title: Liquid formulation of a novel non-fluorinated topical quinolone, T-3912, utilizing the synergic solubilizing effect of the combined use of magnesium ions and hydroxypropyl-beta-cyclodextrin.
abstract: T3912 is a non-fluorinated topical quinolone antimicrobial agent currently under development. Its pK(a1) and pK(a2) values were determined as 5.6 and 7.5, respectively, and its intrinsic solubility at pH 7 was found to be approximately 2 microg/ml. This study evaluates the combined use of Mg(2+) ions, hydroxpyropyl-beta-cyclodextrin (HPbetaCD) and polyvinylpyrrolidone (PVP) in order to obtain a stable aqueous liquid formulation of T-3912. The use of Mg(2+) ions alone resulted in the improved solubility of T-3912 at physiological pH, however, it became unstable during storage. HPbetaCD increased T-3912 solubility with relatively high apparent association constant (K(1:1)=9.6 x 10(3) M(-1)) that was determined by a phase-solubility method at pH 7.5. Moreover, a binary system of Mg(2+) and HPbetaCD exerted a synergetic effect, such that the solubility of T-3912 increased a remarkable 500-fold. Furthermore, the addition of PVP prevented precipitation during storage, and as a result, the liquid formulation of T-3912 (1000 microg/ml) showed good stability under various conditions, i.e., in a refrigerator at 25 degrees C/60% RH and at 40 degrees C/75% RH for 6 months. The effect of light exposure of 1200000 lux.h was also tested. This combined system of Mg(2+) ions, HPbetaCD and PVP has potential as a liquid formulation of T-3912 for topical application, especially for opthalmic use.
authors.affiliation: Research Laboratories of Toyama Chemical Co, Ltd, 2-4-1 Shimookui, Toyama 930-8508, Japan. Tetsumi_yamakawa@toyama-chemical.co.jp
authors.forename: Tetsumi
authors.initials: T
authors.lastname: Yamakawa
authors.forename: Setsuko
authors.initials: S
authors.lastname: Nishimura
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D042462:4-Quinolones; D000287:Administration, Topical; D000890:Anti-Infective Agents / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D003505:Cyclodextrins / Q000737:chemistry*; D004357:Drug Synergism; D008274:Magnesium / Q000737:chemistry*; D011804:Quinolines / Q000737:chemistry*; D012995:Solubility; D047392:beta-Cyclodextrins
chemical_list: D042462:4-Quinolones; D000890:Anti-Infective Agents; D003505:Cyclodextrins; D011804:Quinolines; C464965:T3912; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D008274:Magnesium