U.S. patent application number 15/405409 was filed with the patent office on 2017-07-27 for novel crystalline forms of trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide sodium salt.
The applicant listed for this patent is Forest Laboratories Holdings Limited. Invention is credited to Sisir Bhattacharya, Alain Bonnet, Mahendra G. Dedhiya, Veronique Ducandas, Alexandre Guiliani, Alain Priour, Valerie Ravaux, Peter Spargo.
Application Number | 20170210742 15/405409 |
Document ID | / |
Family ID | 42154208 |
Filed Date | 2017-07-27 |
United States Patent
Application |
20170210742 |
Kind Code |
A1 |
Dedhiya; Mahendra G. ; et
al. |
July 27, 2017 |
NOVEL CRYSTALLINE FORMS OF
TRANS-7-OXO-6-(SULPHOOXY)-1,6-DIAZABICYCLO[3,2,1]OCTANE-2-CARBOXAMIDE
SODIUM SALT
Abstract
The present invention relates to novel crystalline forms of
sodium salt of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
(e.g., NXL-104) thereof. The present invention relates to
compositions comprising a crystalline form of sodium salt of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
(e.g., NXL-104) alone or in combination with an antibacterial agent
(e.g., ceftaroline fosamil). Processes for the preparation of the
crystalline forms and methods of treating bacterial infections by
administering the crystalline forms alone or in combination with an
antibacterial agent (e.g., ceftaroline fosamil) are also
described.
Inventors: |
Dedhiya; Mahendra G.;
(Pomona, NY) ; Bhattacharya; Sisir; (Commack,
NY) ; Ducandas; Veronique; (Vitry Sur Seine, FR)
; Guiliani; Alexandre; (Villecresnes, FR) ;
Ravaux; Valerie; (Reyrieux, FR) ; Bonnet; Alain;
(Chateau-Thierry, FR) ; Priour; Alain; (Paris,
FR) ; Spargo; Peter; (Deal, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Forest Laboratories Holdings Limited |
Hamilton |
|
BM |
|
|
Family ID: |
42154208 |
Appl. No.: |
15/405409 |
Filed: |
January 13, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14711162 |
May 13, 2015 |
9580424 |
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15405409 |
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14454141 |
Aug 7, 2014 |
9062053 |
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14711162 |
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13901724 |
May 24, 2013 |
8835455 |
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14454141 |
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12900567 |
Oct 8, 2010 |
8471025 |
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13901724 |
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61263663 |
Nov 23, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/439 20130101;
C07D 471/08 20130101; A61K 31/675 20130101; C07B 2200/13 20130101;
A61P 31/04 20180101 |
International
Class: |
C07D 471/08 20060101
C07D471/08; A61K 31/675 20060101 A61K031/675; A61K 31/439 20060101
A61K031/439 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 9, 2009 |
FR |
0904864 |
Claims
1. A crystalline form of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
or a pharmaceutically acceptable salt thereof.
2. The crystalline form according to claim 1, wherein the salt is a
sodium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide.
3. The crystalline form according to claim 2, wherein the
crystalline form has an X-Ray powder diffraction pattern comprising
a characteristic peak at about 13.0+/-0.5 degrees 2.theta..
4. The crystalline form according to claim 2, wherein the
crystalline form has an X-Ray powder diffraction pattern comprising
a characteristic peak at about 16.5+/-0.5 degrees 2.theta..
5. The crystalline form according to claim 2, wherein the
crystalline form has an X-Ray powder diffraction pattern comprising
a characteristic peaks at about 17.5+/-0.5 degrees 2.theta..
6. The crystalline form according to any one of claims 3 to 5,
wherein the crystalline form has an X-Ray powder diffraction
pattern further comprising a characteristic peak at about 17.3;
about 22.3+/-0.5 degrees 2.theta. or a combination thereof.
7. The crystalline form according to any one of claims 3 to 5,
wherein the crystalline form has an X-Ray powder diffraction
pattern further comprising a characteristic peak at about 19.2;
about 19.5+/-0.5 degrees 2.theta. or a combination thereof.
8. The crystalline form according to any one of claims 3 to 5,
wherein the crystalline form has an X-Ray powder diffraction
pattern further comprising a characteristic peak at about 19.9;
about 22.0; about 25.2; about 28.2+/-0.5 degrees 2.theta. or a
combination thereof.
9. The crystalline form according to any one of claims 3 to 5,
wherein the crystalline form has an X-Ray powder diffraction
pattern further comprising a characteristic peak at about 23.2;
about 30.2; about 30.9; about 36.1+/-0.5 degrees 2.theta. or a
combination thereof.
10. The crystalline form according to claim 1, wherein the
crystalline form has an X-Ray powder diffraction pattern comprising
a characteristic peak at about 13.0; about 16.5; about 17.3; about
17.5; about 19.2; about 19.5; about 19.9; about 22.0; about 22.3;
about 25.2; about 28.2+/-0.5 degrees 2.theta. or a combination
thereof.
11. The crystalline form according to claim 1, wherein the
crystalline form has an X-Ray powder diffraction pattern comprising
characteristic peaks at about 13.0; about 16.5; about 17.3; about
17.5; about 19.2; about 19.5; about 19.9; about 22.0; about 22.3;
about 23.2; about 25.2; about 28.2; about 30.2; about 30.9 and
about 36.1+/-0.5 degrees 2.theta..
12. The crystalline form according to claim 2, wherein the
crystalline form has an X-Ray powder diffraction pattern comprising
a d-spacing value at about 6.8+/-2 nm.
13. The crystalline form according to claim 2, wherein the
crystalline form has an X-Ray powder diffraction pattern comprising
a d-spacing value at about 5.1+/-2 nm.
14. The crystalline form according to claim 2, wherein the
crystalline form has an X-Ray powder diffraction pattern comprising
a d-spacing value at about 5.4+/-2 nm.
15. The crystalline form according any one of claims 12 to 14,
wherein the crystalline form has an X-Ray powder diffraction
pattern further comprising a d-spacing value at about 3.2; about
3.5; about 4.0; about 4.5; about 4.6+/-2 nm or a combination
thereof.
16. The crystalline form according to claim 1, wherein the
crystalline form has an X-Ray powder diffraction pattern comprising
d-spacing values at about 2.5; about 2.9; about 3.0; about 3.2;
about 3.5; about 3.8; about 4.0; about 4.5; about 4.6; about 5.1;
about 5.4; about 6.8+/-2 nm or a combination thereof.
17. The crystalline form according to claim 1, wherein the
crystalline form has an X-Ray powder diffraction pattern comprising
d-spacing values at about 2.5; about 2.9; about 3.0; about 3.2;
about 3.5; about 3.8; about 4.0; about 4.5; about 4.6; about 5.1;
about 5.4; and about 6.8+/-2 nm.
18. A pharmaceutical composition comprising a crystalline form of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
or a pharmaceutically acceptable salt thereof.
19. A pharmaceutical composition comprising a crystalline form of a
sodium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
according to any one of claims 3 to 5.
20. The composition according to claim 18, wherein the composition
comprises loss than about 1.5% of a decarbonyl compound of Formula
(I): ##STR00020##
21. The composition according to claim 20, wherein the composition
comprises about 0.05% to about 1.5% of the decarbonyl compound.
22. The composition according to claim 18, further comprising an
antibacterial agent.
23. The composition according to claim 22, wherein the
antibacterial agent is ceftaroline or a prodrug of ceftaroline.
24. The composition according to claim 23, wherein the
antibacterial agent is ceftaroline fosamil.
25. The composition according to claim 23, wherein the
antibacterial agent is anhydrous ceftaroline fosamil.
26. The composition according to claim 23, wherein the
antibacterial agent is ceftaroline fosamil monohydrate acetic acid
solvate.
27. The composition according to claim 23, wherein the composition
comprises less than about 10% of impurities.
28. The composition according to claim 23, wherein the composition
comprises less than about 0.6% of a compound of Formula (III):
##STR00021##
29. The composition according to claim 23, wherein the composition
comprises less than about 0.6% of a compound of Formula (IV):
##STR00022##
30. The composition according to claim 23, wherein the composition
comprises less than about 5% of compound of Formula (V):
##STR00023##
31. The composition according to claim 23, wherein the composition
comprises less than about 0.2% of a compound of Formula (VI):
##STR00024##
32. The composition according to claim 23, wherein the composition
comprises less than about 0.2% of a compound of Formula (VII):
##STR00025##
33. The composition according to claim 23, wherein the composition
comprises less than about 0.6% of a compound of Formula (VIII):
##STR00026##
34. The composition according to claim 23, wherein the composition
comprises less than about 0.2% of a compound of Formula (IX):
##STR00027##
35. The composition according to claim 23, wherein the composition
comprises less than about 0.2% of a compound of U Formula (X):
##STR00028##
36. The composition according to claim 23, wherein the composition
comprises less than about 1.0% of a compound of Formula XI:
##STR00029##
37. The composition according to claim 23, wherein the composition
comprises less than about 1.5% of a compound of Formula (XII)
##STR00030##
38. A composition comprising about 200 mg to about 1200 mg of a
crystalline form of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
or a pharmaceutically acceptable salt thereof wherein the
composition provides an in vivo plasma profile for the crystalline
form comprising a mean Cmax of less than about 100 ug/ml.
39. The composition according to claim 38, wherein the composition
comprises the sodium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide.
40. The composition according to claim 38, wherein the composition
comprises about 400 mg of sodium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide.
41. The composition according to claim 38, wherein the composition
comprises about 600 mg of sodium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide.
42. The composition according to claim 38, wherein the composition
comprises Form I.
43. The composition according to claim 38, wherein the in vivo
plasma profile comprises a mean Cmax of about 10 to 50 ug/ml.
44. The composition according to claim 38, further comprising about
200 mg to 1200 mg of ceftaroline or a prodrug of ceftaroline
wherein the composition provides an in vivo plasma profile for
ceftaroline comprising a mean Cmax of less than about 100
ug/ml.
45. The composition according to claim 44, wherein the composition
comprises about 400 mg ceftaroline fosamil.
46. The composition according to claim 44, wherein the composition
comprises about 600 mg ceftaroline fosamil.
47. The composition according to any one of claim 45 or 46, wherein
the composition comprises ceftaroline fosamil monohydrate acetic
acid solvate.
48. A composition comprising about 200 mg to 1200 mg of a
crystalline form of
trans-?-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxa-
mide or a pharmaceutically acceptable salt thereof wherein the
composition provides an in vivo plasma profile for the crystalline
form comprising a mean AUC.sub.0-.infin. of more than about 10 ug
h/ml.
49. The composition according to claim 48, wherein the composition
comprises the sodium salt of sodium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide.
50. The composition according to claim 48, wherein the composition
comprises about 400 mg of sodium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide.
51. The composition according to claim 48, wherein the composition
comprises about 600 mg of sodium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide.
52. The composition according to claim 48, wherein the composition
comprises Form I.
53. The composition according to claim 48, wherein the in vivo
plasma profile comprises a mean AUC.sub.0-.infin. of about 10 to
200 ug h/ml.
54. The composition according to claim 48, further comprising about
200 mg to 1200 mg of ceftaroline or a prodrug of ceftaroline
wherein the composition provides an in vivo plasma profile for
ceftaroline comprising a mean AUC.sub.0-.infin. of more than about
10 ug h/ml.
55. The composition according to claim 54, wherein the composition
comprises about 400 mg ceftaroline fosamil.
56. The composition according to claim 54, wherein the composition
comprises about 600 mg ceftaroline fosamil.
57. The composition according to any one of claim 55 or 56, wherein
the composition comprises ceftaroline fosamil monohydrate acetic
acid solvate.
58. A composition comprising about 200 mg to 1200 mg of a
crystalline form of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxa-
mide or a pharmaceutically acceptable salt thereof wherein the
composition provides an in vivo plasma profile for the crystalline
form comprising a mean Tmax of more than about 10 minutes.
59. The composition according to claim 58, wherein the composition
comprises the sodium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide.
60. The composition according to claim 58, wherein the composition
comprises about 400 mg of sodium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide.
61. The composition according to claim 58, wherein the composition
comprises about 600 mg of sodium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide.
62. The composition according to claim 58, wherein the composition
comprises Form I.
63. The composition according to claim 58, wherein the in vivo
plasma profile comprises a mean Tmax of about 30 minutes to about 2
hours.
64. The composition according to claim 58, further comprising about
200 mg to 1200 mg of ceftaroline or a prodrug of ceftaroline
wherein the composition provides an in vivo plasma profile for
ceftaroline comprising a mean Tmax of more than about 10
minutes.
65. The composition according to claim 54, wherein the composition
comprises about 400 mg ceftaroline fosamil.
66. The composition according to claim 54, wherein the composition
comprises about 600 mg ceftaroline fosamil.
67. The composition according to any one of claim 55 or 56, wherein
the composition comprises ceftaroline fosamil monohydrate acetic
acid solvate.
68. A method of treating a bacterial infection comprising
administering to a patient in need thereof, a therapeutically
effective amount of a crystalline form of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
or a pharmaceutically acceptable salt thereof.
69. A method of treating a bacterial infection comprising
administering to a patient in need thereof, a therapeutically
effective amount of a crystalline form of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
or a pharmaceutically acceptable salt thereof according to any one
of claims 3 to 5.
70. The method of claim 69, wherein the bacterial infection is
selected from the group consisting of complication skin and
structure infection and community acquired pneumonia.
71. A method of treating a bacterial infection comprising
administering to a patient in need thereof, the pharmaceutical
composition according to claim 18.
72. The method of claim 71, wherein the bacterial infection is
selected from the group consisting of complication skin and
structure infection and community acquired pneumonia.
73. The crystalline form according to claim 2, wherein the
crystalline form is Form II.
74. The crystalline form according to claim 2, wherein the
crystalline form has an X-Ray powder diffraction pattern comprising
a characteristic peak at about 17.1+/-0.5 degrees 2.theta..
75. The crystalline form according to claim 2, wherein the
crystalline form has an X-Ray powder diffraction pattern comprising
a characteristic peak at about 16.4+/-0.5 degrees 2.theta..
76. The crystalline form according to claim 2, wherein the
crystalline form has an X-Ray powder diffraction pattern comprising
a characteristic peak at about 8.5+/-0.5 degrees 2.theta..
77. A composition comprising the crystalline form according to any
one of claims 74 to 76.
