TY - JOUR

T1 - Mechanisms of deformable nanovesicles based on insulin-phospholipid complex for enhancing buccal delivery of insulin

AU - Xu, You

AU - Zhang, Xing

AU - Zhang, Yun

AU - Ye, Jun

AU - Wang, Hong-Liang

AU - Xia, Xuejun

AU - Liu, Yuling

PY - 2018

Y1 - 2018

N2 - Background: Non-injectable delivery of peptides and proteins are not feasible due to its large molecular, high hydrophilic and gastrointestinal degradation. Therefore, proposing a new method to solve this problem is a burning issue.Purpose: The objective of this study was to propose a novel protein delivery strategy to vanquish the poor efficacy of buccal mucosa delivery systems for protein delivery and then investigate the detailed mechanisms of the enhanced buccal delivery of protein, using insulin as a model drug.Materials and methods: Insulin-phospholipid complex combined with deformable nanovesicles (IPC-DNVs) were prepared, using deformable nanovesicles based on insulin (INS-DNVs) and conventional nanovesicles based on insulin-phospholipid complex (IPC-NVs) as references. Besides, their physicochemical characterization, in vitro transport behavior, in vivo bioactivity and hypoglycemic effect were systematically characterized and compared. Finally, we evaluated the in vivo safety of IPC-DNVs.Results: First, IPC-DNVs increased insulin permeability through deposition of the IPC and deformability of the DNVs, which was revealed by an in vitro mucosal permeation study. Second, DNVs could act as a drug carrier and penetrate the mucosa to reach the receiver medium as intact nanovesicles, which was supported by the observation of intact nanovesicles in the receiver medium through transmission electron microscopy (TEM). Third, IPC-DNVs exhibited both transcellular and paracellular transport in the form of IPC and DNVs, respectively, which was proved by confocal laser scanning microscopy (CLSM). Unlike the other two formulations, IPC-DNVs exhibited a sustained mild hypoglycemic effect, with a relative bioavailability (Fp) of 15.53% (3.09% and 1.96% for INS-DNVs and IPC-NVs, respectively). Furthermore, buccal administration of IPC-DNVs resulted in no visible mucosal irritation to the buccal mucosa.Conclusion: Our work reveals the mechanisms underlying the enhanced buccal delivery of IPC-DNVs: the DNVs facilitate penetration through the main barrier, and the deposition of IPC enhances buccal absorption. Our results and proposed mechanisms could be an important reference to understand other nanocarriers based on protein (peptide)-phospholipid complexes that penetrate the mucosa and provide a theoretical basis for the future development of buccal delivery systems for insulin.

AB - Background: Non-injectable delivery of peptides and proteins are not feasible due to its large molecular, high hydrophilic and gastrointestinal degradation. Therefore, proposing a new method to solve this problem is a burning issue.Purpose: The objective of this study was to propose a novel protein delivery strategy to vanquish the poor efficacy of buccal mucosa delivery systems for protein delivery and then investigate the detailed mechanisms of the enhanced buccal delivery of protein, using insulin as a model drug.Materials and methods: Insulin-phospholipid complex combined with deformable nanovesicles (IPC-DNVs) were prepared, using deformable nanovesicles based on insulin (INS-DNVs) and conventional nanovesicles based on insulin-phospholipid complex (IPC-NVs) as references. Besides, their physicochemical characterization, in vitro transport behavior, in vivo bioactivity and hypoglycemic effect were systematically characterized and compared. Finally, we evaluated the in vivo safety of IPC-DNVs.Results: First, IPC-DNVs increased insulin permeability through deposition of the IPC and deformability of the DNVs, which was revealed by an in vitro mucosal permeation study. Second, DNVs could act as a drug carrier and penetrate the mucosa to reach the receiver medium as intact nanovesicles, which was supported by the observation of intact nanovesicles in the receiver medium through transmission electron microscopy (TEM). Third, IPC-DNVs exhibited both transcellular and paracellular transport in the form of IPC and DNVs, respectively, which was proved by confocal laser scanning microscopy (CLSM). Unlike the other two formulations, IPC-DNVs exhibited a sustained mild hypoglycemic effect, with a relative bioavailability (Fp) of 15.53% (3.09% and 1.96% for INS-DNVs and IPC-NVs, respectively). Furthermore, buccal administration of IPC-DNVs resulted in no visible mucosal irritation to the buccal mucosa.Conclusion: Our work reveals the mechanisms underlying the enhanced buccal delivery of IPC-DNVs: the DNVs facilitate penetration through the main barrier, and the deposition of IPC enhances buccal absorption. Our results and proposed mechanisms could be an important reference to understand other nanocarriers based on protein (peptide)-phospholipid complexes that penetrate the mucosa and provide a theoretical basis for the future development of buccal delivery systems for insulin.

KW - Administration, Buccal

KW - Animals

KW - Drug Carriers/chemistry

KW - Drug Delivery Systems

KW - Humans

KW - Hypoglycemia/drug therapy

KW - Hypoglycemic Agents/administration & dosage

KW - Insulin/administration & dosage

KW - Male

KW - Mouth Mucosa/metabolism

KW - Nanoparticles/chemistry

KW - Oral Mucosal Absorption

KW - Permeability

KW - Phospholipids/chemistry

KW - Rabbits

KW - Swine

U2 - 10.2147/IJN.S175425

DO - 10.2147/IJN.S175425

M3 - Journal article

C2 - 30519017

VL - 13

SP - 7319

EP - 7331

JO - International Journal of Nanomedicine (Print)

JF - International Journal of Nanomedicine (Print)

SN - 1176-9114

ER -