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Current Drug Therapy

Author(s): Mohammad Mehdi Mahboobian*, Negin Azadi and Shabnam Pourmoslemi

DOI: 10.2174/1574885518666230804120659

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Preparation of Ketoconazole-loaded Nanoemulsions for Ophthalmic Delivery: Characterization and In-vitro Antifungal Activity Evaluation

Page: [327 - 335] Pages: 9

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Abstract

Background: Nanoemulsions (N.E.s) capable of ocular bioavailability elevation can be used for poor water-soluble drugs such as ketoconazole (K.Z.). The current investigation was designed for the purpose of overcoming this issue by developing K.Z. containing N.E.s for ophthalmic drug delivery with appropriate therapeutic efficiency.

Methods: The preparation of ketoconazole N.E.s was performed by the low-energy technique. According to the phase diagram, three stable formulations were selected for more physicochemical analyses, including particle size, polydispersity index, pH, refractive index and viscosity. Finally, drug release patterns and in-vitro antifungal activity were assessed for the final selected formulation.

Results: The developed N.E. formulations with droplet sizes less than 20 nm showed appropriate physicochemical characteristics for ocular delivery. The selected formulation released 100% of the encapsulated drug during 24 h. Moreover, antifungal assessments showed that prepared N.E. had acceptable in-vitro antifungal activity.

Conclusions: Based on our findings, it can be concluded that N.E.s could be applied as effective carriers for the ophthalmic delivery of ketoconazole.

