Preparation and evaluation of levofloxacin microemulsion for ocular drug delivery

Abstract

Levofloxacin is a broad-spectrum antibacterial drug belonging to the third generation of fluoroquinolones. The project aims to develop a novel microemulsion system for effectively delivering levofloxacin to the eye. In addition, this study assessed the physical and chemical characteristics of a substance and its ability to permeate through the eyes of rabbits. The microemulsions (MEs) were evaluated for stability, drug release, viscosity, pH, particle size, and cornea permeability in rabbits. This study employed a three-variable design with two levels to prepare eight samples and ana lyze data. Based on research results, ME formulations had an average size ranging between 8.52 and 25.2 nm and a pH range of 4.45 to 6.01. Content viscosity ranged from 170-400 cps, and based on the drug release curve, 89.49% of the me dicinal product was released within the first day of the trial. Drug sensitivity in rabbit cornea was highest in ME-LEV-5 (50.89%) and lowest in ME-LEV-7 (23.78%). This study demonstrates how the physical properties and permeability of the drug during drug penetration of ME formulations can be modified by changes in the quantity and quantity of ME. This phenomenon may be due to changes in the corneal structure caused by different ME components.

Keywords

• Corneal Permeability
• Microemulsion
• Levofloxacin
• Rabbit
• drug delivery

References

1. [1] Meng T, Kulkarni V, Simmers R, Brar V, Xu Q. Therapeutic implications of nanomedicine for ocular drug delivery. Drug Discov Today. 2019;24(8):1524-1538. https://doi.org/10.1016/j.drudis.2019.05.006. drug delivery
2. [2] Antimisiaris S, Marazioti A, Kannavou M, Natsaridis E, Gkartziou F, Kogkos G, Mourtas S. Overcoming barriers by local with liposomes. https://doi.org/10.1016/j.addr.2021.01.019.
3. [3] Adv Drug Deliv Rev. 2021;174:53-86. Gote V, Sikder S, Sicotte J, Pal D. Ocular drug delivery: Present innovations and future challenges. J Pharmacol Exp Ther. 2019;370(3):602-624. https://doi.org/10.1124/jpet.119.256933.
4. [4] Sakamoto K, Lochhead RY, Maibach HI, Yamashita Y. Cosmetic science and technology: Theoretical principles and applications: Elsevier; 2017.
5. [5] Üstündağ Okur N, Çağlar EŞ, Siafaka PI. Novel ocular drug delivery systems: An update on microemulsions. J Ocul Pharmacol Ther. 2020;36(6):342-354. https://doi.org/10.1089/jop.2019.0135.
6. [6] Mourelatou E, Sarigiannis Y, Petrou C. Ocular Drug Delivery nanoSystems: Recent Developments and Future Challenges. In Drug Delivery Nanosystems: : From Bioinspiration and Biomimetics to Clinical Applications. Pan Stanford Publishing. 2019. p. 93-154
7. [7] Mandavi N, Ansari N, Bharti R, Kader N, Sahu GK, Sharma H. Microemulsion: A Potential novel drug delivery system. Res J Pharm Dosage Form Technol. 2018;10(4):266-271. https://doi.org/10.5958/0975-4377.2018.00039.3.
8. [8] Solanki K, Rathi N, Patani P. Microemulsions: Current trends in novel drug delivery systems. J Pharm Negat Results. 2022:2327-2334. https://doi.org/10.47750/pnr.2022.13.S05.365.

