Injectable formulation comprising a biopharmaceutical agent and a polyacrylamide-based copolymer
Specific polyacrylamide-based copolymers are used to stabilize biological pharmaceutical agents in injectable formulations, addressing stability and pharmacokinetic issues, ensuring effective delivery without altering the agent's properties.
Patent Information
- Authority / Receiving Office
- HK · HK
- Patent Type
- Applications
- Current Assignee / Owner
- THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV
- Filing Date
- 2026-05-08
- Publication Date
- 2026-07-17
AI Technical Summary
Existing formulations of biological pharmaceutical agents face challenges in maintaining stability and pharmacokinetic properties during injection, particularly when using polyacrylamide-based copolymers as stabilizing excipients, which can interact with the agents and alter their properties.
The use of specific polyacrylamide-based copolymers as stabilizing excipients in particulate formulations that do not directly interact with the biological pharmaceutical agent, ensuring stability and maintaining pharmacokinetic properties.
The solution maintains the stability and pharmacokinetic properties of biological pharmaceutical agents during injection, allowing for effective delivery without altering the agent's properties.
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Abstract
Description
Abstract This disclosure provides an injectable pharmaceutical composition comprising suspended particles in a liquid carrier, wherein the particles of the composition comprise a biological pharmaceutical agent and a polyacrylamide-based copolymer. The inventors have demonstrated that specific polyacrylamide-based copolymers can be used as stabilizing excipients in particulate formulations of biological pharmaceutical agents without directly interacting with the biological pharmaceutical agent or altering its pharmacokinetic properties. The pharmaceutical composition can be formulated for injection into a patient. Also provided is a syringe loaded with the injectable pharmaceutical composition, a method for administering a therapeutically effective dose of a biological pharmaceutical agent to a subject in need via injection, and a method for preparing an injectable pharmaceutical composition for a subject.
Claims
WHAT IS CLAIMED IS:
1. An injectable pharmaceutical composition comprising: particles, the particles comprising: a biopharmaceutical agent; and a polyacrylamide-based copolymer; and a liquid carrier in which the particles are suspended.
2. The injectable pharmaceutical composition of claim 1, wherein the particles have a mean diameter of 100 microns or less.
3. The injectable pharmaceutical composition of claim 2, wherein the particles have a mean diameter of from 0.01-100 microns.
4. The injectable pharmaceutical composition of claim 3, wherein the particles have a mean diameter of from 0.1-100 microns.
5. The injectable pharmaceutical composition of claim 4, wherein the particles have a mean diameter of from 0.2-20 microns.
6. The injectable pharmaceutical composition of claim 5, wherein the particles have a mean diameter of from 0.2-10 microns.
7. The injectable pharmaceutical composition of claim 1, further comprising one or more of stabilizing agent, preservative, filler, bulking agent, sugar, polysaccharide, or viscosity modifier.
8. The injectable pharmaceutical composition of claim 7, further comprising a stabilizing agent.
9. The injectable pharmaceutical composition of claim 8, wherein the stabilizing agent is selected from surfactants, poloxamers, povidones, polyvinylpyrrolidone (PVP) polymer, polyvinyl alcohol (PVA) polymer, polysaccharides, cellulosics, amphoteric compounds, sugars, salts, and combinations thereof.
10. The injectable pharmaceutical composition of any one of claims 1 to 9, wherein the biopharmaceutical agent is a polypeptide.11 . The injectable pharmaceutical composition of claim 10, wherein the polypeptide is susceptible to aggregation in an aqueous medium.
12. The injectable pharmaceutical composition of claim 10 or 11, wherein the polypeptide is selected from antibodies and fragments thereof, cytokines, chemokines, hormones, vaccine antigens, cancer antigens, adjuvants, and combinations thereof.
13. The injectable pharmaceutical composition of any one of claims 10 to 12, wherein the polypeptide is a protein.
14. The injectable pharmaceutical composition of claim 13, wherein the protein is an antibody or a fragment thereof.
15. The injectable pharmaceutical composition of claim 14, wherein the protein is a monoclonal antibody, a polyclonal antibody, an immunoglobulin G (IgG) antibody, an IgA antibody, an IgM antibody, a Fc fusion protein, or a fragment thereof.
