REMDESIVIR COCRYSTAL, COMPOSITIONS AND METHODS THEREOF
Provided is a cocrystals of remdesivir (RDV) composed of a 1:1 molar ratio of RDV and benzoic acid derivative. The benzoic acid derivative can be salicylic acid (SA). The RDV-SA cocrystal are formed by either liquid-assisted grinding or spray-drying, followed by thermal annealing to facilitate cocrystal formation. The RDV-SA cocrystals can be formulated as inhalable dry powders and included in a medicament for use in treatments for influenza viral infections, such as COVID-19. The inhalable RDV-SA cocrystal dry powders is suitable for deep lung delivery, with good dissolution performance.
1 . A cocrystal of remdesivir and salicylic acid.
2 . The cocrystal according to claim 1 , belonging to a monoclinic P2 1 space group and having unit cell parameters a=18.3±0.1 Ang, b=5.6±0.1 Ang, c=19.3±0.1 Ang, α=γ=90°, and β=112±1°.
3 . The cocrystal according to claim 1 , characterized by a powder X-ray diffraction (PXRD) pattern measured using an incident beam of Cu Ka radiation comprising at least two X-ray diffraction peaks and the corresponding d-spacing values substantially as shown in Table 4.
4 . The cocrystal according to claim 1 , characterized by a powder X-ray diffraction (PXRD) pattern measured using an incident beam of Cu Ka radiation comprising X-ray diffraction peaks below 20 degree two-theta substantially as shown in Table 4.
5 . The cocrystal according to claim 1 , is characterized by a powder X-ray diffraction (PXRD) pattern measured using an incident beam of Cu Ka radiation substantially as shown in FIG. 7 B (top five panels) or Table 4.
6 . The cocrystal according to claim 1 , is characterized by a Differential Scanning calorimetry (DSC) profile having a melting endotherm at about 138° C. to about 160° C., preferably at about 150° C. to about 155° C.
7 . The cocrystal according to claim 1 , characterized by a Differential Scanning calorimetry (DSC) profile substantially as shown in FIG. 4 B (top five panels) or FIG. 10 .
8 . The cocrystal according to claim 1 , characterized by Fourier-Transform Infrared Spectroscopy (FTIR) profile substantially as shown in FIG. 14 .
9 . The cocrystal according to claim 1 , which is prepared by a process comprising (a) liquid-assisted grinding; and (b) thermal annealing.
10 . The cocrystal according to claim 1 , which is prepared by a process comprising (a) spray drying; and (b) thermal annealing.
11 . A process for preparing the cocrystal of remdesivir and salicylic acid according to claim 1 , the process comprising the steps of:
(a) grinding remdesivir and salicylic acid in the presence of a solvent to produce a mixture; and
(b) thermally annealing the mixture of step (a) at a temperature of at least about 60° C., preferably at least about 80° C., for a time period of at least about 30 minutes.
12 . A process for preparing a powder for inhalation, the powder comprising the cocrystal of remdesivir and salicylic acid according to claim 1 , the process comprising the steps of
(a) spray drying a solution of remdesivir and salicylic acid in a solvent to produce a mixture; and
(b) thermally annealing the mixture of step (a) at a temperature of at least about 60° C., preferably at least about 80° C., for a time period of at least about 30 minutes.
13 . A pharmaceutical composition comprising as an active ingredient a remdesivir cocrystal according to claim 1 .
14 . The pharmaceutical composition according to claim 13 , wherein the composition is in a form of a powder for inhalation.
15 . The pharmaceutical composition according to claim 14 , has a median mass aerodynamic diameter (MMAD) of below 5 microns, and a fine particle fraction (FPF) of at least about 30%.
16 . A method of treating a respiratory viral infection in a subject in need thereof, comprising administering to the respiratory system of the subject a composition comprising a therapeutically-effective amount of a cocrystal of remdesivir and salicylic acid according to claim 1 .
17 . The method of claim 16 , wherein the respiratory virus is selected from the group consisting of a coronavirus, severe acute respiratory syndrome (SARS) coronavirus (SARS-COV), SARS-COV-2 (COVID-19), Middle East Respiratory Syndrome (MERS), respiratory syncytial virus (RSV), influenza virus, parainfluenza virus (PIV), pneumovirus (PMV), metapneumovirus (MPV), respirovirus, and rubulavirus.
18 . The method of claim 16 , wherein the composition is administered by oral inhalation, nasal inhalation, or with a dry powder inhaler (DPI).
19 . A cocrystal of remdesivir and a coformer.
20 . The cocrystal of claim 19 , wherein the remdesivir and a coformer have a molar ratio of 1:1.
21 . The cocrystal according to claim 19 , wherein the coformer comprises at least one functional group selected from the group consisting of carboxylic acid, hydroxy, ether, aldehyde, ketone, ester, amide, amine, phosphonic acid, and sulfonic acid.
22 . The cocrystal according to claim 21 , wherein the coformer comprises a benzoic acid derivative.
23 . The cocrystal according to claim 22 , wherein the coformer is selected from the group consisting of salicylic acid, acetylsalicylic acid, and gentisic acid.
24 . A method of treating a respiratory viral infection in a subject in need thereof, comprising administering to the respiratory system of the subject a composition comprising a therapeutically-effective amount of a cocrystal of remdesivir and a coformer according to claim 1 .