Composition suitable for use in neonates
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- OAK HILL BIO LTD
- Filing Date
- 2026-02-18
- Publication Date
- 2026-06-23
Smart Images
Figure 2026102579000015 
Figure 2026102579000016 
Figure 2026102579000017
Abstract
Claims
1. Recombinant insulin-like growth factor 1 (rIGF-1), recombinant insulin-like growth factor binding agent Protein complex containing protein 3 (rIGFBP-3), and approximately 0.0025% to 0.0 A composition comprising a polysorbate surfactant at a concentration of 0.75%, wherein the rIGF A composition in which -1 and rIGFBP-3 are complexed in equimolar amounts.
2. The aforementioned rIGF-1 / IGFBP-3 is present at approximately 10 micrograms / mL to 1000 micrograms / mL. The composition according to claim 1, having a concentration of 100mg / mL.
3. The polysorbate surfactant is polysorbate 20 (P20) or polysorbate A composition according to claim 1 or 2, selected from 80 (P80).
4. The composition according to claim 3, wherein the polysorbate surfactant is P20.
5. The polysorbate surfactant is present in the composition at a concentration of approximately 0.005%. The composition according to claim 1 or 2.
6. Less than 20% of the aforementioned IGF-1 remains as an oxidized species after being stored at 25°C for approximately 6 months. The composition according to claim 1 or 2.
7. Less than 10% of the aforementioned IGF-1 remains as an oxidized species after being stored at 40°C for approximately 3 months. The composition according to claim 1 or 2.
8. The percentage of oxidized species was determined by reversed-phase ultra-high performance liquid chromatography (RP-UPLC). A composition according to any one of the prior claims.
9. The IGFBP-3 comprises less than 5% trisulfide variants, as described in the prior claim. Any of the compositions described in item one.
10. Prior claim further includes a buffer containing sodium acetate, acetic acid, and / or sodium chloride. The composition described in any one of the items.
11. The sodium acetate or acetic acid is present in a concentration of approximately 10 to 100 mM, as described in claim 10. The composition of.
12. The composition according to claim 10, wherein the sodium acetate or acetic acid is concentrated at a concentration of about 50 mM. 。
13. The sodium chloride is concentrated at concentrations of approximately 20 mM and 200 mM, according to claims 10 to 12. The composition described in any one of the items.
14. The composition according to claim 13, wherein the sodium chloride is concentrated at a concentration of about 105 mM.
15. The composition is a combination according to any one of the prior claims, wherein the pH is about 5.0 to 7.
0. A finished product.
16. The composition according to claim 15, wherein the pH is approximately 5.3 to 5.
8.
17. The aforementioned rIGF-1 / IGFBP-3 is present at a concentration of approximately 45 to 55 micrograms / mL. The composition according to claim 1.
18. The rIGF-1 / IGFBP-3 concentration is approximately 50 micrograms / mL. The composition described in item 17.
19. The composition according to claim 17 or 18, wherein the composition is suitable for intravenous administration.
20. The composition has a storage life of approximately 20 to 24 months at a temperature of 2 to 8°C, prior claim The composition described in any one of the items.
21. Claim 20, wherein the composition has a shelf life of at least 24 months at a temperature of 2 to 8°C. The composition described above.
22. The composition is left at room temperature and / or ambient light for at least 8 hours, 12 hours, 24 hours, and 3 hours. A composition according to any one of the prior claims, which is stable for 6 hours or 48 hours.
23. Recombinant insulin-like growth factor 1 (rIGF-1), recombinant insulin-like growth factor binding agent The composition comprising protein 3 (rIGBP-3) and polysorbate 20 is polysorbate Recombinant insulin-like growth factor 1 (rIGF-1), recombinant insulin-like growth factor 1,20, without Rubate 20. More stable at room temperature than compositions containing thrin-like growth factor-binding protein 3 (rIGFBP-3). The composition according to any one of the prior claims.
24. Recombinant insulin-like growth factor 1 (rIGF-1), recombinant insulin-like growth factor binding agent The composition comprising protein 3 (rIGBP-3) and polysorbate 20 is polysorbate Recombinant insulin-like growth factor 1 (rIGF-1), recombinant insulin-like growth factor 1,20, without Rubate 20. Compositions containing thrin-like growth factor-binding protein 3 (rIGFBP-3) oxidize more easily at room temperature than compositions containing thrin-like growth factor-binding protein 3 (rIGFBP-3). A composition according to any one of claims 1 to 23, wherein the amount is small.