78. A method of treating a bacterial infection comprising
administering to a patient in need thereof, a therapeutically
effective amount of the crystalline form according to any one of
claims 74 to 76.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority under 35 U.S.C. .sctn.119,
based on French Application No. 0904864 filed on Oct. 9, 2009 and
U.S. Provisional Application Ser. No. 61/263,663 filed on Nov. 23,
2009, both of which are hereby incorporated by reference in their
entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to novel crystalline forms of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (e.g., NXL-104) and compositions comprising the
crystalline forms alone or in combination with an antibacterial
agent (e.g., ceftaroline fosamil). Processes for the preparation of
the crystalline forms and methods of treating bacterial infections
by administering the crystalline forms alone or in combination with
an antibacterial agent (e.g., ceftaroline fosamil) are also
described.
BACKGROUND OF THE INVENTION
[0003] U.S. Pat. No. 7,112,592 discloses novel heterocyclic
compounds and their salts, processes for making the compounds and
methods of using the compounds as antibacterial agents. One such
compound is sodium salt of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide.
Application WO 02/10172 describes the production of azabicyclic
compounds and salts thereof with acids and bases, and in
particular,
trans-7-oxo-6-sulphoxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
and its pyridinium, tetrabutylammonium and sodium salts.
Application WO 03/063864 and U.S. Patent Publication No.
2005/0020572 describe the use of compounds including
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt, as .beta.-lactamase inhibitors that can be
administered alone or in combination with .beta.-lactamine
antibacterial agents. These references are incorporated herein by
reference, in their entirety.
[0004] Ceftaroline is a novel parenteral cephalosporin with a broad
spectrum of activity against clinically important
community-acquired and hospital-acquired Gram-negative and
Gram-positive pathogens including methicillin-resistant
Staphylococcus aureus and multidrug-resistant Streptococcus
pneumoniae.
[0005] U.S. Pat. No. 6,417,175 discloses compounds having excellent
antibacterial activities for a broad range of Gram-positive and
Gram-negative bacteria. These compounds are represented by the
general formula:
##STR00001##
[0006] wherein R.sup.1-R.sup.4, Q, X, Y and n are as defined
therein.
[0007] U.S. Pat. No. 6,417,175 discloses methods for preparing the
compounds, and generically discloses formulations of the compounds,
such as aqueous and saline solutions for injection. One such
compound is
7.beta.-[2(Z)-ethoxyimino-2-(5-phosphonoamino-1,2,4-thiadiazole-3-yl)acet-
amido]-3-[4-(1-methyl-4-pyridinio)-2-thiazolythio]-3-cephem-4-carboxylate.
[0008] U.S. Pat. No. 6,906,055 discloses a chemical genus which
includes compounds of formula:
##STR00002##
[0009] Ceftaroline fosamil is a sterile, synthetic, parenteral
prodrug cephalosporin antibiotic. The N-phosphonoamino
water-soluble prodrug is rapidly converted into the bioactive
ceftaroline, which has been demonstrated to exhibit antibacterial
activity. Ceftaroline fosamil is known as
(6R,7R)-7-{(2Z)-2-(ethoxyimino)-2-[5-(phosphonoamino)-1,2,4-thia-
diazol-3-yl]acetamido}-3-{[4-(1-methylpyridin-1-ium-4-yl)-1,3-thiazol-2-yl-
]sulfanyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate.
Ceftaroline fosamil may be an acetic acid hydrous form.
##STR00003##
[0010] U.S. Pat. No. 7,419,973 discloses compositions comprising
ceftaroline fosamil and a pH adjuster, such as, L-arginine.
[0011] U.S. Pat. Nos. 6,417,175 and 6,906,055 and 7,419,973 are
incorporated herein by reference, in their entirety.
[0012] The present invention relates to the solid state physical
properties of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (e.g., NXL-104). These properties may be influenced by
controlling the conditions under which
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (e.g., NXL-104) is obtained in solid form.
[0013] Solid state physical properties include, for example, the
flowability of the milled solid, rate of dissolution and stability.
The physical characteristics are influenced by the conformation and
orientation of molecules in the unit cell, which defines a
particular crystalline form of a substance. A crystalline form may
give rise to thermal behavior different from that of the amorphous
material or another crystalline form. Thermal behavior is measured
in the laboratory using techniques such as capillary melting point,
thermogravimetric analysis (TGA) and differential scanning
calorimetry (DSC). These techniques may be used to distinguish
between different crystalline forms. A particular crystalline form
may show distinct spectroscopic properties that can be detected
using powder X-ray diffractometry (XRPD), nuclear magnetic
resonance (NMR) spectrometry, Raman spectroscopy and infrared (IR)
spectrometry.
[0014] In deciding which crystalline form is preferable, the
numerous properties of the crystalline forms must be compared and
the preferred crystalline form chosen based on the many physical
property variables. A particular crystalline form may be preferable
in certain circumstances in which certain aspects, such as ease of
preparation, stability, etc., are deemed to be critical. In other
situations, a different crystalline form may be preferred for
greater solubility and/or superior pharmacokinetics.
[0015] The discovery of new crystalline forms of a pharmaceutically
useful compound provides a new opportunity to improve the
performance characteristics of a pharmaceutical product. New
crystalline forms of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt have now been discovered.
[0016] There is an existing and continual need in the art for new
and improved compositions and methods for treating bacterial
infections by administering antibacterial agents. Surprisingly and
unexpectedly, compositions comprising a crystalline form of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt and ceftaroline fosamil have been found to stable. Such
formulations may be used for the treatment of bacterial infections,
such as, complicated skin and structure infection and community
acquired pneumonia.
SUMMARY OF THE INVENTION
[0017] The present invention relates to novel crystalline forms of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (e.g., NXL-104).
[0018] The present invention provides compositions comprising a
crystalline form of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (e.g., NXL-104) alone or in combination with an
antibacterial agent (e.g., ceftaroline fosamil). Methods of
treating bacterial infections by administering the crystalline
forms alone or in combination with an antibacterial agent (e.g.,
ceftaroline fosamil) are also described.
BRIEF DESCRIPTION OF THE FIGURES
[0019] FIG. 1 shows the powder X-Ray diffraction pattern of
amorphous
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (NXL-104).
[0020] FIG. 2 shows the powder X-Ray diffraction pattern of Form I
of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (NXL-104).
[0021] FIG. 3 shows the powder X-Ray diffraction pattern of Form II
of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (NXL-104).
[0022] FIG. 4 shows the powder X-Ray diffraction pattern of Form
III of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (NXL-104).
[0023] FIG. 5 shows the powder X-Ray diffraction pattern of Form IV
of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (NXL-104).
[0024] FIG. 6 shows the powder X-Ray diffraction pattern of Form V
of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (NXL-104).
DETAILED DESCRIPTION OF THE INVENTION
[0025] The present invention provides novel crystalline forms of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (e.g., NXL-104). NXL-104 may also be referred to as
monosodium salt of
(1R,2S,5R)-7-oxo-6-sulphoxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide.
##STR00004##
[0026] The crystalline forms may be hydrated (e.g., a monohydrate
or a dihydrate) or anhydrous.
[0027] The present invention also provides compositions comprising
the crystalline forms alone or in combination with an antibacterial
agent (e.g., ceftaroline fosamil), processes for making the
crystalline forms and methods of treating bacterial infections by
administering the crystalline forms alone or in combination with an
antibacterial agent (e.g., ceftaroline fosamil).
[0028] Form I
[0029] In one aspect, the present invention provides a crystalline
form of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt called Form I.
[0030] In specific examples, the present invention provides a
crystalline form of sodium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
called Form I.
[0031] The sodium salt of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide,
in particular,
(1R,2S,5R)-7-oxo-6-sulphoxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,
is a beta-lactamase inhibitor, which reacts with a protein, forming
a covalent bond. This reactive inhibitor, a consequence of the
internal strain of the N-oxosulphoxyurea ring, is intrinsically
sensitive to moisture and to heat, just like the (f-lactams,
although it is not one. The main manner of degradation of the
sodium salt of
(1R,2S,5R)-7-oxo-6-sulphoxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
is by hydrolysis of the N-oxosulphoxyurea ring. To minimize
degradation, it is advantageous to isolate this molecule at room
temperature or at low temperature and minimize the duration of
exposure in aqueous solution. These conditions are fulfilled during
crystallization or lyophilisation but are difficult to fulfil
during concentration of an aqueous solution to dryness, as
described in Application WO 02/10172. In practice, the aqueous
solution containing the sodium salt of
(1R,2S,5R)-7-oxo-6-sulphoxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
can only be concentrated by lyophilisation, in order to obtain the
product in the amorphous form.
[0032] In exemplary embodiments, the Form I is characterized by an
X-Ray powder diffraction pattern comprising a characteristic peak,
such as, at about 13.0+/-0.5 degrees 2.theta.. In other
embodiments, the Form I is characterized by an X-Ray powder
diffraction pattern comprising a characteristic peak at about
16.5+/-0.5 degrees 2.theta.. In still other embodiments, the Form I
is characterized by an X-Ray powder diffraction pattern comprising
a characteristic peak at about 17.5+/-0.5 degrees 2.theta..
[0033] In exemplary embodiments, the Form I is characterized by an
X-Ray powder diffraction pattern comprising a characteristic peak
at about 13.0; about 16.5, about 17.5+/-0.5 degrees 2.theta. or a
combination thereof. In further embodiments, the Form I is
characterized by an X-Ray powder diffraction pattern comprising a
characteristic peak at about 17.3; about 22.3+/-0.5 degrees
2.theta. or a combination thereof. In other embodiments, the Form I
is further characterized by an X-Ray powder diffraction pattern
comprising a characteristic peak at about 19.2 or about 19.5+/-0.5
degrees 2.theta. or a combination thereof. In further embodiments,
the Form I is characterized by an X-Ray powder diffraction pattern
comprising a characteristic peak at about 19.9; about 22.0; about
25.2; about 28.2+/-0.5 degrees 28 or a combination thereof.
[0034] In specific embodiments, the Form I is characterized by an
X-Ray powder diffraction pattern comprising a characteristic peak
at about 13.0; about 16.5; about 17.3; about 17.5; about 19.2;
about 19.5; about 19.9; about 22.0; about 22.3; about 25.2; or
about 28.2+/-0.5 degrees 2.theta. or a combination thereof. In
further embodiments, the Form I is characterized by an X-Ray powder
diffraction pattern comprising a characteristic peak at about 23.2;
about 30.2; about 30.9; about 36.1+/-0.5 degrees 2.theta. or a
combination thereof. In exemplary embodiments, the Form I is
characterized by an X-Ray powder diffraction pattern comprising one
or more characteristic peaks at 2.theta. (.+-.0.1.degree.) 12.97,
16.45, 17.24, 17.45, 22.29.
[0035] In exemplary embodiments, the Form I of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (e.g., NXL-104) is characterized by an X-Ray powder
diffraction pattern comprising characteristic peaks at about 13.0;
about 16.5; about 17.3; about 17.5; about 19.2; about 19.5; about
19.9; about 22.0; about 22.3; about 23.2; about 25.2; about 28.2;
about 30.2; about 30.9 and about 36.1+/-0.5 degrees 2.theta..
[0036] In some embodiments, the Form I is characterized by an X-Ray
powder diffraction pattern comprising a d-spacing value, such as,
at about 6.8+/-2 nm. In other embodiments, the Form I is
characterized by an X-Ray powder diffraction pattern comprising a
d-spacing value at about 5.1+/-2 nm. In still other embodiments,
the Form I is characterized by an X-Ray powder diffraction pattern
comprising a d-spacing value at about 5.4+/-2 nm.
[0037] In exemplary embodiments, the Form I is characterized by an
X-Ray powder diffraction pattern comprising a d-spacing value at
about 5.1; about 5.4; about 6.8+/-2 nm or a combination thereof. In
further embodiments, the Form I is characterized by an X-Ray powder
diffraction pattern comprising a d-spacing value at about 4.0+/-2
nm. In other embodiments, the Form I characterized by an X-Ray
powder diffraction pattern comprising a d-spacing value at about
4.6+/-2 nm. In further embodiments, the Form I is characterized by
an X-Ray powder diffraction pattern comprising a d-spacing value at
about 3.2; about 3.5; about 4.0; about 4.5+/-2 nm or a combination
thereof.
[0038] In certain embodiments, the Form I of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (e.g., NXL-104) is characterized by an X-Ray powder
diffraction pattern comprising d-spacing values at about 2.5; about
2.9; about 3.0; about 3.2; about 3.5; about 3.8; about 4.0; about
4.5; about 4.6; about 5.1; about 5.4 or about 6.8+/-2 nm or a
combination thereof.
[0039] In exemplary embodiments, the Form I of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (e.g., NXL-104) is characterized by an X-Ray powder
diffraction pattern comprising d-spacing values at about 2.5; about
2.9; about 3.0; about 3.2; about 3.5; about 3.8; about 4.0; about
4.5; about 4.6; about 5.1; about 5.4; and about 6.8+/-2 nm.
[0040] Form II
[0041] In another aspect, the present invention provides a
crystalline form of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxa-
mide sodium salt (e.g., NXL-104) called Form II.
[0042] For example, the present invention provides a crystalline
form of sodium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
called Form II.
[0043] In some embodiments, the Form II is characterized by an
X-Ray powder diffraction pattern comprising a characteristic peak
at about 8.5; about 15.4; about 16.4; about 17.1; about 23.5 or
about 24.3+/-0.5 degrees 2.theta. or a combination thereof.
[0044] In exemplary embodiments, the Form II is characterized by an
X-Ray powder diffraction pattern comprising a characteristic peak
at about 17.1+/-0.5 degrees 2.theta.. In other embodiments, the
Form II is characterized by an X-Ray powder diffraction pattern
comprising a characteristic peak at about 16.4+/-0.5 degrees
2.theta.. In still other embodiments, the Form II is characterized
by an X-Ray powder diffraction pattern comprising a characteristic
peak at about 8.5+/-0.5 degrees 2.theta..
[0045] In further embodiments, the Form II characterized by an
X-Ray powder diffraction pattern comprising a characteristic peak
at about 15.4; about 23.5+/-0.5 degrees 2.theta. or a combination
thereof. In other embodiments, the Form II is further characterized
by an X-Ray powder diffraction pattern comprising a characteristic
peak at about 24.3+/-0.5 degrees 2.theta.. In exemplary
embodiments, the Form II of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt is characterized by an X-Ray powder diffraction pattern
comprising characteristic peaks at about 8.5; about 15.4; about
16.4; about 17.1; about 23.5 and about 24.3+/-0.5 degrees 2.theta..