9. [9] Jacob S, Nair AB, Shah J, Gupta S, Boddu SH, Sreeharsha N, Joseph A, Shinu P, Morsy MA. Lipid nanoparticles as a promising drug delivery carrier for topical ocular therapy—An overview on recent advances. Pharmaceutics. 2022;14(3):533. https://doi.org/10.3390/pharmaceutics14030533.
10. [10] Abbasi S, Scanlon MG. Microemulsion: A novel alternative technique for edible oil extraction_a mechanistic viewpoint. Crit Rev Food Sci Nutr. 2022:1-22. https://doi.org/10.1080/10408398.2022.2078786.
11. [11] Chauhan L, Thakur P, Sharma S. Microemulsions: New vista in novel drug delivery system. Innov Pharm Pharmacother. 2019;7(2):37-44. https://doi.org/10.25258/ijddt.v1i2.8838.
12. [12] Castro-Balado A, Mondelo-García C, Zarra-Ferro I, Fernández-Ferreiro A. New ophthalmic drug delivery systems. Farm Hosp. 2020;44(4):149-157. https://doi.org/10.7399/fh.11388.
13. [13] Choradiya BR, Patil SB. A comprehensive review on nanoemulsion as an ophthalmic drug delivery system. J Mol Liq. 2021;339:116751. https://doi.org/10.1016/j.molliq.2021.116751.
14. [14] Yi H, Feng Y, Gappa-Fahlenkamp H. Analysis of topical dosing and administration effects on ocular drug delivery in a human eyeball model using computational fluid dynamics. Comput Biol Med. 2022;141:105016. https://doi.org/10.1016/j.compbiomed.2021.105016.
15. [15] Srinivas SP, Chaiyasan W, Burli A, Guidoboni G, Sacco R, Anand A, Siraj AH, Daima HK, Kompella UB. Transcorneal kinetics of topical drugs and nanoparticles. Ophthalmic Product Development: From Bench to Bedside: Springer; 2022. p. 121-51.
16. [16] German C, Chen Z, Przekwas A, Walenga R, Babiskin A, Zhao L, Fan J,Tan ML. Computational model of in vivo corneal pharmacokinetics and pharmacodynamics of topically administered ophthalmic drug products. AAPS Open. 2023;40(4):961-975. https://doi.org/10.1007/s11095-023-03480-6.
17. [17] Begum G, Leigh T, Courtie E, Moakes R, Butt G, Ahmed Z, Rauz S, Logan A, Blanch RJ. Rapid assessment of ocular drug delivery in a novel ex vivo corneal model. Sci Rep. 2020;10(1):11754. https://doi.org/10.1038/s41598-020 68254-1.
18. [18] Figus M, Posarelli C, Romano D, Nardi M, Rossetti L. Aqueous humour concentrations after topical apPlication of combined levofloxacin-dexamethasone eye dRops and of its single components: a randomised, assessor-blinded, parallel-group study in patients undergoing cataract surgery: The iPERME study. Basic Clin Pharmacol Toxicol. 2020;76:929-937. https://doi.org/10.1007/s00228-020-02863-7
19. [19] Okhrits V, Veliyev E. What is the difference between levofloxacin and ofloxacin. Antibiotic ciprofloxacin: description, indications for use and medicinal properties of the drug. Allergy. https://toreents.ru/en/allergy(accessed June23˛ 2020).
20. [20] Valizadeh A, Shirzad M, Pourmand MR, Farahmandfar M, Sereshti H, Amani A. Levofloxacin nanoemulsion gel has a powerful healing effect on infected wound in streptozotocin-induced diabetic rats. Drug Deliv Transl Res. 2021;11:292-304. https://doi.org/10.1007/s13346-020-00794-5.
21. [21] Iqbal Z, Javaid R, Tahir M, Hasnain S, Abbasi BBK, Shafiq F, Ishaq M. The antibiotic efficacy of levofloxacin tablet was determined utilizing a verification method that included computational and experimental techniques. DFT, UV-VIS, and HPLC-20 AD. Int J Sci Res. http://dx.doi.org/10.29322/IJSRP.12.10.2022.p13079.
22. [22] Zhang J, Michniak-Kohn B. Investigation of microemulsion microstructures and their relationship to transdermal permeation of model drugs: ketoprofen, lidocaine, and caffeine. Int J Pharm. 2011;421(1):34-44. https://doi.org/10.1016/j.ijpharm.2011.09.014.
