Anti-tuberculosis drug combination for controlled oral delivery using 3D printed compartmental dosage forms: From drug product design to in vivo testing

TY - JOUR

T1 - Anti-tuberculosis drug combination for controlled oral delivery using 3D printed compartmental dosage forms: From drug product design to in vivo testing

AU - Genina, Natalja

AU - Boetker, Johan Peter

AU - Colombo, Stefano

AU - Harmankaya, Necati

AU - Rantanen, Jukka

AU - Bohr, Adam

PY - 2017/12/28

Y1 - 2017/12/28

N2 - The design and production of an oral dual-compartmental dosage unit (dcDU) was examined in vitro and in vivo with the purpose of physically isolating and modulating the release profile of an anti-tuberculosis drug combination. Rifampicin (RIF) and isoniazid (ISO) are first line combination drugs for treatment of tuberculosis (TB) that negatively interact with each other upon simultaneous release in acidic environment. The dcDUs were designed in silico by computer aided design (CAD) and fabricated in two steps; first three-dimensional (3D) printing of the outer structure, followed by hot-melt extrusion (HME) of the drug-containing filaments. The structure of the fabricated dcDUs was visualized by scanning electron microscopy (SEM). The 3D printed compartmentalized shells were loaded with filaments containing active pharmaceutical ingredient (API) and selectively sealed to modulate drug dissolution. The drug release profile of the dcDUs was characterized by pH-transfer dissolution in vitro and pharmacokinetics studies in rats, and resulted in modified release of the APIs from the dcDUs as compared to the free filaments. Furthermore, the selective physical sealing of the compartments resulted in an effective retardation of the in vitro API release. The findings of this study support the development of controllable-by-design dcDU systems for combination therapies to enable efficient therapeutic translation of oral dosage forms.

AB - The design and production of an oral dual-compartmental dosage unit (dcDU) was examined in vitro and in vivo with the purpose of physically isolating and modulating the release profile of an anti-tuberculosis drug combination. Rifampicin (RIF) and isoniazid (ISO) are first line combination drugs for treatment of tuberculosis (TB) that negatively interact with each other upon simultaneous release in acidic environment. The dcDUs were designed in silico by computer aided design (CAD) and fabricated in two steps; first three-dimensional (3D) printing of the outer structure, followed by hot-melt extrusion (HME) of the drug-containing filaments. The structure of the fabricated dcDUs was visualized by scanning electron microscopy (SEM). The 3D printed compartmentalized shells were loaded with filaments containing active pharmaceutical ingredient (API) and selectively sealed to modulate drug dissolution. The drug release profile of the dcDUs was characterized by pH-transfer dissolution in vitro and pharmacokinetics studies in rats, and resulted in modified release of the APIs from the dcDUs as compared to the free filaments. Furthermore, the selective physical sealing of the compartments resulted in an effective retardation of the in vitro API release. The findings of this study support the development of controllable-by-design dcDU systems for combination therapies to enable efficient therapeutic translation of oral dosage forms.

KW - Isoniazid

U2 - 10.1016/j.jconrel.2017.10.003

DO - 10.1016/j.jconrel.2017.10.003

M3 - Journal article

C2 - 28993169

SN - 0168-3659

VL - 268

SP - 40

EP - 48

JO - Journal of Controlled Release

JF - Journal of Controlled Release

ER -