Improved Solubility of Itraconazole Binary Dispersions using Neem Gum: Development and Characterization of Topical Gel

Author(s): Manju Nagpal*, Nisha Raj, Gurjeet Singh Thakur, Geeta Aggarwal.

Journal Name: Current Bioactive Compounds

Volume 15 , Issue 4 , 2019

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Graphical Abstract:


Background: Itraconazole is a triazole derivative and possesses structural similarities to the azole group (imidazoles and triazoles). It is a broad spectrum fungistatic. It belongs to BCS class II category i.e. it has poor solubility and high permeability.

Objective: Dissolution enhancement of poorly soluble itraconazole using purified neem gum as a natural carrier via binary dispersions and other methods was studied. Topical gel formulations of binary dispersions were developed and evaluated for in vitro and in vivo antifungal activity.

Methods: Five batches of solid dispersions (SD1-SD5) in various ratios of drug: neem gum were prepared by the solvent evaporation technique. Other mixtures were also prepared by kneading, cogrinding, physical mixing methods and evaluated further. Topical gel formulations were further developed and evaluated for antifungal activity (both in vitro and in vivo).

Results: Equilibrium solubility studies of various mixtures indicated SD3 (1:3) as the optimum batch out of all solid dispersion batches. Equilibrium solubility studies of mixtures (KM, CGM, PM, SM) indicated significant solubility enhancement of kneading mixture in comparison to other mixtures. FTIR studies indicated no interaction of the drug to the polymer. DSC, SEM and XRD studies indicated a transition from crystalline to the amorphous state of the drug. SD3 batch showed remarkably improved dissolution characteristics (100% drug release in 1.5 h) in comparison to the pure drug (38% in 2h). Further, the topical gel of SD3 was evaluated for in vitro diffusion, in vitro and in vivo antifungal activity. Sustained drug release (53% in 24 h) was observed in SD3 based gel formulation which is significantly higher than that in comparison to pure drug based gel (30% in 24 h). The increased area of zone of inhibition of SD3 based gel indicated better antifungal activity of the SD3 gel formulation. Further histopathology examination of skin specimens indicated enhanced efficacy of SD3 based gel in comparison to pure drug based gel.

Conclusion: Solid dispersion based topical gel formulation exhibits better antifungal activity in comparison to pure drug based gel.

Keywords: Cogrinding, dissolution, kneading, solvent evaporation, solid dispersion, topical.

