17 Oral self-emulsifying drug delivery systems, from biopharmaceutical to technical formulation aspects M. Kuentz University of Applied Sciences Northwestern Switzerland, Institute of Pharma Technology, Gründenstr. 40, CH-4132 Muttenz, Switzerland *Correspondence: martin.kuentz@fhnw.ch Self-emulsifying drug delivery systems can include a broad range of oils, surfactants and co-solvents. A spontaneous ine emulsion or micro- emulsion is formed in contact with water or gastro-intestinal luids. There is a growing interest in this pertinent drug delivery approach and a key rationale is to formulate biopharmaceutically challenging drugs. In this review, a structured method is presented for how oral self-emulsifying formulations can be developed. The screening of drug solubility in excipients and the study of phase behavior are discussed in the irst step. This initial development phase should also consider the known biological effects of selected excipients. Following the identiication of candidate formulations, different in vitro tests are performed to mimic the fate of the formulation in vivo. The early dilution and dispersion tests can run in parallel on a small scale to primarily characterize the systems and to screen for unfavorable phase separation or precipitation of the drug. At a later stage, compendial equipment is used and dynamic lipolysis testing can provide valuable information about the digestion of the formulation. The next step is the performance evaluation of selected formulations in animals. Finally, technical aspects of different capsule and illing technolo- gies are addressed in order to connect the early biopharmaceutical considerations with aspects of the dosage form manufacture. Key words: Oral drug absorption – Self-emulsifying drug delivery systems (SEDDS) – Dilution – Dispersion – Lipolysis – Capsule compatibility. J. DRUG DEL. SCI. TECH., 21 (1) 17-26 2011 A substantial proportion of new drug candidates fail during phar- maceutical development because of an erratic oral absorption [1]. Such incomplete intestinal uptake is often a reason for limited oral bioavail- ability, which is typically accompanied by further biopharmaceutical issues. A result is high variability of exposure that can further exhibit a non-linearity with the administered dose. It is a well-recognized issue of many novel drug molecules that they are lacking aqueous drug solubility [2-4]. These drug candidates are challenging with respect to formulating a robust oral formulation. Especially at higher doses there is often a special formulation technol- ogy needed to cope with the solubility issue. Such a key technology is the drug inclusion into a lipid-based delivery system, which was an enabling technology to bring important HIV drugs on the market, such as in the case of amprenavir (Agenerase), ritonavir (Norvir, Kaletra including further lopinavir) or saquinavir (Fortovase). Other biopharmaceutically demanding drugs like cyclosporin A (Neoral) or fenoibrate (Fenogal) provided further cases of successful product developments. The list of market formulations is today considerable [5] and will surely grow in the future. A special interest lies in lipid-based systems that can produce a ine dispersion in the gastro-intestinal tract. Self-emulsifying drug delivery systems (SEDDS) are mixtures of oils and surfactants, which can further include co-surfactants and solvents. The more complex mixtures often result in a nano-dispersed system upon dilution so that the preconcentrate is called a self-microemulsifying drug delivery system (SMEDDS). It is also possible to name the latter formulations self-nano-dispersing systems (SNEDDS), but to avoid any confusion this article consistently uses the initial name SMEDDS. The acronyms SMEDDS and SEDDS are primarily used to distinguish formulations with respect to the evolving particle size. Both formulation types can be summarized as SELF or, alternatively, SEDDS has been used with the additional meaning of an umbrella term for the different kinds of self-dispersing drug delivery systems [6]. A classiication of the different lipid-based systems was introduced by Pouton [7, 8]. Class I stands for pure oils or oily mixtures. These formulations are generally non-dispersing in aqueous media and they often exhibit a poor solvent capacity for hydrophobic drugs having comparatively high melting points. Such drugs are different from other poorly soluble compounds that are basically lipophilic. The latter drugs can reach suitable concentrations in class I systems making it a rather simple and effective formulation option. Adding a non-swellable surfactant to oils can result in SEDDS that typically form emulsions having small droplets of a sub-micron size. These dispersions are turbid, but they mostly retain the solvent capacity of the undiluted formulation. This is different to the class III and IV systems, for which a loss of solvent capacity on dispersion can occur. Type III systems are self-dispersing and typically contain a surfactant of high HLB value. Formulations have a comparatively high concentration of oil (type IIIA) or alternatively, some oil is re- placed by other hydrophilic components like co-solvents (type IIIB). SMEDDS are generally in the latter category, and for compositions without any oil a category IV system is assigned. The use of such pure surfactant and co-solvent mixtures is an attractive system for some drugs, but it comes at some costs. Like with type III systems, the drug can precipitate on dispersion. A high surfactant level in the formulation is an issue per se. Thus, the tolerability of such formulations can be problematic, especially with chronic dosing. Another potential issue of high surfactant levels is the compatibility with the capsule shell. It becomes apparent that lipid-based systems like SEDDS must fulill some technical needs apart from their biopharmaceutical performance. So we must overcome several hurdles before a SEDDS is brought to the level of a market formulation. The present article emphasizes relevant aspects of SEDDS, start- ing from early formulation screening to the technical task of capsule manufacturing. An updated guidance should be given to pharmaceutical scientists that can help to better explore this important formulation principle. I. DEVELOPMENT OF CANDIDATE FORMULATIONS 1. Excipient selection for the screening of drug solubility The formulation development of poorly water soluble compounds starts with a thorough pharmaceutical proiling. Stability and solubility tests should be complemented with a biopharmaceutical assessment. A