USRE49444EActiveUtility
Method of treating osteoporosis comprising administration of PTHrP analog
Est. expiryOct 3, 2026(~0.2 yrs left)· nominal 20-yr term from priority
Inventors:Michael J. DeyNathalie MondolyBenedicte RigaudBart HendersonC. Richard LyttleZhengxin Dong
A61K 47/12A61K 9/0019A61K 9/08A61K 38/29
90
PatentIndex Score
2
Cited by
144
References
79
Claims
Abstract
The present invention provides a storage-stable composition containing a parathyroid hormone-related protein (PTHrP) and methods of using a PTHrP and the PTHrP compositions described herein to treat osteoporosis, to increase bone mass or to increase bone quality. The composition is storage stable, in sterile form, and in general may be stored at room temperature for at least several weeks to allow convenient parenteral administration to human patients.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1. A method of treating osteoporosis comprising daily subcutaneous administration of a composition comprising 80 μg of [Glu 22,25 , Leu 23,28,31 , Aib 29 , Lys 26,30 ]hPTHrP(1-34)NH 2 to a human in need thereof.
2. The method of claim 1 , wherein the composition further comprises an effective amount of buffer to maintain the pH between 2 and 7.
3. The method of claim 1 , wherein the buffer is selected from the group consisting of acetate, tartrate, phosphate and citrate buffers.
4. The method of claim 3 , wherein the buffer is an acetate buffer.
5. The method of claim 4 , wherein the buffer is acetic acid and sodium acetate.
6. The method of claim 2 , wherein the pH is maintained between 3 and 6.
7. The method of claim 6 , wherein the pH is maintained between 4 and 6.
8. The method of claim 7 , wherein the pH is maintained between 4.5 and 5.6.
9. The method of claim 1 , wherein the human is a post-menopausal woman.
10. The method according to claim 9 wherein the dose is 80 μg and wherein said dose results in a plasma C max of [Glu 22,25 , Leu 23,28,31 , Aib 29 , Lys 26,30 ]hPTHrP(1-34)NH 2 from between 255.57 pg/mL and 364.3 pg/mL or from between 367.2 pg/mL and 504.8 pg/mL in said subject.
11. The method according to claim 9 wherein the dose is 80 μg and wherein said dose results in a plasma T max of [Glu 22,25 , Leu 23,28,31 , Aib 29 , Lys 26,30 ]hPTHrP(1-34)NH 2 from between 0.251 hours and 1.01 hours, or from between 0.500 hours and 1.00 hours in said subject.
12. The method according to claim 9 wherein the dose is 80 μg and wherein said dose results in a plasma t 1/2 of [Glu 22,25 , Leu 23,28,31 , Aib 29 , Lys 26,30 ] hPTHrP(1-34)NH 2 from between 1.585 hours and 3.015 hours, or from between 1.265 hours and 2.115 hours in said subject.
13. The method according to claim 9 wherein the dose is 80 μg and wherein said dose results in a plasma C max of [Glu 22,25 , Leu 23,28,31 , Aib 29 , Lys 26,30 ] hPTHrP(1-34)NH 2 from between 255.57 pg/mL and 364.3 pg/mL and a T max from between 0.251 hours and 1.01 hours, or a C max from between 367.2 pg/mL and 504.8 pg/mL and a T max from between 0.500 hours and 1.00 hours in said subject.
14. The method according to claim 9 wherein the dose is 80 μg and wherein said dose results in a plasma C max of [Glu 22,25 , Leu 23,28,31 , Aib 29 , Lys 26,30 ] hPTHrP(1-34)NH 2 from between 255.57 pg/mL and 364.3 pg/mL and a T max from between 0.251 hours and 1.01 hours and a t 1/2 of between 1.585 hours and 3.015 hours, or a C max from between 367.2 pg/mL and 504.8 pg/mL and a T max from between 0.500 hours and 1.00 hours and a t 1/2 of between 1.265 hours and 2.115 hours in said subject.
15. The method according to claim 2, wherein the pH is maintained at about 5.1.
16. A method of treating osteoporosis comprising daily subcutaneous administration of a composition comprising 80 μg of [Glu 22,25 , Leu 23,28,31 , Aib 29 , Lys 26,30 ]hPTHrP(1-34)NH 2 to a human in need thereof, wherein the composition is delivered in a multi-dose injection pen.
