Abstract
In order to incorporate hydrophilic macromolecular drugs into lipid-based formulations (LBF), HIP has shown great potential. In this study, different HIP methods were compared with each other. Hydrophobic complexes were formed between bovine serum albumin (BSA) and either dodecyl sulfate, cetyl trimethylammonium or 1,2-dipalmitoyl-sn-glycero-3-phosphate applying the organic solvent-free method, Bligh-Dyer method and biphasic metathesis reaction either with ethyl acetate or chloroform as organic phase. Complex formation efficiency was determined. Hydrophobicity of the obtained complexes was characterized by their apparent partition coefficient between 1-butanol and water. The highest complex formation efficiency was achieved with the Bligh-Dyer method, followed by the organic solvent-free method and the biphasic metathesis reaction. When applying the organic solvent-free method, complex formation efficiency was hampered at higher surfactant concentrations due to the formation of micelles. Furthermore, this method could only be applied for water-soluble compounds. On the contrary, the Bligh-Dyer method was robust towards high surfactant concentrations. Moreover, it enables the use of water-insoluble compounds. The rank order Bligh-Dyer method > organic solvent-free method > biphasic metathesis reaction was confirmed by the log D. According to these results, the Bligh-Dyer method appears advantageous for HIP. However, the organic-solvent free method is an adequate alternative for water-soluble compounds.
Highlights
Since the 1980s, the number ofpeptide drugs is continuously increasing covering a wide range of therapeutic applications [1,2]
For hydrophobic ion pairing (HIP) with Sodium dodecyl sulfate (SDS) and DPPA-Na, bovine serum albumin (BSA) was dissolved in 0.01 M hydrochloric acid (HCl) (10 mg/ml), whereas for HIP with cetyl trimethylammonium bromide (CTAB), BSA was dissolved in 0.01 M sodium hydroxide (NaOH) (10 mg/ml)
In case of DPPA-Na, the organic solvent-free method leads to significantly lower complex formation efficiencies than the Bligh-Dyer method and the biphasic metathesis reaction with ethyl acetate
Summary
Since the 1980s, the number of (poly)peptide drugs is continuously increasing covering a wide range of therapeutic applications [1,2]. The vast majority of these drugs is administered via the parenteral route. As parenteral administration is associated with pain, risks and low patient compliance, conversions towards non-invasive routes are highly on demand. Among various types of delivery systems, LBF such as self-emulsifying drug delivery systems (SEDDS) have shown potential for non-invasive (poly)peptide delivery. LBF have already shown a remarkable potential for non-invasive (poly)peptide delivery [8,9,10,11], the incorporation of these hydrophilic macromolecular drugs into such lipophilic formulations remains a major challenge
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