16. The injectable pharmaceutical composition of any one of claims 10 to 12, wherein the polypeptide is a hormone or analog thereof.
17. The injectable pharmaceutical composition of claim 16, wherein the polypeptide is insulin or an analog thereof.
18. The injectable pharmaceutical composition of claim 16, wherein the polypeptide is selected from glucagon, GLP-1 receptor agonist, amylin, and analogs thereof.
19. The injectable pharmaceutical composition of any one of claims 1 to 18, wherein the composition comprises 0.1 to 20% by weight of the biopharmaceutical agent.
20. The injectable pharmaceutical composition of claim 19, wherein the biopharmaceutical agent is insulin or an analog thereof.
21. The injectable pharmaceutical composition of claim 19, wherein the biopharmaceutical agent is a peptide.
22. The injectable pharmaceutical composition of any one of claims 19 to 21 , wherein the particles comprise no more than 20% by weight of the biopharmaccutical agent.
23. The injectable pharmaceutical composition of any one of claims 1 to 18, wherein the composition comprises 20% or more by weight of the biopharmaceutical agent.
24. The injectable pharmaceutical composition of claim 23, wherein the composition comprises 20% to 80% by weight of the biopharmaceutical agent.
25. The injectable pharmaceutical composition of claim 23 or 24, wherein the biopharmaceutical agent is an antibody or fragment thereof, or a Fc fusion protein.
26. The injectable pharmaceutical composition of any one of claims 23 to 25, wherein the particles comprise 75% or more by weight of the biopharmaceutical agent.
27. The injectable pharmaceutical composition of any one of claims 1 to 26, wherein the composition comprises 0.01 to 20 wt% of the polyacrylamide-based copolymer.
28. The injectable pharmaceutical composition of claim 27, wherein the composition comprises 0.1 to 10 wt% of the polyacrylamide-based copolymer.
29. The injectable pharmaceutical composition of claim 27, wherein the composition comprises 0.5 to 5 wt% of the polyacrylamide-based copolymer.
30. The injectable pharmaceutical composition of any one of claims 1 to 29, wherein the particles comprise 0.01 to 25 wt% of the polyacrylamide-based copolymer.
31. The injectable pharmaceutical composition of claim 30, wherein the particles comprise 0.1 to 10 wt% of the polyacrylamide-based copolymer.
32. The injectable pharmaceutical composition of claim 30, wherein the particles comprise 1 to 5 wt% of the polyacrylamide-based copolymer.
33. The injectable pharmaceutical composition of any one of claims 1 to 32, wherein composition comprises a 1:500 to 2:1 weight to weight ratio of the polyacrylamide-based copolymer to the biopharmaceutical agent.
34. The injectable pharmaceutical composition of claim 33, wherein composition comprises a 1:50 to 1:1 weight to weight ratio of the polyacrylamide-based copolymer to the biopharmaceutical agent.
35. The injectable pharmaceutical composition of claim 33, wherein composition comprises a 1:25 to 1:10 weight to weight ratio of the polyacrylamide-based copolymer to the biopharmaceutical agent.
36. The injectable pharmaceutical composition of any one of claims 1 to 35, wherein the polyacrylamide-based copolymer comprises: a water-soluble carrier monomer selected from N-(3-methoxypropyl)acrylamide (MP AM), 4-acryloylmorpholine (MORPH), N,N-dimethylacrylamide (DMA), N-hydroxy ethyl acrylamide (HEAM), acrylamide (AM), and combinations thereof; and a functional dopant monomer selected from N-[tris(hydroxymethyl)-methyl]acrylamide (TRI), 2-acrylamido-2-methylpropane sulfonic acid (AMP), (3- acrylamidopropyl)trimethylammonium chloride (TMA), N-isopropylacrylamidc (NIP), N-N- diethylacrylamide (DEA), N-tert-butylacrylamide (TBA), -phenylacrylamide (PHE), and combinations thereof.
