Table 1 GLP-1 analogs and their formulation strategies.
From: Designing GLP-1 delivery: structural perspectives and formulation approaches for optimized therapy
Drug/Route of administration | Formulation Strategies | Core components | Key Outcomes | References |
|---|---|---|---|---|
A. Nano-Formulations | ||||
Exenatide (Oral) | Hybrid Zein NPs: Zein/casein/HP/PC/CA core; COM NPs (241 nm, 79.7% EE), DIS NPs (177 nm, 53.6% EE) | Zein, casein, hypromellose phthalate (HP), phosphatidylcholine (PC), cholic acid (CA) | COM NPs (18.6% bioavailability), DIS NPs (13.1%). HbA1c Reduction: COM NPs (6.79%), DIS NPs (7.08%). Sustained glycemic control (36% BGL reduction). Stability: >90% EXE integrity post-lyophilization | [76] |
Aptamer Liposomes: DSPC/cholesterol with Apt-T-M3 aptamer (93 nm, 40% EE) | DSPC, cholesterol and Apt-T-M3 | Aptamer liposomes (2.4x M-cell uptake), Glucose reduction ranged from 36–67.53% over 5 to 12 h (Fc-NPs) | ||
Fc-Modified polyethylene glycol-Poly lactic-co-glycolic acid (PEG-PLGA) NPs: 130 nm, >80% EE | PEG-PLGA (PEG5000-PLGA20000) | |||
SNEDDS: (26–230 nm) | Ethyl oleate (oil phase), Cremophor EL® (surfactant), Labrasol® (surfactant), propylene glycol (co-surfactant) | SNEDDS (73% proteolysis protection) 6.45% relative bioavailability with transferrin NPs (1.57-fold), and 13.29% bioavailability with CS-EDB achieving 67.53% glucose reduction over 12 h. | ||
Transferrin-PEG-PLGA NPs (120.6 nm) | PEG-PLGA | |||
Chitosan-coated NPs (CS-EDB, +28.4 mV) | Chitosan | |||
Multilamellar lipid-polymer hybrids | Pluronic F-68 and lecithin anchoring polypropylene oxide blocks to lipid bilayers | lipid-polymer hybrids: Delayed Tmax to 0.75 h compared to 0.5 h for free drug 54.8% glucose reduction over 5 h | [82] | |
Zinc ion-complexed PEG-PLGA. | PEG-PLGA, Zinc ions | Ex-4@DFO NPs: Neuroprotective benefits included 45% TNF-α suppression 85% dopaminergic neuron preservation. Zinc systems preserve 83% α-helix. | ||
Deferoxamine nanoparticles | Exendin-4-conjugated deferoxamine | |||
Folate receptor-targeted FA-RM-LNC | Folic acid, PEG, lipid | 7.5% bioavailability, sustaining glucose reduction for 5 days | ||
Cell penetrating peptide (CPP)-modified liposomes (150 nm) with tetraether lipids | - | CPP liposomes: A 20-fold increase in bioavailability was achieved via bile salt resistance. | ||
Liraglutide (Oral) | PLGA NPs Eudragit-Coated (159 nm, 75% EE) for enhanced gastric stability | Eudragit, PLGA, Polyvinyl alcohol (PVA), Mannitol/Trehalose, sucrose | PLGA systems:~50% fasting glucose reduction in HFD/STZ rats, sustained 48 h release. | |
PB-optimized PLGA systems (188 nm, 51.8%) | ||||
Cationic amphiphilic cyclodextrin nanoparticles (101 nm) | Cyclodextrin, dextran sulfate | Cyclodextrin NPs: 54% hyperglycemic AUC reduction, 62.6% yield, 7-month stability. | [88] | |
Sodium deoxycholate-based nanomicelles (LDD [1:2:4]-NM). | Sodium deoxycholate | Nanomicelles: 59% adipose mass reduction, Cmax 1143 ng/mL, all systems preserved α-helix structure | [89] | |
Semaglutide (Oral) | Ionic Nanocomplex (EAMP-Sema): 318 nm, 92.5% EE | 3-aminopropyl-functionalized magnesium phyllosilicate (AMP), Eudragit S100 | EAMP-Sema: 18% HbA1c reduction, 12% weight loss | [90] |
SEMA-RM-LNC: Reverse micelles (188 nm, 90.5% EE) | Labrafac® WL 1349, Span® 80 encapsulating semaglutide. Lipid nanocapsules (LNC) with Lipoid® S100 (soybean lecithin), Kolliphor® HS15, Peceol®, NaCl. | SEMA-RM-LNC: Fasting glucose 135.9 mg/dL (vs. 165.7 mg/dL Rybelsus®) | [91] | |
