# US 10,500,218 B2 · Uptake of pharmaceuticals within cyclodextrin-based porous materials > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,500,218 B2 - Document ID: US10500218B2 - Status: Granted - Kind: B2 - Application number: 15/350,975 - Filed: 2016-11-14 - Published: 2017-05-18 - Granted: 2019-12-10 - Earliest claimed: 2015-11-15 - Assignees: Northwestern University; King Abdulaziz City for Science and Technology - Applicants: Northwestern University; King Abdulaziz City for Science and Technology - Inventors: Karel J. Hartlieb; James M. Holcroft; James Fraser Stoddart; Daniel Patrick Ferris - Web page: https://patentgrep.com/patent/US10500218B2 ## CPC - A61K 31/616: by carboxylic acids, e.g. acetylsalicylic acid - A61K 31/192: having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid {(cannabinoids A61K31/658)} - A61K 47/6951: {using cyclodextrin (cyclodextrins used as simple excipients A61K47/40)} - C08B 37/0015: {Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes} - C08L 5/16: Cyclodextrin; Derivatives thereof - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - C08B: POLYSACCHARIDES; DERIVATIVES THEREOF (polysaccharides containing less than six saccharide radicals attached to each other by glycosidic linkages C07H; fermentation or enzyme-using processes C12P19/00; sugar industry C13; production of cellulose D21) - C08L: COMPOSITIONS OF MACROMOLECULAR COMPOUNDS (compositions based on polymerisable monomers C08F, C08G; artificial filaments or fibres D01F; textile treating compositions D06) ## Abstract Pharmaceutical complexes composed of drug molecules entrapped in cyclodextrin-based MOFs (CD-MOFs) are provided. Pharmaceutical tablets incorporating crystals of the pharmaceutical complexes for oral administration to a patient are also provided. In addition, methods of making the pharmaceutical complexes using anion-exchange reactions and methods of making the pharmaceutical complexes based on the co-crystallization of the drug molecules with cyclodextrin are provided. The pharmaceutical complexes include a CD-MOF and deprotonated drug anions associated with alkali metal cations in the CD-MOF superstructure. ## Claims ### Claim 1 A pharmaceutical complex comprising: a metal organic framework comprising γ-cyclodextrin tori coordinated to alkali metal cations on primary and secondary faces of the γ-cyclodextrin tori; wherein the metal organic framework is an offset channel metal organic framework comprising γ-cyclodextrin tori linked to one another through the alkali metal cations to form channels that are stacked in an offset manner down the crystallographic a-axis of the metal organic framework and has the chemical formula C96H169X3O84.5, 3H2O, where X is an alkali metal element, and crystallizes in the P1 space group; deprotonated drug molecules associated with the alkali metal cations as charge-balancing anions; and wherein the pharmaceutical complex has a drug molecule loading of at least 10 wt. %. ### Claim 2 (depends on 1) The complex of claim 1, wherein the alkali metal element is Na. ### Claim 3 (depends on 1) The complex of claim 1, wherein the alkali metal element is K. ### Claim 4 (depends on 1) The complex of claim 1, wherein the deprotonated drug molecules are deprotonated ibuprofen molecules. ### Claim 5 (depends on 2) The complex of claim 2, wherein the deprotonated drug molecules are deprotonated ibuprofen molecules and the pharmaceutical complex has an ibuprofen loading of at least 20 wt. %. ### Claim 6 (depends on 1) The complex of claim 1, wherein the deprotonated drug molecules are deprotonated naproxen molecules or deprotonated aspirin molecules. ### Claim 7 (depends on 2) The complex of claim 2, wherein the deprotonated drug molecules are deprotonated naproxen molecules or deprotonated aspirin molecules. ### Claim 8 (depends on 1) The complex of claim 1, wherein the metal organic framework is CD-MOF-3 comprising six γ-cyclodextrin tori that are coordinated to cesium cations on the primary face of the cyclodextrin tori in an alternating manner, forming cubes, wherein the cubes are linked together in three dimensions by coordination of a cesium cation