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ABSTRACT
Introduction
Diabetes mellitus is one of the challenging health problems worldwide. Multiple daily subcutaneous injection of insulin causes poor compliance in patients. Development of efficient oral formulations to improve the quality of life of such patients has been an important goal in pharmaceutical industry. However, due to serious issues such as low bioavailability and instability, it has not been achieved yet.
Areas covered
Due to functional properties of the vesicles and the fact that hepatic-directed vesicles of insulin could reach the clinical phases, we focused on three main vesicular delivery systems for oral delivery of insulin: liposomes, niosomes, and polymersomes. Recent papers were thoroughly discussed to provide a broad overview of such oral delivery systems.
Expert opinion
Although conventional liposomes are unstable in the presence of bile salts, their further modifications such as surface coating could increase their stability in the GI tract. Bilosomes showed good flexibility and stability in GI fluids. Also, niosomes were stable, but they could not induce significant hypoglycemia in animal studies. Although polymersomes were effective, they are expensive and there are some issues about their safety and industrial scale-up. Also, we believe that other modifications such as addition of a targeting agent or surface coating of the vesicles could significantly increase the bioavailability of insulin-loaded vesicles.
Graphical abstract
Article highlights
Conventional liposomes are unstable in acidic conditions and in the vicinity of bile salts or pancreatic lipases.
Surface coating of liposomes with polymers like chitosan (CS) and silica enhances the stability of the liposomes in GI tract through protecting the liposomes from acidic pH and degradation by GI enzymes and could enhance the absorption rate.
Targeted liposomal formulation such as the biotinylated ones could successfully target liver and enhance the hypoglycemic effect.
Incorporation of exogenous bile salts into the lipid bilayers (developing bilosomes) increased the stability of lipid bilayers. Also, they could reversibly open the tight junctions leading to enhancement of absorption.
In-vivo analysis of niosomes in diabetic rats showed lower bioavailability, which needs more effort to be optimized to reach an acceptable formulation.
Insulin-loaded polymersomes showed promising hypoglycemic effects in animal models; however, these platforms are expensive and there are limited experiences in scaling up such nanoparticles.
Abbreviation
| Ba | = | Relative Bioavailability |
| BLPs | = | Biotinylated Liposomes |
| BSA | = | Bovine Serum Albumin |
| Chol | = | Cholesterol |
| CLips | = | Cationic Liposomes |
| CLPs | = | Conventional Liposomes |
| CS | = | Chitosan |
| DEX | = | Dextran |
| DOTAP | = | Dioleoyl-3-Trimethylammonium Propane |
| DPPC | = | Dipalmitoyl Phosphatidyl Choline |
| DSPE | = | Distearoyl Phosphatidyl Ethanolamine |
| EDTA | = | Ethylenediaminetetraacetic Acid |
| EE | = | Encapsulation Efficiency |
| EPC | = | Egg Phosphatidyl Choline |
| FA | = | Folic Acid |
| FaSSGF | = | Fasted State Simulated Gastric Fluid |
| FaSSIF | = | Fasted State Simulated Intestinal Fluid |
| GI | = | Gastrointestinal |
| h | = | Hour(s) |
| HDV-I | = | Hepatic-Directed Vesicle-Insulin |
| HPMCAS-MF | = | Hydroxypropyl Methylcellulose Acetate Succinate, M Grade Fine Powders |
| HSPC | = | Hydrogenated Soya Phosphatidylcholine |
| Ins | = | Insulin |
| LC | = | Loading Capacity |
| MDCK | = | Madin-Darby Canine Kidney |
| MLVs | = | Multilamellar Vesicles |
| NA | = | Niacin |
| NPs | = | Nanoparticles |
| OGTT | = | Oral glucose tolerance test |
| PA | = | Palmitic Acid |
| PAA | = | Poly (Acrylic Acid) |
| PAH | = | Poly (Allylamine Hydrochloride) |
| PBS | = | Phosphate Buffer Saline |
| PC | = | Phosphatidylcholine |
| PcCLs | = | Protein Corona Liposomes |
| PDI | = | Poly Dispersity Index |
| PE | = | Phosphatidyl Ethanolamine |
| PEG | = | Poly Ethylene Glycol |
| PEO | = | Polyethylene Oxide |
| PLA | = | Poly (Lactic Acid) |
| PLGA | = | Poly Lactic-Co-Glycolic Acid |
| PPG | = | Postprandial glucose |
| PPO | = | polyphenylene oxide |
| PTX | = | Paclitaxel |
| QbD | = | Quality by design |
| REV | = | Reversed-Phase Evaporation |
| rhINS | = | Recombinant Human Insulin |
| SA | = | Stearyl Amine |
| SBE | = | Soya Beans Seed Extract |
| SC | = | Subcutaneous |
| SDC | = | Sodium Deoxycholate |
| SGC | = | Sodium Glycocholate |
| SGF | = | Simulated Gastric Fluid |
| SIF | = | Simulated Intestinal Fluid |
| SNCL | = | Silica Nanoparticles Coated Liposomes |
| SPC | = | Soybean Phosphatidylcholine |
| STC | = | Sodium Taurocholate |
| STZ | = | Streptozotocin |
| TEER | = | Transepithelial Electrical Resistance |
| TFH | = | Thin Film Hydration |
| TH | = | Thiamine |
| TL | = | Tomato Lectin |
| TMC | = | N-Trimethyl Chitosan |
| UEA1 | = | Ulex Europaeus Agglutinin 1 |
| US | = | United States |
| WGA | = | Wheat Germ Agglutinin |
| ZP | = | Zeta Potential |
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/17425247.2023.2266992