Formulations of an antiviral prodrug
Patent Information
- Application Number
- HK62026125329
- Authority / Receiving Office
- HK · HK
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2023-03-17
- Filing Date
- 2026-06-25
- Publication Date
- 2026-09-18
- Estimated Expiration
- 2044-03-12
Smart Images
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Abstract
Description
Abstract This invention partially discloses pharmaceutical compositions comprising antiviral prodrugs and methods of using them in the treatment of viral infections.
Claims
CLAIMSWhat is claimed is:
1. A pharmaceutical composition comprising:(i) a crystalline form of a compound represented by:; and(ii) a cryoprotectant.
2. The pharmaceutical composition of claim 1, wherein the cryoprotectant is a sugar.
3. The pharmaceutical composition of claim 2, wherein the cryoprotectant is selected from the group consisting of trehalose, sucrose, mannitol, and any combination thereof.
4. The pharmaceutical composition of any one of claims 1-3, wherein the cryoprotectant is trehalose.
5. The pharmaceutical composition of any one of claims 1-4, comprising about 3 weight percent to about 10 weight percent of the cryoprotectant, based on the total weight of the pharmaceutical composition.
6. The pharmaceutical composition of any one of claims 1-5, comprising about 5 weight percent of the cryoprotectant, based on the total weight of the pharmaceutical composition.
7. The pharmaceutical composition of any one of claims 1-6, comprising a surfactant.
8. The pharmaceutical composition of claim 7, comprising about 3 weight percent to about 5 weight percent of the surfactant, based on the total weight of the pharmaceutical composition.
9. The pharmaceutical composition of any one of claims 1-8, comprising a polyethylene glycol.
10. The pharmaceutical composition of claim 9, comprising about 3 weight percent to about 5 weight percent of the polyethylene glycol, based on the total weight of the pharmaceutical composition.
11. The pharmaceutical composition of any one of claims 1-10, comprising a phosphate buffer.
12. The pharmaceutical composition of any one of claims 1-11, wherein the pH of the composition is from about 6.0 to about 7.5.
13. The pharmaceutical composition of any one of claims 1-12, wherein the pH of the composition is about 7.0.
14. The pharmaceutical composition of any one of claims 1-13, comprising about 25 weight percent to about 45 weight percent of the crystalline form, based on the total weight of the pharmaceutical composition.
15. The pharmaceutical composition of any one of claims 1-14, comprising a plurality of nanoparticles comprising the crystalline form of the compound.
16. The pharmaceutical composition of any one of claims 7-15, comprising a plurality of nanoparticles comprising the crystalline form of the compound and the surfactant.
17. The pharmaceutical composition of any one of claims 7-16, comprising a plurality of nanoparticles comprising the crystalline form of the compound and the polyethylene glycol.
18. The pharmaceutical composition of any one of claims 7-17, comprising a plurality of nanoparticles comprising the crystalline form of the compound, the surfactant, and the polyethylene glycol.
19. The pharmaceutical composition of any one of claims 15-18, wherein the plurality of nanoparticles has a particle size distribution (DIO) of about 250 nm to about 650 nm, a particle size distribution (D50) of about 350 nm to about 900 nm, and a particle size distribution (D90) of about 600 nm to about 1300 nm.
20. The pharmaceutical composition of any one of claims 15-19, wherein the plurality of nanoparticles has a z-average particle size of 200 nm to 900nm.
21. The pharmaceutical composition of any one of claims 15-20, wherein the plurality of nanoparticles has a z-average particle size of 275 nm to 425 nm.
22. The pharmaceutical composition of any one of claims 15-21, wherein the plurality of nanoparticles has a poly dispersity index of about 0. 15 to about 0.4.
23. The pharmaceutical composition of any one of claims 15-22, wherein the plurality of nanoparticles a polydispersity index of about 0.25 to about 0.35.
24. A pharmaceutical composition comprising:(i) a mixture of crystalline forms of a compound represented by:; and(ii) a cryoprotectant.
25. The pharmaceutical composition of claim 24, wherein the cryoprotectant is a sugar.
26. The pharmaceutical composition of claim 24 or 25, wherein the cryoprotectant is selected from the group consisting of trehalose, sucrose, mannitol, and any combination thereof.
27. The pharmaceutical composition of any one of claims 24-26, wherein the cryoprotectant is selected from the group consisting of trehalose, sucrose, and mannitol.