Graphical Abstract

[1]
Khiev D, Mohamed ZA, Vichare R, et al. Emerging nano-formulations and nanomedicines applications for ocular drug delivery. Nanomaterials 2021; 11(1): 173.
[http://dx.doi.org/10.3390/nano11010173] [PMID: 33445545]
[2]
Pandey M, Choudhury H, Abdul-Aziz A, et al. Advancement on sustained antiviral ocular drug delivery for herpes simplex virus keratitis: Recent update on potential investigation. Pharmaceutics 2020; 13(1): 1.
[http://dx.doi.org/10.3390/pharmaceutics13010001] [PMID: 33374925]
[3]
Jumelle C, Gholizadeh S, Annabi N, Dana R. Advances and limitations of drug delivery systems formulated as eye drops. J Control Release 2020; 321: 1-22.
[http://dx.doi.org/10.1016/j.jconrel.2020.01.057] [PMID: 32027938]
[4]
de Oliveira IF, Barbosa EJ, Peters MCC, et al. Cutting-edge advances in therapy for the posterior segment of the eye: Solid lipid nanoparticles and nanostructured lipid carriers. Int J Pharm 2020; 589: 119831.
[http://dx.doi.org/10.1016/j.ijpharm.2020.119831] [PMID: 32877729]
[5]
Occhiutto ML, Maranhão RC, Costa VP, Konstas AG. Nanotechnology for medical and surgical glaucoma therapy—a review. Adv Ther 2020; 37(1): 155-99.
[http://dx.doi.org/10.1007/s12325-019-01163-6] [PMID: 31823205]
[6]
Dhahir RK, Al-Nima AM, Fadia AB. Nanoemulsion as ophthalmic drug delivery systems. Turk J Pharm Sci 2021; 18(5): 652-64.
[http://dx.doi.org/10.18231/j.ijpp.2020.029]
[7]
Brunella G, Ylenia Z, Bernkop-Schnürch A. Strategies to prolong the residence time of drug delivery systems on ocular surface. Adv Colloid Interface Sci 2020; 288: 102342.
[http://dx.doi.org/10.1016/j.cis.2020.102342]
[8]
Halnor VV, Pande VV, Borawake DD, Nagare HS. Nanoemulsion: A novel platform for drug delivery system. J Mat Sci Nanotechol 2018; 6(1): 104.
[9]
Weng Y, Liu J, Jin S, Guo W, Liang X, Hu Z. Nanotechnology-based strategies for treatment of ocular disease. Acta Pharm Sin B 2017; 7(3): 281-91.
[http://dx.doi.org/10.1016/j.apsb.2016.09.001] [PMID: 28540165]
[10]
Terreni E, Zucchetti E, Tampucci S, Burgalassi S, Monti D, Chetoni P. Combination of nanomicellar technology and in situ gelling polymer as ocular drug delivery system (ODDS) for cyclosporine-A. Pharmaceutics 2021; 13(2): 192.
[http://dx.doi.org/10.3390/pharmaceutics13020192] [PMID: 33535607]
[11]
Terreni E, Chetoni P, Burgalassi S, et al. A hybrid ocular delivery system of cyclosporine-A comprising nanomicelle-laden polymeric inserts with improved efficacy and tolerability. Biomater Sci 2021; 9(24): 8235-48.
[http://dx.doi.org/10.1039/D1BM01453F] [PMID: 34753159]
[12]
Ismail A, Nasr M, Sammour O. Nanoemulsion as a feasible and biocompatible carrier for ocular delivery of travoprost: Improved pharmacokinetic/pharmacodynamic properties. Int J Pharm 2020; 583: 119402.
[http://dx.doi.org/10.1016/j.ijpharm.2020.119402] [PMID: 32387308]
[13]
Bazán Henostroza MA, Curo Melo KJ, Nishitani Yukuyama M, Löbenberg R, Araci Bou-Chacra N. Cationic rifampicin nanoemulsion for the treatment of ocular tuberculosis. Colloids Surf A Physicochem Eng Asp 2020; 597: 124755.
[http://dx.doi.org/10.1016/j.colsurfa.2020.124755]
[14]
Fernandes AR, Sanchez-Lopez E, Santos T, Garcia ML, Silva AM, Souto EB. Development and characterization of nanoemulsions for ophthalmic applications: Role of cationic surfactants. Materials 2021; 14(24): 7541.
[http://dx.doi.org/10.3390/ma14247541] [PMID: 34947136]
[15]