17. The method according to claim 16, wherein the composition further comprises an anti-microbial agent.
18. The method according to claim 17, wherein the anti-microbial agent is selected from phenol, chlorocresol, and methylparaben/propylparaben, or a combination thereof.
19. The method according to claim 18, wherein the anti-microbial agent is phenol.
20. The method according to claim 19, wherein the composition comprises 5 mg/mL phenol.
21. The method according to claim 16 or claim 17, wherein the composition further comprises a buffer.
22. The method according to claim 21, wherein the composition comprises a buffer in an amount effective to maintain the pH at about 5.1.
23. The method according to claim 22, wherein the pH is maintained at about 5.1.
24. The method according to claim 21, wherein the buffer is selected from a citrate buffer and an acetate buffer, or a combination thereof.
25. The method according to claim 22, wherein the buffer is selected from a citrate buffer and an acetate buffer, or a combination thereof.
26. The method according to claim 23, wherein the buffer is selected from a citrate buffer and an acetate buffer, or a combination thereof.
27. The method according to claim 24, wherein the buffer is an acetate buffer.
28. The method according to claim 25, wherein the buffer is an acetate buffer.
29. The method according to claim 26, wherein the buffer is an acetate buffer.
30. The method according to claim 27, wherein the acetate buffer comprises acetic acid and sodium acetate.
31. The method according to claim 28, wherein the acetate buffer comprises acetic acid and sodium acetate.
32. The method according to claim 29, wherein the acetate buffer comprises acetic acid and sodium acetate.
33. The method according to claim 30, wherein the sodium acetate is sodium acetate trihydrate.
34. The method according to claim 31, wherein the sodium acetate is sodium acetate trihydrate.
35. The method according to claim 32, wherein the sodium acetate is sodium acetate trihydrate.
36. The method according to claim 17, wherein the anti-microbial agent is present in an amount effective to limit the number of colony forming units (cfu) of a bacterium selected from Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli in the composition to less than 5 cfu/mL six hours following bacterial exposure.
37. The method according to claim 36, wherein the anti-microbial agent is present in an amount effective to limit the number of colony forming units (cfu) of a bacterium selected from Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli in the composition to less than 5 cfu/mL 24 hours following bacterial exposure.
38. The method according to claim 36, wherein the anti-microbial agent is present in an amount effective to limit the number of colony forming units (cfu) of a bacterium selected from Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli in the composition to less than 5 cfu/mL 28 days following bacterial exposure.
39. The method according to claim 36, wherein the composition is stored for 3 months at 25° C. prior to bacterial exposure.
40. The method according to claim 37, wherein the composition is stored for 3 months at 25° C. prior to bacterial exposure.
41. The method according to claim 38, wherein the composition is stored for 3 months at 25° C. prior to bacterial exposure.
42. The method according to claim 36, wherein the composition is stored for 4.5 months at 5° C. prior to bacterial exposure.
43. The method according to claim 37, wherein the composition is stored for 4.5 months at 5° C. prior to bacterial exposure.
44. The method according to claim 38, wherein the composition is stored for 4.5 months at 5° C. prior to bacterial exposure.
45. The method according to claim 17, wherein the anti-microbial agent is present in an amount effective to limit the number of colony forming units (cfu) of a yeast or mold selected from Aspergillus niger and Candida albicans in the composition to less than 5 cfu/mL 7 days following exposure to the yeast or mold.
46. The method according to claim 45, wherein the anti-microbial agent is present in an amount effective to limit the number of colony forming units (cfu) of a yeast or mold selected from Aspergillus niger and Candida albicans in the composition to less than 5 cfu/mL 7 days following exposure to the yeast or mold.
47. The method according to claim 45, wherein the anti-microbial agent is present in an amount effective to limit the number of colony forming units (cfu) of a yeast or mold selected from Aspergillus niger and Candida albicans in the composition to less than 5 cfu/mL 28 days following exposure to the yeast or mold.