28. The pharmaceutical composition of any one of claims 24-27, wherein the cryoprotectant is trehalose.
29. The pharmaceutical composition of any one of claims 24-28, comprising about 3 weight percent to about 10 weight percent of the cryoprotectant, based on the total weight of the pharmaceutical composition.
30. The pharmaceutical composition of any one of claims 24-29, comprising about 5 weight percent of the cryoprotectant, based on the total weight of the pharmaceutical composition.
31. The pharmaceutical composition of any one of claims 24-30, comprising a surfactant.
32. The pharmaceutical composition of claim 31, comprising about 3 weight percent to about 5 weight percent of the surfactant, based on the total weight of the pharmaceutical composition.
33. The pharmaceutical composition of any one of claims 24-32, comprising a polyethylene glycol.
34. The pharmaceutical composition of claim 33, comprising about 3 weight percent to about 5 weight percent of the polyethylene glycol, based on the total weight of the pharmaceutical composition.
35. The pharmaceutical composition of any one of claims 24-34, comprising a phosphate buffer.
36. The pharmaceutical composition of any one of claims 24-35, wherein the pH of the composition is from about 6.0 to about 7.5.
37. The pharmaceutical composition of any one of claims 24-36, wherein the pH of the composition is about 7.0.
38. The pharmaceutical composition of any one of claims 24-37, wherein the mixture of crystalline forms of the compound has two crystalline forms.
39. The pharmaceutical composition of any one of claims 24-38, wherein one of the two crystalline forms is present in about 10 to 30 weight percent of the mixture and the other crystalline form in about 70 to 90 weight percent of the mixture.
40. The pharmaceutical composition of any one of claims 24-39, wherein the mixture of crystalline forms of the compound is characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 20 at about 21.6.
41. The pharmaceutical composition of any one of claims 24-40, wherein the mixture of crystalline forms of the compound is characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 20 at about 7.0, 17.8, and 21.6.
42. The pharmaceutical composition of any one of claims 24-41, wherein the mixture of crystalline forms of the compound is characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 20 at about 7.0, 7.4, 17.8, 21.6, and 23.6.
43. The pharmaceutical composition of any one of claims 24-42, wherein the mixture of crystalline forms of the compound is characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 20 at about 7.0, 7.4, 14.0, 16.3, 16.8, 17.8, 21.6, 23.6, 24.3, and 26.1.
44. The pharmaceutical composition of any one of claims 24-43, wherein the mixture of crystalline forms of the compound is characterized by an XRPD pattern substantially as depicted in FIG 2.
45. The pharmaceutical composition of any one of claims 24-44, comprising about 25 weight percent to about 45 weight percent of the mixture of crystalline forms of the compound, based on the total weight of the pharmaceutical composition.
46. The pharmaceutical composition of any one of claims 24-45, comprising a plurality of nanoparticles comprising the mixture of crystalline forms of the compound.
47. The pharmaceutical composition of any one of claims 31-46, comprising a plurality of nanoparticles comprising the mixture of crystalline forms of the compound and the surfactant.
48. The pharmaceutical composition of any one of claims 31-47, comprising a plurality of nanoparticles comprising the mixture of crystalline forms of the compound and the polyethylene glycol.
49. The pharmaceutical composition of any one of claims 31-48, comprising a plurality of nanoparticles comprising the mixture of crystalline forms of the compound, the surfactant, and the polyethylene glycol.
50. The pharmaceutical composition of any one of claims 46-49, wherein the plurality of nanoparticles has a particle size distribution (DIO) of about 250 nm to about 650 nm, a particle size distribution (D50) of about 350 nm to about 900 nm, and a particle size distribution (D90) of about 600 nm to about 1300 nm.
51. The pharmaceutical composition of any one of claims 46-50, wherein the plurality of nanoparticles has a z-average particle size of 200 nm to 900 nm.
52. The pharmaceutical composition of any one of claims 46-51, wherein the plurality of nanoparticles has a z-average particle size of 275 nm to 425 nm.
53. The pharmaceutical composition of any one of claims 46-52, wherein the plurality of nanoparticles has a poly dispersity index of about 0. 15 to about 0.4.
54. The pharmaceutical composition of any one of claims 46-53, wherein the plurality of nanoparticles has a polydispersity index of about 0.25 to about 0.35.
55. A method of treating, inhibiting, and / or preventing a viral infection in a patient in need thereof, comprising administering to the patient an effective amount of the pharmaceutical composition of any one of claims 1-54.