37. The injectable pharmaceutical composition of claim 33, wherein the water-soluble carrier monomer is selected from MORPH, MPAM, and combinations thereof.
38. The injectable pharmaceutical composition of claim 34, wherein the water-soluble carrier monomer comprises MORPH.
39. The injectable pharmaceutical composition of claim 34, wherein the water-soluble carrier monomer comprises MPAM.
40. The injectable pharmaceutical composition of any one of claims 33-36, wherein the functional dopant monomer is selected from AMP, TMA, TBA, PHE, and combinations thereof.
41. The injectable pharmaceutical composition of any one of claims 33-36, wherein the functional dopant monomer is selected from DEA, PHE, NIP, and combinations thereof.
42. The injectable pharmaceutical composition of any one of claims 33-36, wherein the functional dopant monomer comprises TRI.
43. The injectable pharmaceutical composition of any one of claims 33-36, wherein the functional dopant monomer comprises PHE.
44. The injectable pharmaceutical composition of any one of claims 33-36, wherein the functional dopant monomer comprises NIP.
45. The injectable pharmaceutical composition of any one of claims 33-36, wherein the functional dopant monomer comprises DEA.
46. The injectable pharmaceutical composition of claim 33, wherein: the water-soluble carrier monomer is selected from MPAM, MORPH, and combinations thereof; and the functional dopant monomer is selected from NIP, PHE, and combinations thereof.
47. The injectable pharmaceutical composition of claim 33, wherein: the water-soluble carrier monomer is selected from MPAM, MORPH, and combinations thereof; and the functional dopant monomer is selected from AMP, TMA, TBA, PHE, and combinations thereof.
48. The injectable pharmaceutical composition of claim 33, wherein the water-soluble carrier monomer is MPAM, and the functional dopant monomer is PHE.
49. The injectable pharmaceutical composition of claim 33, wherein the water-soluble carrier monomer is MORPH, and the functional dopant monomer is PHE.
50. The injectable pharmaceutical composition of claim 33, wherein the water-soluble carrier monomer is MORPH, and the functional dopant monomer is NIP.
51. The injectable pharmaceutical composition of any one of claims 33-50, wherein the polyacrylamide-based copolymer comprises:70 wt% to 98 wt% of the water-soluble carrier monomer; and2 wt% to 30 wt% of the functional dopant monomer.
52. The injectable pharmaceutical composition of any one of claims 33-50, wherein the polyacrylamidc-bascd copolymer comprises:80 wt% to 95 wt% of the water-soluble carrier monomer; and5 wt% to 20 wt% of the functional dopant monomer.
53. The injectable pharmaceutical composition of any one of claims 33-50, wherein the polyacrylamide-based copolymer comprises:83 wt% to 98 wt% of the water-soluble carrier monomer; and2 wt% to 17 wt% of the functional dopant monomer.
54. The injectable pharmaceutical composition of claim 33, wherein the polyacrylamidebased copolymer comprises:70 wt% to 85 wt% of MORPH; and15 wt% to 30 wt% of NIP.
55. The injectable pharmaceutical composition of claim 33, wherein the polyacrylamidebased copolymer comprises:74 wt% to 80 wt% of MORPH; and20 wt% to 26 wt% of NIP.
56. The injectable pharmaceutical composition of claim 33, wherein the polyacrylamidebased copolymer comprises:77 wt% of MORPH; and23 wt% of NIP.
57. The injectable pharmaceutical composition of any one of claims 33-56, wherein the degree of polymerization of the polyacrylamide-based copolymer is 10 to 500.
58. The injectable pharmaceutical composition of claim 57, wherein the degree of polymerization of the polyacrylamide -based copolymer is 20 to 200.
59. The injectable pharmaceutical composition of claim 58, wherein the degree of polymerization of the polyacrylamide -based copolymer is 50.
60. The injectable pharmaceutical composition of any one of claims 22-59, wherein a number- average molecular weight of the polyacrylamide-based copolymer is 1,000 g / mol to 40,000 g / mol.
