo-ternary phase diagrams were prepared, and then the microemulsions were characterised to confirm formation of oil in water microemulsions via optical isotropy, refractive index, droplet size, electrical conductivity, rheological behaviour and morphological analysis. In vitro permeation of ETD through porcine skin was evaluated using Franz diffusion cells for stable ETD loaded microemulsions. ATR-FTIR spectroscopy analysis was performed to elucidate interaction between the microemulsion components and stratum corneum structure on the molecular level. Confocal laser scanning microscopy analysis was further carried out to visualize skin penetration enhancement effect of the microemulsion formulation consisting of a model lipophilic fluorescent marker, Nile Red. The results indicated that the developed microemulsion formulation consisting of oleic acid, Labrasol, Transcutol P and water offer a potential approach to enhance skin delivery of ETD for topical treatment of inflammatory diseases.

Keywords

• Microemulsions
• colloidal nanocarriers
• non-steroidal anti-inflammatory drugs
• etodolac
• skin delivery
• topical treatment

References

1. [1] Lionberger D, Brennan M. Topical Nonsteroidal Anti-Inflammatory Drugs for the Treatment of Pain due to Soft Tissue Injury: Diclofenac Epolamine Topical Patch. J Pain Res. 2010;3:223–233.
2. [2] Okyar A, Özsoy Y, Güngör S. Novel Formulation Approaches for Topical and Transdermal Delivery of Non-Steroidal Anti-Inflammatory Drugs. In: Lemmey A.Editor. Rheumatoid Arthritis– Treatment, Rijeka: IntechOpen; 2012, pp. 25–48.[CrossRef]
3. [3] Varga Z, Sabzwari SRA, Vargova V. Cardiovascular Risk of Nonsteroidal Anti-Inflammatory Drugs: An Under-Recognized Public Health Issue. Cureus. 2017;9(4): i1144.
4. [4] Alomrani AH, Badran MM. Flexosomes for Transdermal Delivery of Meloxicam: Characterization and Anti-Inflammatory Activity. Artif Cells, Nanomedicine, Biotechnol. 2017;45(2):305–312.
5. [5] Brown M, Martin G, Jones S, Akomeah F. Dermal and Transdermal Drug Delivery Systems: Current and Future Prospects. Drug Deliv. 2006;13(3):175–187. [CrossRef]
6. [6] Erdal MS, Güngör S, Özsoy Y. Biopolymers: Dermal and Transdermal Drug Delivery Systems. In: Mishra A.Editor.Encyclopedia of Biomedical Polymers and Polymeric Biomaterials. 1st Edition, New York: Taylor & Francis; 2015, pp. 2606–2019.
7. [7] https://pubchem.ncbi.nlm.nih.gov/compound/Etodolac
8. [8] Benbow T, Campbell J. Microemulsions as Transdermal Drug Delivery Systems for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): A Literature Review. Drug Dev Ind Pharm. 2019;45(12):1849–1855.