56. The method of claim 55, wherein the viral infection is a retroviral infection.
57. The method of claim 55 or 56, wherein the viral infection is an HIV infection.
58. The method of any one of claims 55-57, comprising administering the pharmaceutical composition intramuscularly to the individual.
59. A process for preparing a pharmaceutical composition comprising:(i) a crystalline form of a compound represented by:(ii) a cryoprotectant; the process comprising:(a) providing a suspension comprising the crystalline form of the compound;(b) mixing the suspension using a ball milling rotor, thereby preparing a ball-milled mixture; and(c) combining the ball-milled mixture with the cryoprotectant, thereby preparing the pharmaceutical composition.
60. The process of claim 59, wherein the suspension comprises one or more excipients selected from the group consisting of a polyethylene glycol, a surfactant, and combinations thereof.
61. The process of claim 59 or 60, wherein the cryoprotectant is a sugar.
62. The process of any one of claims 59-61, wherein the cryoprotectant is selected from the group consisting of trehalose, sucrose, mannitol, and any combination thereof.
63. The process of any one of claims 59-62, wherein the cryoprotectant is trehalose.
64. The process of any one of claims 59-63, wherein the pharmaceutical composition comprises about 3 weight percent to about 10 weight percent of the cryoprotectant, based on the total weight of the pharmaceutical composition.
65. The process of any one of claims 59-64, wherein the pharmaceutical composition comprises about 5 weight percent of the cryoprotectant, based on the total weight of the pharmaceutical composition.
66. The process of any one of claims 51-65, wherein the pharmaceutical composition comprises a surfactant.
67. The process of any one of claim 66, wherein the pharmaceutical composition comprises about 3 weight percent to about 5 weight percent of the surfactant, based on the total weight of the pharmaceutical composition.
68. The process of any one of claims 51-59, wherein the pharmaceutical composition comprises a polyethylene glycol.
69. The process of claim 68, wherein the pharmaceutical composition comprises about 3 weight percent to about 5 weight percent of the polyethylene glycol, based on the total weight of the pharmaceutical composition.
70. The process of any one of claims 59-69, combining the ball-milled mixture with the cryoprotectant with a phosphate buffer.
71. The process of any one of claims 59-70, wherein the pH of the composition is from about 6.0 to about 7.5.
72. The process of any one of claims 59-71, wherein the pH of the composition is about 7.0.
73. The process of any one of claims 59-72, wherein the pharmaceutical composition comprises about 25 weight percent to about 45 weight percent of the crystalline form, based on the total weight of the pharmaceutical composition.
74. The process of any one of claims 59-73, wherein the pharmaceutical composition comprises a plurality of nanoparticles comprising the crystalline form of the compound.
75. The process of any one of claims 66-74, wherein the pharmaceutical composition comprises a plurality of nanoparticles comprising the crystalline form of the compound and the surfactant.
76. The process of any one of claims 66-75, wherein the pharmaceutical composition comprises a plurality of nanoparticles comprising the crystalline form of the compound and the polyethylene glycol.
77. The pharmaceutical composition of any one of claims 66-76, wherein the pharmaceutical composition comprises a plurality of nanoparticles comprising the crystalline form of the compound, the surfactant, and the polyethylene glycol.
78. The process of any one of claims 74-77, wherein the plurality of nanoparticles has a particle size distribution (DIO) of about 250 nm to about 650 nm, a particle size distribution(D50) of about 350 nm to about 900 nm, and a particle size distribution (D90) of about 600 nm to about 1300 nm.
79. The process of any one of claims 74-78, wherein the plurality of nanoparticles has a z- average particle size of 200 nm to 900 nm.
80. The process of any one of claims 74-79, wherein the plurality of nanoparticles has a z- average particle size of 275 nm to 425 nm.
81. The process any one of claims 74-80, wherein the plurality of nanoparticles has a polydispersity index of about 0. 15 to about 0.4.
82. The process of any one of claims 74-81, wherein plurality of nanoparticles in the pharmaceutical composition has a polydispersity index of about 0.25 to about 0.35.
83. A process for preparing a pharmaceutical composition comprising:(i) a mixture of crystalline forms of a compound represented by:; and(ii) a cryoprotectant; the process comprising:(a) providing a suspension comprising the mixture of crystalline forms of the compound;(b) mixing the suspension using a ball milling rotor, thereby preparing a ball-milled mixture; and(c) combining the ball-milled mixture with the cryoprotectant, thereby preparing the pharmaceutical composition.
