Ocular delivery of natamycin based on monoolein/span 80/poloxamer 407 nanocarriers for the effectual treatment of fungal keratitis
Ocular delivery of natamycin based on monoolein/span 80/poloxamer 407 nanocarriers for the effectual treatment of fungal keratitis
A 32 factorial design was used to develop Natamycin cubosome nanoparticles with enhanced cornealpermeation, so as to effectively treat ocular fungal keratitis. Probe sonication technique was deployed to disperse thedry lipidic film to obtain colloidal dispersion. The colloidal dispersion was characterized for critical quality attributessuch as particle size, poly dispersibility index (PDI), zeta potential and entrapment efficiency. The optimized batchexhibited a particle size of 158.2 nm, zeta potential -40 mV, PDI 0.328 in addition, entrapment efficiency of 99.85%. Thein vitro drug release of natamycin from optimized cubosome demonstrated a cumulative %drug release of 84.29% atthe end of 8 hours. The optimized cubosomal dispersion exhibited enhanced in vitro antifungal activity againstCandida albicans and Aspergillus fumigatus as compared to a pure drug suspension. The optimized formulation wasfurther analyzed for polarized light microscopy (PLM), transmission electron microscopy (TEM) and small angle Xray scattering (SAXS) to state the morphology of formed cubosome nanoparticles and was noted to be Im3mbicontinous cubic mesophasic structure. X-ray diffraction (XRD) studies affirmed the complete encapsulation ofnatamycin into cubosome vesicles. Ex vivo corneal permeation studies of optimized formulation revealed enhancedcorneal permeation in comparison to a pure drug suspension. The ocular irritation studies performed on rabbitsindicated the cubosome to be non-irritant. Finally, the developed natamycin cubosome nanoparticles demonstratedsustained drug release and increased corneal penetration. Thus, these cubosome nanocarriers present a propitiousdelivery system for effective management of ocular fungal keratitis.
___
- [1] Chandasana H, Prasad YD, Chhonker YS, Chaitanya TK, Mishra NN, Mitra K, Shukla PK, Bhatta RS. Corneal targeted nanoparticles for sustained natamycin delivery and their PK/PD indices: an approach to reduce dose and dosing frequency. Int J Pharm. 2014; 477(1–2): 317–325. [CrossRef]
- [2] Ansari Z, Miller D, Galor A. Current Thoughts in Fungal Keratitis: Diagnosis and Treatment. Curr Fungal Infect Rep. 2013; 7(3): 209–218. [CrossRef]
- [3] Kaur IP, Kanwar M. Ocular preparations: the formulation approach. Drug Dev Ind Pharm. 2002; 28(5): 473–493. [CrossRef]
- [4] Hamalainen KM, Kananen K, Auriola S, Kontturi K, Urtti A. Characterization of paracellular and aqueous penetration routes in cornea, conjunctiva, and sclera. Invest Ophthalmol Vis Sci. 1997; 38(3): 627–34.
- [5] Keister JC, Cooper ER, Missel PJ, Lang JC, Hager DF. Limits on optimizing ocular drug delivery. J Pharm Sci. 1991; 80(1): 50–53. [CrossRef]
- [6] Shen HH, Chan EC, Lee JH, Bee YS, Lin TW, Dusting GJ, et al. Nanocarriers for treatment of ocular neovascularization in the back of the eye: new vehicles for ophthalmic drug delivery. Nanomed. 2015; 10(13): 2093– 2107. [CrossRef]
- [7] Boyd BJ, Dong Y-D, Rades T. Nonlamellar liquid crystalline nanostructured particles: advances in materials and structure determination. J Liposome Res. 2009; 19(1): 12–28. [CrossRef]
- [8] Chung H, Kim J, Um JY, Kwon IC, Jeong SY. Self-assembled “nanocubicle” as a carrier for peroral insulin delivery. Diabetologia. 2002; 45(3): 448–451.[CrossRef]
- [9] Lalu L, Tambe V, Pradhan D, Nayak K, Bagchi S, Maheshwari R, Kalia K,Tekade RK. Novel nanosystems for the treatment of ocular inflammation: Current paradigms and future research directions. J Control Release Off J Control Release Soc. 2017; 268: 19–39. [CrossRef]
- [10] Almeida H, Amaral MH, Lobao P, Frigerio C, Sousa Lobo JM. Nanoparticles in Ocular Drug Delivery Systems for Topical Administration: Promises and Challenges. Curr Pharm Des. 2015; 21(36): 5212–5224. [CrossRef].
