Octreotide Acetate

Oral delivery of peptide drugs (BCS Class III) is limited by gastrointestinal instability, low permeability, and poor systemic bioavailability. FDA-approved oral octreotide capsule Mycapssa® (octreotide, an 8-amino-acid cyclic peptide) shows only 0.7% bioavailability in humans despite permeation enhancers. To enhance octreotide (OCT) absorption, hydrophobic ion pairing (HIP) complexes with sodium deoxycholate (NaDC) or sodium ursodeoxycholate (NaUDC) were formulated into PVP-K30 solid dispersions (HIP:PVP-K30 = 1:3). In vitro dissolution (100 mL pH 6.8 PBS, 37°C, 100 rpm) showed complete release within 10 min for both solid dispersions, which was six-fold faster than OCT-NaDC HIP and three-fold faster than OCT-NaUDC HIP complexes. In everted gut sac studies, NaDC enhanced OCT permeability more effectively than NaUDC. Below CMC, 5 mM NaDC and NaUDC increased the apparent permeability coefficient (P_app) by 3.2-fold and 2.2-fold versus free OCT, respectively. The OCT-NaDC HIP solid dispersion further enhanced P_app by 2.1-fold compared with OCT and 1.5-fold compared with the NaUDC solid dispersion. Caco-2 studies demonstrated a reversible TEER reduction of approximately 30%, as well as ASBT-mediated uptake with OSTα/β efflux and clathrin/caveolin-dependent endocytosis. In vivo, OCT-NaDC HIP solid dispersion achieved a relative oral bioavailability of 11.54% in SD rats versus subcutaneous injection, exceeding OCT-NaDC HIP complexes (6.04%) and the OCT-NaUDC HIP solid dispersion (8.60%). Overall, OCT-NaDC HIP solid dispersion integrates rapid dissolution with bile acid-assisted absorption, offering a practical strategy for oral peptide delivery.

While an oral octreotide formulation (Mycapssa®) utilizing transient permeability enhancement has recently been FDA-approved, its clinical utility is often constrained by strict fasting requirements and reliance on the transient disruption of intestinal tight junctions. To develop a more biomimetic and efficient alternative, we developed the first oral formulation of Octreotide (OCT) using donkey-milk exosomes (DME). These naturally derived vesicles are enriched with membrane-fusion and transcytosis proteins that protect biologics from gastric degradation and facilitate endogenous epithelial transport. Exosomes were isolated from donkey milk powder, characterized by nanoparticle tracking analysis, western blotting, and proteomics, and found to possess a mean size of 138.4 ± 4.37 nm, and zeta potential of -42.07 ± 0.99 mV, and abundant transport-associated proteins including PIGR, MFGE8, ANXA2, CD9, CD63, and CD81. OCT was encapsulated using a pH-gradient method, achieving 7.25% entrapment efficiency. Analytical techniques including ATR-FTIR and DSC reveals the characteristic functional groups and thermal transitions of the components, confirming that octreotide was effectively integrated into the DME formulation. In-vitro dissolution studies demonstrated protective release behavior, while MDCK monolayer assays revealed a 37-fold enhancement in permeability compared to free OCT. Pharmacokinetic performance was predicted by GastroPlus™, which projected a rise in fraction absorbed from 8.5% to 88.2%, a reduction in Tmax from 5.5 to 2.2 h, and a four-fold increase in AUC. These predictions were confirmed in-vivo, where oral administration of OCT-exosomes (2 mg/kg) in BALB/c mice achieved a 16-fold increase in systemic exposure (AUC_0-24: 435,200 pg·h/mL) compared with free OCT, alongside targeted biodistribution to the liver, spleen, kidney, and intestine. This study provides the first proof-of-concept that donkey-milk exosomes can enable effective oral delivery of octreotide. By combining stable encapsulation, epithelial transport facilitation, predictive modeling, and in-vivo validation, this platform offers a scalable and broadly applicable strategy for transforming injectable peptides and biologics into oral therapeutics.