CS.HCL-NIO: Chitosan-coated niosomes (166–187 nm, 62–66% EE) | Niosomes (Span 60, cholesterol) with nonionic surfactants (Brij 58 or poloxamer F127) as permeation enhancers. Chitosan hydrochloride (CS.HCL) - coating | CS.HCL-NIO: 50% BGL reduction in 24 h (Brij 58 outperformed poloxamer F127) | [92] | |
FcRn-targeted NPs: PLGA-PEG- Maleimide (Mal) with FcBP/ZFcRn ligands (<200 nm, 56–69% EE) | PLGA-PEG- Mal NPs | FcRn NPs: 30–45% glycemic control, 2x insulin content restoration | [93] | |
MWCNT-HSA complexes, Reverse micelle SEDDS (ELA/docusate) | sodium taurocholate, PVA, cationic ethyl lauroyl arginate (ELA) | MWCNTs: 2.11x HSA binding affinity. RM-SEDDS: 96.8% EE, 6.45% bioavailability (1.57x non-targeted). | ||
pH-responsive mExos@DSPE-Hyd-PMPC, and milk-derived sEVs (100–200 nm). | Distearoylphosphatidylethanolamine (DSPE)-PMPC liposomes, bovine milk | mExos: 8.7% bioavailability, 24 h plasma persistence. sEVs: 56.4% EE, 45–60% glucose reduction (matches subcutaneous). | ||
Exenatide (Subcutaneous) | Exenatide-loaded lecithin nanoparticles (Ex-NPs) (5.29 µm and 66% EE) via S/O/W encapsulation | PLGA (50:50, Mw = 40 kDa), Trehalose | Ex-NPs: 30-day sustained release, AUC₀–∞ 10,298.89 ng·h/mL, | [98] |
EXT-SBA-15 mesoporous silica (920 nm, 15% LE) with 6 nm pores. | Hexagonal mesoporous silica nanoparticles | Silica: 25- day glycemic control, extending half-life 24-fold (14.53 h vs. 0.60 h free drug). | [99] | |
Hyaluronic acid-coated RMs-O/W-HA (pH-responsive) | Hyaluronic acid | RMs-O/W-HA: 85% intestinal release (pH 6.8), matches subcutaneous efficacy within 8 h. | [100] | |
Dendritic Silica Nanoparticles (DSNPs): Silica with radial dendritic pores (226–742 nm, 25–40% LE) | Large-pore (~10 nm) silica. Phosphonate (PDSNPs), amino-propyl (ADSNPs), succinic anhydride (SDSNPs), and chitosan-coated PDSNPs (CPDSNPs). | Permeability - 1.7-fold increase vs. free exenatide (PDSNPs/CPDSNPs) PDSNPs: 70% burst release at pH 1.2, 80% cumulative release at pH 6.8. CPDSNPs: Reduced burst release (18% at pH 1.2, 30% at pH 6.8) | [101] | |
Lixisenatide (Subcutaneous) | Leverages ternary PA/Lix/Fe³⁺ nanoparticles (50–61 nm) assembled via flash nanocomplexation. | Phytic acid (PA), Fe³⁺ ions | Sustained BGL < 10 mmol/L for 180 h post-single dose 24.1% HbA1c reduction 67.5% cholesterol reduction. Fe³⁺-phytic acid - enables 7.5-day glucose control post-single dose | [102] |
B. Microparticles | ||||
Exenatide (Pulmonary and Injections) | Spray-dried microparticles using a 20:80 BMS-686117/mannitol ratio | Mannitol | Achieved 45% bioavailability and a rapid onset, with Tmax reduced to 0.67 h (50% faster than SC). | [103] |
Chitosan-modified PLGA microspheres | PLGA, chitosan (0.2% w/v) | CS-PLGA: The systems provided 53.97% EE, 30-day sustained release, 40% increased bone-implant contact | [104] | |
Palmitic acid-conjugated exenatide in multivesicular liposomes (MVLs). | Palmitic acid, DSPC, cholesterol | MVLs: a half-life of 77.28 h (vs 1.67 h native), and a 664.18% improvement in bioavailability. | [105] | |
Semaglutide (Oral and Injections) | Gelatin-alginate-succinic acid/ethylcellulose-methacrylic acid CoCo microparticles via spray drying | Ethylcellulose, methacrylic acid copolymer | CoCo: 6.8% oral bioavailability, 82% intestinal release | |
PLGA microspheres (SEM-MS-M/SEM-MS-T) | 30 kDa:10 kDa PLGA (9:1), Tween 20 | SEM-MS-M/SEM-MS-T: Linear release over 41 days, matches weekly SC efficacy | ||
