Quality by design aided self-nano emulsifying drug delivery systems development for the oral delivery of Benidipine: Improvement of biopharmaceutical performance

Abstract

The primary objective of the research effort is to establish efficient solid self-nanoemulsifying drug delivery systems (S-SNEDDS) for benidipine (BD) through the systematic application of a quality-by-design (QbD)-based paradigm. Utilizing Labrafil M 2125 CS, Kolliphor EL, and Transcutol P, the BD-S-SNEDDS were created. The central composite design was adopted to optimize numerous components. Zeta potential, drug concentration, resistance to dilution, pH, refractive index, viscosity, thermodynamic stability, and cloud point were further investigated in the most efficient formulation, BD14, which had a globule size of 156.20 ± 2.40 nm, PDI of 0.25, zeta potential of −17.36 ± 0.18 mV, self-emulsification time of 65.21 ± 1.95 s, % transmittance of 99.80 ± 0.70%, and drug release of 92.65 ± 1.70% at 15 min. S-SNEDDS were formulated using the adsorption process and investigated via Fourier transform infrared spectroscopy, Differential scanning calorimeter, Scanning electron microscopy, and powder X-ray diffraction. Optimized S-SNEDDS batch BD14 dramatically decreased blood pressure in rats in contrast to the pure drug and the commercial product, according to a pharmacodynamics investigation. Accelerated stability tests validated the product’s stability. Therefore, the development of oral S-SNEDDS of BD may be advantageous for raising BD's water solubility and expanding their releasing capabilities, thereby boosting oral absorption.

Keywords:

• Benidipine
• solid self-nanoemulsifying drug delivery systems
• S-SNEDDS
• ternary phase diagram
• central composite design
• CCD
• quality by design: QBD

Acknowledgments

The authors extend their appreciation to the Deanship of Scientific Research at King Khalid University, Saudi Arabia, for funding this work through the Large Program (grant number RGP-2/374/44). We are very thankful to Nikishan Pharmaceuticals (India), Gettefosse (India), BASF (India), Fuji Chemical Industries (USA), and Torrent Research Center (India) for providing respective gift samples. We are thankful to Faculty of Pharmacy, Noble University, Junagadh, and School of Pharmaceutical Science, Atmiya University, Rajkot for providing the facilities to carry out the research work.

Ethical approval statement

The animal study protocol was approved by the IAEC of 20th Institutional Animal Ethics Committee, Accuprec Research Labs Pvt. Ltd., Ahmedabad, dated 7/10/2022 (Letter No. ARI/PT/712/2022). Self-emulsifying drug delivery systems (SNEDDS) are recognized for increasing the solubility and bioavailability of hydrophobic drugs like Benidipine, a BCS class II agent with low solubility and high permeability. Benidipine also binds effectively to proteins (98%), causing issues with its solubility during formulation. Our work attempts to explore the pharmacodynamic impact of a newly built self-nanoemulsifying drug delivery system (SNEDDS) for Benidipine. Using animals in this study is an appropriate technique to examine the pharmacodynamics impact of a newly built SNEDDS for delivering Benidipine with solubility and bioavailability challenges.

Animals had been kept in a polypropylene cage with a stainless steel grill on top. The bedding material was dried wheat husk (post-hulled) that was replaced every morning during acclimatization periods. The rats were given a typical rat pellet diet. The drinking water was given in polypropylene bottles with stainless steel sipper tubes at all times. Animals were subjected to 12 h of day and night cycles with a standard temperature of 23 ± 3 °C and a relative humidity of 50–60%. No use of anesthetics or analgesics was allowed for the performance of the study, and clinical signs and mortality were checked out at least once a day. The authors have adhered to the ARRIVE guidelines.

Author contributions

Conceptualization: S.B and M.R.; data curation: S.B and I.P.; formal analysis: S.B. and K.G.; investigation: S.B.; methodology: S.B.; K.G.; validation: M.M.A., and S.A.F..; visualization: S.A.F. and M.R.; writing—original draft preparation: S.B., K.G. and S.S.; writing—review and editing: S.A.F., I.P., B.B., and M.R; funding acquisition: M.R.; project administration: S.B; resources: S.B., I.P. and S.A.F.; software: S.B. and K.G. All authors have read and agreed to the published version of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

The data presented in this study are available on request from the corresponding author.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This project was funded by the Deanship of Scientific Research at King Khalid University, Saudi Arabia, through the Large Program (grant number RGP-2/264/44).