61. The injectable pharmaceutical composition of 60, wherein a number- average molecular weight of the polyacrylamide-based copolymer is 2,000 g / mol to 10,000 g / mol.
62. The injectable pharmaceutical composition of 61, wherein a number-average molecular weight of the polyacrylamide-based copolymer is 4,000 g / mol to 6,000 g / mol.
63. The injectable pharmaceutical composition of any one of claims 1 to 62, wherein the polyacrylamide-based copolymer is amphiphilic.
64. The injectable pharmaceutical composition of any one of claims 1 to 63, wherein the liquid carrier comprises a mixture of an organic solvent and an aqueous solution.
65. The injectable pharmaceutical composition of any one of claims 1 to 63, wherein the liquid carrier comprises an organic solvent, an oil, or a combination thereof.
66. The injectable pharmaceutical composition of any one of claims 1 to 65, wherein the liquid carrier comprises one or more liquids selected from triacylglyccridc, diacylglyccridc, monoacylglyceride, an acetamide, alkyl alcohol, aryl alcohol, aralkyl alcohol, fatty acid, fatty acid ester, oil, alkane, perfluoroalkane, propylene glycol monoester, propylene glycol diester, butylene glycol monoester, butylene glycol diester, polyethylene glycol diester, and combinations thereof.
67. The injectable pharmaceutical composition of claim 66, wherein the liquid carrier comprises an aralkyl benzoate.
68. The injectable pharmaceutical composition of claim 67, wherein the aralkyl benzoate is benzyl benzoate.
69. The injectable pharmaceutical composition of claim 66, wherein the liquid carrier comprises a triacylglyceride, diacylglyceride, monoacylglyceride, or a combination thereof.
70. The injectable pharmaceutical composition of claim 69, wherein the liquid carrier comprises a triacylglyccridc that is triacctin.
71. The injectable pharmaceutical composition of claim 66, wherein the liquid carrier comprises N,N-dimethylacetamide (DMAc).
72. The injectable pharmaceutical composition of claim 66, wherein the liquid carrier comprises a fatty acid ester.
73. The injectable pharmaceutical composition of claim 72, wherein the fatty acid ester is ethyl oleate.
74. The injectable pharmaceutical composition of claim 66, wherein the liquid carrier comprises a propylene glycol diester and / or a butylene glycol diester.
75. The injectable pharmaceutical composition of claim 74, wherein the liquid carrier comprises Miglyol 840.
76. The injectable pharmaceutical composition of claim 65 or 66, wherein the liquid carrier comprises a blend of a tri acylglyceride and one or more organic solvents that is less viscous than the triacylglyccridc.
77. The injectable pharmaceutical composition of claim 76, wherein the triacylglyceride is triacetin.
78. The injectable pharmaceutical composition of claim 77, wherein the liquid carrier comprises a 1:1 to 9:1 volume to volume (v / v) ratio of triacetin to one or more organic solvents that is less viscous than triacetin.
79. The injectable pharmaceutical composition of claim 76, wherein the liquid carrier comprises a 1:1 v / v ratio of triacetin to one or more organic solvents that is less viscous than triacetin.
80. The injectable pharmaceutical composition of claim 76, wherein the liquid carrier comprises a 3:1 v / v ratio of triacctin to one or more organic solvents that is less viscous than triacetin.
81. The injectable pharmaceutical composition of claim 76, wherein the liquid carrier comprises a 9:1 v / v ratio of triacetin to one or more organic solvents that is less viscous than triacetin.
82. The injectable pharmaceutical composition of any one of claims 76 to 81, wherein the organic solvent that is less viscous that triacetin is selected from an acetamide, an alkyl benzoate, an aryl benzoate, an aralkyl benzoate, an aryl alcohol, an aralkyl alcohol, or any combination thereof.
83. The injectable pharmaceutical composition of claim 82, wherein the organic solvent that is less viscous that triacetin is an acetamide.
