International Journal of Pharmaceutics 390 (2010) 150–159 Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm Novel milk-based oral formulations: Proof of concept Georgia Charkoftaki, John Kytariolos, Panos Macheras ∗ Laboratory of Biopharmaceutics-Pharmacokinetics, Faculty of Pharmacy, University of Athens, Panepistimiopolis, 157 71 Athens, Greece article info Article history: Received 19 November 2009 Received in revised form 22 January 2010 Accepted 23 January 2010 Available online 1 February 2010 Keywords: Milk NSAIDs Danazol Cyclosporine Aspirin Oral formulations 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): mefe- namic 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 for- mulations 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 150–200 ml 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 15 mg meloxicam–, a 100 mg cyclosporine– and a 500 mg 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. © 2010 Elsevier B.V. All rights reserved. 1. Introduction Lipophilic drugs are insoluble or practically insoluble in water. It is very well known that the aqueous solubility of a drug is a key parameter which governs its oral bioavailability. Therefore, the improvement of the rate and extent of absorption of lipophilic drugs is highly desirable. Various approaches have been utilized to increase the solubility of a drug by modifying its crystallinity and its non-polarity. The former approach is accomplished by microniza- tion, spray drying or freeze drying (Rasenack and Müller, 2002; Rasenack et al., 2003a,b; Rogers et al., 2003a; Hu et al., 2003; Wu et al., 2009). The latter approach can be accomplished by modify- ing the media in which the drug is dissolved (Larrucea et al., 2002; Rogers et al., 2003b; Seedher and Bhatia, 2003; Mutalik et al., 2008; Larsen et al., 2008; Yeh et al., 2009). The modification of the media can be achieved by either adjusting the pH and/or the use of solu- bilizing agents, namely, cosolvents, surfactants, complexing agents and oil/lipids. However, a satisfactory effect with such methods cannot always be achieved. Besides, some of the solubilizing agents are used in quantities which can produce undesired effects. Over- all, these approaches are limited in the range and quantity of drugs which they can accommodate and also in their ability to promote the access of drug throughout the gastrointestinal wall. ∗ Corresponding author. Tel.: +30 210 7274026; fax: +30 210 7274027. E-mail address: macheras@pharm.uoa.gr (P. Macheras). The present work focuses on the use of milk as the basic com- ponent for what we call milk-based formulations; milk is a natural, abundant and inexpensive carrier with the desired characteristics for oral drug delivery. In fact, synthetic emulsions are used for oral administration of sparingly soluble drugs, e.g. cyclosporine is formulated as a microemulsion (Neoral ® ). Milk, a daily ritual, is an oil-in-water natural emulsion since nearly all of the fat milk is in separate small globules (Walstra and Jenness, 1984). Several reports in literature suggest that the solubility of lipophilic drugs in milk is much higher than their aqueous solubility (Macheras et al., 1986, 1989, 1990, 1991). Also, the rate of dissolution of lipophilic drugs used in a powder form was found to be much higher in milk than in aqueous media (Macheras et al., 1986; Galia et al., 1998). A number of dissolution studies has shown that drug dissolution is higher from drug–milk dispersed systems than drug–milk phys- ical mixtures (Topaloglou et al., 1998, 1999; Kumar and Mishra, 2006; Sahin and Arslan, 2007). A series of in vitro and in vivo stud- ies with reconstituted freeze-dried drug–milk formulations have demonstrated their superiority in regard to solubility and disso- lution (Macheras et al., 1986; Topaloglou et al., 1999) as well as the absorbability when compared to conventional capsule formula- tions of lipophilic drugs (Macheras and Reppas, 1986a,b; Macheras et al., 1991). Finally, a large number of drugs like non-steroidal anti- inflammatory drugs (NSAIDs) when taken orally in various dosage forms such as tablets, capsules, caplets, as well as chewable forms, create stomach irritation. A warning on the label of the commer- cial packages of NSAIDs refers “this product may cause stomach 0378-5173/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2010.01.038