In further specific embodiments, the Form II of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt is characterized by one or more peaks at 2.theta.
(.+-.0.1.degree.) 8.48, 15.34, 16.38, 17.04, 24.28.
[0046] In specific embodiments, the Form II is characterized by an
X-Ray powder diffraction pattern comprising a d-spacing value at
about 3.7; about 3.8; about 5.2; about 5.4; about 5.8 or about
10.4+/-2 nm or a combination thereof.
[0047] In some embodiments, the Form II is characterized by an
X-Ray powder diffraction pattern comprising a d-spacing value, such
as, at about 5.2+/-2 nm.
[0048] In other embodiments, the Form II is characterized by an
X-Ray powder diffraction pattern comprising a d-spacing value at
about 5.4+/-2 nm. In still other embodiments, the Form II is
characterized by an X-Ray powder diffraction pattern comprising a
d-spacing value at about 10.4+/-2 nm. In further embodiments, the
Form II characterized by an X-Ray powder diffraction pattern
comprising a d-spacing value at about 3.8 or about 5.8+/-2 nm or a
combination thereof.
[0049] In exemplary embodiments, the Form II of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (e.g., NXL-104) is characterized by an X-Ray powder
diffraction pattern comprising d-spacing values at about 3.7; about
3.8; about 5.2; about 5.4; about 5.8 and about 10.4+/-2 nm.
[0050] Form III
[0051] In another aspect, the present invention relates to a
crystalline form of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxa-
mide sodium salt (e.g., NXL-104) called Form III.
[0052] For example, the present invention provides a crystalline
form of sodium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
called Form III.
[0053] In exemplary embodiments, the Form III is characterized by
an X-Ray powder diffraction pattern comprising characteristic peaks
at about 9.8; about 13.6; about 15.0; about 15.8; about 19.5; about
19.7; about 22.5; about 22.8; about 23.5; about 24.3; about 24.6;
about 27.6; about 27.9; about 29.8 or about 31.7+/-0.5 degrees
2.theta. or a combination thereof.
[0054] In exemplary embodiments, the Form III is characterized by
an X-Ray powder diffraction pattern comprising a characteristic
peak at about 9.8+/-0.5 degrees 2.theta.. In other embodiments, the
Form III is characterized by an X-Ray powder diffraction pattern
comprising a characteristic peak at about 19.5+/-0.5 degrees
2.theta.. In still other embodiments, the Form III is characterized
by an X-Ray powder diffraction pattern comprising a characteristic
peak at about 15.0; about 15.8 or about 22.5+/-0.5 degrees 2.theta.
or a combination thereof.
[0055] In some embodiments, the Form III is characterized by an
X-Ray powder diffraction pattern comprising a characteristic peak
at about 13.6; about 19.7; about 23.5; about 24.6 or about
29.8+/-0.5 degrees 2.theta. or a combination thereof. In further
embodiments, the Form III is characterized by an X-Ray powder
diffraction pattern comprising a characteristic peak at about 22.8;
about 24.3; about 27.6; about 27.9 or about 31.7+/-0.5 degrees
2.theta. or a combination thereof.
[0056] In exemplary embodiments, the Form III is characterized by
an X-Ray powder diffraction pattern comprising characteristic peaks
at about 9.8; about 13.6; about 15.0; about 15.8; about 19.5; about
19.7; about 22.5; about 22.8; about 23.5; about 24.3; about 24.6;
about 27.6; about 27.9; about 29.8; about 31.7 and +/-0.5 degrees
2.theta.. In exemplary embodiments, the Form III is characterized
by an X-Ray powder diffraction pattern comprising one or more
characteristic peaks at 2.theta. (.+-.0.1.degree.) 13.65, 15.01,
15.38, 15.72, 19.42.
[0057] In some embodiments, the Form III is characterized by an
X-Ray powder diffraction pattern comprising d-spacing values at
about 2.8; about 3.0; about 3.2; about 3.6; about 3.7; about 3.8;
about 3.9; about 4.0; about 4.5; about 4.6; about 5.6; about 5.9;
about 6.5 or about 9.0+/-2 nm or a combination thereof.
[0058] In exemplary embodiments, the Form III is characterized by
an X-Ray powder diffraction pattern comprising a d-spacing value,
such as, at about 9.0+/-2 nm. In other embodiments, the Form III is
characterized by an X-Ray powder diffraction pattern comprising a
d-spacing value at about 4.6+/-2 nm. In still other embodiments,
the Form III is characterized by an X-Ray powder diffraction
pattern comprising a d-spacing value at about 4.0; about 4.5; about
5.6; about 5.9 or about 6.5+/-2 nm or a combination thereof.
[0059] In further embodiments, the Form III is characterized by an
X-Ray powder diffraction pattern comprising a d-spacing value at
about 2.8; about 3.0; about 3.2; about 3.6; about 3.7; about 3.8 or
about 3.9+/-2 nm or a combination thereof.
[0060] In exemplary embodiments, the Form III is characterized by
an X-Ray powder diffraction pattern comprising d-spacing values at
about 2.8; about 3.0; about 3.2; about 3.6; about 3.7; about 3.8;
about 3.9; about 4.0; about 4.5; about 4.6; about 5.6; about 5.9;
about 6.5 and about 9.0+/-2 nm.
[0061] Form IV
[0062] In another aspect, the present invention provides the
present invention provides a crystalline form of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (e.g., NXL-104) called Form IV.
[0063] For example, the present invention provides a crystalline
form of sodium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
called Form IV.
[0064] In some embodiments, the Form IV is characterized by an
X-Ray powder diffraction pattern comprising a characteristic peak,
such as, at about 8.7; about 113; about 12.5; about 16.3; about
17.5; about 17.8; about 18.6; about 21.0; about 22.3; about 26.2;
about 26.6; about 26.9; about 27.6; about 28.7; about 29.8; about
30.4; about 31.2; about 32.9; about 33.4; about 34.4; about 37.1;
about 37.3; about 37.6 or about 38.5+/-0.5 degrees 2.theta. or a
combination thereof.
[0065] In exemplary embodiments, the Form IV is characterized by an
X-Ray powder diffraction pattern comprising a characteristic peak
at about 18.6+/-0.5 degrees 2.theta.. In other embodiments, the
Form IV is characterized by an X-Ray powder diffraction pattern
comprising a characteristic peak at about 17.5+/-0.5 degrees
2.theta.. In still other embodiments, the Form IV is characterized
by an X-Ray powder diffraction pattern comprising a characteristic
peak at about 17.8+/-0.5 degrees 2.theta.. In certain embodiments,
the Form IV is characterized by an X-Ray powder diffraction pattern
comprising a characteristic peak at about 16.3+/-0.5 degrees
2.theta..
[0066] In some embodiments, the Form IV is characterized by an
X-Ray powder diffraction pattern comprising a characteristic peak,
such as, at about 8.7 or about 22.3+/-0.5 degrees 2.theta..
[0067] The Form IV may be further characterized by an X-Ray powder
diffraction pattern comprising a characteristic peak at about 12.5;
about 21.0; about 26.6 or about 26.9; +/-0.5 degrees 2.theta. or a
combination thereof. In other embodiments, the Form IV may be
further characterized by an X-Ray powder diffraction pattern
comprising a characteristic peak at about 11.3; about 26.2; about
27.6; about 28.7; about 29.8; about 30.4; about 31.2; about 32.9;
about 33.4; about 34.4; about 37.1; about 37.3; about 37.6 or about
38.5+/-0.5 degrees 2.theta. or a combination thereof.
[0068] In exemplary embodiments, the Form IV is characterized by an
X-Ray powder diffraction pattern comprising a characteristic peak,
such as, at about 8.7; about 11.3; about 12.5; about 16.3; about
17.5; about 17.8; about 18.6; about 21.0; about 22.3; about 26.2;
about 26.6; about 26.9; about 27.6; about 28.7; about 29.8; about
30.4; about 31.2; about 32.9; about 33.4; about 34.4; about 37.1;
about 37.3; about 37.6 and about 38.5+/-0.5 degrees 2.theta. or a
combination thereof.
[0069] In specific embodiments, the Form IV is characterized by an
X-Ray powder diffraction pattern comprising d-spacing values at
about 2.3; about 2.4; about 2.6; about 2.7; about 2.9; about 3.0;
about 3.1; about 3.2; about 3.3; about 3.4; about 4.0; about 4.2;
about 4.8; about 5.0; about 5.1; about 5.4; about 7.1; about 7.8 or
about 10.1+/-2 nm or a combination thereof.
[0070] In exemplary embodiments, the Form IV is characterized by an
X-Ray powder diffraction pattern comprising a d-spacing value, such
as, at about 4.8+/-2 nm. In other embodiments, the Form IV is
characterized by an X-Ray powder diffraction pattern comprising a
d-spacing value at about 5.1+/-2 nm. In still other embodiments,
the Form IV is characterized by an X-Ray powder diffraction pattern
comprising a d-spacing value at about 4.0; about 5.0; about 5.4 or
about 10.1+/-2 nm or a combination thereof.
[0071] In some embodiments, the Form IV is further characterized by
an X-Ray powder diffraction pattern comprising a d-spacing value at
about 3.3; about 4.2 or about 7.1+/-2 nm or a combination thereof.
In other embodiments, the Form IV is further characterized by an
X-Ray powder diffraction pattern comprising a d-spacing value at
about 2.3; about 2.4; about 2.6; about 2.7; about 2.9; about 3.0;
about 3.1; about 3.2; about 3.4 or about 7.8+/-2 nm or a
combination thereof.
[0072] For example, the Form IV is characterized by an X-Ray powder
diffraction pattern comprising d-spacing values at about 2.3; about
2.4; about 2.6; about 2.7; about 2.9; about 3.0; about 3.1; about
3.2; about 3.3; about 3.4; about 4.0; about 4.2; about 4.8; about
5.0; about 5.1; about 5.4; about 7.1; about 7.8 and about 10.1+/-2
nm.
[0073] Form V
[0074] In another aspect, the present invention provides a
crystalline form of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxa-
mide sodium salt (e.g., NXL-104) called Form V.
[0075] For example, the present invention provides a crystalline
form of sodium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
called Form V.
[0076] In exemplary embodiments, the Form V is characterized by an
X-Ray powder diffraction pattern comprising a characteristic peak,
such as, at about 6.5; about 8.5; about 13.4; about 14.4; about
15.4; about 15.5; about 16.4; about 17.1; about 18.0; about 19.3;
about 19.5; about 21.0; about 22.9; about 24.3; about 27.3 or about
31.9+/-0.5 degrees 2.theta. or a combination thereof.
[0077] In some embodiments, the Form V is characterized by an X-Ray
powder diffraction pattern comprising a characteristic peak at
about 6.5+/-0.5 degrees 2.theta.. In other embodiments, the Form V
is characterized by an X-Ray powder diffraction pattern comprising
a characteristic peak at about 18.0+/-0.5 degrees 2.theta.. In
still other embodiments, the Form V is characterized by an X-Ray
powder diffraction pattern comprising a characteristic peak at
about 19.3+/-0.5 degrees 2.theta.. The Form V may be further
characterized by an X-Ray powder diffraction pattern comprising a
characteristic peak at about 14.4; about 15.5; about 16.4; about
17.1 or about 19.5+/-0.5 degrees 2.theta. or a combination thereof.
In still other embodiments, the Form V may be further characterized
by an X-Ray powder diffraction pattern comprising a characteristic
peak at about 8.5; about 13.4; about 15.4; about 21.0; about 22.9;
about 24.3; about 27:3 or about 31.9+/-0.5 degrees 2.theta. or a
combination thereof.
[0078] In exemplary embodiments, the Form V is characterized by an
X-Ray powder diffraction pattern comprising characteristic peaks at
about 6.5; about 8.5; about 13.4; about 14.4; about 15.4; about
15.5; about 16.4; about 17.1; about 18.0; about 19.3; about 19.5;
about 21.0; about 22.9; about 24.3; about 27.3 and about 31.9+/-0.5
degrees 2.theta..
[0079] In some embodiments, the Form V is characterized by an X-Ray
powder diffraction pattern comprising a d spacing value at about
2.8; about 3.3; about 3.7; about 3.9; about 4.2; about 4.5; about
4.6; about 4.9; about 5.2; about 5.4; about 5.7; about 5.8; about
6.1; about 6.6; about 10.4 or about 13.6+/-2 nm or a combination
thereof.
[0080] In some embodiments, the Form V is characterized by an X-Ray
powder diffraction pattern comprising a d spacing value at about
13.6+/-2 nm. In other embodiments, the Form V is characterized by
an X-Ray powder diffraction pattern comprising a d spacing value at
about 4.6+/-2 nm. In still other embodiments, the Form V is
characterized by an X-Ray powder diffraction pattern comprising a d
spacing value at about 4.9+/-2 nm. In certain embodiments, the Form
V is characterized by an X-Ray powder diffraction pattern
comprising a d spacing value at about 6.1+/-2 nm. The X-Ray powder
diffraction pattern may further comprise a d spacing value at about
2.8; about 3.3; about 3.7; about 3.9; about 4.2; about 4.5; about
5.2; about 5.4; about 5.7; about 5.8; about 6.6 or about 10.4+/-2
nm or a combination thereof.
[0081] In exemplary embodiments, the Form V is characterized by an
X-Ray powder diffraction pattern comprising a d spacing value at
about 2.8; about 3.3; about 3.7; about 3.9; about 4.2; about 4.5;
about 4.6; about 4.9; about 5.2; about 5.4; about 5.7; about 5.8;
about 6.1; about 6.6; about 10.4 and about 13.6+/-2 nm.
[0082] In exemplary embodiments, the Form II is a monohydrate
containing 5.90% water (weight/weight) and the Form III is a
dihydrate. By coupling thermogravimetric analysis (TGA) with
differential thermal analysis (SDTA) at 10.degree. C./min, the Form
II displays a weight loss of 5.7% at approximately 110.degree. C.,
corresponding to the dehydration of the salt, followed by a
decomposition exotherm with weight loss between 220 and 240.degree.
