There has been growing interest in the use of lipidic excipients in formulations and, in particular, in self-emulsifying lipid
formulations (SELFs) because of their ability to solubilize poorly water-soluble 'lipophilic' drugs and overcome the problem
of poor drug absorption.These formulations have also attracted interest because they can improve the bioavailability of compounds that fall into Class
II of the biopharmaceutical classification system (BCS). Class II compounds are poorly water soluble and highly permeable.1This bioavailability enhancing property has been associated with a number ofin vivoproperties of lipidic formulation including:
- The formation of fine dispersions and micellar suspensions to prevent precipitation and recrystallization of the drug compound.
- The ability of certain lipid compounds and their metabolites to initiate changes in the gastrointestinal fluid to favour improved
drug absorption.
- The inhibition of cellular efflux mechanisms, which keep drugs out of the circulation.
- Certain lipidic excipients are associated with selective drug uptake into the lymphatic transport system, thereby reducing
the effect of first-pass drug metabolism in the liver.2
The mechanisms by which lipids influence drug delivery, digestion and absorption are complex and not yet fully understood.
Nevertheless, it is well known that lipidic excipients provide a safe and effective way of enhancing bioavailability, and
offer an additional approach to 'mechanical' or 'chemical' strategies for dealing with poorly water-soluble compounds (i.e.,
techniques such as nanomilling and altering the physicochemical properties of the compound).
Provided the formulator succeeds in addressing the challenges of drug solubility and absorption, the next big challenge is
the delivery of the drug in an acceptable dosage form. It is an undisputed fact that oral dosage forms are the preferred drug
administration route, and lipid formulations offer versatility for oral dosage forms because they can be formulated as solutions,
and semi-solid and solid forms.
Figure 1 Schematic diagram of SEDDS and SMEDDS.
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Within these oral dosage forms, lipids are formulated as simple emulsions, self-emulsifying and self-micro-emulsifying formulations.
SELF systems comprise a defined mixture of lipid excipients, including simple oils, nonionic surfactants and cosurfactants.
SELF systems act as carriers for drugs by forming fine emulsions, or micro-emulsions, under gentle stirring when diluted in
water or physiological media with physiological motion. Drug molecules are either dissolved or suspended in the SELF system,
which maintains the drug in very fine dispersion droplets inside the intestinal lumen, providing optimal conditions for absorption.Two types of SELF systems exist: self-emulsifying drug delivery systems (SEDDSs) and self-micro-emulsifying drug delivery
systems (SMEDDSs). Both SEDDSs and SMEDDSs have distinct features associated with improved drug delivery properties. SEDDS
formulations can be simple binary systems: lipophilic phase and drug, or lipophilic phase, surfactant and drug. The formation
of a SMEDDS requires the use of a cosurfactant to generate a micro-emulsion. SEDDS formulations are characterized byin vitrolipid droplet sizes of 200 nm–5 mm and the dispersion has a turbid appearance.
SMEDDSs, however, have a smaller lipid droplet size (<200 nm) and the dispersion has an optically clear-to-translucent appearance.
Both systems are associated with the generation of large surface area dispersions that provide optimum conditions for the
increased absorption of poorly soluble drugs. The choice of whether a SEDDS or a SMEDDS is the preferred formulation option
often depends on the interplay between the intrinsic properties of the drug compound and its solubility and dissolution profile
duringin vitroscreening with a number of excipients. The two systems are illustrated schematically in Figure 1.
Table 1 Examples of pharmaceutical products formulated as self-emulsifying systems.
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In terms of dosage form, SELFs are principally liquid or semi-solid formulations and, therefore, ideal for soft or hard capsule
filling. Currently, drugs that utilize SEDDs are exclusively developed in soft or hard gelatin capsules (Table 1). This is
because, until recently, getting a SELF into tablet form was a formulation challenge because of the nature of excipients and
formulation techniques. That is not to say that formulating for a solid dosage form that utilizes a SELF is impossible, but
the starting point for such a formulation requires the use of semi-solid excipients.SELFs have been transformed into solid dosage forms using techniques such as melt granulation, where the lipid excipient acts
as a binder and solid granules are produced on cooling. Solvents or supercritical fluids can be used with semi-solid excipients,
which are solubilized and then the solvent evaporated to produce a waxy powder. Spraying techniques can be used to produce
powder form formulations. These techniques enable the production of granules or powders that can then be compressed into a
tablet form or filled into capsules. In all cases, the lipidic excipients used must be semi-solid at room temperature.
However, in many cases, because of the nature of lipidic excipients, the SELF system is a liquid-based formulation rather
than a semi-solid formulation and, therefore, an alternative approach is required. This article describes the development
and optimization of a solid SELF system to produce a tablet from a liquid SELF.
The concept works by the adsorption/absorption of a liquid SELF onto a neutral carrier (i.e., neutral silicate). Although
surprisingly straightforward, developing this solid dosage form technique has required extensive investigation of critical
success parameters including:
- Extensive screening of different neutral carriers to evaluate their ability to adsorb maximum levels of the liquid SELF.
- Maximum loading value of the carrier and effect on tablet compression.
- Absorption onto the carrier and effect on flowability — an essential feature for tablet compression.
- Evaluation of the integrity of the system with a poorly soluble API to examine the effect of transforming a liquid into a
powder on drug solubility and dissolution rate.