Singh M, Bharadwaj S, Lee KE, Kang SG. Therapeutic nanoemulsions in ophthalmic drug administration: Concept in formulations and characterization techniques for ocular drug delivery. J Control Release 2020; 328: 895-916.
[http://dx.doi.org/10.1016/j.jconrel.2020.10.025] [PMID: 33069743]
[16]
Gawin-Mikołajewicz A, Nartowski KP, Dyba AJ, Gołkowska AM, Malec K, Karolewicz B. Ophthalmic nanoemulsions: From composition to technological processes and quality control. Mol Pharm 2021; 18(10): 3719-40.
[http://dx.doi.org/10.1021/acs.molpharmaceut.1c00650] [PMID: 34533317]
[17]
Ali A, Ansari V, Ahmad U, Akhtar J, Jahan A. Nanoemulsion: An advanced vehicle for efficient drug delivery. Drug Res 2017; 67(11): 617-31.
[http://dx.doi.org/10.1055/s-0043-115124] [PMID: 28738427]
[18]
Singh Y, Meher JG, Raval K, et al. Nanoemulsion: Concepts, development and applications in drug delivery. J Control Release 2017; 252: 28-49.
[http://dx.doi.org/10.1016/j.jconrel.2017.03.008] [PMID: 28279798]
[19]
Dudhipala N, Ay AA. Amelioration of ketoconazole in lipid nanoparticles for enhanced antifungal activity and bioavailability through oral administration for management of fungal infections. Chem Phys Lipids 2020; 232: 104953.
[http://dx.doi.org/10.1016/j.chemphyslip.2020.104953] [PMID: 32814084]
[20]
El-Emam GA, Girgis GNS, El-Sokkary MMA, El-Azeem SOA, Abd El Gawad AEGH. Ocular inserts of voriconazole-loaded proniosomal gels: Formulation, evaluation and microbiological studies. Int J Nanomedicine 2020; 15: 7825-40.
[http://dx.doi.org/10.2147/IJN.S268208] [PMID: 33116503]
[21]
Mohammadi M, Elahimehr Z, Mahboobian MM. Acyclovir-loaded nanoemulsions: Preparation, characterization and irritancy studies for ophthalmic delivery. Curr Eye Res 2021; 46(11): 1646-52.
[http://dx.doi.org/10.1080/02713683.2021.1929328] [PMID: 33979552]
[22]
Kassaee SN, Mahboobian MM. Besifloxacin-loaded ocular nanoemulsions: Design, formulation and efficacy evaluation. Drug Deliv Transl Res 2022; 12(1): 229-39.
[PMID: 33575973]
[23]
Pathak MK, Chhabra G, Pathak K. Design and development of a novel pH triggered nanoemulsified in-situ ophthalmic gel of fluconazole: Ex-vivo transcorneal permeation, corneal toxicity and irritation testing. Drug Dev Ind Pharm 2013; 39(5): 780-90.
[http://dx.doi.org/10.3109/03639045.2012.707203] [PMID: 22873799]
[24]
Dhaval M, Devani J, Parmar R, Soniwala MM, Chavda J. Formulation and optimization of microemulsion based sparfloxacin in-situ gel for ocular delivery: In vitro and ex vivo characterization. J Drug Deliv Sci Technol 2020; 55: 101373.
[http://dx.doi.org/10.1016/j.jddst.2019.101373]
[25]
Tavakoli M, Mahboobian MM, Nouri F, Mohammadi M. Studying the ophthalmic toxicity potential of developed ketoconazole loaded nanoemulsion in situ gel formulation for ophthalmic administration. Toxicol Mech Methods 2021; 31(8): 572-80.
[http://dx.doi.org/10.1080/15376516.2021.1941461] [PMID: 34126859]
[26]
Shafiq S, Shakeel F. Stability and self-nanoemulsification efficiency of ramipril nanoemulsion containing labrasol and plurol oleique. Clin Res Regul Aff 2010; 27(1): 7-12.
[http://dx.doi.org/10.3109/10601330903571691]
[27]
Shafiq S, Shakeel F, Talegaonkar S, Ahmad FJ, Khar RK, Ali M. Development and bioavailability assessment of ramipril nanoemulsion formulation. Eur J Pharm Biopharm 2007; 66(2): 227-43.
[http://dx.doi.org/10.1016/j.ejpb.2006.10.014] [PMID: 17127045]
[28]
Butani D, Yewale C, Misra A. Amphotericin B topical microemulsion: Formulation, characterization and evaluation. Colloids Surf B Biointerfaces 2014; 116: 351-8.
