Preparation and evaluation of a lipid-based drug delivery system to ımprove valsartan oral bioavailability: pharmacokinetic and pharmacodynamic analysis

Abstract

Antihypertensive treatment reduces the risk of cardiovascular complications in patients with high mortality with hypertension. Valsartan is highly selective antihypertensive that is rapidly absorbed after oral administration, but its oral bioavailability is only 25%. It is absorbed from the upper part of the gastrointestinal tract but is less soluble in this acidic environment. We aimed to develop a lipid-based formulation to produce a self-emulsifying drug delivery system (SEDDS) for valsartan. Solubility studies were performed to identify the components of the SEDDS that provided the best dissolution of valsartan. Ternary phase diagrams were drawn using the titration method with oil, surfactants and co-surfactants in which valsartan was highly soluble, and microemulsion formulations with the highest area were determined. Characterization and in vitro release studies were performed to optimize the formulation. In vitro release profiles of commercial and SEDDS formulations showed the F2 formulation release rate increased at pH 1.2 fasted state simulated gastric fluid. After oral administration, plasma drug concentrations in rats indicate that the F2 formulation provided a 4.2-fold greater AUC for valsartan than the commercial formulaiton, resulting in an 8.5-fold greater Cmax. These findings suggest the F2 formulation increases valsartan solubility, resulting in an improved oral pharmacokinetic profile. According to the pharmacodynamic study, the F2 formulation is more effective than the commercial formulation in restoring systolic and diastolic blood pressure within a few hours.

Keywords:

• Valsartan
• antihypertensive
• lipid-based drug delivery
• self-emulsifying drug delivery systems
• SEDDS
• PK/PD

Acknowledgement

We are grateful to Ege University Planning and Monitoring Coordination of Organizational Development and Directorate of Library and Documentation for their support in editing and proofreading service of this study.

Author contributions

Eda Gülmezoğlu: Conceptualization, Methodology, Validation, Formal Analysis, Investigation, Writing–Original Draft Preparation, Visualization. Gülbeyaz Yıldız Türkyılmaz: Conceptualization, Methodology, Software, Validation, Formal Analysis, Investigation, Resources, Data Curation, Writing–Original Draft Preparation, Writing–Review & Editing. H. Yeşim Karasulu: Conceptualization, Methodology, Software, Formal Analysis, Investigation, Resources, Writing–Original Draft Preparation, Writing–Review & Editing, Supervision, Project Administration, Funding Acquisition.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This study was supported by The Scientific and Technological Council of Turkey [TUBİTAK Project No: 117S821].