C. By the same technique, the Form II displays a first weight loss
of 5% at approximately 60.degree. C. and then a second weight loss
of 5% at approximately 100.degree. C. before decomposition between
220 and 240.degree. C. This loss of water in 2 stages corresponds
to a dihydrated form with two non-equivalent molecules of water in
the crystal lattice.
[0083] In exemplary embodiments, the Forms I, IV or V are
anhydrous. A maximum amount of water from 0 to 0.6% is detected by
Karl Fischer analysis in a product of Form I prepared as described
later in the application. The polymorphic forms I and IV display an
exothermic decomposition peak between 220 and 240.degree. C.
measured by DSC (Differential Scanning Calorimetry).
[0084] In some embodiments, the experimental powder diffraction
patterns are obtained by diffraction of X-rays on powder in a
Rigaku Miniflex X-ray diffractometer with the K.alpha. radiation of
copper (.lamda.=1.541 .ANG.). The samples, without grinding, are
put on a glass plate and are analyzed at ambient temperature and
humidity. Data are collected at 0.05.degree. interval,
2.degree./minute from 30-40.degree. 2.theta.. In some examples, the
peaks with a relative intensity of more than about 10% are
considered as characteristic peaks.
[0085] In other embodiments, the experimental powder diffraction
patterns are obtained by diffraction of X-rays on powder in an
X'pert Pro Philips instrument with the K.alpha. radiation of copper
(.lamda.=L 0.5406 .ANG.). The samples, without grinding, are put on
a glass plate and are analyzed at ambient temperature and humidity
with an angle 2.theta. from 5 to 500. In some examples, the
characteristic peaks of each form are determined using five lines
that are generally the most intense. The mean value of each peak
and its standard deviation are calculated from the experimental
values of representative samples of each form.
[0086] In some embodiments, the crystal structures of the
monocrystals of the dihydrate forms are obtained at 296K on a
Rigaku Rapid R axis diffractometer equipped with a rotating copper
anode (l=1.5406 .ANG.). The crystals structures of monocrystal of
the monohydrate form are obtained at 233K on a Bruker Nonius
diffractometer with the K.alpha. radiation of molybdenum (l=0.7093
.ANG.). Powder diffraction patterns are normally measured using
copper Ka radiation. For comparison with the experimental powder
patterns, the theoretical powder diffraction patterns for the
hydrate forms are calculated from the corresponding crystal
structure data using the appropriate 1 value for copper Ka
radiation (1.5406 .ANG.).
[0087] One skilled in the art will understand that the relative
intensities and positions of the peaks obtained by X-Ray powder
diffraction may vary depending upon factors such as, the sample
preparation technique, the sample mounting procedure and the
particular instrument employed. For example, in additional
embodiments, the listed X-Ray powder diffraction pattern peaks for
the crystalline form of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (e.g., NXL-104) may be about +/-0.2 degrees
2.theta..
[0088] It is known that an X-ray powder diffraction pattern may be
obtained which has one or more measurement errors depending on
measurement conditions (such as equipment or machine used).
Intensities in an X-ray powder diffraction pattern may fluctuate
depending on measurement conditions. Therefore, it should be
understood that the crystalline forms of the present invention are
not limited to the crystals that provide X-ray powder diffraction
patterns identical to the X-ray powder diffraction patterns
described in this application, and any crystals providing X-ray
powder diffraction patterns substantially the same as those
described in the application fall within the scope of the present
invention. For example, relative intensity of peaks can be affected
by grains above 30 microns in size and non-unitary aspect ratios,
which may affect analysis of samples. A person skilled in the art
will recognize that the position of reflections can be affected by
the precise height at which the sample sits in the diffractometer
and the zero calibration of the diffractometer. The surface
planarity of the sample may also have a small effect. Therefore,
the diffraction pattern data described herein are not to be taken
as absolute values. (Jenkins, R & Snyder, R. L. `Introduction
to X-Ray Powder Diffractometry` John Wiley & Sons 1996; Bunn,
C. W. (1948), Chemical Crystallography, Clarendon Press, London;
Klug, H. P. & Alexander, L. E. (1974), X-Ray Diffraction
Procedures).
[0089] Generally, a measurement error of a diffraction angle in an
X-ray powder diffractogram is about 5% or less, in particular plus
or minus 0.5.degree. 2-theta, and such degree of a measurement
error should be taken into account when considering the X-ray
powder diffraction patterns described in this application.
Furthermore, it should be understood that intensities may fluctuate
depending on experimental conditions and sample preparation
(preferred orientation).
[0090] The standard deviation for d-spacing is calculated based on
an angle of 5.degree. 2-theta. In some embodiments, the standard
deviation for d-spacing may be between +/-0.1 nm and +/-2 nm. For
example, the d-spacing values for the crystalline forms described
in the application may vary by +/-0.2 nm, +/-0.3 nm, +/-0.5 nm,
+/-1 nm, +/-1.5 nm or about +/-2 nm.
[0091] In one aspect, substantially pure crystalline forms of the
present invention are provided. For example, the present invention
includes Forms I-V of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxam-
ide sodium salt (e.g., NXL-104) as described in this application
that are about .gtoreq.95% pure. For example, the forms may be
about .gtoreq.95%, .gtoreq.96%, .gtoreq.97%, .gtoreq.98% or
.gtoreq.99% pure.
[0092] In exemplary embodiments, the present invention provides
Forms I-V of sodium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
as described in this application that are .gtoreq.95% pure. For
example, the forms may be .gtoreq.95%, .gtoreq.96%, .gtoreq.97%,
.gtoreq.98% or .gtoreq.99% pure.
[0093] In some embodiments, the Form I of sodium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
is isolated in a substantially pure form. In other embodiments, the
Form II of sodium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
is isolated in a substantially pure form. In still other
embodiments, the Form III of sodium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
is isolated in a substantially pure form. In other examples, the
Form IV or Form V of sodium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
is isolated in a substantially pure form. The Forms described
herein may have purity of more than about 90%, about 91%, about
92%, about 93%, about 94%, about 95%, about 96%, about 97%, about
98%, or about 99% by weight. In specific embodiments, the forms may
have a purity of more than about 95% by weight. For example, the
forms may be .gtoreq.95%, .gtoreq.96%, .gtoreq.97%, .gtoreq.98% or
.gtoreq.99% pure.
[0094] Processes
[0095] In another aspect, the present invention provides processes
for preparing the crystalline forms of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (e.g., NXL-104) described in this application.
[0096] For example, the present invention relates to a method for
the preparation of the sodium salt of the
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
enantiomer shown below:
##STR00005##
[0097] In exemplary embodiments, tetrabutylammonium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
is treated in a (1-6 C) alkanol containing between 0 and 50% water,
with a sodium salt that is soluble in the reaction mixture, and
then the crystals obtained are isolated. The sodium salt used may
be an acetate, a butyrate, a hexanoate, an ethyl-hexanoate or a
dodecylsulphate. In specific embodiments, the salt may be
2-ethyl-hexanoate. The process of the reaction is an equilibrium
that is displaced by the crystallization of the expected sodium
salt, which can be applied advantageously on an industrial scale,
making the method particularly useful. Either the alcoholic
solution of sodium 2-ethylhexanoate is added to the alcoholic
solution of the tetrabutylammonium salt, or vice versa. The (1-6 C)
alkanol may be ethanol, propanol or linear or branched butanol. In
specific embodiments, the alkanol may be ethanol. The operation may
be carried out in the presence of 0 to 10% water, at a temperature
between 15 and 40.degree. C.
[0098] The invention in particular relates to a method as defined
above, for the preparation of the sodium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,
in an anhydrous form called Form I as described herein. In
exemplary embodiments, a solution of sodium 2-ethylhexanoate in
pure ethanol is added to a solution of the tetrabutylammonium salt
of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
in an ethanol/water mixture in such a way that the final proportion
of water is from 0 to 5 wt. % of the solvent, operating at a
temperature from 10 to 40.degree. C., in the presence of seed
crystals of Form I or Form II as described herein. The parameters,
such as the proportion of water in the reaction mixture, the
duration of addition, the temperature and the concentration are
interdependent on the crystalline form. In order to obtain pure
Form I, it is preferable to operate in the presence of seed
crystals of Form I and of a final proportion of water less than 2%,
introducing the solution of sodium 2-ethylhexanoate over a period
of 1 to 7 hours and operating at a temperature from 10 to
40.degree. C., and more preferably, 30 to 35.degree. C. In other
embodiments, an ethanolic solution of the tetrabutylammonium salt
of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
is added to an ethanol/water mixture of sodium 2-ethylhexanoate,
moreover operating under the same conditions of solvent and
temperatures as those described above.
[0099] The invention also relates to a method as defined above, for
the preparation of the sodium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,
in a monohydrate Form called Form II, as described herein. In
exemplary embodiments, a solution of sodium 2-ethylhexanoate in
pure ethanol is added to a solution of the tetrabutylammonium salt
of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
in an ethanol/water mixture in such a way that the final proportion
of water is from 3 to 10 wt. % of the solvent, operating at a
temperature from 10 to 40.degree. C. Crystallization is carried out
in the absence of seed crystals or by adding seed crystals of Form
II. The parameters, such as the proportion of water in the reaction
mixture, the duration of addition, the temperature and the
concentration act interdependently on the crystalline form. In
order to obtain the pure Form II, it is preferable to operate at a
temperature from 20 to 35.degree. C. and more preferably, at room
temperature, in the presence of seed crystals of the Form II, a
final proportion of water greater than 5 wt. % of the solvent, and
introducing the solution of sodium 2-ethylhexanoate over a period
of 30 minutes to 2 hours.
[0100] In other embodiments, an ethanolic solution of the
tetrabutylammonium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
is added to an ethanol/water mixture of sodium 2-ethylhexanoate,
operating under the same conditions of solvent and temperatures as
those described above.
[0101] The invention also relates to a method as defined above, for
the preparation of the sodium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,
in an anhydrous polymorphic called Form IV, as described herein. In
exemplary embodiments, an ethanolic solution of sodium
2-ethylhexanoate is added to an ethanolic solution of the
tetrabutylammonium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,
operating at room temperature. Crystallization is carried out in
the absence of seed crystals or by adding seed crystals of the
polymorphic Form IV or optionally of the Form II. The parameters
such as the proportion of water in the reaction mixture, the
duration of addition, the temperature and the concentration act
interdependently on the crystalline form. In order to obtain pure
Form IV, it is preferable to operate in the absence of seed
crystals, introducing the solution of sodium 2-ethylhexanoate over
a period of 30 minutes or less, and operating at room
temperature.
[0102] In other embodiments, an ethanolic solution of the
tetrabutylammonium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
is added to an ethanolic solution of sodium 2-ethylhexanoate,
operating under the same conditions of solvent and temperature as
those described above.
[0103] The invention also relates to processes for making a
dihydrate form of the sodium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
called Form III. In exemplary embodiments, crystals of Form II are
suspended in water, and the suspension is then left to evaporate
slowly in a humid atmosphere. Crystals can also been obtained by
trituration of crystals of Form II in water or in an alkanol-water
mixture, or by conversion, in a humid atmosphere, of the anhydrous
Form I and Form IV to the monohydrated Form II and then to the
dihydrated Form III. This Form III is particularly stable at higher
humidities.
[0104] In exemplary embodiments, the methods comprise warming a
filtered solution of the tetrabutylammonium salt of
trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
in ethanol and mixing with a filtered solution of sodium
2-ethylhexanoate in ethanol, cooling the mixture, isolating the
crystals by filtration and drying the crystals under vacuum. For
example, Form I may be prepared by this method.
[0105] In another example, 3.798 g of sodium 2-ethyl hexanoate (1.2
equivalent), 100 ml ethanol and 5 ml distilled ionized water are
stirred until full dissolution at room temperature. 10 g
sulfaturamide dissolved in 90 ml ethanol is added in 45 minutes and
the addition funnel is rinsed with 5 ml ethanol. The suspension is
stirred for 18 h at room temperature and cooled to 5.degree. C. The
suspension is stirred for 1-2 h at 5.degree. C. and filtered by
gravity. The solid is washed with 2.5% aqueous ethanol (3.times.30
ml) and dried at 20 mbar at 20.degree. C. for 2-18 h until constant
weight.
[0106] In other embodiments, the methods comprise mixing Form I
seed crystals with a filtered and warmed solution of
tetrabutylammonium salt of
trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
in ethanol in a reactor and adding a filtered solution of sodium
2-ethylhexanoate in ethanol, stirring the mixture, cooling the
mixture, isolating the crystals by filtration, washing with ethanol
and drying the crystals under vacuum.
[0107] In still other embodiments, the methods comprise mixing a
warmed and filtered solution of tetrabutylammonium salt of
trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
in isobutanol with a filtered solution of sodium 2-ethylhexanoate
in isobutanol, cooling the mixture, isolating the crystals by
filtration; washing with an ice-cold mixture of isobutanol and
water and drying the crystals under vacuum.
[0108] In exemplary embodiments, the methods comprise mixing a
solution of sulfaturamide (SU) in ethanol with a solution of sodium
2-ethylhexanoate (SEH) in ethanol. The crystalline form may be
obtained under anhydrous conditions using anhydrous SU and SEH. For
example, Form IV may be prepared by this method.
[0109] In further embodiments, the Form I crystals may be vortexed
in a salt solution, e.g., sodium chloride, to provide Form III.
[0110] In some embodiments, seed crystals of Form I may be obtained
by dissolving the amorphous sodium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
in 33 volumes of methanol, adding 10 volumes of ethanol at
60.degree. C., concentration of the solution to about 10 volumes at
room temperature and then distillation of the methanol to constant
volume, still at room temperature, with ethanol (25 volumes are
added), The Form I thus obtained is filtered and then dried.
[0111] In some embodiments, seed crystals of Form II may be
obtained by adding, over forty-five minutes, 19 volumes of ethanol
to a solution of the amorphous sodium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
in one volume of water, cooling to 5.degree. C. in one hour and
then holding at this temperature, filtration and finally
drying.