48. The method according to claim 45, wherein the composition is stored for 3 months at 25° C. prior to exposure to the yeast or mold.
49. The method according to claim 46, wherein the composition is stored for 3 months at 25° C. prior to exposure to the yeast or mold.
50. The method according to claim 47, wherein the composition is stored for 3 months at 25° C. prior to exposure to the yeast or mold.
51. The method according to claim 45, wherein the composition is stored for 4.5 months at 5° C. prior to exposure to the yeast or mold.
52. The method according to claim 46, wherein the composition is stored for 4.5 months at 5° C. prior to exposure to the yeast or mold.
53. The method according to claim 47, wherein the composition is stored for 4.5 months at 5° C. prior to exposure to the yeast or mold.
54. The method according to claim 16, wherein the concentration of [Glu 22,25 , Leu 23,28,31 , Aib 29 , Lys 26,30 ]hPTHrP(1-34)NH 2 in the composition is at least 98.9% of its initial concentration at t=0 after 1 month.
55. The method according to claim 16, wherein the concentration of [Glu 22,25 , Leu 23,28,31 , Aib 29 , Lys 26,30 ]hPTHrP(1-34)NH 2 in the composition is at least 96.3% of its initial concentration at t=0 after 3 months.
56. The method according to claim 16, wherein the concentration of [Glu 22,25 , Leu 23,28,31 , Aib 29 , Lys 26,30 ]hPTHrP(1-34)NH 2 in the composition is at least 99.5% of its initial concentration at t=0 after 4.5 months.
57. The method according to claim 54, wherein the concentration of [Glu 22,25 , Leu 23,28,31 , Aib 29 , Lys 26,30 ]hPTHrP(1-34)NH 2 in the composition is at least 98.9% of its initial concentration at t=0 after 1 month at 25° C.
58. The method according to claim 55, wherein the concentration of [Glu 22,25 , Leu 23,28,31 , Aib 29 , Lys 26,30 ]hPTHrP(1-34)NH 2 in the composition is at least 96.3% of its initial concentration at t=0 after 3 months at 25° C.
59. The method according to claim 56, wherein the concentration of [Glu 22,25 , Leu 23,28,31 , Aib 29 , Lys 26,30 ]hPTHrP(1-34)NH 2 in the composition is at least 99.5% of its initial concentration at t=0 after 4.5 months at 5° C.
60. A method of treating osteoporosis comprising daily subcutaneous administration of a composition comprising 80 μg of [Glu 22,25 , Leu 23,28,31 , Aib 29 , Lys 26,30 ]hPTHrP(1-34)NH 2 to a human in need thereof, wherein the composition is prepared according to a process comprising:
(a) dissolving [Glu 22,25 , Leu 23,28,31 , Aib 29 , Lys 26,30 ]hPTHrP(1-34)NH 2 , an anti-microbial agent, and a buffer in water to form a solution; and
(b) filtering the solution through a 0.2 micron filter.
61. The method according to claim 60, wherein the anti-microbial agent is selected from phenol, chlorocresol, and methylparaben/propylparaben, or a combination thereof.
62. The method according to claim 61, wherein the anti-microbial agent is phenol.
63. The method according to claim 62, wherein the composition comprises 5 mg/mL phenol.
64. The method according to claim 60, wherein the composition comprises a buffer in an amount effective to maintain the pH at about 5.1.
65. The method according to claim 64, wherein the buffer is selected from a citrate buffer and an acetate buffer, or a combination thereof.