9. [9] Sharma AK, Garg A, Goyal A, Rath G. Role of Microemulsions in Advanced Drug Delivery. Artif Cells,Nanomedicine, Biotechnol An Int J. 2016;44(4):1177–1185.
10. [10] Todosijevic M, Savic M, Batinic B, Markovic B, Gašperlin M, Ranpelovic D, et al. Biocompatible Microemulsions of a Model NSAID for Skin Delivery: A Decisive Role of Surfactants in Skin Penetration/Irritation Profiles and Pharmacokinetic Performance. Int J Pharm. 2015;496(2):931–941. [CrossRef]
11. [11] Güngör S, Erdal MS, Güngördük S. Colloidal Carriers in the Topical Treatment of Dermatological Diseases. In: Naik J.Editor. Nano Based Drug Delivery, Zagreb: IAPC publishing; 2015, pp. 391–409.
12. [12] Mahrhauser D, Kählig H, Partyka-Jankowska E, Peterlik H, Binder L, Kwizda K, et al. Investigation of Microemulsion Microstructure and its Impact on Skin Delivery of Flufenamic Acid. Int J Pharm. 2015;490(1-2):292–297.[CrossRef]
13. [13] Sintov A. Transdermal Delivery of Curcumin viaMicroemulsion. Int J Pharm. 2015;481(1-2):97–103, [CrossRef]
14. [14] Goindi S, Kaur R, Kaur R. An Ionic Liquid-in-Water Microemulsion as a Potential Carrier for Topical Delivery of Poorly Water Soluble Drug: Development, Ex-vivo and In-vivo Evaluation. Int J Pharm. 2015;495(2):913–923.[CrossRef]
15. [15] Zhang Y, Zhang K, Wang Z, Hu H, Jing Q, Li Y, et al. Transcutol® P/Cremophor® EL/Ethyl Oleate–Formulated Microemulsion Loaded into Hyaluronic Acid–Based Hydrogel for Improved Transdermal Delivery and Biosafety of Ibuprofen. AAPS PharmSciTech. 2019;21(1):22.[CrossRef]
16. [16] Hoppel M, Juric S, Ettl H, Valenta C. Effect of Monoacyl Phosphatidylcholine Content on the Formation of Microemulsions and Dermal Delivery of Flufenamic Acid. Int J Pharm. 2015;479(1):70–76.[CrossRef]
17. [17] Erdal MS, Ozhan G, Mat MC, Ozsoy Y, Gungor S. Colloidal Nanocarriers for the Enhanced Cutaneous Delivery of Naftifine: Characterization Studies and In-vitro and In-vivo Evaluations. Int J Nanomedicine. 2016;11:1027–1037.[CrossRef]
18. [18] Javadzadeh Y, Adibkia K, Hamishekar H.Transcutol® (Diethylene Glycol Monoethyl Ether): A Potential Penetration Enhancer. In: Dragicevic N, Maibach HI. Editors. Percutaneous Penetration Enhancers Chemical Methods in Penetration Enhancement. Heidelberg: Springer-Verlag. 2015, pp. 195–205.[CrossRef]
19. [19] Rhee YS, Choi JG, Park ES, Chi SC. Transdermal Delivery of Ketoprofen Using Microemulsions. Int J Pharm.2001;228(1-2):161–170.[CrossRef]
20. [20] Lopes LB. Overcoming the Cutaneous Barrier with Microemulsions. Pharmaceutics. 2014;6(1):52–77. [CrossRef]
21. [21] Formariz T, Urban M, Silva Júnior A. Microemulsion and Liquid Crystals as Drug Delivery Systems. Brazilian J Pharm Sci. 2005;41:301–313.
22. [22] Coneac G, Vlaia V, Olariu I, Muţ AM, Anghel DF, Ilie C, et al. Development and Evaluation of New Microemulsion-Based Hydrogel Formulations for Topical Delivery of Fluconazole. AAPS PharmSciTech. 2015;16:889–904.[CrossRef]
23. [23] Hathout R, Woodman T, Mansour S, Mortada N, Geneidi A, Guy R. Microemulsion Formulations for the Transdermal Delivery of Testosteron. Eur J Pharm Sci. 2010;40(3):188–196.[CrossRef]
24. [24] Mahboobian MM, Mohammadi M, Mansouri Z. Development of Thermosensitive In-situ Gel Nanoemulsions for Ocular Delivery of Acyclovir. J Drug Deliv Sci Technol. 2020;55:101400.[CrossRef]
25. [25] Mehta S, Kaur G. Microemulsions: Thermodynamic and Dynamic Properties. In: Tadashi M.Editor.Thermodynamics, In Tech; 2011, pp. 382–409.[CrossRef]