[0112] In some embodiments, sulphaturamide or tetrabutylammonium
salt of
(1R,2S,5R)-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamid-
e may be prepared by chiral resolution of its racemic precursor
trans-7-oxo-6-(phenylmethoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide-
, the preparation of which is described in Example 33a Stage A in
Application WO 02/10172. In exemplary embodiments, injection of 20
.mu.l of a sample of 0.4 mg/mL of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,
eluted on a Chiralpak ADH column (5 .mu.m, 25 cm.times.4.6 mm) with
heptane-ethanol-diethylamine mobile phase 650/350/0.05 vol at 1
mL/min makes it possible to separate the (1R,2S,5R) and (1S,2R,5S)
enantiomers with retention times of 17.4 minutes and 10.8 minutes
respectively. The sulphaturamide is then obtained by conversion
according to the conditions described in Example 33a Stage B then
Stage C and finally in Example 33b of Application WO 02/10172.
[0113] In other embodiments, the sulphaturamide can be prepared
from the mixture of the oxalate salt of
(2S)-5-benzyloxyamino-piperidine-2-carboxylic acid, benzyl ester
(mixture (2S,5R)/(2S,5S).about.50/50) described in application
FR2921060.
[0114] For example, the preparation may proceed in the following
stages:
##STR00006##
[0115] In stage A, dibenzoxurea or
(2S)-7-oxo-6-(2-phenylmethoxy)-1,6-diaza-bicyclo[3.2.1] octane
2-benzyl 2-carboxylate is prepared. A 10% saturated aqueous
solution of sodium bicarbonate (16 L) is added to a suspension of
the oxalate salt of (2S)-5-benzyloxyamino-piperidine-2-carboxylic
acid, benzyl ester (mixture (2S,5R)/(2S,5S).about.50/50) described
in application FR2921060 (2 kg, 4.65 mol) in water (12 L) and ethyl
acetate (10 L). The aqueous phase is separated and then
re-extracted with ethyl acetate (8 L). The organic phases are
combined, washed with water (4 L) and then dried over sodium
sulphate (2 kg). The solution is filtered and then concentrated in
order to replace the ethyl acetate with acetonitrile (35 L). The
solution is cooled to 0-5.degree. C. before adding triethylamine
(1.25 L) and then diphosgene (290 mL). The reaction mixture is
stirred at 0-5.degree. C. for one hour before adding
N,N-dimethylaminopyridine (270 g). After stirring for two hours at
room temperature, the reaction mixture is concentrated and then
diluted with dichloromethane (15 L). The solution is added to a 20%
aqueous solution of ammonium chloride (15 L). The organic phase is
isolated. The aqueous phase is re-extracted with dichloromethane (4
L). The organic phases are combined, dried over sodium sulphate and
concentrated to dryness to produce the expected compound (1645 g,
yield 96% as is, weight/weight).
[0116] In stage B, benzoxuracid or
(1R,2S,5R)-7-oxo-6-(phenylmethoxy)-1,6-diazabicyclo[3.2.1]octane-2-carbox-
ylic acid and its cyclohexylamine salt is prepared. A solution of
lithium hydroxide (79.2 g, 3.3 mol) in water (3.3 L) is added in 30
minutes to a stirred solution at 0-5.degree. C. of the compound
obtained in Stage A (1.028 kg, 2.80 mol) in water (10.3 L) and
tetrahydrofuran (1.5 L). The reaction mixture is stirred for 1.5 h
before adding a mixture of isopropyl ether-ethyl acetate (8/2
vol/vol, 9.25 L). The aqueous phase is isolated at room
temperature. The organic phase is extracted with water
(2.times.2.57 L). The aqueous phases are combined and then washed
with a mixture of isopropyl ether-ethyl acetate (8/2 vol/vol, 2 L).
The aqueous solution is stirred with ethyl acetate (10.3 L),
acidified with 2N hydrochloric acid (1.9 L) to pH 2 and then
saturated with sodium chloride (4.8 kg). The aqueous phase is
isolated and re-extracted with ethyl acetate (5.14 L). The organic
phases are combined and dried over sodium sulphate (1 kg). The
solution is concentrated under vacuum at 40.degree. C. to produce
the expected compound (473 g, 61% yield as is, weight/weight).
[0117] The cyclohexylamine salt is prepared according to the method
described in Example 32b of Application WO 02/10172.
[0118] In stage C, benzoxuramide or
(1R,2S,5R)-7-oxo-6-(phenylmethoxy)-1,6-diazabicyclo[3.2.1]octane-2-carbox-
amide may be prepared. This operation is carried out under the
conditions described in Example 33a Stage A of Application WO
02/10172 starting with the compound obtained in Stage B above to
obtain the expected compound.
[0119] In stages D and E, sulphaturamide is prepared. This
operation is carried out starting with the compound obtained in
Stage C above, under the conditions described in Example 33a Stage
B and then Stage C and finally in Example 33b of Application WO
02/10172. The expected compound is obtained in solid form.
[0120] In some embodiments, sodium salt of the amorphous
(1R,2S,5R)-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamid-
e enantiomer may be prepared. For example, a solution of
sulphaturamide (6.92 kg, 13.66 mol) in water (56 L) is eluted on a
column of Dowex 50WX8 resin (83 kg, 100-200 mesh) preconditioned by
elution of an aqueous solution of sodium hydroxide and then washing
with water until a neutral pH is reached. The fractions containing
the product are combined, filtered, weighed (76 kg net) and then
lyophilized to produce the expected sodium salt in amorphous form
(3.72 kg, yield 94.8%, HPLC purity >99%.).
[0121] WO 02/10172 describes the preparation of the racemic sodium
salt of
trans-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,
which is obtained indirectly from a compound described in Example
33b of WO 02/10172, by exchange of the tetrabutylammonium
counter-ion with sodium, eluting an aqueous solution of the salt on
ion exchange resin, treated beforehand with sodium hydroxide. The
sodium salt is obtained in solid form, after elimination of the
water. The racemic product crystallizes as mentioned in Example 33c
of WO 02/10172. Concentration to dryness is carried out in the
laboratory by evaporation. In practice, the water is removed by
lyophilisation to obtain a homogeneous solid form. This solid form
is hygroscopic and of low density, which makes it difficult to
handle and store, and consequently makes the method difficult to
scale up to an industrial level. In itself, lyophilisation carried
out in the laboratory is already a technique that is difficult to
scale up to the industrial level. Moreover, the method of ion
exchange on resin that precedes it is expensive and of low
productivity on account of the large amounts of resin, the dilution
with water that is necessary for quantitative ion exchange, the
very long duration of the operation and the high energy costs
required, and for these reasons as well, the method is difficult to
apply industrially.
[0122] The present invention relates to a novel and improved method
of preparation of the sodium salt of the
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
enantiomer making it possible to obtain said salt in perfectly
crystallized and stable form, without having recourse to the ion
exchange technique nor to lyophilization under the conditions
described above. The method according to the invention therefore
offers the dual advantage of simplifying the technique and thus
permitting its scaling up to the industrial level, while supplying
a crystallized form that is stable, and is easy to isolate, handle,
store and formulate.
Compositions
[0123] The crystalline forms of the present invention can be
administered alone or in combination with an antibacterial agent,
such as, for example, ceftaroline or a prodrug of ceftaroline. The
present invention includes pharmaceutical compositions comprising
the crystalline forms of the invention alone or in combination with
an antibacterial agent, such as, for example, ceftaroline or a
prodrug of ceftaroline. The compositions may further comprise one
or more pharmaceutically acceptable carriers.
[0124] In one aspect, the present invention provides a composition
comprising a crystalline form of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (e.g., NXL-104). The crystalline form may be Form I,
Form II, Form III, Form IV or Form V of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (e.g., NXL-104) as described above. In exemplary
embodiments, the compositions comprise Form I. In other
embodiments, the composition comprises Form II. In still other
embodiments, the compositions may comprise Form III, IV or V.
[0125] In specific embodiments, the compositions comprise a
crystalline form of sodium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide.
For example, the compositions may comprise Form I. In other
examples, the compositions may comprise Form II. In still other
examples, the compositions may comprise Form III, Form IV or Form
V.
[0126] The compositions comprising
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (e.g., NXL-104) may comprise related substances that
are process impurities or degradants of NXL-104. For example, the
compositions may comprise a decarbonyl compound or a disulfate
compound.
[0127] In some embodiments, the compositions may comprise a
crystalline form of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxa-
mide sodium salt (e.g., NXL-104) and less than about 2% of a
decarbonyl compound of formula (I):
##STR00007##
[0128] In some embodiments, the compositions comprise about 0.05%
to about 1.5% of the decarbonyl compound. In exemplary embodiments,
the compositions comprise about 0.05 to about 1.0% of the
decarbonyl compound. In other exemplary embodiments, the
compositions comprise between about 0.05 to about 0.5% of the
decarbonyl compound. For example, the compositions may comprise
about 0.1, about 0.2, about 0.3, about 0.4 or about 0.5% of the
decarbonyl compound.
[0129] In some embodiments, the compositions may comprise the
crystalline form and less than about 2% of a disulfate compound of
the formula (II):
##STR00008##
[0130] In some embodiments, the compositions may comprise a
crystalline form of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxa-
mide sodium salt (e.g., NXL-104) and ceftaroline or a prodrug of
ceftaroline. The prodrug of ceftaroline may be a phosphono prodrug,
such as, ceftaroline fosamil. The ceftaroline fosamil may be
anhydrous. In other embodiments, the ceftaroline fosamil may be a
monohydrate. In still other embodiments, the ceftaroline fosamil
may be a solvate, such as, an acetic acid solvate or a propionic
acid solvate.
[0131] In exemplary embodiments, the compositions may comprise Form
I of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (e.g., NXL-104) and ceftaroline fosamil. In other
exemplary embodiments, the compositions may comprise Form II of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-S
carboxamide sodium salt (e.g., NXL-104) and ceftaroline fosamil. In
still other exemplary embodiments, the compositions may comprise
Form III, IV or V of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (e.g., NXL-104) and ceftaroline fosamil.
[0132] In some embodiments, the compositions may comprise a
crystalline form of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxa-
mide sodium salt (e.g., NXL-104) and ceftaroline fosamil and less
than about 10% of total impurities. The impurities may include, but
are not limited, to process impurities and degradants of the
crystalline form or ceftaroline fosamil. The impurities related to
the crystalline form include decarbonyl compound of Formula (I) and
disulfate compound of Formula (II).
[0133] The impurities related to ceftaroline fosamil include
ceftaroline related substances that may be process impurities or
degradants of ceftaroline fosamil. Examples of such ceftaroline
fosamil related substances are listed below.
[0134] U1 refers to ring opened ceftaroline of Formula (III):
##STR00009##
[0135] U2 refers to diphosphoric-type ceftaroline of Formula
(IV):
##STR00010##
[0136] U3 refers to ceftaroline (active metabolite) of Formula
(V):
##STR00011##
[0137] U4 refers to dimer of ceftaroline acetate of Formula
(VI):
##STR00012##
[0138] U5 refers to delta 2-type ceftaroline acetate of Formula
(VII):
##STR00013##
[0139] U6 refers to a ring-opened ceftaroline of Formula
(VIII):
##STR00014##
[0140] U7 refers to amide-type U-1 of Formula (IX):
##STR00015##
[0141] U8 refers to des-methyl-type ceftaroline acetate of Formula
(X):
##STR00016##
[0142] U9 refers to acetyl-type ceftaroline acetate of Formula
(XI):
##STR00017##
[0143] Adduct refers to an adduct of ceftaroline and L-arginine of
Formula (XII)
##STR00018##
[0144] In some embodiments, the compositions comprise a crystalline
form of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (e.g., NXL-104) and ceftaroline fosamil and less than
about 1 to 10% of impurities. In specific embodiments, the
compositions may comprise about 0.05 to about 10% of
impurities.
[0145] In exemplary embodiments, the compositions may comprise less
than 5% of impurities. For example, the compositions may comprise
less than 0.6% U1; less than 0.6% U2, less than 5% U3, less than
0.2% U4, less than 0.2% U5, less than 0.6% U6, less than 0.2% U7,
less than 0.2% U8, less than 1.0% U9, or less than 1.5%
adducts.
[0146] In exemplary embodiments, the compositions comprise about
0.05 to about 0.2% of U4, U5, U7 or U8. In other exemplary
embodiments, the compositions comprise about 0.05 to about 0.6% of
U1, U2 or U6. In still other exemplary embodiments, the
compositions comprise about 0.05 to about 1% of U9. In certain
embodiments, the compositions comprise about 0.05 to about 5% of
U9. In other embodiments, the compositions comprise about 0.05 to
about 1.5% of adduct.
[0147] The present invention provides formulations comprising about
200 mg to 1200 mg of a crystalline form of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
or a salt thereof (e.g., NXL-104) that provide an in vivo plasma
profile for the crystalline form comprising a mean Cmax of less
than about 100 ug/ml. For example, the plasma profile comprises a
mean Cmax of less than about 80 ug/ml; about 70 ug/ml; about 60
ug/ml; about 50 ug/ml; about 40 ug/ml or about 30 ug/ml. In
exemplary embodiments, the plasma profile comprises a mean Cmax of
about 10 to about 50 ug/ml. In other embodiments, the plasma
profile comprises a mean Cmax of about 20 to about 40 ug/ml.
[0148] In further embodiments, the present invention provides
compositions comprising about 200 mg to 1200 mg ceftaroline fosamil
that provide an in vivo plasma profile for ceftaroline comprising a
mean Cmax of less than about 100 ug/ml. For example, the plasma
profile comprises a mean Cmax of less than about 80 ug/ml; about 70
ug/ml; about 60 ug/ml; about 50 ug/ml; about 40 ug/ml or about 30
ug/ml. In exemplary embodiments, the plasma profile comprises a
mean Cmax of about 10 to about 50 ug/ml. In other embodiments, the
plasma profile comprises a mean Cmax of about 10 to about 40
ug/ml.
[0149] The present invention provides formulations comprising about
200 mg to 1200 mg of a crystalline form of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
or a salt thereof (e.g., NXL-104) that provide an in vivo plasma
profile for the crystalline form comprising a mean
AUC.sub.0-.infin. of more than about 10 ug h/ml. For example, the
plasma profile comprises a mean AUC.sub.0-.infin. of about 10 to
500 ug h/ml; about 10 to 400 ug h/ml ug h/ml; about 10 to 300 ug
h/ml; about 10 to 200 ug h/ml or about 10 to 100 ug h/ml. In
exemplary embodiments, the plasma profile comprises a mean
AUC.sub.0-.infin. of about 10 to 200 ug h/ml. In further
embodiments, the present invention provides compositions comprising
about 200 mg to 1200 mg ceftaroline fosamil that provide an in vivo
plasma profile for ceftaroline comprising a mean AUC.sub.0-.infin.
of more than about 10 ug h/ml. For example, the plasma profile
comprises a mean AUC.sub.0-.infin. of about 10 to 500 ug h/ml;
about 10 to 400 ug h/ml ug h/ml; about 10 to 300 ug h/ml; about 10
to 200 ug h/ml or about 10 to 100 ug h/ml. In exemplary
embodiments, the plasma profile comprises a mean AUC.sub.0-.infin.
of about 10 to 200 ug h/ml.
