Formulation, Optimization, and Evaluation of Ketoconazole Loaded Nanostructured Lipid Carrier Gel for Topical Delivery

Author(s): Hemant A. Ranpise, Kishore N. Gujar, Sachin C. Pawar, Rajendra Awasthi, Kamal Dua, Dyandevi Mathure, Jyotsana R. Madan*

Journal Name: Drug Delivery Letters

Volume 10 , Issue 1 , 2020

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Abstract:

Objective: Ketoconazole is used in the treatment of superficial and systemic fungal infections. It acts by blocking the synthesis of ergosterol, an essential component of the fungal cell membrane. The purpose of this work was to formulate ketoconazole loaded nanostructured lipid carriers formulation for skin targeting to minimize the adverse side effects and to prolong release.

Methods: The ketoconazole loaded nanostructured lipid carriers were optimized using 32 factorial design to evaluate the effects of process and formulation variables. The nanostructured lipid carriers were prepared by melt-dispersion ultra-sonication method. The formulations were finally incorporated into polymeric gels of Carbopol 940 for convenient application. The gels were evaluated comparatively with commercially available formulations of ketoconazole with respect to ex vivo skin permeation and deposition study on human cadaver skin.

Results: Nanostructured lipid carriers showed average particle size, zeta potential, and percentage entrapment in the range of 125.8 ± 1.8 to 295.0 ± 3.8 nm, -13.2 ± 1.1 to -30.9 ± 2.2 mV, and 69.47 ± 2.8 to 95.49 ± 4.5, respectively. Thermal studies revealed no drug-excipient incompatibility and amorphization of ketoconazole. Ex vivo study of the gel exhibited prolonged drug release up to 12 h. In vitro drug deposition study showed that the gel formulation can avoid the systemic uptake, better accumulative uptake of the drug, and nonirritant to the skin compared to marketed formulation. Optimized formulation exhibited better antifungal activity when compared to ketoconazole loaded gel and marketed cream (Keto ® cream). Histolopathology results indicated no toxic effect on the skin.

Conclusions: These results indicate that developed nanostructured lipid-carriers gel formulation represents a promising carrier for topical delivery of ketoconazole, having controlled drug release, and potential of skin targeting.

Keywords: Ketoconazole, nanostructured lipid carrier, nanocarriers, topical gel, skin targeting, anti-fungal activity.