- [11] Dong Y, Chang Y, Qian W, Tong J, Zhou J. Effects of surfactants on size and structure of amylose nanoparticles prepared by precipitation. Bull Mater Sci. 2016; 39(1): 35-39. [CrossRef]
- [12] Hu FQ, Jiang SP, Du YZ, Yuan H, Ye YQ, Zeng S. Preparation and characterization of stearic acid nanostructured lipid carriers by solvent diffusion method in an aqueous system. Colloids Surf B Biointerfaces. 2005; 45(3–4): 167– 173. [CrossRef]
- [13] Zirak M, Pezeshki A. Effect of Surfactant Concentration on the Particle Size, Stability and Potential Zeta of Beta carotene Nano Lipid Carrier. IntJCurrMicrobiolAppSci. 2015; 4: 924–932.
- [14] McClements DJ. Crystals and crystallization in oil-in-water emulsions: implications for emulsion-based delivery systems. Adv Colloid Interface Sci. 2012; 174: 1–30. [CrossRef]
- [15] Hao J, Fang X, Zhou Y, Wang J, Guo F, Li F, Peng X. Development and optimization of solid lipid nanoparticle formulation for ophthalmic delivery of chloramphenicol using a Box-Behnken design. Int J Nanomedicine. 2011; 6: 683–692. [CrossRef]
- [16] Ali Z, Sharma P, Warsi M. Fabrication and Evaluation of Ketorolac Loaded Cubosome for Ocular Drug Delivery. J Appl Pharm Sci. 2016; 6: 204–208. [CrossRef]
- [17] Magenheim B, Levy MY, Benita S. A new in vitro technique for the evaluation of drug release profile from colloidal carriers - ultrafiltration technique at low pressure. Int J Pharm. 1993; 94(1): 115–123. [CrossRef]
- [18] Han S, Shen J, Gan Y, Geng H, Zhang X, Zhu C, et al. Novel vehicle based on cubosomes for ophthalmic delivery of flurbiprofen with low irritancy and high bioavailability. Acta Pharmacol Sin. 2010; 31(8): 990–998. [CrossRef]
- [19] Cevher E, Sensoy D, Zloh M, Mulazimoglu L. Preparation and characterisation of natamycin: gamma-cyclodextrin inclusion complex and its evaluation in vaginal mucoadhesive formulations. J Pharm Sci. 2008; 97(10): 4319–4335. [CrossRef]
- [20] Liu Q, Wu X, Qian F, Zhang T, Mu G. Influence of natamycin loading on the performance of transglutaminase‐ induced crosslinked gelatin composite films. Int J Food Sci Technol.2019; 54(7): 2425-2436. [CrossRef]
- [21] Bei D, Marszalek J, Youan B BC. Formulation of dacarbazine-loaded cubosomes-part I: influence of formulation variables. AAPS PharmSciTech. 2009; 10(3): 1032–1039. [CrossRef]
- [22] Ali MA, Noguchi S, Iwao Y, Oka T, Itai S. Preparation and Characterization of SN-38-Encapsulated Phytantriol Cubosomes Containing alpha-Monoglyceride Additives. Chem Pharm Bull (Tokyo). 2016; 64(6): 577–584. [CrossRef]
- [23] El Nabarawi MA, Abd El Rehem RT, Teaima M, Abary M, El-Mofty HM, Khafagy MM, Lofty NM,Salah M. Natamycin niosomes as a promising ocular nanosized delivery system with ketorolac tromethamine for dual effects for treatment of candida rabbit keratitis; in vitro/in vivo and histopathological studies. Drug Dev Ind Pharm. 2019; 45(6): 922–936. [CrossRef]
- [24] Abdelbary G, El Gendy N. Niosome-encapsulated gentamicin for ophthalmic controlled delivery. AAPS PharmSciTech. 2008; 9(3): 740–747. [CrossRef]
- [25] Petrikkou E, Rodriguez T JL, Cuenca EM, Gomez A, Molleja A, Mellado E. Inoculum standardization for antifungal susceptibility testing of filamentous fungi pathogenic for humans. J Clin Microbiol. 2001; 39(4): 1345–1347. [CrossRef]
- [26] Khames A, Khaleel MA, El-Badawy MF, El-Nezhawy AOH. Natamycin solid lipid nanoparticles - sustained ocular delivery system of higher corneal penetration against deep fungal keratitis: preparation and optimization. Int J Nanomedicine. 2019; 14: 2515–2531. [CrossRef]