title: Preformulation, formulation, and in vivo efficacy of topically applied apomine.
abstract: Apomine is a novel compound that inhibits the mevalonate/isoprenoid pathway of cholesterol synthesis and may prove effective as a skin cancer chemoprevention therapy. This research was focused on the development of a new delivery approach for chemoprevention of melanoma using topically delivered apomine. This included evaluating the effect of several factors on the stability of apomine in solution, utilizing these to develop a topical formulation, and conducting efficacy studies with the developed topical formulation in the TPras mouse model. Preformulation included the influence of pH, buffer species, ionic strength, and organic solvents on the stability of apomine at four different temperatures. Apomine was determined to undergo apparent first-order degradation kinetics for all conditions evaluated. Apomine undergoes base-catalyzed degradation. Less than 15% degradation is observed after >200 days under acidic conditions. Long-term stability studies were performed on two different topical cream formulations and indicate that both formulations are chemically stable for over 1 year at both 4 and 23 degrees C. The efficacy of topically applied apomine, from ethanol and developed 1% cream, was evaluated in vivo against the incidence of melanoma. Regardless of delivery vehicle apomine treatment caused a significant reduction in tumor incidence. Ethyl alcohol application of apomine resulted in a greater tumor incidence reduction when compared to the development cream formulation; however, this difference was not significant.
authors.affiliation: Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM 87108, United States. pkuehl@lrri.org
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Kuehl
authors.forename: Steven P
authors.initials: SP
authors.lastname: Stratton
authors.forename: Marianne B
authors.initials: MB
authors.lastname: Powell
authors.forename: Paul B
authors.initials: PB
authors.lastname: Myrdal
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000287:Administration, Topical; D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage* / Q000737:chemistry; D002021:Buffers; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D004164:Diphosphonates / Q000008:administration & dosage* / Q000737:chemistry; D004355:Drug Stability; D000431:Ethanol / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008546:Melanoma, Experimental / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D051379:Mice; D009824:Ointments; D009994:Osmolar Concentration; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D013678:Technology, Pharmaceutical / Q000379:methods; D013696:Temperature; D018631:ras Proteins / Q000235:genetics
chemical_list: D016588:Anticarcinogenic Agents; D002021:Buffers; D004164:Diphosphonates; D009824:Ointments; D012997:Solvents; C407151:apomine; D000431:Ethanol; D015127:9,10-Dimethyl-1,2-benzanthracene; D018631:ras Proteins
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