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C. Durairaj, P. Tyagi, J. Chandler, U. Kompella; A Novel Dendrimer Formulation for Enhanced Solubility and Delivery of Gatifloxacin, Ketorolac Tromethamine, and Tropicamide. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2421.
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© ARVO (1962-2015); The Authors (2016-present)
Cell penetrating dendrimeric polyguanidilyated translocators (DPTs), a new class of polymers, potentially enhance topical ocular delivery across epithelial barriers. Ophthalmic drop dosage forms require high drug solubility. The study objective was to determine whether a g6 DPT dendrimer is suitable for enhancing the solubility of gatifloxacin (zwitterion), ketorolac tromethamine (KT, negatively charged), and tropicamide (positively charged), three topical ophthalmic drugs.
Equilibrium drug solubility studies in the presence of 1 and 10 mg/ml dendrimer were carried out in isotonic PBS (pH 5.65, 6.30, and 7.37) using HPLC analysis. Drug and dendrimer interactions were characterized using isothermal titration calorimetry (ITC) and Fourier-transformed infrared spectroscopy (FTIR). Molecular size of the dendrimer was ensured using membrane filtration.
The dendrimer was highly soluble (> 200 mg/ml) at all pH conditions and permeated completely through a 3,000 MW cutoff membrane, indicating that its molecular, nano-form. The dendrimer increased the solubility of all three drugs in a pH dependent manner. The maximum solubility increase was 2.8-, 2-, and 1.8-fold, respectively, for gatifloxacin (pH 6.3), KT (5.65), and tropicamide (pH 5.65). ITC studies revealed >1 stoichiometry of gatifloxacin:dendrimer association. Competitive ITC inhibition studies in the presence of sodium chloride or Triton-X confirmed ionic and hydrophobic interactions, respectively, in gatifloxacin-dendrimer binding. FTIR studies confirmed ionic interactions (between guanidine groups of dendrimer and carboxylic group of gatifloxacin) and hydrogen bonding (between amide bonds in branching units of dendrimer and electronegative atoms in gatifloxacin) in the complex. FTIR analysis indicated hydrogen bond based interactions for KT and tropicamide with dendrimer.
Dendrimer increases solubility of all three drugs and is capable of participating in ionic, hydrophobic, or hydrogen bonds with drug molecules. DPT g6 dendrimer is a new nanosystem that might allow enhanced drug solubility as well as delivery.
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