Hydrogel of Ketoconazole and PAMAM Dendrimers: Formulation and Antifungal Activity

Ketoconazole (KET), an imidazole derivative with well-known antifungal properties, is lipophilic and practically insoluble in water, therefore its clinical use has some practical disadvantages. The aim of the present study was to investigate the influence of PAMAM-NH2 and PAMAM-OH dendrimers generation 2 and generation 3 on the solubility and antifungal activity of KET and to design and evaluate KET hydrogel with PAMAM dendrimers. It was shown that the surface charge of PAMAM dendrimers strongly affects their influence on the improvement of solubility and antifungal activity of KET. The MIC and MFC values obtained by broth dilution method indicate that PAMAM-NH2 dendrimers significantly (up to 16-fold) increased the antifungal activity of KET against Candida strains (e.g., in culture Candida albicans 1103059/11 MIC value was 0.008 μg/mL and 0.064 μg/mL, and MFC was 2 μg/mL and 32 μg/mL for KET in 10 mg/mL solution of PAMAM-NH2 G2 and pure KET, respectively). Antifungal activity of designed KET hydrogel with PAMAM-NH2 dendrimers measured by the plate diffusion method was definitely higher than pure KET hydrogel and than commercial available product. It was shown that the improvement of solubility and in the consequence the higher KET release from hydrogels seems to be a very significant factor affecting antifungal activity of KET in hydrogels containing PAMAM dendrimers.

[1]  Analette I. Lopez,et al.  Antibacterial activity and cytotoxicity of PEGylated poly(amidoamine) dendrimers. , 2009, Molecular bioSystems.

[2]  Xu Tongwen,et al.  Transdermal delivery of nonsteroidal anti-inflammatory drugs mediated by polyamidoamine (PAMAM) dendrimers. , 2007 .

[3]  C. Nombela,et al.  Inhibitory and morphological effects of several antifungal agents on three types of Candida albicans morphological mutants. , 1994, Journal of medical and veterinary mycology : bi-monthly publication of the International Society for Human and Animal Mycology.

[4]  J. Solecka,et al.  Design of Antimicrobially Active Small Amphiphilic Peptide Dendrimers , 2009, Molecules.

[5]  M. Şenel,et al.  Synthesis, characterization and antimicrobial activity of water soluble dendritic macromolecules. , 2009, European journal of medicinal chemistry.

[6]  H. Lennernäs,et al.  The effect of ketoconazole on the in vivo intestinal permeability of fexofenadine using a regional perfusion technique. , 2003, British journal of clinical pharmacology.

[7]  N. K. Jain,et al.  Dendimer-mediated solubilization, formulation development and in vitro-in vivo assessment of piroxicam. , 2009, Molecular pharmaceutics.

[8]  K. Viras,et al.  A DSC and Raman spectroscopy study on the effect of PAMAM dendrimer on DPPC model lipid membranes. , 2006, International journal of pharmaceutics.

[9]  M. Borgers Mechanism of action of antifungal drugs, with special reference to the imidazole derivatives. , 1980, Reviews of infectious diseases.

[10]  D. Nesseem Formulation and evaluation of itraconazole via liquid crystal for topical delivery system. , 2001, Journal of pharmaceutical and biomedical analysis.

[11]  I. Alberti,et al.  Effect of ethanol and isopropyl myristate on the availability of topical terbinafine in human stratum corneum, in vivo. , 2001, International journal of pharmaceutics.

[12]  István Antal,et al.  Aqueous solvent system for the solubilization of azole compounds. , 2009, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[13]  A. D'emanuele,et al.  Crossing cellular barriers using dendrimer nanotechnologies. , 2006, Current opinion in pharmacology.

[14]  Anil K Patri,et al.  Dendritic polymer macromolecular carriers for drug delivery. , 2002, Current opinion in chemical biology.

[15]  Sonke Svenson,et al.  Dendrimers as versatile platform in drug delivery applications. , 2009, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[16]  D. Tomalia Dendrimer research. , 1991, Science.

[17]  T. Xu,et al.  Polyamidoamine (PAMAM) dendrimers as biocompatible carriers of quinolone antimicrobials: an in vitro study. , 2007, European journal of medicinal chemistry.

[18]  C. Kauffman,et al.  Use of azoles for systemic antifungal therapy. , 1997, Advances in pharmacology.

[19]  M. T. Hampton Atlas of Clinical Fungi , 1997 .

[20]  J. Pemán,et al.  Minimum fungicidal concentrations of amphotericin B for bloodstream Candida species. , 2003, Diagnostic microbiology and infectious disease.

[21]  J. Senger Monsanto dioxin studies. , 1991, Science.

[22]  M S Marriott,et al.  Inhibition of sterol biosynthesis in Candida albicans by imidazole-containing antifungals. , 1980, Journal of general microbiology.

[23]  A. Carlucci,et al.  Study of In Vitro Drug Release and Percutaneous Absorption of Fluconazole from Topical Dosage Forms , 2010, AAPS PharmSciTech.

[24]  T. Aoyagi,et al.  Polymerization of benzalkonium chloride-type monomer and application to percutaneous drug absorption enhancer , 1990 .

[25]  T. Xu,et al.  Dendrimers as drug carriers: applications in different routes of drug administration. , 2008, Journal of pharmaceutical sciences.

[26]  B. Ongpipattanakul,et al.  Characterization of the permselective properties of excised human skin during iontophoresis. , 1987, Journal of pharmaceutical sciences.

[27]  T. Aoyagi,et al.  Polymeric percutaneous drug penetration enhancer: Synthesis and enhancing property of PEG/PDMS block copolymer with a cationic end group , 1997 .

[28]  Venkata Vamsi K Venuganti,et al.  Poly(amidoamine) dendrimers as skin penetration enhancers: Influence of charge, generation, and concentration. , 2009, Journal of pharmaceutical sciences.

[29]  Lajos P. Balogh,et al.  Dendrimer−Silver Complexes and Nanocomposites as Antimicrobial Agents , 2001 .

[30]  Z. Knežević-Jugović,et al.  Microbial polysaccharides and their derivatives as current and prospective pharmaceuticals. , 2008, Current pharmaceutical design.

[31]  Omathanu Perumal,et al.  Effect of poly(amidoamine) (PAMAM) dendrimer on skin permeation of 5-fluorouracil. , 2008, International journal of pharmaceutics.

[32]  K. Winnicka,et al.  Poly(amidoamine) dendrimers increase antifungal activity of clotrimazole. , 2011, Biological & pharmaceutical bulletin.

[33]  D. Tomalia Birth of a new macromolecular architecture: dendrimers as quantized building blocks for nanoscale synthetic polymer chemistry , 2005 .

[34]  S. Milewski,et al.  Novel dendrimeric lipopeptides with antifungal activity. , 2012, Bioorganic & medicinal chemistry letters.

[35]  Mark Bradley,et al.  Antibacterial single-bead screening , 2003 .

[36]  Xiaomin Wang,et al.  Transdermal delivery of nonsteroidal anti-inflammatory drugs mediated by polyamidoamine (PAMAM) dendrimers. , 2007, Journal of pharmaceutical sciences.

[37]  Clinical,et al.  Reference method for broth dilution antifungal susceptibility testing of yeasts : Approved standard , 2008 .