[0150] The present invention provides formulations comprising about
200 mg to 1200 mg of a crystalline form of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
or a salt thereof (e.g., NXL-104) that provides an in vivo plasma
profile for the crystalline form comprising a mean Tmax of more
than about 10 min. For example, the plasma profile comprises a mean
Tmax of more than about 15 minutes, 30 minutes, 45 minutes, 1 hour,
1.5 hours or about 2 hours. In exemplary embodiments, the plasma
profile comprises a mean Tmax of about 30 minutes to about 2 hours.
In further embodiments, the present invention provides compositions
comprising about 200 mg to 1200 mg ceftaroline fosamil that provide
an in vivo plasma profile for ceftaroline comprising a mean Tmax of
more than about 10 min. For example, the plasma profile comprises a
mean Tmax of more than about 15 minutes, 30 minutes, 45 minutes, 1
hour, 1.5 hours or about 2 hours. In exemplary embodiments, the
plasma profile comprises a mean Tmax of about 30 minutes to about 2
hours.
[0151] The compositions may comprise the crystalline forms in
combination with other antibacterial agents. Some examples of
antibacterial agents that may be combined with the crystalline
forms, include, but are not limited to, antibiotics of the
.beta.-lactamine type, for example, penams, penems, cephems,
carbacephems, oxacephems, cephamycins, penicillins such as
amoxicillin, ampicillin, azlocillin, mezlocillin, apalcillin,
hetacillin, bacampicillin, carbenicillin, sulbenicillin,
ticarcillin, piperacillin, mecillinam, pivmecillinam, methicillin,
ciclacillin, talampicillin, aspoxicillin, oxacillin, cloxacillin,
dicloxacillin, flucloxacillin, nafcillin or pivampicillin,
cephalosporins such as cephalothin, cephaloridine, cefaclor,
cefadroxil, cefamandole, cefazolin, cephalexin, cephradine,
ceftizoxime, cefoxitin, cephacetrile, cefotiam, cefotaxime,
cefsulodin, cefoperazone, ceftizoxime, cefmenoxime, cefmetazole,
cephaloglycin, cefonicid, cefodizime, cefpirome, ceftazidime,
ceftriaxone, cefpiramide, cefbuperazone, cefozopran, cefepime,
cefoselis, cefluprenam, cefuzonam, cefpimizole, cefclidin,
cefixime, ceftibuten, cefdinir, cefpodoxime axetil, cefpodoxime
proxetil, cefteram pivoxil, cefetamet pivoxil, cefcapene pivoxil,
or cefditoren, pivoxil, cefuroxime, cefuroxime axetil, loracarbacef
or latamoxef, carbapenems such as imipenem, meropenem, biapenem or
panipenem and also monobactams such as aztreonam and carumonam, as
well as their salts.
[0152] In exemplary embodiments, the compositions may comprise the
crystalline form in combination with an antibacterial agent, such
as, ceftazidime. For example, the compositions may comprise Form I
and ceftazidime, Form II and ceftazidime, Form III and ceftazidime,
Form IV and ceftazidime or Form V and ceftazidime.
[0153] Numerous standard references are available that describe
procedures for preparing various compositions suitable for
administering the compounds according to the invention. Examples of
potential compositions and preparations are contained, for example,
in the Handbook of Pharmaceutical Excipients, American
Pharmaceutical Association (current edition); Pharmaceutical Dosage
Forms: Tablets (Lieberman, Lachman and Schwartz, editors) current
edition, published by Marcel Dekker, Inc., as well as Remington's
Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (current
edition).
[0154] The compositions may be solid or liquid and be presented in
the pharmaceutical forms, such as for example, plain or
sugar-coated tablets, gelatin capsules, granules, suppositories,
injectable preparations, ointments, creams, gels, and prepared
according to the usual methods. The active ingredient or
ingredients can be incorporated with excipients usually employed in
these pharmaceutical compositions, such as talc, gum arabic,
lactose, starch, magnesium stearate, cocoa butter, aqueous or
non-aqueous vehicles, fatty substances of animal or vegetable
origin, paraffin derivatives, glycols, various wetting, dispersing
or emulsifying agents and preservatives.
[0155] Various solid oral dosage forms can be used for
administering the crystalline forms of the invention including such
solid forms as tablets, gelcaps, capsules, caplets, granules,
lozenges and bulk powders. The crystalline forms of the present
invention can be administered alone or combined with various
pharmaceutically acceptable carriers, diluents (such as sucrose,
mannitol, lactose, starches) and excipients known in the art,
including, but not limited to suspending agents, solubilizers,
buffering agents, binders, disintegrants, preservatives, colorants,
flavorants, lubricants and the like. Time release capsules, tablets
and gels may also be used in administering the crystalline forms of
the present invention.
[0156] Various liquid oral dosage forms can also be used for
administering the crystalline forms of the inventions, including
aqueous and non-aqueous solutions, emulsions, suspensions, syrups,
and elixirs. Such dosage forms can also contain suitable inert
diluents known in the an such as water and suitable excipients
known in the art such as preservatives, wetting agents, sweeteners,
flavorants, as well as agents for emulsifying and/or suspending the
compounds of the invention. The crystalline forms of the present
invention may be injected, for example, intravenously, in the form
of an isotonic sterile solution. Other preparations are also
possible.
[0157] The compositions may also be presented in the form of a
lyophilisate intended to be dissolved extemporaneously in an
appropriate vehicle, e.g., apyrogenic sterile water.
[0158] Suppositories for rectal administration of the crystalline
forms of the present invention can be prepared by mixing the
compound with a suitable excipient such as cocoa butter,
salicylates and polyethylene glycols.
[0159] For topical administration, the pharmaceutical composition
can be in the form of creams, ointments, liniments, lotions,
emulsions, suspensions, gels, solutions, pastes, powders, sprays,
and drops suitable for administration to the skin, eye, ear or
nose. Topical administration may also involve transdermal
administration via means such as transdermal patches.
[0160] Aerosol formulations suitable for administering via
inhalation also can be made. For example, for treatment of
disorders of the respiratory tract, the compounds according to the
invention can be administered by inhalation in the form of a powder
(e.g., micronized) or in the form of atomized solutions or
suspensions. The aerosol formulation can be placed into a
pressurized acceptable propellant.
Methods of Treatment
[0161] In one aspect, the present invention provides methods of
treating bacterial infections comprising administering a
crystalline form of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt alone (e.g., NXL-104) or in combination with an
antibacterial agent, such as, ceftaroline or a prodrug of
ceftaroline.
[0162] The bacterial infections include, but are not limited to,
complicated skin and structure infection, community acquired
pneumonia, complicated urinary tract infections and complicated
intra-abdominal infections (cIAIs). Complicated intra-abdominal
infections include infections requiring surgical intervention and
infections that extend beyond the hollow viscus into the peritoneal
space.
[0163] In some embodiments, the community acquired pneumonia may be
due to a microorganism, such as, Streptococcus, Staphylococcus,
Haemophilus, Klebsiella, Escherichia and Moraxella. In further
embodiments, the community acquired bacterial pneumonia may be due
to a microorganism, including, but not limited to, Streptococcus
pneumoniae, Staphylococcus aureus, Haemophilus influenzae,
Haemophilus parainfluenzae, Klebsiella pneumoniae, Escherichia coli
and Morarella catarrhalis. In other embodiments, the community
acquired pneumonia may be due to Enterobacter, Proteus or Serratia.
In further embodiments, the community acquired bacterial pneumonia
may be due to Enterobacter aerogenes, Proteus mirabilis or Serratia
marcescens.
[0164] In exemplary embodiments, the microorganism may be
Streptococcus pneumoniae. The strain of Streptococcus pneumoniae
may be penicillin-susceptible, penicillin-resistant or multidrug
resistant. In exemplary embodiments, the microorganism may be
Streptococcus pneumoniae serotype 19A. In some embodiments, the
community acquired pneumonia may be associated with concurrent
bacteremia. In other exemplary embodiments, the microorganism may
be Staphylococcus aureus. The strain or isolate of Staphylococcus
aureus may be methicillin-susceptible or methicillin-resistant. In
still other exemplary embodiments, the microorganism may be
Haemophilus influenzae, Klebsiella pneumoniae or Escherichia coli.
In exemplary embodiments, the microorganism may be a
.beta.-lactamase-nonproducing ampicillin-resistant (BLNAR) strain
of Haemophilus influenzae.
[0165] In some embodiments, the methods comprise administering one
or more of the crystalline forms of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (e.g., NXL-104), for example, Form I, II, III, IV or V
as described above. In exemplary embodiments, the methods comprise
administering Form I of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt. In other exemplary embodiments, the methods comprise
administering Form II of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt. In still other exemplary embodiments, the methods
comprise administering Form III, IV or V of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt.
[0166] Some examples of antibacterial agents that may be
administered in combination with the crystalline forms described in
this application, include, but are not limited to, antibiotics of
the .beta.-lactamine type, for example, penams, penems, cephems,
carbacephems, oxacephems, cephamycins, penicillins such as
amoxicillin, ampicillin, azlocillin, mezlocillin, apalcillin,
hetacillin, bacampicillin, carbenicillin, sulbenicillin,
ticarcillin, piperacillin, mecillinam, pivmecillinam, methicillin,
ciclacillin, talampicillin, aspoxicillin, oxacillin, cloxacillin,
dicloxacillin, flucloxacillin, nafcillin or pivampicillin,
cephalosporins such as cephalothin, cephaloridine, cefaclor,
cefadroxil, cefamandole, cefazolin, cephalexin, cephradine,
ceftizoxime, cefoxitin, cephacetrile, cefotiam, cefotaxime,
cefsulodin, cefoperazone, ceftizoxime, cefmenoxime, cefmetazole,
cephaloglycin, cefonicid, cefodizime, cefpirome, ceftazidime,
ceftaroline or a prodrug thereof such as ceftaroline fosamil,
ceftriaxone, cefpiramide, cefbuperazone, cefozopran, cefepime,
cefoselis, cefluprenam, cefuzonam, cefpimizole, cefclidin,
cefixime, ceftibuten, cefdinir, cefpodoxime axetil, cefpodoxime
proxetil, cefteram pivoxil, cefetamet pivoxil, cefcapene pivoxil,
or cefditoren, pivoxil, cefuroxime, cefuroxime axetil, loracarbacef
or latamoxef, carbapenems such as imipenem, meropenem, biapenem or
panipenem and also monobactams such as aztreonam and carumonam, as
well as their salts.
[0167] In exemplary embodiments, the methods include administering
the crystalline forms in combination with ceftazidime. In specific
embodiments, Form I may be combined with ceftazidime. In other
embodiments, Form II may be combined with ceftazidime. In still
other embodiments, Form III may be combined with ceftazidime. In
other examples, Form IV or V may be combined with ceftazidime.
[0168] In some embodiments, the methods comprise administering a
composition comprising a crystalline form of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (e.g., NXL-104) as described above. The composition may
further comprise an antibacterial agent, e.g., ceftaroline fosamil
as described above.
[0169] In other embodiments, the methods comprise administering a
crystalline form of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (e.g., NXL-104) and an antibacterial agent, such as,
ceftaroline or a prodrug of ceftaroline. The prodrug of ceftaroline
may be a phosphono prodrug, such as, ceftaroline fosamil. In
exemplary embodiments, the methods comprise administering Form I of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt and ceftaroline fosamil. In other exemplary
embodiments, the methods comprise administering Form II of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt and ceftaroline fosamil. In still other exemplary
embodiments, the methods comprise administering Form III, IV or V
and ceftaroline fosamil.
[0170] The crystalline forms of the present invention can be
administered at the same time as the dose of an antibacterial
agent, or separately. In exemplary embodiments, the crystalline
form may be administered in combination with the antibacterial
agent, e.g., ceftaroline fosamil in one composition. In other
embodiments, a composition comprising the crystalline form may be
administered concurrently with a composition comprising the
antibacterial agent (e.g., ceftaroline fosamil).
[0171] The dose of the crystalline forms may vary according to
several factors, including, but not limited to the type of
bacterial infection and the microorganism causing the
infection.
[0172] In some embodiments, the daily dose of the crystalline form
may range from about 0.1 to approximately about 10 g. In specific
embodiments, the daily dose of the crystalline form may be about
100 mg to 10 g. In other embodiments, the daily dose of the
crystalline form may be about 200 mg to 5 g. In still other
embodiments, the daily dose of the crystalline form may be about
200 mg to 2000 mg. In exemplary embodiments, the daily dose of the
crystalline form may be about 200 mg, about 300 mg, about 400 mg,
about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900
mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg,
about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about
1800 mg, about 1900 mg and about 2000 mg. In some exemplary
embodiments, the daily dose is 500 mg. In other exemplary
embodiments, the daily dose is 800 mg. In still other exemplary
embodiments, the daily dose is 1200 mg.
[0173] In some embodiments, the methods comprise administering the
crystalline form in combination with about 100 mg and about 2400 mg
of ceftaroline or a prodrug thereof (e.g., ceftaroline fosamil). In
further embodiments, ceftaroline or a prodrug thereof may be
administered in an amount between about 100 mg and about 1200 mg.
In some embodiments, ceftaroline or a prodrug thereof may be
administered in an amount between about 200 mg and 1000 mg. In
exemplary embodiments, the amount may be about 100 mg, 200 mg, 300
mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100
mg or 1200 mg. In certain embodiments, the amount may be about 400
mg. In other embodiments, the amount may be about 600 mg. In still
other embodiments, the amount may be about 800 mg. In certain
embodiments, the amount may be about 1200 mg.
[0174] In some embodiments, the methods comprise administering the
crystalline form in combination with between about 100 mg and about
2400 mg of ceftazidime. In further embodiments, ceftazidime may be
administered in an amount between about 100 mg and about 1200 mg.