on the secondary face of the γ-cyclodextrin tori, leading to an extended porous superstructure. ### Claim 9 (depends on 1) A solution comprising the complex of claim 1 in a water-soluble, polar organic solvent, wherein the drug molecule has a free-acid form and the water-soluble, polar organic solvent facilitates the deprotonation of the free-acid form of the drug molecule. ### Claim 10 A pharmaceutical complex comprising: an offset channel metal organic framework comprising γ-cyclodextrin tori linked to one another through the alkali metal cations to form channels that are stacked in an offset manner down the crystallographic a-axis of the metal organic framework and has the chemical formula C96H169X3O84.5, 3H2O, where X is an alkali metal element, and crystallizes in the P1 space group; and deprotonated drug molecules associated with the alkali metal cations as charge-balancing anions. ### Claim 11 (depends on 10) The complex of claim 10, wherein the alkali metal element is Na. ### Claim 12 (depends on 10) The complex of claim 10, wherein the alkali metal element is K. ### Claim 13 (depends on 10) The complex of claim 10, the pharmaceutical complex has an drug molecule loading of at least 10 wt. %. ### Claim 14 (depends on 10) The complex of claim 10, the pharmaceutical complex has an drug molecule loading of at least 20 wt. %. ### Claim 15 (depends on 10) The complex of claim 10, wherein the deprotonated drug molecules are deprotonated ibuprofen molecules. ### Claim 16 (depends on 10) The complex of claim 10, wherein the deprotonated drug molecules are deprotonated naproxen molecules or deprotonated aspirin molecules. ### Claim 17 (depends on 10) A solution comprising the complex of claim 10 in a water-soluble, polar organic solvent, wherein the drug molecule has a free-acid form and the water-soluble, polar organic solvent facilitates the deprotonation of the free-acid form of the drug molecule. ### Claim 18 A method of forming a pharmaceutical complex, the method comprising: forming a solution comprising the free-acid form of acidic drug molecules and metal organic frameworks in a water-soluble, polar organic solvent, wherein the metal organic frameworks comprise γ-cyclodextrin tori coordinated to alkali metal cations on primary and secondary faces of the γ-cyclodextrin tori and further comprises charge compensating anions associated with the alkali metal cations, wherein the metal organic framework is an offset channel metal organic framework comprising γ-cyclodextrin tori linked to one another through the alkali metal cations to form channels that are stacked in an offset manner down the crystallographic a-axis of the metal organic framework and has the chemical formula C96H169X3O84.5, 3H2O, where X is an alkali metal element, and crystallizes in the P1 space group, and further wherein the polar organic solvent facilitates the deprotonation of the free-acid form of the acidic drug molecules; and allowing the deprotonated acidic drug molecules to undergo anion exchange with the charge compensating anions of the metal organic frameworks to form metal organic frameworks loaded with deprotonated acidic drug molecules. ### Claim 19 A method of forming a pharmaceutical complex, the method comprising: forming a solution comprising an alkali metal salt of a drug molecule, γ-cyclodextrin, and an organic alcohol; and co-crystallizing the alkali metal salt of the drug molecule and the γ-cyclodextrin in the presence of the organic alcohol to form a metal organic framework comprising γ-cyclodextrin tori coordinated to alkali metal cations on primary and secondary faces of the γ-cyclodextrin tori, wherein the metal organic framework is an offset channel metal organic framework comprising γ-cyclodextrin tori linked to one another through the alkali metal cations to form channels that are stacked in an offset manner down the crystallographic a-axis of the metal organic framework and has the chemical formula C96H169X3O84.5bl , 3H2O, where X is an alkali metal element, and crystallizes in the P1 space group, wherein the drug molecules are associated with the alkali metal cations as charge-balancing anions.