84. The injectable pharmaceutical composition of claim 83, wherein the acetamide is DMAc.
85. The injectable pharmaceutical composition of claim 82, wherein the organic solvent that is less viscous that triacetin is an aralkyl alcohol.
86. The injectable pharmaceutical composition of claim 85, wherein the aralkyl alcohol is benzyl alcohol.
87. The injectable pharmaceutical composition of claim 82, wherein the organic solvent that is less viscous that triacetin is an aralkyl benzoate.
88. The injectable pharmaceutical composition of claim 87, wherein the aralkyl benzoate is benzyl benzoate.
89. The injectable pharmaceutical composition of claim 82, wherein the organic solvent that is less viscous that triacetin comprises a combination of an acetamide and an aralkyl alcohol.
90. The injectable pharmaceutical composition of claim 89, wherein the acetamide is DMAc, and the aralkyl alcohol is benzyl alcohol.91 . The injectable pharmaceutical composition of claim 90, wherein the less viscous organic solvent comprises a 3:1 to 2:1 v / v ratio of DMAc to benzyl alcohol.
92. The injectable pharmaceutical composition of claim 65 or 66, wherein the organic solvent is an alkyl benzoate, an aryl benzoate, an aralkyl benzoate, or any combination thereof.
93. The injectable pharmaceutical composition of claim 92, wherein the organic solvent is benzyl benzoate.
94. The injectable pharmaceutical composition of claim 64 or 65, wherein the organic solvent is a polar aprotic solvent.
95. The injectable pharmaceutical composition of claim 94, wherein the polar aprotic solvent is dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), or a mixture thereof.
96. The injectable pharmaceutical composition of claim 65, wherein the liquid carrier comprises an oil (e.g., a plant-based oil or an animal-based oil).
97. The injectable pharmaceutical composition of claim 96, wherein the oil is coconut oil, cottonseed oil, fish oil, grape seed oil, hazelnut oil, hydrogenated vegetable oils, lime oil, olive oil, palm seed oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, sunflower oil, walnut oil, or any combination thereof.
98. The injectable pharmaceutical composition of claim 97, wherein the oil is sesame oil.
99. The injectable pharmaceutical composition of any one of claims 1 to 98, wherein the composition comprises a 1:5 to 4:1 weight to weight ratio of the liquid carrier to the particles.
100. The injectable pharmaceutical composition of claim 99, wherein the composition comprises a 1:1 to 2:1 weight to weight ratio of the liquid carrier to the particles.
101. An injectable pharmaceutical composition comprising: particles, the particles comprising: a biopharmaceutical agent; and a polyacrylamide-based copolymer comprising:a water-soluble carrier monomer selected from N-(3- mcthoxypropyljacrylamidc (MP AM), 4-acryloylmorpholinc (MORPH), N,N- dimethylacrylamide (DMA), N-hydroxyethyl acrylamide (HEAM), acrylamide (AM), and combinations thereof; and a functional dopant monomer selected from N-[tris(hydroxymethyl)- methyl] acrylamide (TRI), 2-acrylamido-2-methylpropane sulfonic acid (AMP), (3-acrylamidopropyl)trimethylammonium chloride (TMA), N- isopropylacrylamide (NIP), N-N-diethylacrylamide (DEA), N-tert- butylacrylamide (TBA), N-phenylacrylamide (PHE), and combinations thereof; and a liquid carrier in which the particles are suspended, wherein the liquid earner is selected from triacylglyceride, diacylglyceride, monoacylglyceride, an acetamide, alkyl alcohol, aryl alcohol, aralkyl alcohol, fatty acid, fatty acid ester, oil, alkane, perfluoroalkane, propylene glycol monoester, propylene glycol diester, butylene glycol monoester, butylene glycol diester, polyethylene glycol diester, and combinations thereof.
102. The injectable pharmaceutical composition of claim 101, wherein the water-soluble carrier monomer is selected from MORPH, MP AM, and combinations thereof.
103. The injectable pharmaceutical composition of any one of claims 101-102, wherein the functional dopant monomer is selected from AMP, TMA, TBA, PHE, and combinations thereof.