In some embodiments, ceftazidime may be administered in an amount
between about 200 mg and 1000 mg. In exemplary embodiments, the
amount may be about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg,
700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg or 1200 mg. In certain
embodiments, the amount may be about 500 mg. In other embodiments,
the amount of ceftazidime may be between about 1 g and about 3 g.
In some embodiments, the amount may be about 1 g. In other
embodiments, the amount may be about 2 g. In still other
embodiments, the amount may be about 3 g. In some embodiments, the
amount may be between about 4 g and 6 g, for example, about 4 g,
about 5 g or about 6 g.
[0175] The amount of the crystalline form and antibacterial agent
may be administered in a single dose or multiple divided doses per
day. For example, the amount may be administered as a single daily
dose.
[0176] In exemplary embodiments, about 800 mg of Form I, 11, III,
IV or V of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt may be administered daily with about 800 mg of
ceftaroline or a prodrug thereof (e.g., ceftaroline fosamil). In
other exemplary embodiments, about 1200 mg of Form I, II, III, IV
or V of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt may be administered daily with about 1200 mg of
ceftaroline or a prodrug (e.g., ceftaroline fosamil) thereof. In
some embodiments, the amount may be administered in two to eight
doses per day. For example, about 400 mg of the crystalline form
and about 400 mg of ceftaroline or a prodrug thereof (e.g.,
ceftaroline fosamil) may be administered every 12 hours (i.e. twice
a day). In some examples, about 600 mg of the crystalline form and
about 600 mg of ceftaroline or a prodrug thereof (e.g., ceftaroline
fosamil) may be administered every 12 hours (i.e. twice a day).
[0177] In some embodiments, the ratio of the crystalline form to
the antibacterial agent may range from about 1:20 to about 10:1.
The ratio may vary according to the type of infection and the
antibacterial agent. In exemplary embodiments, the ratio of
crystalline form to antibacterial agent may be between about 1:10
to 5:1.
[0178] In specific embodiments, the methods comprise administering
the crystalline form in combination with ceftaroline or a prodrug
of ceftaroline, such as, ceftaroline fosamil. In exemplary
embodiments, the methods include administering the crystalline form
and ceftaroline fosamil in a ratio of about 1:1 to 5:1, such as,
for example, 1:1, 2:1, 3:1, 4:1, 5:1. In exemplary embodiments, the
methods comprise administering Form I, II, III, IV or V of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (e.g., NXL-104) and ceftaroline fosamil in a ratio of
1:1. For example, about 400 mg of Form I may be administered in
combination with about 400 mg of ceftaroline fosamil. In some
embodiments, about 600 mg of Form I may be administered with about
600 mg of ceftaroline fosamil.
[0179] The crystalline forms of the present invention may be
administered according to patient needs, for example, orally,
nasally, parenterally, by inhalation, rectally, vaginally,
topically and by ocular administration. Parenteral administration
may be intravenous, intra-arterial, intrathecal, intramuscular,
subcutaneous, intramuscular, intrasternal or intra-abdominal (e.g.,
intraperitoneal) etc. In some embodiments, the parenteral
administration may be effected by infusion pumps (external or
implantable) or any other suitable means appropriate to the desired
administration modality.
[0180] In exemplary embodiments, the crystalline form and
ceftaroline or a prodrug thereof may be administered parenterally.
Suitable methods for parenteral administration include, but are not
limited to, administering a sterile aqueous preparation of the
crystalline form alone or in combination with an antibacterial
agent, which preferably is isotonic with the blood of the recipient
(e.g., physiological saline solution). Such preparations may
include suspending agents and thickening agents and liposomes or
other microparticulate systems, which are designed to target the
compound to blood components or one or more organs. The preparation
may be presented in a unit-dose or multi-dose form.
[0181] Ceftaroline or a prodrug thereof (e.g., ceftaroline fosamil)
may be administered as a solution or suspension in a solvent, such
as water, physiological saline, about a 5% to about 10% sugar
(e.g., glucose, dextrose) solution, and combinations thereof. In
exemplary embodiments, ceftaroline or a prodrug thereof may be
administered intravenously, such as, by infusion. In some
embodiments, ceftaroline or a prodrug thereof may be administered
by intravenous infusion over one hour. In other embodiments,
ceftaroline or a prodrug thereof may be administered through
continuous or prolonged intravenous infusion. In still other
embodiments, ceftaroline or a prodrug thereof may be administered
intramuscularly. For intramuscular administration of higher doses,
the injection may occur at two or more intramuscular sites.
[0182] In some embodiments, methods of treating community acquired
pneumonia may include administering ceftaroline or a prodrug
thereof every 4 hours, 6 hours, 8 hours, 12 hours, 18 hours or
every 24 hours. For example, ceftaroline or a prodrug thereof may
be administered every 12 hours intravenously by infusion over one
hour. In other embodiments, the methods may include administering
ceftaroline or a prodrug thereof through continuous or prolonged
infusion. For example, ceftaroline or a prodrug thereof may be
administered by infusion over 2 hours, 3 hours, 4 hours, 5 hours, 6
hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours or 12 hours.
In other embodiments, the duration of infusion may be more than 12
hours, e.g., 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18
hours, 19 hours, 20 hours, 21 hours or 22 hours, 23 hours or 24
hours. For example, about 400 mg of ceftaroline or a prodrug
thereof may be administered by infusion over 12 hours. In another
example, about 600 mg of ceftaroline or a prodrug thereof may be
administered by infusion over 12 hours.
[0183] The duration of treatment may depend on the severity and
site of infection and the subject's clinical and bacteriological
progress. In some embodiments, the treatment may last between about
5 to 14 days. In other embodiments, the treatment may last between
about 5 to 7 days. For example, about 400 mg of ceftaroline or a
prodrug thereof may be administered every 24 hours for five to
fourteen days. In further embodiments, about 400 mg of ceftaroline
or a prodrug thereof may be administered every 24 hours for five to
ten days. In other embodiments, about 400 mg of ceftaroline or a
prodrug thereof may be administered every 24 hours for five to
seven days.
[0184] In other embodiments, about 400 mg of ceftaroline or a
prodrug thereof may be administered every 12 hours for five to
fourteen days. In other embodiments, about 400 mg of ceftaroline or
a prodrug thereof may be administered every 12 hours for five to
ten days. In still other embodiments, about 400 mg of ceftaroline
or a prodrug thereof may be administered every 12 hours for five to
seven days.
[0185] In other embodiments, about 400 mg of ceftaroline or a
prodrug thereof may be administered every 8 hours for five to
fourteen days. For example, about 400 mg of ceftaroline or a
prodrug thereof may be administered every 8 hours for five to ten
days. In further embodiments, about 400 mg of ceftaroline or a
prodrug thereof may be administered every 8 hours for five to seven
days.
[0186] In other embodiments, about 600 mg of ceftaroline or a
prodrug thereof may be administered every 24 hours for five to
fourteen days. For example, about 600 mg of ceftaroline or a
prodrug thereof may be administered every 24 hours for five to ten
days. In exemplary embodiments, about 600 mg of ceftaroline or a
prodrug thereof may be administered every 24 hours for five to
seven days. In some embodiments, about 600 mg of ceftaroline or a
prodrug thereof may be administered every 12 hours for five to
fourteen days. In other embodiments, about 600 mg of ceftaroline or
a prodrug thereof may be administered every 12 hours for five to
ten days. In still other embodiments, about 600 mg of ceftaroline
or a prodrug thereof may be administered every 12 hours for five to
seven days. In further embodiments, about 600 mg of ceftaroline or
a prodrug thereof may be administered every 8 hours for five to
fourteen days. In some embodiments, about 600 mg of ceftaroline or
a prodrug thereof may be administered every 8 hours for five to ten
days. In other embodiments, about 600 mg of ceftaroline or a
prodrug thereof may be administered every 8 hours for five to seven
days.
[0187] Unless defined otherwise, all technical and scientific terms
used herein generally have the same meaning as commonly understood
by one of ordinary skill in the art to which this invention
belongs.
[0188] NXL-104 refers to the monosodium salt of
(1R,2S,5R)-7-oxo-6-sulphooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide.
The structure of NXL-104 is as shown below:
##STR00019##
[0189] The term "prodrug" means a compound that is a drug
precursor, which upon administration to a subject undergoes
chemical conversion by metabolic or chemical processes to yield a
compound, which is an active moiety. Suitable prodrugs of
ceftaroline include, but are not limited to, phosphonocepehem
derivatives, such as, e.g.,
7.beta.-[2(Z)-ethoxyimino-2-(5-phosphonoamino-1,2,4-thiadiazol-3-yl)aceta-
mido]-3-[4-(1-methyl-4-pyridinio)-2-thiazolythio]-3-cephem-4-carboxylate.
[0190] Solvates of a compound may form when a solvent molecule(s)
is incorporated into the crystalline lattice structure of
ceftaroline or a prodrug thereof molecule during, for example, a
crystallization process. Suitable solvates include, e.g., hydrates
(monohydrate, sesquihydrate, dihydrate), solvates with organic
compounds (e.g., CH.sub.3CO.sub.2H, CH.sub.3CH.sub.2CO.sub.2H,
CH.sub.3CN), and combinations thereof.
[0191] The term "substantially pure" means a compound having a
purity greater then, e.g., about 90% by weight, for example,
greater than about 91% by weight, greater than about 92% by weight,
greater than about 93% by weight, greater than about 94% by weight,
greater than about 95% by weight, greater than about 96% by weight,
greater than about 97% by weight, greater than about 97.5% by
weight, greater than about 98% by weight, greater than about 99% by
weight, greater than about 99.5% by weight, or greater than about
99.9% by weight.
[0192] The term "about" or "approximately" means within an
acceptable error range for the particular value as determined by
one of ordinary skill in the art, which will depend in part on how
the value is measured or determined, i.e., the limitations of the
measurement system. For example, "about" can mean within 1 or more
than 1 standard deviation, per practice in the art. Alternatively,
"about" with respect to the compositions can mean plus or minus a
range of up to 20%, preferably up to 10%, more preferably up to 5%.
Alternatively, particularly with respect to biological systems or
processes, the term can mean within an order of magnitude,
preferably within 5-fold, and more preferably within 2-fold, of a
value. Where particular values are described in the application and
claims, unless otherwise stated the term "about" means within an
acceptable error range for the particular value. For example, when
referring to a period of time, e.g., hours, the present values
(.+-.20%) are more applicable. Thus, 6 hours can be, e.g., 4.8
hours, 5.5 hours, 6.5 hours, 7.2 hours, as well as the usual 6
hours.
[0193] The terms "treat," "treatment," and "treating" refer to one
or more of the following: relieving or alleviating at least one
symptom of a bacterial infection in a subject; relieving or
alleviating the intensity and/or duration of a manifestation of
bacterial infection experienced by a subject; and arresting,
delaying the onset (i.e., the period prior to clinical
manifestation of infection) and/or reducing the risk of developing
or worsening a bacterial infection.
[0194] The term "community acquired pneumonia" as used herein is
equivalent and has been used interchangeably with the term
"community acquired bacterial pneumonia."
[0195] The term "therapeutically effective" applied to dose or
amount refers to that quantity of a compound or pharmaceutical
composition that is sufficient to result in a desired activity upon
administration to a mammal in need thereof. An "effective amount"
means the amount of a compound according to the invention that,
when administered to a patient for treating an infection or disease
is sufficient to effect such treatment. The "effective amount" will
vary depending on the active ingredient, the state of infection,
disease or condition to be treated and its severity, and the age,
weight, physical condition and responsiveness of the mammal to be
treated.
[0196] MPTT refers to
4-(1-methylpyridin-1-ium-4-yl)thiazole-2-thiol.
[0197] In the examples, ND refers to a not detectable (quantity)
and UNK refers to an unknown impurity and w/o U3 refers to total
impurities without U3.
[0198] In some embodiments, the compounds of the present invention
are administered as a mono-therapy. In other embodiments, the
compounds of the present invention are administered as part of a
combination therapy. For example, a compound of the invention may
be used in combination with other drugs or therapies that are used
in the treatment/prevention/suppression or amelioration of the
diseases or conditions for which compounds of the invention are
useful.
[0199] Such other drug(s) may be administered, by a route and in an
amount commonly used therefore, contemporaneously or sequentially
with a compound of the invention. When a compound of the present
invention is used contemporaneously with one or more other drugs, a
pharmaceutical unit dosage form containing such other drugs in
addition to the compound of the invention may be employed.
Accordingly, the pharmaceutical compositions of the present
invention include those that also contain one or more other active
ingredients, in addition to a compound of invention.
[0200] The following examples are merely illustrative of the
present invention and should not be construed as limiting the scope
of the invention in any way as many variations and equivalents that
are encompassed by the present invention will become apparent to
those skilled in the art upon reading the present disclosure.
EXAMPLES
Example 1
Preparation and Characterization of Amorphous
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
Sodium Salt
[0201] Amorphous
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
can be prepared as described in U.S. Pat. No. 7,112,592. The XRD
pattern was obtained by mounting samples on a sample holder of
Rigaku Miniflex X-ray diffractometer with the K.alpha. radiation of
copper (=1.541 .ANG.). The samples, without grinding, were put on a
glass plate and were analyzed at ambient temperature and humidity.
Data were collected at 0.05.degree. interval, 2.degree./minute from
3.degree.-40.degree. 2.theta.. FIG. 1 shows the X-ray diffraction
(XRD) pattern for amorphous
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt.
[0202] A solution, in a water-acetone mixture (1-1), of the sodium
salt of the racemic
trans-7-oxo-6-(sulphoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
described in Example 33c of Application WO 02/10172 is evaporated
under reduced pressure, under the conditions of concentration
described in said example. The salt is obtained in crystallized
form. The X-ray spectra ("XRPD diffraction patterns") of the
polymorphic Forms were compared. The diffraction pattern of the
racemic form obtained according to the prior art is different from
each of those of the polymorphic Forms.
