Development andin vitroevaluation of an oral SEDDS for desmopressin

Abstract

Context: Self-emulsifying drug delivery systems (SEDDS) are among most promising tools for improving oral peptide bioavailability. Objective: In this study, in vitro protective effect of SEDDS containing desmopressin against presystemic inactivation by glutathione and a-chymotrypsin was evaluated. Materials and methods: The partitioning coefficient (log P) of desmopressin was increased via hydrophobic ion pairing using anionic surfactants. Solubility studies were performed to select the appropriate solvents for SEDDS preparation. Subsequently, droplet size and emulsification properties of 22 SEDDS formulations were evaluated. Moreover, the peptide-surfactant complex was dissolved in two chosen SEDDS formulations. Finally, SEDDS containing desmopressin were characterized regarding lipase stability, toxicity, and in vitro protective effect toward glutathione and a-chymotrypsin. Results: Desmopressin log P was increased from initial À6.13 to 0.33 using sodium docusate. The resulting desmopressin docusate complex (DES/AOT) was incorporated in two different SEDDS formulations, containing Capmul 907 P as main solvent. DES/AOT-SEDDS-F4 (containing 0.07% w/w DES/AOT) was composed of 50% Capmul 907P, 40% Cremophor RH40, and 10% Transcutol. The comparatively more hydrophilic formulation DES/AOT-SEDDS-F15 (containing 0.25% w/w DES/AOT) consisted of 20% Capmul 907P, 40% Acconon MC8-2, and 40% Tween 20. Both formulations were stable toward digestion by lipase and protected desmopressin toward a-chymotrypsin degradation. Moreover, DES/AOT-SEDDS-F4 also protected the peptide from thiol/disulfide exchange reactions with glutathione and was not cytotoxic at a concentration of 0.375% (w/w). Conclusion: DES/AOT-SEDDS-F4 protected desmopressin from in vitro glutathione and a-chymotrypsin degradation. DES/AOT-SEDDS-F4 was metabolically stable and nontoxic. Therefore, it could be considered as a potential delivery system for oral desmopressin administration.

Hydrophobic ion pairing: encapsulating small molecules, peptides, and proteins into nanocarriers

“…Losartan Arginine-nonyl ester 41 Desmopressin Oleic acid 77 SEDDS 45,77,86,170 Sodium docusate 45,77,86,170 Sodium dodecyl sulfate 77,86 Sodium stearate 77 (note: less effective than SDS, AOT, and oleate) Sodium stearyl sulfate 77…”

“…For example, Zupancic et al paired cationic desmopressin with both sodium n-octadecyl sulfate and sodium stearate. 77 The two have aliphatic tails of similar lengths, but the former has a sulfate head group and the latter has a carboxylic acid. If paired with a cationic API and encapsulated (ceteris paribus, and in a system with no other ionic or pH-sensitive components), we would expect the n-octadecyl sulfate system's release prole not to vary between pH values of e.g.…”

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“…[9] However, in some cases, ion pairing agents have been utilized to enhance the oil solubility of peptides with very low log P values such as desmopressin (log P =−6.13) and enhance the oral bioavailability by prevention against glutathione and α-chymotrypsin mediated presystemic inactivation. [10]…”

Sistemas de entrega de fármacos autoemulsificables: una plataforma de desarrollo alternativa para la industria farmacéutica colombiana

“…Las potenciales ventajas que ofrecen estos sistemas incluyen: una biodisponibilidad oral aumentada, posibilidad de reducción en la dosis, perfiles de absorción del fármaco más reproducibles [50], evitar el metabolismo de primer paso hepático [25,51], orientación selectiva del fármaco a sitios de absorción específica en el tracto gastrointestinal, control en los perfiles de entrega, variabilidad reducida, protección del fármaco (ambiente hostil en el tracto gastrointestinal y fármacos sensibles) [52], mayor capacidad de carga del fármaco y, finalmente, selección de formas de dosificación sólidas y líquidas [53].…”

“…La lipofilicidad del principio activo es un criterio a tener en cuenta para considerar su incorporación en los SEDDS. El coeficiente de partición log P (octanol/agua) es un indicador de la lipofilicidad de un compuesto y de acuerdo a la literatura los principios activos con valores de log P que oscilan entre 2 y 4 son los candidatos adecuados para ser incluidos en estos sistemas [52,66]. En la tabla 4 se muestran algunos principios activos que han sido utilizados en investigaciones relacionadas a la formulación de SEDDS.…”