84. The process of claim 83, wherein the cryoprotectant is a sugar.
85. The process of claim 83 or 84, wherein the cryoprotectant is selected from the group consisting of trehalose, sucrose, mannitol, and any combination thereof.
86. The process of any one of claims 83-85, wherein the cryoprotectant is selected from the group consisting of trehalose, sucrose, and mannitol.
87. The pharmaceutical composition of any one of claims 83-86, wherein the cryoprotectant is trehalose.
88. The process of any one of claims 83-87, wherein the pharmaceutical composition comprises about 3 weight percent to about 10 weight percent of the cryoprotectant, based on the total weight of the pharmaceutical composition.
89. The process of any one of claims 83-88, wherein the pharmaceutical composition comprises about 5 weight percent of the cryoprotectant, based on the total weight of the pharmaceutical composition.
90. The process of any one of claims 83-89, wherein the pharmaceutical composition comprises a surfactant.
91. The process of claim 90, wherein the pharmaceutical composition comprises about 3 weight percent to about 5 weight percent of the surfactant, based on the total weight of the pharmaceutical composition.
92. The process of any one of claims 83-91, wherein the pharmaceutical composition comprises a polyethylene glycol.
93. The process of claim 92, wherein the pharmaceutical composition comprises about 3 weight percent to about 5 weight percent of the polyethylene glycol, based on the total weight of the pharmaceutical composition.
94. The process of any one of claims 83-93, wherein the pharmaceutical composition comprises a phosphate buffer.
95. The process of any one of claims 83-94, wherein the pH of the composition is from about 6.0 to about 7.5.
96. The process of any one of claims 83-95, wherein the pH of the composition is about 7.0.
97. The process of any one of claims 83-96, wherein the mixture of crystalline forms of the compound has two crystalline forms.
98. The process of any one of claims 83-97, wherein one of the two crystalline forms is present in about 10 to 30 weight percent of the mixture and the other crystalline form is about 70 to 90 weight percent of the mixture.
99. The process of any one of claims 83-98, wherein the mixture of crystalline forms of the compound is characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 20 at about 21.6.
100. The process of any one of claims 83-99, wherein the mixture of crystalline forms of the compound is characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 20 at about 7.0, 17.8, and 21.6.
101. The process of any one of claims 83-100, wherein the mixture of crystalline forms of the compound is characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 20 at about 7.0, 7.4, 17.8, 21.6, and 23.6.
102. The process of any one of claims 83-101, wherein the mixture of crystalline forms of the compound is characterized by a powder X-ray diffraction pattern having a characteristic peak in degrees 20 at about 7.0, 7.4, 14.0, 16.3, 16.8, 17.8, 21.6, 23.6, 24.3, and 26.1.
103. The process of any one of claims 83-102, wherein the mixture of crystalline forms of the compound is characterized by an XRPD pattern substantially as depicted in FIG. 2.
104. The process of any one of claims 83-103, comprising about 25 weight percent to about 45 weight percent of the mixture of crystalline forms of the compound, based on the total weight of the pharmaceutical composition.
105. The process of any one of claims 83-104, wherein the pharmaceutical composition comprises a plurality of nanoparticles comprising the mixture of crystalline forms of the compound.
106. The process of any one of claims 83-105, wherein the pharmaceutical composition comprises a plurality of nanoparticles comprising the mixture of crystalline forms of the compound and the surfactant.
107. The process of any one of claims 90-106, wherein the pharmaceutical composition comprises a plurality of nanoparticles comprising the mixture of crystalline forms of the compound and the polyethylene glycol.
108. The process of any one of claims 90-107, wherein the pharmaceutical composition comprises a plurality of nanoparticles comprising the mixture of crystalline forms of the compound, the surfactant, and the polyethylene glycol.
109. The process of any one of claims 90-108, wherein the plurality of nanoparticles has a particle size distribution (D10) of about 250 nm to about 650 nm, a particle size distribution (D50) of about 350 nm to about 900 nm, and a particle size distribution (D90) of about 600 nm to about 1300 nm.
110. The process of any one of claims 105-109, wherein the plurality of nanoparticles has a z-average particle size of 200 nm to 900 nm.
111. The process of any one of claims 105-110, wherein the plurality of nanoparticles has a z-average particle size of 275 nm to 425 nm.
112. The process of any one of claims 105- 111, wherein the plurality of nanoparticles has a polydispersity index of about 0. 15 to about 0.4.
113. The process of any one of claims 105- 112, wherein the plurality of nanoparticles has a polydispersity index of about 0.25 to about 0.35.