[http://dx.doi.org/10.1016/j.colsurfb.2014.01.014] [PMID: 24521698]
[29]
Chen H, Mou D, Du D, et al. Hydrogel-thickened microemulsion for topical administration of drug molecule at an extremely low concentration. Int J Pharm 2007; 341(1-2): 78-84.
[http://dx.doi.org/10.1016/j.ijpharm.2007.03.052] [PMID: 17570625]
[30]
Djordjevic L, Primorac M, Stupar M. In vitro release of diclofenac diethylamine from caprylocaproyl macrogolglycerides based microemulsions. Int J Pharm 2005; 296(1-2): 73-9.
[http://dx.doi.org/10.1016/j.ijpharm.2005.02.014] [PMID: 15885457]
[31]
Sadozai SK, Khan SA, Baseer A, Ullah R, Zeb A, Schneider M. In vitro, ex vivo, and in vivo evaluation of nanoparticle-based topical formulation against candida albicans infection. Front Pharmacol 2022; 13: 909851.
[http://dx.doi.org/10.3389/fphar.2022.909851]
[32]
Sadozai SK, Khan SA, Karim N, et al. Ketoconazole-loaded PLGA nanoparticles and their synergism against Candida albicans when combined with silver nanoparticles. J Drug Deliv Sci Technol 2020; 56: 101574.
[http://dx.doi.org/10.1016/j.jddst.2020.101574]
[33]
Mahboobian MM, Foroutan SM, Aboofazeli R. Brinzolamide-loaded nanoemulsions: In vitro release evaluation. Iran J Pharm Sci 2016; 12(3): 75-93.
[34]
Handa M, Ujjwal RR, Vasdev N, Flora SJS, Shukla R. Optimization of surfactant-and cosurfactant-aided pine oil nanoemulsions by isothermal low-energy methods for anticholinesterase activity. ACS Omega 2021; 6(1): 559-68.
[http://dx.doi.org/10.1021/acsomega.0c05033] [PMID: 33458508]
[35]
Raval N, Khunt D, Misra M. Microemulsion-based delivery of triamcinolone acetonide to posterior segment of eye using chitosan and butter oil as permeation enhancer: an in vitro and in vivo investigation. J Microencapsul 2018; 35(1): 62-77.
[http://dx.doi.org/10.1080/02652048.2018.1425750] [PMID: 29307286]
[36]
Tayel SA, El-Nabarawi MA, Tadros MI, Abd-Elsalam WH. Promising ion-sensitive in situ ocular nanoemulsion gels of terbinafine hydrochloride: Design, in vitro characterization and in vivo estimation of the ocular irritation and drug pharmacokinetics in the aqueous humor of rabbits. Int J Pharm 2013; 443(1-2): 293-305.
[http://dx.doi.org/10.1016/j.ijpharm.2012.12.049] [PMID: 23333217]
[37]
Shakeel F, Baboota S, Ahuja A, Ali J, Aqil M, Shafiq S. Nanoemulsions as vehicles for transdermal delivery of aceclofenac. AAPS PharmSciTech 2007; 8(4): 191.
[http://dx.doi.org/10.1208/pt0804104] [PMID: 18181525]
[38]
Kumar M, Pathak K, Misra A. Formulation and characterization of nanoemulsion-based drug delivery system of risperidone. Drug Dev Ind Pharm 2009; 35(4): 387-95.
[http://dx.doi.org/10.1080/03639040802363704] [PMID: 19016058]
[39]
Azeem A, Rizwan M, Ahmad FJ, et al. Nanoemulsion components screening and selection: A technical note. AAPS PharmSciTech 2009; 10(1): 69-76.
[http://dx.doi.org/10.1208/s12249-008-9178-x] [PMID: 19148761]
[40]
Fialho SL, da Silva-Cunha A. New vehicle based on a microemulsion for topical ocular administration of dexamethasone. Clin Exp Ophthalmol 2004; 32(6): 626-32.
[http://dx.doi.org/10.1111/j.1442-9071.2004.00914.x] [PMID: 15575833]
[41]
Kesavan K, Pandit JK, Kant S, Muthu MS. Positively charged microemulsions of dexamethasone: Comparative effects of two cosurfactants on ocular drug delivery and bioavailability. Ther Deliv 2013; 4(11): 1385-95.
[http://dx.doi.org/10.4155/tde.13.106] [PMID: 24228989]
[42]
Ammar HO, Salama HA, Ghorab M, Mahmoud AA. Nanoemulsion as a potential ophthalmic delivery system for dorzolamide hydrochloride. AAPS PharmSciTech 2009; 10(3): 808-19.