25. The percentage of the aforementioned IGF-1 oxidized species increased by more than 12% after 6 months when stored at a temperature of approximately 25°C. The composition according to any one of claims 1 to 24.
26. The percentage of the aforementioned IGF-1 oxidized species increased by more than 10% after 6 months when stored at a temperature of approximately 25°C. The composition according to any one of claims 1 to 24.
27. A medical device comprising the composition described in any one of the prior claims and a pharmaceutically acceptable carrier. A pharmaceutical composition.
28. Intraventricular hemorrhage (IVH), bronchopulmonary dysplasia (BPD), or chronic lung disease (CL) in premature infants A method for treating or preventing D), wherein the subject requiring treatment is any of the prior claims A method comprising administering the composition described in paragraph one.
29. Intraventricular hemorrhage (IVH), bronchopulmonary dysplasia (BPD), or chronic lung disease (CL) in premature infants. D) A method for treating or preventing the condition, wherein the subject requiring such treatment or prevention is recombinant A Insulin-like growth factor 1 (rIGF-1), recombinant insulin-like growth factor binding protein 3 Administer a composition containing (rIGFBP-3) and polysorbate 20 surfactant. Methods that include...
30. Intraventricular hemorrhage (IVH), bronchopulmonary dysplasia (BPD), or chronic lung disease (CL) in premature infants D) A method for treating or preventing the condition, wherein the subject requiring such treatment or prevention is recombinant A Insulin-like growth factor 1 (rIGF-1), recombinant insulin-like growth factor binding protein 3 (rIGFB-3), and polysorbate in concentrations of approximately 0.0025% to 0.0075% The process includes administering a composition containing a surfactant, and the rIGGF-1 and rIGBP-3 However, when complexed in equimolar amounts, the rIGF-1 / IGFBP-3 is approximately 10 micrograms. A method with a concentration of ram / mL to 1000 micrograms / mL.
31. Intraventricular hemorrhage (IVH), bronchopulmonary dysplasia (BPD), or chronic lung disease (CL) in premature infants D) A method for treating or preventing the condition, wherein the subject requiring such treatment or prevention is recombinant A Insulin-like growth factor 1 (rIGF-1), recombinant insulin-like growth factor binding protein 3 The procedure involves administering a composition containing (rIGFBP-3), wherein the required subject is 23 Method for a gestational period of up to 25 weeks + 6 days.
32. Intraventricular hemorrhage (IVH), bronchopulmonary dysplasia (BPD), or chronic lung disease (CL) in premature infants D) A method for treating or preventing the condition, wherein the subject requiring such treatment or prevention is recombinant A Insulin-like growth factor 1 (rIGF-1), recombinant insulin-like growth factor binding protein 3 A composition containing (rIGFBP-3) achieves a reduction in the incidence of intraventricular hemorrhage compared to a control. A method including administering a sufficient therapeutic dose.
33. The reduction in the aforementioned incidence rate is evaluated by ultrasound or magnetic resonance imaging (MRI) at approximately 36%. The method according to claim 32, which is achieved during a gestational period of up to 40 weeks.
34. The method according to claim 33, wherein the reduction in the incidence rate is achieved by 36 weeks.
35. The method according to claim 33, wherein the reduction in the incidence rate is achieved by 40 weeks.
36. The method according to claim 32, wherein the reduction in the incidence rate is evaluated by ultrasound.
37. The reduction in the incidence of intraventricular hemorrhage (IVH) is grade II, grade III, or grade The method according to claim 32, which reduces the incidence of IVH in IV-4 patients by at least about 30%. Law.
38. Intraventricular hemorrhage (IVH), bronchopulmonary dysplasia (BPD), or chronic lung disease (CL) in premature infants A method for treating or preventing D), wherein the subject requiring such treatment or prevention is as described in claim 1 A method comprising administering the composition described in 2.
39. The polysorbate surfactant is polysorbate 20 (P20) or polysorbate The method according to claim 29 or 30, selected from 80 (P80).
