Effective Oral Delivery of Teriparatide Using Organoclay-Polymethacrylate Nanocomposites for Osteoporosis Therapy.

Background

Although teriparatide is efficacious, its once-daily subcutaneous injections cause local adverse events, inconvenience, and higher cost, limiting long-term adherence. Therefore, this research aims to engineer a pH-responsive oral formulation of teriparatide for osteoporosis therapy.

Methods

A layered silicate nanocomplex was obtained by spontaneous self-assembly of teriparatide (Teri) with 3-aminopropyl magnesium phyllosilicate (AC). The nanocomplex (AC-Teri) was then coated with a 1:1 blend of two polymethacrylic acid derivatives (Eudragit® L100 and Eudragit® S 100) to provide pH-triggered drug release along the gastrointestinal tract.

Results

AC-Teri and the coated nanocomplex (EE/AC-Teri) displayed high encapsulation efficiency (>90%) with narrow size distributions. In a stepwise buffer transition system, EE/AC-Teri demonstrated pH-dependent release, with less than 25% drug liberated at pH 1.2, approximately 54% at pH 6.8, and 74% at pH 7.4 over 24 h. Particle size and ζ-potential of EE/AC-Teri shifted in parallel with dissolution of the outer polymer shell. EE/AC-Teri also protected the peptide against enzymatic degradation, preserving the secondary structure of encapsulated teriparatide in simulated intestinal fluids. Compared with free drug, EE/AC-Teri enhanced transcellular drug permeation 2.7-fold in Caco-2 cells. In dexamethasone-induced osteoporotic rats, oral EE/AC-Teri significantly stimulated bone formation while suppressing resorption; micro-CT and histology confirmed recovery of trabecular architecture.

Conclusions

EE/AC-Teri represents a promising oral teriparatide formulation for the effective management of osteoporosis.