[http://dx.doi.org/10.1208/s12249-009-9268-4] [PMID: 19536653]
[43]
Zignani M, Tabatabay C, Gurny R. Topical semi-solid drug delivery: Kinetics and tolerance of ophthalmic hydrogels. Adv Drug Deliv Rev 1995; 16(1): 51-60.
[http://dx.doi.org/10.1016/0169-409X(95)00015-Y]
[44]
Solans C, Izquierdo P, Nolla J, Azemar N, Garcia-Celma MJ. Nano-emulsions. Curr Opin Colloid Interface Sci 2005; 10(3-4): 102-10.
[http://dx.doi.org/10.1016/j.cocis.2005.06.004]
[45]
Kumar R, Sinha VR. Preparation and optimization of voriconazole microemulsion for ocular delivery. Colloids Surf B Biointerfaces 2014; 117: 82-8.
[http://dx.doi.org/10.1016/j.colsurfb.2014.02.007] [PMID: 24632034]
[46]
Mahran A, Ismail S, Allam AA. Development of triamcinolone acetonide-loaded microemulsion as a prospective ophthalmic delivery system for treatment of uveitis: In vitro and in vivo evaluation. Pharmaceutics 2021; 13(4): 444.
[http://dx.doi.org/10.3390/pharmaceutics13040444] [PMID: 33805986]
[47]
Moghimipour E, Farsimadan N, Salimi A. Ocular delivery of quercetin using microemulsion system: Design, characterization, and ex-vivo transcorneal permeation. Iran J Pharm Res 2022; 21(1): e127486.
[http://dx.doi.org/10.5812/ijpr-127486] [PMID: 36945341]
[48]
Morais JM, Burgess DJ. In vitro release testing methods for vitamin E nanoemulsions. Int J Pharm 2014; 475(1-2): 393-400.
[http://dx.doi.org/10.1016/j.ijpharm.2014.08.063] [PMID: 25178829]
[49]
Gupta A, Nayak K, Misra M. Cow ghee fortified ocular topical microemulsion; in vitro, ex vivo, and in vivo evaluation. J Microencapsul 2019; 36(7): 603-21.
[http://dx.doi.org/10.1080/02652048.2019.1662121] [PMID: 31500482]
[50]
Youssef AAA, Thakkar R, Senapati S, Joshi PH, Dudhipala N, Majumdar S. Design of topical moxifloxacin mucoadhesive nanoemulsion for the management of ocular bacterial infections. Pharmaceutics 2022; 14(6): 1246.
[http://dx.doi.org/10.3390/pharmaceutics14061246] [PMID: 35745818]
[51]
Sakulku U, Nuchuchua O, Uawongyart N, Puttipipatkhachorn S, Soottitantawat A, Ruktanonchai U. Characterization and mosquito repellent activity of citronella oil nanoemulsion. Int J Pharm 2009; 372(1-2): 105-11.
[http://dx.doi.org/10.1016/j.ijpharm.2008.12.029] [PMID: 19162149]
[52]
Miastkowska M, Sikora E, Ogonowski J, Zielina M, Łudzik A. The kinetic study of isotretinoin release from nanoemulsion. Colloids Surf A Physicochem Eng Asp 2016; 510: 63-8.
[http://dx.doi.org/10.1016/j.colsurfa.2016.07.060]
[53]
Ali HH, Hussein AA. Oral nanoemulsions of candesartan cilexetil: Formulation, characterization and in vitro drug release studies. AAPS Open 2017; 3(1): 4.
[http://dx.doi.org/10.1186/s41120-017-0016-7]
[54]
Üstündağ Okur N, Çağlar EŞ Siafaka PI. Novel ocular drug delivery systems: An update on microemulsions. J Ocul Pharmacol Ther 2020; 36(6): 342-54.
[http://dx.doi.org/10.1089/jop.2019.0135] [PMID: 32255728]
[55]
Suriyaamporn P, Opanasopit P, Rangsimawong W, Ngawhirunpat T. Optimal design of novel microemulsions-based two-layered dissolving microneedles for delivering fluconazole in treatment of fungal eye infection. Pharmaceutics 2022; 14(3): 472.
[http://dx.doi.org/10.3390/pharmaceutics14030472] [PMID: 35335855]
[56]
Youssef AAA, Cai C, Dudhipala N, Majumdar S. Design of topical ocular ciprofloxacin nanoemulsion for the management of bacterial keratitis. Pharmaceuticals 2021; 14(3): 210.
[http://dx.doi.org/10.3390/ph14030210] [PMID: 33802394]