104. The injectable pharmaceutical composition of any one of claims 101-102, wherein the functional dopant monomer is selected from DEA, PHE, NIP, and combinations thereof.
105. The injectable pharmaceutical composition of claim 104, wherein: the water-soluble carrier monomer is selected from MP AM, MORPH, and combinations thereof; and the functional dopant monomer is selected from NIP, PHE, and combinations thereof.
106. The injectable pharmaceutical composition of claim 104, wherein the water-soluble carrier monomer is MORPH, and the functional dopant monomer is NIP.
107. The injectable pharmaceutical composition of any one of claims 101-106, wherein the liquid carrier comprises an aralkyl benzoate.
108. The injectable pharmaceutical composition of claim 107, wherein the aralkyl benzoate is benzyl benzoate.
109. The injectable pharmaceutical composition of any one of claims 101-106, wherein the liquid carrier comprises a triacylglyceride.
110. The injectable pharmaceutical composition of claim 109, wherein the triacylglyceride is triacetin.
111. The injectable pharmaceutical composition of any one of claims 101-106, wherein the liquid carrier comprises N,N-dimethylacetamide (DMAc).
112. The injectable pharmaceutical composition of any one of claims 101-106, wherein the liquid carrier comprises a fatty acid ester.
113. The injectable pharmaceutical composition of claim 112, wherein the fatty acid ester comprises ethyl oleate.
114. The injectable pharmaceutical composition of any one of claims 101-106, wherein the liquid carrier comprises a propylene glycol diester and / or a butylene glycol diester.
115. The injectable pharmaceutical composition of claim 114, wherein: the propylene glycol diester is Miglyol 840; and the butylene glycol diester is Miglyol 8810.
116. A syringe, loaded with a composition of any one of claims 1-115.
117. The syringe of claim 116, configured to dispense the composition at a flow rate of 0.1 mL / min or more in response to a force applied to the syringe of 70 N or less.
118. The syringe of claim 116, configured to dispense the composition at a flow rate of 0.1 mL / min or more in response to a force applied to the syringe of 50 N or less.
119. The syringe of any one of claims 1 16 to 1 18, wherein the syringe comprises a needle having a size of 18 to 32 Gauge (G).
120. The syringe of claim 119, wherein the needle is an 22G needle.
121. The syringe of claim 119, wherein the needle is a 24G needle.
122. The syringe of claim 119, wherein the needle is a 25G needle.
123. The syringe of claim 119, wherein the needle is a 26G needle.
124. The syringe of claim 119, wherein the needle is a 27G needle.
125. The syringe of claim 119, wherein the needle is a 30G needle.
126. The syringe of claim 119, wherein the needle is a 32G needle.
127. The syringe of any one of claims 119-126, wherein the needle is an ultra-thin walled needle.
128. A method of administering a biopharmaccutical to a subject by injection, the method comprising: injecting a composition according to any one of claims 1-115 to administer a therapeutically effective dose of the biopharmaceutical to a subject in need thereof.
129. The method of claim 128, wherein the injecting is performed using a loaded syringe of any one of claims 116-127.
130. A method of preparing an injectable pharmaceutical composition, the method comprising: d) providing a mixture comprising: a biopharmaceutical agent; and a polyacrylamide-based copolymer in water; e) removing the water from the mixture to obtain particles comprising the biopharmaceutical agent and the polyacrylamide-based copolymer;f) contacting a liquid carrier with the particles to form a suspension of the particles in the liquid carrier.
131. The method of claim 130, wherein in step b) the water is removed via spray drying.
132. The method of claim 130, wherein in step b) the water is removed via electrospray drying.
133. The method of claim 130, wherein in step b) the water is removed via lyophilization.
134. The method of claim 130, wherein the method further comprises a milling step after the lyophilization but prior to step c).
135. The method of any one of claims 130 to 134, wherein the particles obtained in step b) have a mean diameter of 100 microns or less.
136. The method of any one of claims 130 to 135, wherein step c) comprises sonicating the particles in the liquid carrier.