(28ae) Application of Metal-Organic Frameworks for Pharmaceutics Fields: Improvement of Water Solubility and Multi-Drugs Carrier

Metal-organic frameworks (MOFs) are a new class of porous materials, which consist of metal ions and organic ligands formed through the self-assembly process with coordination bond in between them [1]. MOFs shows a regularly arranged pore structure, a larger surface area, and tunable pore size by choosing the combinations of metal ions and organic ligands. These advantages are promising for various applications such as gas separations, gas storages, and molecular sensors. Furthermore, MOFs are being widely investigated for application in the pharmaceutical field. This study investigated the solubilization of poorly water-soluble drugs using MOFs and the inclusion ability of multiple drugs into MOFs.

The present study demonstrated a novel improvement technology of drug solubility based on MOFs.[2,3] Zeolite imidazolate framework-8 (ZIF-8) was selected as a model MOF, while the analgesic and antipyretic indomethacin (IDM) was selected as a model poorly water-soluble drug. The loading test of IDM onto ZIF-8 particles indicated that IDM was loaded by deposition on the particle surface. The amount of IDM loaded on ZIF-8 was found to be 1.21 g IDM/g ZIF-8. X-ray diffraction measurements revealed that the IDM loaded on ZIF-8 assumed a new crystal phase similar to the η-form IDM. Finally, water solubility of IDM loaded on ZIF-8 was 45 times higher than that of the original γ-form IDM. It was concluded that use of ZIF-8 MOF dramatically improves water solubility of active pharmaceutical ingredients.

As the inclusion ability of multiple drugs into MOFs, γ-CD-MOFs, which are composed of γ- cyclodextrin (CD) and potassium ions, was focused on. The CD has a cyclic structure with a hydrophilic outer surface and hydrophobic cavities. Therefore, γ-CD-MOF also has hydrophobic and hydrophilic pores. 5-fluorouracil (5FU) and ascorbic acid (ASC) were selected as model hydrophobic and hydrophilic drugs, respectively. The inclusion amounts of each drug in the experiments were measured. Single drug inclusion experiments were performed under various initial drug concentration conditions. The molecular simulations using grand canonical Monte Carlo method (GCMC) were also performed to investigate which of the hydrophilic and hydrophobic pores would encapsulate the drugs. Furthermore, the multiple-drug inclusion ability of γ-CD-MOF was evaluated. In the single-drug inclusion experiments, both 5FU and ASC were included in γ-CD-MOF with comparable inclusion amounts. The GCMC simulation suggested that 5FU was included in the hydrophobic pore of γ-CD-MOF, followed by the hydrophilic pore. On the other hand, ASC was suggested to be included in hydrophobic and hydrophilic pores at an early phase. The multiple-drug inclusion experiments of 5FU and ASC confirmed that both drugs were simultaneously included in γ-CD-MOF. Comparison with the GCMC simulations suggested that drug-solvent interactions were involved in the actual drug inclusion.

[1] S. Kitagawa et al., Angew. Chem. Int. Ed. Engl., 43, 2334 (2004).

[2] S. Ohsaki et al., J. Drug Deliv. Sci. Technol., 63, 102490 (2021).

[3] K. Ohshima et al., Chem. Pharm. Bell., 70, 383-390 (2022)