[1]
Bikkad, M.L.; Nathani, A.H.; Mandlik, S.K.; Shrotriya, S.N.; Ranpise, N.S. Halobetasol propionate-loaded solid lipid nanoparticles (SLN) for skin targeting by topical delivery. J. Liposome Res., 2014, 24(2), 113-123.
[http://dx.doi.org/10.3109/08982104.2013.843192] [PMID: 24131382]
[2]
Mottaghitalab, F.; Farokhi, M.; Shokrgozar, M.A.; Atyabi, F.; Hosseinkhani, H. Silk fibroin nanoparticle as a novel drug delivery system. J. Control. Release, 2015, 206, 161-176.
[http://dx.doi.org/10.1016/j.jconrel.2015.03.020] [PMID: 25797561]
[3]
Abedini, F.; Ebrahimi, M.; Roozbehani, A.H.; Domb, A.J.; Hosseinkhani, H. Overview on natural hydrophilic polysaccharide polymers in drug delivery. Polym. Adv. Technol., 2018, 29, 2564-2573.
[http://dx.doi.org/10.1002/pat.4375]
[4]
He, W.; Hosseinkhani, H.; Mohammadinejad, R.; Roveimiab, Z.; Hueng, D.Y.; Ou, K.L.; Domb, A.J. Polymeric nanoparticles for therapy and imaging. Polym. Adv. Technol., 2014, 25, 1216-1225.
[http://dx.doi.org/10.1002/pat.3381]
[5]
Ghadiri, M.; Vasheghani-Farahani, E.; Atyabi, F.; Kobarfard, F.; Mohamadyar-Toupkanlou, F.; Hosseinkhani, H. Transferrin-conjugated magnetic dextran-spermine nanoparticles for targeted drug transport across blood-brain barrier. J. Biomed. Mater. Res. A, 2017, 105(10), 2851-2864.
[http://dx.doi.org/10.1002/jbm.a.36145] [PMID: 28639394]
[6]
Jin, H.; Abu-Raya, Y.S.; Haick, H. Advanced materials for health monitoring with skin-based wearable devices. Adv. Healthc. Mater., 2017, 6(11)1700024
[http://dx.doi.org/10.1002/adhm.201700024] [PMID: 28371294]
[7]
Gaba, B.; Fazil, M.; Khan, S.; Ali, A.; Baboota, S.; Ali, J. Nanostructured lipid carrier system for topical delivery of terbinafine hydrochloride. Bull. Fac. Pharm. Cairo Univ., 2015, 53, 147-159.
[http://dx.doi.org/10.1016/j.bfopcu.2015.10.001]
[8]
Uprit, S.; Kumar Sahu, R.; Roy, A.; Pare, A. Preparation and characterization of minoxidil loaded nanostructured lipid carrier gel for effective treatment of alopecia. Saudi Pharm. J., 2013, 21(4), 379-385.
[http://dx.doi.org/10.1016/j.jsps.2012.11.005] [PMID: 24227958]
[9]
Utreja, S.; Jain, N.K. Solid lipid nanoparticles.Advances in controlled and novel drug delivery; Jain, N.K; Publishers, C.B.S., Ed.; New Delhi, 2001, p. 425.
[10]
Shah, R.; Eldridge, D.; Palombo, E.; Harding, I. Lipid nanoparticles: Production, characterization and stability; Springer International Publishing: New York, 2015.
[11]
Wissing, S.; Müller, R. The influence of the crystallinity of lipid nanoparticles on their occlusive properties. Int. J. Pharm., 2002, 242(1-2), 377-379.
[http://dx.doi.org/10.1016/S0378-5173(02)00220-X] [PMID: 12176283]
[12]
Wissing, S.A.; Müller, R.H. The influence of solid lipid nanoparticles on skin hydration and viscoelasticity--in vivo study. Eur. J. Pharm. Biopharm., 2003, 56(1), 67-72.
[http://dx.doi.org/10.1016/S0939-6411(03)00040-7] [PMID: 12837483]
[13]
Müller, R.H.; Radtke, M.; Wissing, S.A. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) in cosmetic and dermatological preparations. Adv. Drug Deliv. Rev., 2002, 54(Suppl. 1), S131-S155.
[http://dx.doi.org/10.1016/S0169-409X(02)00118-7] [PMID: 12460720]
[14]
Ghannoum, M.A.; Rice, L.B. Antifungal agents: mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance. Clin. Microbiol. Rev., 1999, 12(4), 501-517.
[http://dx.doi.org/10.1128/CMR.12.4.501] [PMID: 10515900]
[15]
Kaur, I.P.; Kakkar, S. Topical delivery of antifungal agents. Expert Opin. Drug Deliv., 2010, 7(11), 1303-1327.
[http://dx.doi.org/10.1517/17425247.2010.525230] [PMID: 20961206]
[16]
Fang, C.L.; Al-Suwayeh, S.A.; Fang, J.Y. Nanostructured lipid carriers (NLCs) for drug delivery and targeting. Recent Pat. Nanotechnol., 2013, 7(1), 41-55.
[http://dx.doi.org/10.2174/187221013804484827] [PMID: 22946628]
[17]
Gasco, M.R. Method for producing Nanostructured lipid carrier’s microspheres having a narrow size distribution U.S. Patent 5250236, 1993.
[18]