23. [23] Scioli Montoto S, Muraca G, Ruiz ME. Solid lipid nanoparticles for drug delivery: pharmacological and biopharmaceutical aspects. Front Mol Biosci. 2020;7:319. https://doi.org/10.3389/fmolb.2020.587997. [24] Lingayat VJ, Zarekar NS, Shendge RS. Solid lipid nanoparticles: a review. Sci Rep 2017;4(2):67-72. https://doi.org/10.12691/nnr-4-2-5.
24. [25] Ganesan P, Narayanasamy D. Lipid nanoparticles: Different preparation techniques, characterization, hurdles, and strategies for the production of solid lipid nanoparticles and nanostructured lipid carriers for oral drug delivery. Sustain Chem Pharm. 2017;6:37-56. https://doi.org/10.1016/j.scp.2017.07.002.
25. [26] Ghasemiyeh P, Mohammadi-Samani S. Solid lipid nanoparticles and nanostructured lipid carriers as novel drug delivery systems: Applications, advantages and disadvantages. Res Pharm Sci. 2018;13(4):288-303. https://doi.org/10.4103/1735-5362.235156.
26. [27] Shrotriya S, Ranpise N, Vidhate B. Skin targeting of resveratrol utilizing solid lipid nanoparticle-engrossed gel for chemically induced irritant contact dermatitis. Drug Deliv Transl Res. 2017;7:37-52. https://doi.org/10.1007/s13346-016-0350-7.
27. [28] Rigon RB, Gonçalez ML, Severino P, Alves DA, Santana MH, Souto EB, Chorilli M. Solid lipid nanoparticles optimized by 22 factorial design for skin administration: Cytotoxicity in NIH3T3 fibroblasts. Colloids Surf B Biointerfaces. 2018;171:501-505. https://doi.org/10.1016/j.colsurfb.2018.07.065.
28. [29] Salimi A, Sharif Makhmal Zadeh B, Moghimipour E. Preparation and characterization of cyanocobalamin (Vit B12) microemulsion properties and structure for topical and transdermal application. Iran J Basic Med Sci. 2013;16(7):865.
29. [30] Poh Y, Ng S, Ho K. Formulation and characterisation of 1-ethyl-3-methylimidazolium acetate-in-oil microemulsions as the potential vehicle for drug delivery across the skin barrier. J Mol Liq. 2019;273:339-345. https://doi.org/10.1016/j.molliq.2018.10.034.
30. [31] Khater D, Nsairat H, Odeh F, Saleh M, Jaber A, Alshaer W, Al Bawab A, Mubarak MS. Design, preparation, and characterization of effective dermal and transdermal lipid nanoparticles: A review. Cosmetics. 2021;8(2):39. https://doi.org/10.3390/cosmetics8020039.
31. [32] Zhang J, Froelich A, Michniak-Kohn B. Topical delivery of meloxicam using liposome and microemulsion formulation approaches. Pharmaceutics. 2020;12(3):282. https://doi.org/10.3390/pharmaceutics12030282.
32. [33] Zhang X, Song M, Chai J, Cui X, Wang J. Preparation, characterization and application of a surfactant-free microemulsion containing 1-octen-3-ol, ethanol, and water. J Mol Liq. 2020;300:112278. https://doi.org/10.1016/j.molliq.2019.112278.
33. [34] Sujatha B, Himabindu E, Bttu S, Abbulu K. Microemulsions-A review. J Pharm Sci Res. 2020;12(6):750-753.
34. [35] Nazar MF, Saleem MA, Bajwa SN, Yameen B, Ashfaq M, Zafar MN, Zubair M. Encapsulation of antibiotic levofloxacin in biocompatible microemulsion formulation: Insights from microstructure analysis. J Phys Chem B. 2017;121(2):437-443. https://doi.org/10.1021/acs.jpcb.6b09326.
35. [36] Otake H, Goto R, Ogata F, Isaka T, Kawasaki N, Kobayakawa S, Matsunaga T, Nagai N. Fixed-combination eye drops based on fluorometholone nanoparticles and bromfenac/levofloxacin solution improve drug corneal penetration. Int J Nanomed. 2021:5343-5356. https://doi.org/10.2147/ijn.s317046
36. [37] Imam SS, Bukhari SNA, Ahmad J, Ali A. Formulation and optimization of levofloxacin loaded chitosan nanoparticle for ocular delivery: In-vitro characterization, ocular tolerance and antibacterial activity. Int J Biol Macromol. 2018;108:650-659. https://doi.org/10.1016/j.ijbiomac.2017.11.170.
37. [38] Janagam DR, Wu L, Lowe TL. Nanoparticles for drug delivery to the anterior segment of the eye. Adv Drug Deliv Rev. 2017;122:31-64. https://doi.org/10.1016/j.addr.2017.04.001.