40. The method according to claim 39, wherein the polysorbate surfactant is P20.
41. The method according to claim 29 or 30, wherein the polysorbate has a concentration of 0.005%. 。
42. Less than 20% of the aforementioned IGF-1 remains as an oxidized species after being stored for approximately three months, according to the claim. The method described in paragraph 29 or 30.
43. The method according to claim 29 or 30, wherein the percentage of oxidized species is determined by RP-UPLC. 。
44. Claim 29 or otherwise, wherein the IGFBP-3 comprises less than 5% trisulfide variants. The method described in 30.
45. The method according to claims 29 to 44, wherein the subject requiring the treatment is an infant.
46. The infant said to have been at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, Born 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 1 month, 2 months, or 3 months early The method according to claim 45.
47. The method according to claim 45, wherein the infant was born with a gestational age (GA) of less than 32 weeks.
48. The method according to claim 45, wherein the infant was born with a gestational age (GA) of less than 28 weeks.
49. The method according to claim 45, wherein the infant was born during a gestational age (GA) of less than 26 weeks. 。
50. The method according to claim 45, wherein the infant is approximately 23 to 34 weeks postmenstrual (PMA).
51. The method according to claim 50, wherein the infant is approximately 23 weeks postmenstrual (PMA).
52. The method according to claim 50, wherein the infant is less than 34 weeks postmenstrual (PMA).
53. The method according to any one of claims 29 to 52, wherein the composition is administered intravenously.
54. The composition is administered at a dosage of approximately 100 to 1000 micrograms / kg / 24 hours. The method according to any one of claims 29 to 52.
55. The composition is administered at a dosage of approximately 800 micrograms / kg / 24 hours, according to the claim. The method described in item 54.
56. The composition is administered at a dosage of approximately 400 micrograms / kg / 24 hours, according to the claim. The method described in item 54.
57. The composition is administered at a dosage of approximately 250 micrograms / kg / 24 hours, according to the claim. The method described in item 54.
58. Claim 5, wherein the composition is administered once, twice, three times, or four times during a 24-hour period. The method described in any one of items 1 to 54.
59. The method according to claim 58, wherein the composition is administered once over a 24-hour period.
60. The method according to claim 58, wherein the composition is administered by continuous infusion over a period of 24 hours. Law.
61. The composition is administered from birth until approximately 23 to 34 weeks postmenstrual age (PMA), according to the claim. The method described in any one of paragraphs 29 to 60.
62. Claims 29-60, wherein the composition is administered from birth until approximately 23 to 32 weeks of age (PMA). The method described in any one of the items.
63. Claim 29 to The method described in any one of paragraphs 60.
64. The subject is one of claims 29 to 63, in which the IGF-1 serum level is reduced. Methods used.
65. Administration of the composition results in an increase in IGF-1 serum levels compared to baseline levels. The method according to any one of claims 29 to 64.
66. The IGF-1 serum level is at least about 25% to 50% compared to the baseline value. The method according to claim 65, which increases.
67. Claim that the IGF-1 serum level remains elevated for at least 24 hours after administration. The method described in 65.
68. The method according to claim 65, wherein the IGF-1 serum level remains elevated for approximately 48 hours. Law.
69. Claim 65, wherein the IGF-1 serum level remains elevated for at least about 7 days. Method of description.
70. The aforementioned IGF-1 serum levels remain elevated until at least approximately 23 to 34 weeks postmenstruation (PMA). The method according to claim 65, wherein the temperature remains elevated.
71. The aforementioned IGF-1 serum levels remain elevated for at least approximately 23 weeks to 12 months postmenstrual age (PMA). The method according to claim 65, wherein the temperature remains elevated.
72. The administration of the composition occurred at postmenstrual age (PMA) weeks 23, 24, 25, 26, and 27. Week, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 Weeks, 38 weeks, 39 weeks, 40 weeks, 6 months, 8 months, 10 months, 12 months, or up to 24 months The method according to any one of claims 29 to 71, which results in a reduction in the incidence of intraventricular hemorrhage. 。
73. The administration of the composition is further performed at 23, 24, 25, and 26 weeks postmenstrual age (PMA). , 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks 37 weeks, 38 weeks, 39 weeks, 40 weeks, 6 months, 8 months, 10 months, 12 months, or 24 months Any one of claims 29 to 72, which results in a reduction in the incidence of bronchopulmonary dysplasia up to the moon. Methods used.