Patil, G.B.; Patil, N.D.; Deshmukh, P.K.; Patil, P.O.; Bari, S.B. Nanostructured lipid carriers as a potential vehicle for Carvedilol delivery: Application of factorial design approach. Artif. Cells Nanomed. Biotechnol., 2016, 44(1), 12-19.
[http://dx.doi.org/10.3109/21691401.2014.909820] [PMID: 24866725]
[19]
Doktorovova, S.; Souto, E.B. Nanostructured lipid carrier-based hydrogel formulations for drug delivery: a comprehensive review. Expert Opin. Drug Deliv., 2009, 6(2), 165-176.
[http://dx.doi.org/10.1517/17425240802712590] [PMID: 19239388]
[20]
Patel, D.; Dasgupta, S.; Dey, S.; Ramani, Y.R.; Ray, S.; Mazumder, B. Nanostructured lipid carriers (NLC)-based gel for the topical delivery of aceclofenac: preparation, characterization, and in vivo evaluation. Sci. Pharm., 2012, 80(3), 749-764.
[http://dx.doi.org/10.3797/scipharm.1202-12] [PMID: 23008819]
[21]
Chawla, V.; Saraf, S.A. Rheological studies on solid lipid nanoparticle based carbopol gels of aceclofenac. Colloids Surf. B Biointerfaces, 2012, 92, 293-298.
[http://dx.doi.org/10.1016/j.colsurfb.2011.12.006] [PMID: 22221454]
[22]
Ranpise, N.S.; Korabu, S.S.; Ghodake, V.N. Second generation lipid nanoparticles (NLC) as an oral drug carrier for delivery of lercanidipine hydrochloride. Colloids Surf. B Biointerfaces, 2014, 116, 81-87.
[http://dx.doi.org/10.1016/j.colsurfb.2013.12.012] [PMID: 24445002]
[23]
Madan, J.R.; Kamate, V.J.; Awasthi, R.; Dua, K. Formulation, Characterization and In-vitro evaluation of fast dissolving tablets containing gliclazide hydrotropic solid dispersions. Recent Pat. Drug Deliv. Formul., 2017, 11(2), 147-154.
[http://dx.doi.org/10.2174/1872211311666170427100213] [PMID: 28460615]
[24]
Madan, J.R.; Kamate, V.J.; Dua, K.; Awasthi, R. Improving the solubility of nevirapine by hydrotropy and mixed hydrotropy. Polym. Med., 2018, 47(2), 83-90.
[PMID: 30009585]
[25]
Madan, J.R.; Patil, S.; Mathure, D.; Bahirat, S.P.; Awasthi, R.; Dua, K. Improving dissolution profile of poorly water-soluble drug using non-ordered mesoporous silica. Marmara Pharm. J., 2018, 22, 249-258.
[http://dx.doi.org/10.12991/mpj.2018.62]
[26]
Madan, J.R.; Khude, P.A.; Dua, K. Development and evaluation of solid lipid nanoparticles of mometasone furoate for topical delivery. Int. J. Pharm. Investig., 2014, 4(2), 60-64.
[http://dx.doi.org/10.4103/2230-973X.133047] [PMID: 25006550]
[27]
Phatak, A.A.; Chaudhari, P.D. Development and evaluation of nanostructured lipid carrier (NLC) based topical delivery of an anti-inflammatory drug. J. Pharm. Res., 2003, 7, 677-685.
[http://dx.doi.org/10.1016/j.jopr.2013.08.020]
[28]
Bhalekar, M.R.; Pokharkar, V.; Madgulkar, A.; Patil, N.; Patil, N. Preparation and evaluation of miconazole nitrate-loaded solid lipid nanoparticles for topical delivery. AAPS PharmSciTech, 2009, 10(1), 289-296.
[http://dx.doi.org/10.1208/s12249-009-9199-0] [PMID: 19294517]
[29]
Vijayan, V.; Jayachandran, E.; Anburaj, J. Preparation and characterization of anti-diabetic drug loaded solid lipid nanoparticles. J. Inno. Trends Pharm. Sci., 2010, 1, 320-328.
[30]
Dandagi, P.; Dessai, G.; Gadad, A.; Desai, V. Formulation and evaluation of nanostructured lipid carrier (NLC) of lornoxicam. Int. J. Pharm. Pharm. Sci., 2014, 6, 73-77.
[31]
Swidan, S.; Mansour, Z.; Mourad, Z.; Nahla, A. DOE, formulation, and optimization of Repaglinide nanostructured lipid carriers., Journal of Applied Pharmaceutical Science. 2018, 8(10), 008-016.
[32]
Westesen, K.; Siekmann, B. Investigation of the gel formation of phospholipid stabilized solid lipid nanoparticles. Int. J. Pharm., 1997, 151, 35-45.
[http://dx.doi.org/10.1016/S0378-5173(97)04890-4]
[33]
Aburahma, M.H.; Badr-Eldin, S.M. Compritol 888 ATO: a multifunctional lipid excipient in drug delivery systems and nanopharmaceuticals. Expert Opin. Drug Deliv., 2014, 11(12), 1865-1883.
[http://dx.doi.org/10.1517/17425247.2014.935335] [PMID: 25152197]


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VOLUME: 10
ISSUE: 1
Year: 2020
Page: [61 - 71]
Pages: 11
DOI: 10.2174/2210303109666190717155731
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