38. [39] Ponte MP, Bianco M, Longhi M, Aloisio C. Study and development of microemulsion formulations to increase the permeability of acyclovir. J Mol Liq. 2022;348:118408. https://doi.org/10.1016/j.molliq.2021.118408.
39. [40] Bhat AR, Wani FA, Behera K, Khan AB, Patel R. Formulation of biocompatible microemulsions for encapsulation of anti-TB drug rifampicin: A physicochemical and spectroscopic study. Colloids Surf A Physicochem Eng Asp. 2022;645:128846. https://doi.org/10.1016/j.colsurfa.2022.128846.
40. [41] Roge AB, Firke SN, Sarje SK, Bhambar KV, Kasliwal A. Formulation, characterization and evaluation of topical biodegradable film loaded with levofloxacin solid-lipid nano carriers. Nat Volatiles Essent Oils. 2021:5608-5619. https://doi.org/10.1208/s12249-021-02189-2.
41. [42] Siddique MY, Alamgir I, Nazar MF, Sumrra SH, Ashfaq M, Safdar M, Khan SUD, Ahmad A, Khan R, Al Swaidan HM, Al-Zaid OS. Structural and probing dynamics of Brij-35-based microemulsion for fluoroquinolone antibiotics. Colloid Polym Sci. 2021;299:1479-1488. https://doi.org/10.1007/s00396-021-04871-0.
42. [43] Hady MA, Sayed OM, Akl MA. Brain uptake and accumulation of new levofloxacin-doxycycline combination through the use of solid lipid nanoparticles: Formulation; Optimization and in-vivo evaluation. Colloids Surf B Biointerfaces. 2020;193:111076. https://doi.org/10.1016/j.colsurfb.2020.111076.
43. [44] Sabry HS, Al-Shohani ADH, Mahmood SZ. Formulation and evaluation of levofloxacin and betamethasone ophthalmic emulgel. J Pharm Bioallied Sci. 2021;13(2):205. https://doi.org/10.4103/jpbs.JPBS_338_20 .
44. [45] Mehanna MM, Mneimneh AT, Abed El Jalil K. Levofloxacin-loaded naturally occurring monoterpene-based nanoemulgel: A feasible efficient system to circumvent MRSA ocular infections. Drug Dev Ind Pharm. 2020;46(11):1787-1799. https://doi.org/10.1080/03639045.2020.1821048 .
45. [46] Arredondo-Ochoa T, Silva-Martínez GA. Microemulsion based nanostructures for drug delivery. Front Nanotechnol. 2022;3:753947. https://doi.org/10.3389/fnano.2021.753947 .
46. [47] Mehta SK, Kaur G. Microemulsions as carriers for therapeutic molecules. Recent Pat Drug Deliv Formul. 2010;4(1):35-48. https://doi.org/10.2174/187221110789957282.
47. [48] Moiseev RV, Morrison PW, Steele F, Khutoryanskiy VV. Penetration enhancers in ocular drug delivery. Pharmaceutics. 2019;11(7):321. https://doi.org/10.3390/pharmaceutics11070321.
48. [49] Moghimipour E, Salimi A, Leis F. Preparation and evaluation of tretinoin microemulsion based on pseudo-ternary phase diagram. Adv Pharm Bull. 2012;2(2):141. https://doi.org/10.5681/apb.2012.022.
49. [50] Infante V, Campos PM, Calixto L, Darvin M, Kröger M, Schanzer S, Lohan SB, Lademann J, Meinke MC. Influence of physical–mechanical properties on SPF in sunscreen formulations on ex vivo and in vivo skin. Int J Pharm. 2021;598:120262. https://doi.org/10.1016/j.ijpharm.2021.120262.
50. [51] Navarro-Pérez YM, Cedeño-Linares E, Norman-Montenegro O, Ruz-Sanjuan V, Mondeja-Rivera Y, Hernández Monzón AM, González-Bedia MM . Prediction of the physical stability and quality of O/W cosmetic emulsions using full factorial design. J Pharm Pharmacogn Res. 2021;9(1):98-112. https://doi.org/10.1007/s00396-021-04871-0.
51. [52] Abdelkader H, Ismail S, Kamal A, Alany RG. Design and evaluation of controlled-release niosomes and discomes for naltrexone hydrochloride ocular delivery. J Pharm Sci. 2011;100(5):1833-1846. https://doi.org/10.1002/jps.22422.
52. [53] Moghimipour E, Salimi A, Saadati Rad A. A microemulsion system for controlled corneal delivery of Timolol. Int J Appl Biol Pharm. 2013;3(4):32-39.