Grant, S.M.; Clissold, S.P. Itraconazole: A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in superficial and systemic mycoses. Drugs, 1989, 37(3), 310-344.
Lortholary, O.; Denning, D.W.; Dupont, B. Endemic mycoses: A treatment update. J. Antimicrob. Chemother., 1999, 43(3), 321-331.
Van Cauteren, H.; Heykants, J.; De Coster, R.; Cauwenbergh, G. Itraconazole: Pharmacologic studies in animals and humans. Rev. Infect. Dis., 1987, 9(Suppl. 1), S43-S46.
Jung, J.Y.; Yoo, S.D.; Lee, S.H.; Kim, K.H.; Yoon, D.S.; Lee, K.H. Enhanced solubility and dissolution rate of itraconazole by a solid dispersion technique. Int. J. Pharm., 1999, 187(2), 209-218.
Heykants, J.; Van Peer, A.; Van de Velde, V.; Van Rooy, P.; Meuldermans, W.; Lavrijsen, K.; Woestenborghs, R.; Van Cutsem, J.; Cauwenbergh, G. The clinical pharmacokinetics of itraconazole: An overview. Mycoses, 1989, 32(Suppl. 1), 67-87.
Maghraby, G.M. El.; Alomrani, A.H. Synergistic enhancement of itraconazole dissolution by ternary system formation with pluronic F68 and Hydroxypropylmethylcellulose. Sci. Pharm., 2009, 77(2), 401-417.
Janssens, S.; de Armas, H.N.; Remon, J.P.; Van den Mooter, G. The use of a new hydrophilic polymer, Kollicoat IR® in the formulation of solid dispersions of Itraconazole. Eur. J. Pharm. Sci., 2007, 30(3-4), 288-294.
Ye, G.; Wang, S.; Heng, P.W.S.; Chen, L.; Wang, C. Development and optimization of solid dispersion containing pellets of itraconazole prepared by high shear pelletization. Int. J. Pharm., 2007, 337(1-2), 80-87.
Wang, X.; Michoel, A.; Van den Mooter, G. Solid state characteristics of ternary solid dispersions composed of PVP VA64, Myrj 52 and itraconazole. Int. J. Pharm., 2005, 303(1-2), 54-61.
Janssens, S.; Nagels, S.; de Armas, H.N.; D’Autry, D.; Van Schepdael, A.; Van den Mooter, G. Formulation and characterization of ternary solid dispersions made up of Itraconazole and two excipients, TPGS 1000 and PVPVA 64, that were selected based on a supersaturation screening study. Eur. J. Pharm. Biopharm., 2008, 69(1), 158-166.
Janssens, S.; Roberts, C.; Smith, E.F.; Van den Mooter, G. Physical stability of ternary solid dispersions of itraconazole in polyethyleneglycol6000/hydroxypropyl methyl cellulose 2910 E5 blends. Int. J. Pharm., 2008, 355(1-2), 100-107.
Hassan, H.A.; Al-Marzouqi, A.H.; Jobe, B.; Hamza, A.A.; Ramadan, G.A. Enhancement of dissolution amount and in vivo bioavailability of itraconazole by complexation with β-cyclodextrin using supercritical carbon dioxide. J. Pharm. Biomed. Anal., 2007, 45(2), 243-250.
Lee, S.Y.; Jung, I.; Kim, J.K.; Lim, G.B.; Ryu, J.H. Preparation of itraconazole/HP-β-CD inclusion complexes using supercritical aerosol solvent extraction system and their dissolution characteristics. J. Supercrit. Fluids, 2008, 44(3), 400-408.
Mellaerts, R.; Mols, R.; Jammaer, J.A.G.; Aerts, C.A.; Annaert, P.; Van Humbeeck, J.; Mooter, G.V.; Augustijns, P.; Martens, J.A. Increasing the oral bioavailability of the poorly water soluble drug itraconazole with ordered mesoporous silica. Eur. J. Pharm. Biopharm., 2008, 69(1), 223-230.
Hong, J.Y.; Kim, J.K.; Song, Y.K.; Park, J.S.; Kim, C.K. A new self-emulsifying formulation of itraconazole with improved dissolution and oral absorption. J. Control. Release, 2006, 110(2), 332-338.
Park, M.J.; Ren, S.; Lee, B.J. In vitro and in vivo comparative study of itraconazole bioavailability when formulated in highly soluble self-emulsifying system and in solid dispersion. Biopharm. Drug Dispos., 2007, 28(4), 199-207.
Panghal, D.; Nagpal, M.; Thakur, G.S.; Arora, S. Dissolution improvement of atorvastatin calcium using modified locust bean gum by the solid dispersion technique. Sci. Pharm., 2013, 82(1), 177-192.
Nagpal, M.; Rajera, R.; Nagpal, K.; Rakha, P.; Singh, S.K.; Mishra, D.N. Dissolution enhancement of glimepiride using modified gum karaya as a carrier. Int. J. Pharm. Investig., 2012, 2(1), 42-47.
Gangurde, A.B.; Malode, S.S.; Bhambar, R.S. Preliminary evaluation of neem gum as tablet binder. Ind. J. Pharm. Educ. Res., 2008, 42(4), 344-347.
Abayomi, T.; Ogunjimi Gbenga, A. Material and Tableting Properties of Azadirachta Indica Gum With Reference to Official Acacia Gum. Acta Pol. Pharm., 2014, 71(1), 107-118.
Kulkarni, A.P.; Yunus, R.S.; Dehghan, M.H.D. Application of Neem Gum for Aqueous Film Coating of Ciprofloxacin Tablets. Int. J. Appl. Res. Nat. Prod., 2013, 6(3), 11-19.
Goswamiand, D.S.; Sharma, M. Development of new mucoadhesive polymer from natural source. Asian J. Pharm. Clin. Res, 2012, 5(3), 247-250.
Abayomi, T.O.; Gbenga, A. Neem Gum as a Binder in a Formulated Paracetamol Tablet with Reference to Acacia Gum BP. AAPS PharmSciTech, 2014, 10(5), 500-510.
Rodde, M.S.; Divase, G.T.; Devkar, T.B.; Tekade, A.R. Solubility and bioavailability enhancement of poorly aqueous soluble atorvastatin: In vitro, ex vivo, and in vivo studies. BioMed Res. Int., 2014, 2014463895
Nagpal, M.; Aggarwal, G.; Sharma, P.; Mahan, P.; Thakur, G.S. Neem gum based solid dispersion in development of aceclofenac tablet with enhanced bioavailability. Drug Deliv. Lett., 2017, 7(2), 115-124.
Schaefer, H.; Redelmeier, T.E. Prediction and measurements of percutaneous absorption. In: Skin Barrier: principles of percutaneous absorption; Schaefer H, Redelmeier TE, Ed.; Basel, Karge:. , 1996, pp. 118-152.
Ghosh, T.K.; Pfister, W.R.; Yum, S.I. Transdermal and Topical Drug Delivery Systems; Buffalo Grove, IL: Interpharm Press, 1997, pp. 33-112.
Aggarwal, G.; Nagpal, M.; Kaur, G. Development and comparison of nanosponge and niosome based gel for the topical delivery of tazarotene. Pharm. Nanotechnol., 2016, 4(3), 213-228.
Van-Abbe, N.J.; Nicholas, P.; Boon, E. Exaggerated exposure in topical irritancy and sensitization testing. J. Soc. Cosmet. Chem., 1975, 26, 173-187.

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Article Details

Year: 2019
Page: [399 - 407]
Pages: 9
DOI: 10.2174/1573407214666180926120619
Price: $58

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