Ocular delivery of ketorolac tromethamine usingmicroemulsion as a vehicle: Design, evaluation, andtranscorneal permeation

Ketorolac is a nonsteroidal anti-inflammatory drug with analgesic properties. Different clinical studies have established the safeness and efficacy of using 0.5% ketorolac formulations for alleviating ocular inflammation and pain. Ketorolac’s eye drops have a short period of action because of its solubility in tear fluids, which resulting to its quick drainage from the eye, meaning that the patient has to administer it frequently. The present study describes the design of an microemulsion vehicle to be used for the ocular delivery of ketorolac. Ketorolac-loaded microemulsion (ME) was supplied using oleic acid-Transcutol P (oily phase), Tween 80, Span 20 (surfactant), and propylene glycol (cosurfactant). The physicochemical properties of the prepared MEs were evaluated according to their viscosities, pH, droplet sizes, surface tension, physical and chemical stability, drug release, and transcorneal rabbit permeation. The drug release profile revealed that 23.65-38.64% of the drug was released during the 24-hour experiment. The maximum permeated drug percentage was observed for ME-K-1 (9.041%). The whole of prepared MEs with various components and properties significantly increased the cornea permeation rate and permeation percentage after 6 hours (%P6h) from the rabbit cornea. The flux and diffusivity coefficient in ME-K-2 formulation were obtained 0.125 mg/cm2/h and 0.0126 cm2/h, which are 3.49 and 6.464 times higher, respectively, then the values for ketorolac drops (KT 0.5%). The MEs developed in the present work were within the range of acceptable droplet sizes for ocular use and possessed physical and chemical stability. Furthermore, the values recorded for the physicochemical parameters support their suitability for ophthalmic use.

