title: Novel milk-based oral formulations: proof of concept.
abstract: The aim of this study is to develop milk-based formulations for ionized and unionized lipophilic drugs. Solubility studies of the following non-steroidal anti-inflammatory drugs (NSAIDs): mefenamic acid, tolfenamic acid, ketoprofen, meloxicam, tenoxicam and nimesulide in phosphate- and glycine-NaOH buffers at nominal pH 8-12, were performed. The solubilities of cyclosporine and danazol in water-ethanol solutions were studied. NSAIDs-, cyclosporine-, danazol-, aspirin-milk oral liquid formulations were prepared by adding the appropriate volume of (i) NSAIDs-alkaline buffer solutions, (ii) water-ethanol solutions of cyclosporine and danazol and (iii) aspirin aqueous solution to 150-200ml of milk. All the non-steroidal anti-inflammatory drugs exhibited increased solubility in the alkaline buffers. The actual pH values (range 6.7-7.7) of the final NSAIDs-milk formulations were very close to milk pH. The higher ethanol content in ethanol-water mixtures increased the solubility of danazol and cyclosporine. A 15mg meloxicam-, a 100mg cyclosporine- and a 500mg aspirin-milk formulation was administered orally to healthy volunteers. All these formulations showed a satisfactory in vivo performance. The strong buffering capacity of milk that was observed and the high solubility of unionized drugs in ethanol allow the preparation of drug-milk formulations with enhanced pharmacokinetic properties.
authors.affiliation: Laboratory of Biopharmaceutics-Pharmacokinetics, Faculty of Pharmacy, University of Athens, Panepistimiopolis, 157 71 Athens, Greece.
authors.forename: Georgia
authors.initials: G
authors.lastname: Charkoftaki
authors.forename: John
authors.initials: J
authors.lastname: Kytariolos
authors.forename: Panos
authors.initials: P
authors.lastname: Macheras
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D001241:Aspirin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D002021:Buffers; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D016572:Cyclosporine / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D003613:Danazol / Q000008:administration & dosage / Q000737:chemistry; D000431:Ethanol / Q000737:chemistry; D006801:Humans; D008297:Male; D000077239:Meloxicam; D008892:Milk / Q000737:chemistry*; D012995:Solubility; D013843:Thiazines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D013844:Thiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002021:Buffers; D013843:Thiazines; D013844:Thiazoles; D000431:Ethanol; D016572:Cyclosporine; D003613:Danazol; D001241:Aspirin; D000077239:Meloxicam