66. The method according to claim 65, wherein the buffer is an acetate buffer.
67. The method according to claim 66, wherein the acetate buffer comprises acetic acid and sodium acetate.
68. The method according to claim 67, wherein the sodium acetate is sodium acetate trihydrate.
69. A method of treating osteoporosis, the method comprising daily subcutaneous administration to a human in need thereof a composition comprising 80 μg of [Glu 22,25 , Leu 23,28,31 , Aib 29 , Lys 26,30 ]hPTHrP(1-34)NH 2 , wherein the composition is formulated to achieve one or more of the following pharmacokinetic parameters:
Pharmacokinetic
Parameters
Mean ± SD
C max (pg/mL)
310 ± 54.3
T max (hr)#
0752 (0.251, 1.01)
T last (hr)#
7.00 (4.00.12.01
AUC 0-t (pg * hr/mL)
949.89 ± 493.58
AUC 0-inf (pg * hr/mL)
1055.6 ± 513.61
AUC 0-tau (pg * hr/mL)
1053.2 ± 511.27
t 1/2 (hr)
2.30 ± 0715
K el (1/hr)
0.335 ± 0.127
AUCR
0.892 ± 0.0369
CL/F (L/hr)
94.61 ± 51.09
ln (C max )
5.722 ± 0.1732
ln (AUC 0-t )
6.740 ± 0.5206
ln (AUC 0-inf )
6.855 ± 0.5063
ln (AUC 0-tau )
6.853 ± 0.5050
#= Tmax and Tlast are presented as Median (minimum, Maximum).
70. The method according to claim 69, wherein the dosing regimen has been determined to achieve a C max plasma levels of [Glu 22,25 , Leu 23,28,31 , Aib 29 , Lys 26,30 ]hPTHrP(1-34)NH 2 between 255.7 pg/mL and 364.3 pg/mL.
71. The method according to claim 69, wherein the dosing regimen has been determined to achieve a plasma T max for [Glu 22,25 , Leu 23,28,31 , Aib 29 , Lys 26,30 ]hPTHrP(1-34)NH 2 between 0.251 hours and 1.01 hours.
72. The method according to claim 69, wherein the dosing regimen has been determined to achieve a plasma t 1/2 of [Glu 22,25 , Leu 23,28,31 , Aib 29 , Lys 26,30 ]hPTHrP(1-34)NH 2 between 1.585 hours and 3.015 hours.
73. The method according to claim 69, wherein the dosing regimen has been determined to achieve a net plasma AUC (0-inf) of [Glu 22,25 , Leu 23,28,31 , Aib 29 , Lys 26,30 ]hPTHrP(1-34)NH 2 between 541.99 pg h/mL and 1569.21 pg h/mL.
74. A method of treating osteoporosis, the method comprising daily subcutaneous administration to a human in need thereof a composition comprising 80 μg of [Glu 22,25 , Leu 23,28,31 , Aib 29 , Lys 26,30 ]hPTHrP(1-34)NH 2 , wherein the composition is formulated to achieve one or more of the following pharmacokinetic parameters:
Pharmacokinetic
Parameters
Mean ± SD
C max (pg/mL)
436 ± 68.8
T max (hr)#
0.507 (0.500, 1.00)
T last (hr)#
6.00 (4.00, 8.02)
AUC 0-t (pg * hr/mL)
1003.0 ± 383.45
AUC 0-tau (pg * hr/mL)
1080.3 ± 408.57
t 1/2 (hr)
1.69 ± 0.425
K el (1/hr)
0.437 ± 0.124
CL/F (L/hr)
82.74 ± 26.95
AI
1.12 ± 0.353
ln (C max )
6.065 ± 0.1628
ln (AUC 0-t )
6.851 ± 0.3623
ln (AUC 0-tau )
6.927 ± 0.3581
#= Tmax and Tlast are presented as Median (minimum, Maximum).
75. The method according to claim 74, wherein the dosing regimen has been determined to achieve a C max plasma levels of [Glu 22,25 , Leu 23,28,31 , Aib 29 , Lys 26,30 ]hPTHrP(1-34)NH 2 between 367.2 pg/mL and 504.8 pg/mL.
76. The method according to claim 74, wherein the dosing regimen has been determined to achieve a plasma T max for [Glu 22,25 , Leu 23,28,31 , Aib 29 , L 26,30 ]hPTHrP(1-34)NH 2 between 0.500 hours and 1.00 hours.
77. The method according to claim 74, wherein the dosing regimen has been determined to achieve a plasma t 1/2 of [Glu 22,25 , Leu 23,28,31 , Aib 29 , Lys 26,30 ]hPTHrP(1-34)NH 2 between 1.265 hours and 2.115 hours.
78. The method according to claim 69, wherein the composition is delivered in a multi-dose injection pen.
79. The method according to claim 74, wherein the composition is delivered in a multi-dose injection pen.Cited by (0)
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