Hydroxyethyl starch (HES) in a W₁/O/W₂ emulsion stabilized semaglutide via hydrogen bonding | PLGA, HES | HES: 94.38% EE, 21.38 µm size, and sustained release (83.23% over 44 days) 32.29% decrease in fasting glucose (25-day control) | ||
W/O/W emulsion method using Resomer® polymers | Resomer® polymers, NaCl, methionine | Resomer® polymers: 15.5% weight loss (obese rats) 96.6–97.8% EE Sustained release over 28 days | ||
C. Microneedles | ||||
Exenatide (Transdermal) | Double-layered PLGA microparticle-dissolving microneedle (MPs-DMN) | PLGA, HA, sucrose | MP’s DMN: Higher drug loading (22.76%, 4.6× Bydureon®) and superior cutaneous delivery (92.86%) with a long plasma half-life (466.4 h) and 89.71% bioavailability. Glucose levels <20 mmol/L for 14 days, indicating long-term glycemic control | |
Sodium alginate (SA) sustained-release microneedles (TS-MNs) | SA, PVA/PVP, CaCl2 | TS-MNs: 83.04% bioavailability vs. subcutaneous and sustained 81.06% drug release over 48 h. 24 h hypoglycemia, no drug resistance over 6 days showed >85% stability at 40 °C over 2 months | ||
Liraglutide (Transdermal) | Egg-inspired MN (EMN) suitable for transdermal insertion | HA (shell), sucrose/trehalose (core) | EMN: strong peptide stability (85% at 40 °C for 2 months) enhanced oxidative protection (9.06% degradation vs. 35.32% in conventional systems) moderate mechanical strength (0.11 N/needle) | |
PLGA nanoparticle-embedded PVP/PVA MNs supports robust skin penetration | PLGA nanoparticles (353 nm, PDI 0.413), PVP/PVA | PVP/PVA MNs: Superior mechanical strength (5.31 N vs. 4.32 N pure drug) Biphasic release: 80% in 8 days + 15-day sustained delivery 94.42% drug integrity (4 °C/30 days) | ||
Semaglutide (Transdermal) | Dynamic omnidirectional adhesive microneedle system (DOAMS) | Polycaprolactone, Carbopol®, SNAC enhancer | 0.25 N mucosal adhesion force 6× higher plasma concentrations (72 h, swine) Spring-actuated gastric deployment | [114] |
D. Injectable Hydrogels | ||||
Exenatide | pH/temperature-responsive pentablock copolymer composed of oligoester serine (OS) blocks (OS-PLA-PEG-PLA-OS) with chitosan nanospheres | OS-PLA-PEG-PLA-OS, chitosan (3.5 wt%) | 26% reduction in burst release (vs. free drug) Therapeutic levels >72 h Electrostatic interactions (ζ-potential: -5 mV to -1.4 mV) | [45] |
Liraglutide | Thermogelling polyester-PEG systems: 1. PLGA-PEG-PLGA 2. PCGA-PEG-PCGA | PLGA-PEG-PLGA, PCGA-PEG-PCGA | 56% release over 9 days 2. 85% release (flexible chains) Blended hydrogel: Triphasic release (<10% burst, linear over 9 d) | [115] |
Lixisenatide | 1:1 blended hydrogel (PLGA-PEG-PLGA + PCGA-PEG-PCGA) | PLGA-PEG-PLGA, PCGA-PEG-PCGA | 89.7% bioavailability 1.5% HbA1c reduction, 136% plasma insulin increase 35% LDL-C decrease (3 monthly injections) | [116] |
E. Implants | ||||
Exenatide | NanoPortal Implant (NPM-115): Titanium-oxide nanoporous membrane. | Biocompatible titanium-oxide, Nanoporous membrane | NPM-115 - 82% liver fat reduction (obese mice), Twice-yearly administration. Phase – 1 trial compared with Bydureon BCise® and Wegovy® | [117] |
OKV-119: Miniature subdermal implant (tracking chip-sized) | - | OKV-119 - 84-day sustained release, 1.5 to 4 ng/ml plasma concentrations, Significant weight loss in obese cats | ||
ITCA 650 Osmotic Mini-Pump: Titanium cylinder (4 ×44 mm). | Titanium substrate, adjustable pore sizesOsmotic engine (NaCl), semipermeable membrane | ITCA 650: HbA1c reduction: 1.1–1.2% vs. placebo (0.1%), Weight loss: 2.3–3.0 kg vs. placebo (1.0 kg), 3 to 6-month duration | [120] | |
