Role of self-emulsifying drug delivery systems in optimizing the oral delivery of hydrophilic macromolecules

Self-emulsifying drug delivery systems (SEDDS) have been widely employed to improve the oral bioavailability of poorly soluble drugs. In the past few years, SEDDS were extensively investigated to overcome various barriers encountered in the oral delivery of hydrophilic macromolecules (e.g., protein/peptide therapeutics and plasmid DNA (pDNA)), as well as in lowering the effect of food on drugs‘ bioavailability. However, the main mechanism(s) by which SEDDS could achieve such promising effects remains not fully understood. This review summarizes the recent progress in the use of SEDDS for protecting protein therapeutics and/or pDNA against enzymatic degradation and increasing the oral bioavailability of various drug substances regardless of the dietary condition. Understanding the underlying mechanism(s) of such promising applications will aid in the future development of rationally designed SEDDS. Entrapment of hydrophilic macromolecules in the oil phase of the formed emulsion is critical for protection of the loaded cargoes against enzymatic degradation and the enhancement of oral bioavailability. On the other hand, drug administration as a preconcentrated solution in the SEDDS preconcentrate allows the process of drug absorption to occur independently of the dietary condition, and thus reducing interindividual variability that results from concomitant food intake.

 

Highlights

• Incorporation of hydrophilic molecules in SEDDS oil phase is a challenge.

• Loading of protein/genetic material inside SEDDS oil phase is crucial.

• Slow release of proteins from the ultrafine oil droplets avoids their degradation.

• SEDDS eliminate food effects on oral bioavailability.

 

Conclusion

The incorporation of hydrophilic macromolecules into SEDDS preconcentrates represents a major obstacle due to their hydrophilic nature. Various approaches were employed to overcome this obstacle, among them, hydrophobic ion pairing was the most widely studied. Protein therapeutic or pDNA incorporated into the ultrafine oil droplets as HIP complexes showed a significantly higher stability against enzymatic degradation compared to free solutions or a suspension of the HIP complex. The formulation of protein therapeutic as a physical mixture with SEDDS excipients (i.e., surfactants or oils) or its co-administration with SEDDS preconcentrate significantly enhanced its Papp value, yet, this effect was absent in vivo due to the lack of protective effect against enzymatic degradation. Hence, the entrapment of a given protein in the oil phase of the resultant emulsion is critical for its protection against enzymatic degradation and the enhancement of its oral bioavailability. SEDDS mediated enhancement in the oral bioavailability of protein therapeutics or pDNA could be further augmented by the bioactive effects of their ingredients, such as, the slight opening of tight junction between intestinal epithelial cells. Another interesting application of SEDDS is the abolishment of food effect on the bioavailability of drugs, which is a major source of interindividual variability in drug response. The oral bioavailability of such drugs was comparable in different dietary conditions following its administration as SEDDS. The reduced food effect by SEDDS is mainly attributed to drug administration as a preconcentrated solution, and thus allowing drug absorption to occur independently of the dietary state. Additionally, other formulation aspects, such as, the nanometric size range of the resultant oil droplets and the bioactive effects of various ingredients could further enhance drugs‘ bioavailability regardless of the dietary condition.

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Graphic which explains the mechanisme of self-emulsifying drug delivery systems protecting proteins or DNA
SEDDS shield proteins and genetic materials against harsh GI conditions

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