26. [26] Pidaparthi K, Suares D. Comparison of Nanoemulsion and Aqueous Micelle Systems of Paliperidone for Intranasal Delivery. AAPS PharmSciTech. 2017;18:1710–1719.[CrossRef]
27. [27] Ma H, Yu M, Lei M, Tan F, Li N. A Novel Topical Targeting System of Caffeine Microemulsion for Inhibiting UVB-Induced Skin Tumor: Characterization, Optimization, and Evaluation. AAPS PharmSciTech. 2015;16:905–913.[CrossRef]
28. [28] Martindale the Complete Drug Delivery. 34th ed. Londra: 2005.
29. [29] Lou H, Qiu N, Crill C, Helms R, Almoazen H. Development of W/O Microemulsion for Transdermal Delivery of Iodide Ions. AAPS PharmSciTech. 2013;14:168–176.[CrossRef]
30. [30] Patel MR, Patel RB, Parikh JR, Solanki AB, Patel BG. Effect of Formulation Components on the In-vitro Permeation of Microemulsion Drug Delivery System of Fluconazole. AAPS PharmSciTech. 2009;10:917–923.[CrossRef]
31. [31] Goindi S, Arora P, Kumar N, Puri A. Development of Novel Ionic Liquid-Based Microemulsion Formulation for Dermal Delivery of 5-Fluorouracil. AAPS PharmSciTech. 2014;15:810–821.[CrossRef]
32. [32] Chaiyana W, Anuchapreeda S, Leelapornpisid P, Phongpradist R, Viernstein H, Mueller M. Development of Microemulsion Delivery System of Essential Oil from Zingiber cassumunar Roxb. Rhizome for Improvement of Stability and Anti-Inflammatory Activity. AAPS PharmSciTech. 2017;18:1332–1342.[CrossRef]
33. [33] Sousa GD, Kishishita J, Aquino KAS, Presgrave OAF, Leal LB, Santana DP. Biopharmaceutical Assessment and Irritation Potential of Microemulsions and Conventional Systems Containing Oil from Syagrus cearensis for Topical Delivery of Amphotericin B Using Alternative Methods. AAPS PharmSciTech. 2017;18:1833–1842.[CrossRef]
34. [34] Gürbüz A, Özhan G, Güngör S, Erdal MS. Colloidal Carriers of Isotretinoin for Topical Acne Treatment: Skin Uptake, ATR-FTIR and In-vitro Cytotoxicity Studies. Arch Dermatol Res. 2015;307:607–615.[CrossRef]
35. [35] Osborne DW, Musakhanian J. Skin Penetration and Permeation Properties of Transcutol(R)-Neat or Diluted Mixtures. AAPS PharmSciTech. 2018;19:3512–3533.[CrossRef]
36. [36] Carvalho ALM, Silva JA, Lira AAM, Almeida EDP, Nunes R de S, Sarmento VHV, et al. Third-Generation Transdermal Delivery Systems Containing Zidovudine: Effect of the Combination of Different Chemical Enhancers and a Microemulsion System. AAPS PharmSciTech. 2018;19:3219–3227.[CrossRef]
37. [37] Caddeo C, Manconi M, Valenti D, Maccioni AM, Fadda AM, Sinico C. The Role of Labrasol® in the Enhancement of the Cutaneous Bioavailability of Minoxidil in Phospholipid Vesicles. Res J Pharm Technol. 2012;5(12):1563–1569.
38. [38] Hathout RM, Mansour S, Geneidi AS, Mortada ND. Visualization, Dermatopharmacokinetic Analysis and Monitoring the Conformational Effects of a Microemulsion Formulation in the Skin Stratum Corneum. J Colloid Interface Sci. 2011;354(1):124–130.[CrossRef]
39. [39] Rossetti F, Depieri L, Bentley M. Confocal Laser Scanning Microscopy as a Tool for the Investigation of Skin Drug Delivery Systems and Diagnosis of Skin Disorders. In: Lagali N. Editor. Confocal Laser Microscopy - Principles and Applications in Medicine, Biology, and the Food Sciences. Croatia: IntechOpen; 2013, pp. 99–140.[CrossRef]
40. [40] Qurt M, Esentürk İ, Birteksöz Tan S, Erdal MS, Araman A, Güngör S. Voriconazole and Sertaconazole Loaded Colloidal Nano-Carriers for Enhanced Skin Deposition and Improved Topical Fungal Treatment. J Drug Deliv Sci Technol. 2018;48:215–222.[CrossRef]