74. The administration of the composition occurred at 23, 24, 25, 26, and 27 weeks postmenstrual age (PMA). 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, PREMature Infant Index (P) up to 38, 39, or 40 weeks Any of claims 29 to 73 that result in an increase in the functional state as evaluated by REMII) The method described in any one of the items.
75. Administration of the above composition resulted in an increase in IGF-1 serum target levels of approximately 28 to 109 ng / ml. The method according to any one of claims 29 to 74, which brings about the present invention.
76. The reduction in the incidence rate is at least approximately 20% to 50% compared to untreated controls. The method described in item 72 or 73.
77. The aforementioned reduction in incidence is at least 20-50% compared to controls receiving standard treatment. The method according to claim 72 or 73.
78. The aforementioned increase in functional status is at least approximately 20% to 50% compared to untreated controls. The method according to claim 74.
79. The aforementioned increase in functional status is at least about 20–5 compared to a control receiving standard treatment. The method according to claim 74, wherein the percentage is 0%.
80. A method for producing a pharmaceutical composition, wherein the method involves insulin-like growth factor 1 (I Proteins containing GF-1 and insulin-like growth factor-binding protein 3 (IGFB-3) The method comprises providing a crystalline complex, wherein the complex is mixed with a formulation solution, and Therefore, the use of disposable bags during the production of the pharmaceutical composition is included, and the increase is in the pharmaceutical composition The method involves determining that the amount of oxidized species of IGF-1 in the substance is less than 20% when stored at 25°C for 6 months. 。
81. The method according to claim 80, wherein the formulation solution contains a surfactant.
82. The method according to claim 80, wherein the disposable bag is further used during the filtration step.
83. The method wherein, during the mixing step and / or the filtering step, the disposable bag The method according to claim 82, comprising filling at least 30% with the protein complex. Law.
84. The method wherein, during the mixing step and / or the filtering step, the disposable bag The method according to claim 82, comprising filling at least 40% with the protein complex. Law.
85. The method wherein, during the mixing step and / or the filtering step, the disposable bag The method according to claim 82, comprising filling at least 75% with the protein complex. Law.
86. The method wherein, during the mixing step and / or the filtering step, the disposable bag The method according to claim 82, comprising filling 75-90% with the protein complex.
87. The disposable bag is approximately 500L or more than 500L, as described in claims 80 to 86. method.
88. The increase in the oxidized species of IGF-1 is less than 5% when stored at 25°C for 6 months. The method described in claims 80 to 87.
89. Less than 2% of the IGF-1, when stored at 25°C for 6 months, is present in the protein complex. The method according to claims 80 to 88, wherein the oxidized species is present.
90. Less than 10% of the aforementioned protein complex, when stored at 40°C for 3 months, becomes a low molecular weight species. The method according to claims 80 to 89.
91. Less than 5% of the aforementioned protein complex, when stored at 40°C for 6 months, becomes a low molecular weight species. The method according to claims 80 to 90 exists.
92. Insulin-like growth produced by the method described in any one of claims 80 to 91 Factor 1 (IGF-1) and insulin-like growth factor-binding protein 3 (IGFB-3) A composition containing an isolated protein complex.
93. The aforementioned composition has a pH of 5.5 and contains 50 mM sodium acetate and 105 mM sodium chloride. The composition according to claim 92, comprising mu and 0.005% (v / v) of P20.
94. Equimolar amounts of recombinant insulin-like growth factor 1 (rIGF-1) and recombinant insulin-like growth factor A protein complex containing long factor-binding protein 3 (rIGFBP-3) and approximately 0.005 A % (v / v) concentration of polysorbate 20 surfactant, sodium acetate, acetic acid, and / A composition comprising a buffer containing sodium chloride, wherein the composition is approximately 5.3 to It has a pH of 5.8, and the rIGF-1 / IGFBP-3 is present at approximately 50 micrograms / m³. The concentration is L, and less than 1.5% of the IGF-1 is present as an oxidized species at the time of product release. a composition.