Development of 1 month core-shell microspheres combination formulation containing teriparatide for osteoporosis treatment.

Teriparatide is a representative anabolic agent for the treatment of osteoporosis; however, its therapeutic efficacy relies on intermittent exposure, necessitating frequent administration and thereby limiting long-term patient compliance. To address this limitation, we developed a programmable pulsatile delivery platform based on uniform core-shell microspheres fabricated via a W1/O/W2 double-emulsion process combined with premix membrane emulsification (PME). Through precise regulation of polymer phase separation, teriparatide is preferentially localized within the microsphere core. Core-shell microspheres constructed with PLLA shells of 7, 36, and 78 kDa exhibit well-defined pulsatile release profiles in vitro, each generating a major release event at approximately 7, 14, and 21 days, respectively, with about 40% of the loaded drug discharged during each pulse. In ovariectomized mice, a single administration of the combined microsphere combination formulation enhances bone formation, suppresses bone resorption, and markedly restores trabecular bone microarchitecture over a one-month treatment period, achieving therapeutic outcomes comparable to those of weekly teriparatide solution injections. Collectively, these findings demonstrate that PME-assisted phase separation core-shell microspheres enable synchronized and temporally programmable pulsatile delivery of teriparatide, offering a versatile platform for long-acting peptide therapeutics in osteoporosis management.