PDF

___

[1] Alami-Milani M, Zakeri-Milani P, Valizadeh H, Salehi R, Salatin S, Naderinia A, et al. Novel Pentablock Copolymers as Thermosensitive Self-Assembling Micelles for Ocular Drug Delivery. Adv Pharm Bull. 2017; 7(1): 11-20. [CrossRef]
[2] Shen J, Wang Y, Ping Q, Xiao Y, Huang X. Mucoadhesive effect of thiolated PEG stearate and its modified NLC for ocular drug delivery. J Control Release. 2009; 137(3): 217-223. [CrossRef]
[3] Le Bourlais C, Acar L, Zia H, Sado PA, Needham T, Leverge R. Ophthalmic drug delivery systems—recent advances. Prog Retin Eye Res. 1998; 17(1): 33-58. [CrossRef]
[4] Araújo J, Gonzalez E, Egea MA, Garcia ML, Souto EB. Nanomedicines for ocular NSAIDs: safety on drug delivery. Nanomedicine. 2009; 5(4): 394-401. [CrossRef]
[5] Gao X-C, Qi H-P, Bai J-H, Huang L, Cui H. Effects of oleic acid on the corneal permeability of compounds and evaluation of its ocular irritation of rabbit eyes. Curr Eye Res. 2014; 39(12): 1161-1168. [CrossRef]
[6] Zhang W, Prausnitz MR, Edwards A. Model of transient drug diffusion across cornea. J Control Release. 2004; 99(2): 241-258. [CrossRef]
[7] de la Fuente M, Raviña M, Paolicelli P, Sanchez A, Seijo B, Alonso MJ. Chitosan-based nanostructures: a delivery platform for ocular therapeutics. Adv Drug Deliv Rev. 2010; 62(1): 100-117. [CrossRef]
[8] Alany R, Rades T, Nicoll J, Tucker I, Davies N. W/O microemulsions for ocular delivery: evaluation of ocular irritation and precorneal retention. J Control Release. 2006; 111(1-2): 145-152. [CrossRef]
[9] Sahoo SK, Dilnawaz F, Krishnakumar S. Nanotechnology in ocular drug delivery. Drug Discov Today. 2008; 13(3-4): 144-151. [CrossRef]
[10] Attar M, Schiffman R, Borbridge L, Farnes Q, Welty D. Ocular pharmacokinetics of 0.45% ketorolac tromethamine. Clin Ophthalmol. 2010; 4: 1403. [CrossRef]
[11] Reddy R, Kim S. J W. Critical appraisal of ophthalmic ketorolac in treatment of pain and inflammation following cataract surgery. Clin Ophthalmol. 2011; 5: 751-758. [CrossRef]
[12] Waterbury D. L, Silliman D, Jolas T. Comparison of cyclooxygenase inhibitory activity and ocular anti-inflammatory effects of ketorolac tromethamine and bromfenac sodium. Curr Med Res Opin. 2006; 22(6): 1133-1140. [CrossRef]
[13] Üstündağ Okur N, Şefik Çağlar E, Siafaka PI. Novel ocular drug delivery systems: An update on microemulsions. J Ocul Pharmacol Ther. 2020; 30(4): 342-354. [CrossRef]
[14] Fialho SL, Da Silva‐ Cunha A. New vehicle based on a microemulsion for topical ocular administration of dexamethasone. Clin Exp Ophthalmol. 2004; 36(6): 626-632. [CrossRef]
[15] Vandamme TF. Microemulsions as ocular drug delivery systems: recent developments and future challenges. Prog Retin Eye Res. 2002; 21(1): 15-34. [CrossRef]
[16] Lawrence MJ, Rees GD. Microemulsion-based media as novel drug delivery systems. Adv Drug Deliv Rev. 2000; 45(1): 89-121. [CrossRef]
[17] Wang H, Li Q, Reyes S, Zhang J, Xie L, Melendez V, Hickman M, Kozar M P. Formulation and particle size reduction improve bioavailability of poorly water-soluble compounds with antimalarial activity. Malaria Research and Treatment. 2013; 3: 769234. [CrossRef]
[18] Salimi A, Panahi-Baza M R , Panahi-Bazaz E. A novel mincroemulsion system for ocular delivery of azithromycin: design, characterization and ex-vivo rabbit corneal permeability. Jundishapur J Nat Pharm Prod. 2017; 12(2): e13938. [CrossRef]
[19] Tiffany J, Winter N, Bliss G. Tear film stability and tear surface tension. Curr Eye Res. 1989; 8(5): 507-515. [CrossRef]
[20] Nair R, Chakrapani M, Kaza R. Preparation and evaluation of vancomycin microemulsion for ocular drug delivery. Drug Deliv Lett. 2012; 2(1): 26-34. [CrossRef]
[21] U¨ stu¨ ndag-Okur N, Homan Go¨ kce E, Eg˘rilmez S, O¨ zer O, Ertan OK. Novel ofloxacin-loaded microemulsion formulations for ocular delivery. J Ocul Pharmacol Ther. 2014; 30(4): 319-332. [CrossRef]
[22] van der Bijl P, Engelbrecht A, van Eyk AD, Meyer D. Comparative permeability of human and rabbit corneas to cyclosporin and tritiated water. J Ocul Pharmacol Ther. 2002;18(5): 419-427. [CrossRef]
[23] Sant T, Moreira A, de Sousa VP, Pierre MBR. Influence of oleic acid on the rheology and in vitro release of lumiracoxib from poloxamer gels. J Pharm Pharm Sci. 2010; 13(2): 286-302. [CrossRef]
[24] Rolewski SL. Clinical review: topical retinoids. Dermatol Nurs. 2003; 15(5): 447-50: 59-65.
[25] Notman R,. Noro MG, Anwar J. Interaction of Oleic Acid with Dipalmitoylphosphatidylcholine (DPPC) Bilayers Simulated by Molecular Dynamics J. J. Phys. Chem. B. 2007, 111, 12748-12755. [CrossRef]
[26] Moiseev RV, Morrison PW, Steele F, Khutoryanskiy VV. Penetration enhancers in ocular drug delivery. Pharmaceutics. 2019; 11(7): 321. [CrossRef]
[27] Kaur IP, Smitha R. Penetration enhancers and ocular bioadhesives: two new avenues for ophthalmic drug delivery. Drug Dev Ind Pharm. 2002; 28(4): 353-369. [CrossRef]
[28] Tang‐ Liu DDS, Richman JB, Weinkam RJ, Takruri H. Effects of four penetration enhancers on corneal permeability of drugs in vitro. J Pharm Sci. 1994; 83(1): 85-90. [CrossRef]
[29] 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. [CrossRef]
[30] Wilk KA, Zielińska K, Hamerska-Dudra A, Jezierski A. Biocompatible microemulsions of dicephalic aldonamidetype surfactants: formulation, structure and temperature influence. J Colloid Interface Sci. 2009; 334(1): 87-95. [CrossRef]
[31] Moghimipour E, Salimi A, Eftekhari S. Design and characterization of microemulsion systems for naproxen. Adv Pharm Bull. 2013; 3(1): 63-71. [CrossRef]
[32] Shah RR, Magdum CS, Patil SS, Niakwade NS. Preparation and evaluation of aceclofenac topical microemulsion. Iran J Pharm Res. 2010; 9(1): 5-11. [CrossRef]
[33] Zhang X, Sun X, Li J, Zhang X, Gong T, Zhang Z. Lipid nanoemulsions loaded with doxorubicin-oleic acid ionic complex: characterization, in vitro and in vivo studies. Pharmazie. 2011; 66(7): 496-505. [CrossRef]
[34] Mergler S, Pleyer U. The human corneal endothelium: new insights into electrophysiology and ion channels. Prog Retin Eye Res. 2007; 26(4): 359-378. [CrossRef]
[35] Greenbaum A, Hasany S, Rootman D. Optisol vs Dexsol as storage media for preservation of human corneal epithelium. Eye. 2004; 18(5): 519-524. [CrossRef]
[36] Moghimipour E, Salim A, Rad AS. A microemulsion system for controlled corneal delivery of Timolol. Int Res J Pharm App Sci. 2013; 3(4): 32-39.
[37] 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. [CrossRef]
[38] 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. [CrossRef]