Example 2
Preparation and Characterization of Form I of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
Sodium Salt
[0203] Method I
[0204] A solution of the 5.067 g (10 mmoles) of the
tetrabutylammonium salt of
trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxam-
ide in 12.5 ml of 200 proof ethanol and 12.5 ml of 190 proof
ethanol was filtered through a 1.6 .mu.m filter and added to a 100
ml jacketed-reactor equipped with magnetic stirrer. The solution
was warmed to an internal temperature of 35.degree. C. Separately,
a solution of 3.3 g (20 mmoles) of sodium 2-ethylhexanoate in 25 ml
200 proof ethanol was filtered through a 1.6 .mu.m filter. 2.5 ml
of this solution was added to the reactor and the mixture was
stirred for 1 h at 35.degree. C. Crystallization occurred during
this time. The remainder of the sodium 2-ethylhexanoate solution
was added over 20 min. The mixture was stirred for an additional 1
h at 35.degree. C., followed by 12 h at 25.degree. C. The mixture
was cooled to 0.degree. C. for 2 h. The crystals were isolated by
filtration and washed with 10 ml ethanol. The crystals were dried
under vacuum at 35.degree. C. for 16 h. 2.72 g of the sodium salt
of
trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
(Form I) was obtained, corresponding to a yield of 95%.
[0205] Method II
[0206] A solution of the 50.67 g (100 mmoles) of the
tetrabutylammonium salt of
trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxam-
ide in 338 ml of ethanol and 8.33 ml of water was filtered through
a 0.45 .mu.m filter and added to a 1 liter jacketed-reactor
equipped with overhead stirrer and internal temperature probe. The
solution was warmed to an internal temperature of 30.degree. C. 287
mg (1 mmole) of Form I seed crystals were added. A solution of
35.125 g (205 mmoles) of sodium 2-ethylhexanoate in 338 ml ethanol
was filtered through a 0.45 .mu.m filter and added to the reactor
over 4 h. The mixture was stirred an additional 12 h at 30.degree.
C., then cooled to 5.degree. C. for 4 h. The crystals were isolated
by filtration and washed with 40 ml ethanol three times. The
crystals were dried under vacuum at 20.degree. C. for 4 h. 27.14 g
of the sodium salt of
trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
(Form I) was obtained, corresponding to a yield of 93.5%.
[0207] Method III
[0208] A solution of sodium 2-ethylhexanoate (13.12 g, 79 mmol) in
ethanol (126 mL) is added over five hours to a solution of
sulphaturamide (20 g, 39.5 mmol) in ethanol (126 mL) stirred at
30.degree. C. and seeded with a few crystals of polymorphic Form I.
The suspension is stirred overnight. The suspension is cooled to
0-5.degree. C. for 1 to 2 hours, filtered and then washed with
ethanol at 5.degree. C. (3.times.40 mL). The crystals are dried
under reduced pressure of 20 mbar at 20.degree. C. The expected
polymorphic Form I is obtained (10.79 g, 37.5 mmol, yield
95.1%).
[0209] Method IV
[0210] A solution of sulphaturamide (10 g, 19.7 mmol) in ethanol
(100 ml) is added over forty-five minutes to a solution of sodium
2-ethylhexanoate (3.80 g, 22.9 mmol) in ethanol (95 ml) and water
(5 ml; 3.1% of the total weight of the solvent), stirred at room
temperature and seeded with a few crystals of polymorphic Form II.
The suspension is stirred overnight. The suspension is cooled down
to 0-5.degree. C. for 1 to 2 hours, filtered and then washed with
ethanol at 5.degree. C. (3.times.30 ml). The crystals are dried
under reduced pressure of 20 mbar at 20.degree. C. The polymorphic
Form I is obtained (4.277 g, 14.9 mmol, yield 75.4%).
[0211] The XRD pattern was obtained as described in Example 1. FIG.
2 shows the XRD pattern for Form I.
Example 3
Preparation and Characterization of Form II of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
Sodium Salt
[0212] Method I
[0213] A solution of the 10.134 g (20 mmoles) of the
tetrabutylammonium salt of
trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxam-
ide in 48.1 ml of isobutanol and 2.53 ml water was filtered through
a 1.6 .mu.m filter and added to a 500 ml jacketed-reactor equipped
with overhead stirrer and internal temperature probe. The solution
was warmed to an internal temperature of 35.degree. C. A solution
of 6.65 g (40 mmoles) of sodium 2-ethylhexanoate in 49.5 ml
isobutanol and 0.5 ml water was filtered through a 1.6 .mu.m filter
and added dropwise to the reactor. Crystallization occurred during
the addition. The mixture was stirred for an additional th at
35.degree. C. followed by 16 h at 25.degree. C. The mixture was
cooled to 0.degree. C. for 2 h. The crystals were isolated by
filtration and washed with an ice-cold mixture of 19.5 ml
isobutanol and 0.5 ml water. The crystals were dried under vacuum
at 35.degree. C. for 20 h. 5.48 g of the sodium salt of
trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
monohydrate (Form II) was obtained, corresponding to a yield of
90%.
[0214] Method II
[0215] A solution of sodium 2-ethylhexanoate (6.56 g, 39.4 mmol) in
ethanol (70 mL) is added over forty-five minutes to a solution of
sulphaturamide (10 g, 19.7 mmol) in a mixture of ethanol (63 mL)
and water (7 mL, 6.23% of the total weight of the solvent), stirred
at 20.degree. C. and seeded with the Form II. The suspension is
stirred overnight. The suspension is cooled down to 0-5.degree. C.
for 1 to 2 hours, filtered and then washed with aqueous ethanol
(5%) cooled down to 5.degree. C. (3.times.20 mL). The crystals are
dried under reduced pressure of 20 mbar at 20.degree. C. The
expected Form II is obtained (5.35 g, 17.5 mmol, yield 88.8%).
[0216] Method III
[0217] A solution of sulphaturamide (1 g, 1.97 mmol) in ethanol
(9.5 ml) and water (0.5 ml) is added over thirty minutes to a
solution of sodium 2-ethylhexanoate (0.506 g, 3.04 mmol) in ethanol
(9.5 ml) and water (0.5 ml). It is stirred at room temperature. The
solution (6.23% of the total weight of water) is seeded with a few
crystals of Form II to produce a suspension, which is stirred
overnight. The suspension is cooled down to 0-5.degree. C. for 1 to
2 hours, filtered and then washed with ethanol at 5.degree. C.
(3.times.6 ml). The crystals are dried under reduced pressure of 20
mbar at 20.degree. C. The expected Form II is obtained (0.378 g,
1.24 mmol, yield 62.7%).
[0218] The XRD pattern was obtained as described in Example 1. FIG.
3 shows the XRD pattern for Form II.
Example 4
Preparation and Characterization of Form III of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
Sodium Salt
[0219] Form III can be made on mg scale by vortexing Form I (100
mg) in 0.9% aqueous sodium chloride solution (40 .mu.l).
[0220] A sample of sodium salt of the
(1R,2S,5R)-7-oxo-6-(sulphoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
enantiomer, monohydrate--Form II (1 g) is suspended in water (2
ml). The suspension, unstirred, is left to evaporate slowly at
ambient temperature, pressure and humidity. The crystallized solid
is recovered after complete evaporation. The expected Form III is
obtained (1.056 g). The XRD pattern was obtained as described in
Example 1. FIG. 4 shows the XRD pattern for Form III.
Example 5
Preparation and Characterization of Form IV of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
Sodium Salt
Method I
[0221] Sulfaturamide (SU) is dissolved in ethanol (EtOH). Sodium
2-ethylhexanoate (SEH), dissolved in ethanol, is added rapidly to
SU solution. SU, SEH and the byproduct (tetrabutylammonium
ethylhexanoate) are all soluble in EtOH, but the sodium salt of
NXL-104 has a poor solubility and so crystallizes out of solution.
Form IV is obtained under anhydrous conditions (anhydrous SU and
SEH) and rapid addition of SEH. Yield was 85% using this
process.
Method II
[0222] A solution of sodium 2-ethylhexanoate (3.28 g, 19.7 mmol) in
ethanol (25 ml) is added over thirty minutes to a solution of
sulphaturamide (4 g, 9.87 mmol) in ethanol (25 ml), stirred at
20.degree. C. and seeded with the polymorphic form II. The
suspension is stirred overnight. The suspension is filtered and
then washed with ethanol at 5.degree. C. (3.times.10 ml). The solid
is dried under reduced pressure of 20 mbar at 20.degree. C. The
expected polymorphic form IV is obtained (2.50 g, 8.70 mmol, yield
88.2%).
[0223] The XRD pattern was obtained as described in Example 1. FIG.
5 shows the XRD pattern for Form IV.
Example 6
Stability of Amorphous
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
Sodium Salt (NXL-104)
[0224] A solution containing 400 mg/ml (on free acid basis)
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt was prepared by dissolving the compound in water. The
solution was then filled into 10 cc Type I glass vials and
lyophilized by freezing at -50.degree. C. for 1-4 hours, primary
drying at temperatures ranging from -25 to -10.degree. C. for 30-50
hours and pressures from 100 to 400 mTorr and secondary drying at
25.degree. C. for 10-20 hours.
[0225] Assay for NXL-104 and Related Substances
[0226] NXL-104 and related substances in compositions comprising
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt were determined by a reverse phase gradient HPLC method
with UV detection at 195 nm.
[0227] The following parameters were used for analysis:
[0228] Column: Inertsil ODS-3, 250 mm.times.4.6 mm, 5 .mu.m
[0229] Mobile Phase A: 100 mM KH.sub.2PO.sub.4 Solution
[0230] Mobile Phase B: Acetonitrile: Water, [50:50 (v:v)]
[0231] Flow Rate; 1.0 ml/min
[0232] Column Temperature: 25.degree. C.
[0233] Autosampler Temperature: 5.degree. C.
[0234] Detector/Setting: UV/195 nm
[0235] Injection Volume: 10 .mu.L
[0236] Run Time: about 25 minutes
[0237] injector Washing Solution: Acetonitrile:Water, [10:90
(v:v)]
[0238] Approximate relative retention times (RRT) values for
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt and disulfate were 1.00 and 0.37.
[0239] The decarbonyl degradation product of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt was determined by a reverse phase gradient HPLC method
with UV detection at 195 nm.
[0240] The following parameters were used for analysis:
[0241] Column: Inertsil ODS-3, 250 mm.times.4.6 mm, 5 .mu.m
[0242] Mobile Phase A: Deionized Water
[0243] Mobile Phase B: 50 mM KH.sub.2PO.sub.4
solution:Acetonitrile, [50:50 (v:v)]
[0244] Flow Rate: 1.0 ml/min
[0245] Column Temperature: 25.degree. C.
[0246] Detector/Setting: UV/195 nm
[0247] Injection Volume: 10 .mu.L
[0248] Run Time (Approximate): 35 minutes
[0249] Injector Washing Solution: Acetonitrile:Water, [50:50 (v:v)]
(Recommended)
[0250] Approximate relative retention time (RRT) for decarbonyl was
0.17.
[0251] The stability of amorphous
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt stored in a vial stored at 25.degree. C. with a
relative humidity of 60% (25.degree. C./60% RH) was evaluated using
the NXL-104 assay described above.
[0252] Table 1 provides the stability data for amorphous NXL-104 in
vial stored at 25.degree. C./60% RH.
TABLE-US-00001 TABLE 1 Stability of amorphous NXL-104 in vial
stored at 25.degree. C./60% RH Impurities - NXL-104 Related (%)
Total pH NXL-104 % Decarbonyl Disulfate Impurities Initial 7.0
106.4 0.63 0.19 0.90 1 month 7.3 111.3 0.46 0.19 0.89 3 months 7.2
108.0 0.48 0.17 0.92 6 months 7.3 106.1 0.33 0.17 0.87
Example 7
Stability of Amorphous
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
Sodium Salt (NXL-104) and Amorphous Ceftaroline Fosamil
[0253] A solution was prepared by dissolving ceftaroline fosamil
monohydrate acetic acid solvate (668.4 mg/vial),
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (649.8 mg/vial) and L-Arginine (434.3 mg/vial) in Water
for Injection, USP. The concentration of both ceftaroline fosamil
(anhydrous and non-solvate) and
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
free acid was 120 mg/ml.
[0254] Lyophilization cycle was designed based on the glass
transition temperatures of frozen solutions of ceftaroline fosamil
monohydrate acetic acid solvate,
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt and L-Arginine determined using Differential Scanning
Calorimetry. 5 ml of the solution was filled into each 20 cc Type I
glass vial and lyophilized (Telstar LyoBeta25) by freezing at
-50.degree. C. for 1-5 hours, primary drying at temperatures
ranging from -40 to -10.degree. C. for 30-50 hours and pressures
from 100 to 400 mTorr and secondary drying at 25.degree. C. for
10-20 hours. Intact lyophilized cakes were obtained at the end of
the process and the vials were stored at different conditions to
monitor stability.
[0255] NXL-104 and related substances were measured according to
the assay described in Example 6.
[0256] Assay for Ceftaroline Fosamil and Related Substances
[0257] Ceftaroline fosamil assay and related substances in
compositions comprising
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt and ceftaroline fosamil were quantified by a gradient
method using ultra high performance liquid chromatography (UPLC).
The analytical wavelength setting was 245 nm.
[0258] The following parameters were used for analysis:
[0259] Analytical Column: Waters Acquity UPLC BEH C18 Column,
2.1.times.100 mm,
[0260] 1.7 .mu.m particle size
[0261] Guard Column: Waters Acquity UPLC BEH C18 VanGuard
Pre-Column,
[0262] 2.1.times.5 mm, 1.7 .mu.m particle size
[0263] Mobile Phase A: 100 mM Ammonium Acetate:Acetonitrile (95:5,
v:v)
[0264] Mobile Phase B: 100 mM Ammonium Acetate:Acetonitrile (60:40,
v:v)
[0265] Flow Rate: 0.5 ml/min
[0266] Column Temperature: 40.degree. C.
[0267] Detector: UV/245 nm
[0268] Injection Volume: 4 .mu.L
[0269] Injection Type: Partial Loop with Needle Overfill
[0270] Weak Needle Wash Solution: Water:Acetonitrile (90:10,
v:v)
[0271] Strong Needle Wash Solution:
Methanol:Acetonitrile:Isopropanol:Water (25:25:25:25, v:v:v:v) with
0.1% Formic Acid
[0272] Seal Wash Solution: Water:Acetonitrile (95:5, v:v)
[0273] Run Time: about 12 minutes
[0274] Approximate relative retention times (RRT) for the
ceftaroline related substances were as follows:
[0275] U1--0.31
[0276] U2--0.94
[0277] U3--1.57
[0278] U4--1.74
[0279] U6--0.80
[0280] U9--1.78
[0281] Adduct--0.66
[0282] Tables 2-4 show the stability data for composition
comprising amorphous
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carbo-
xamide sodium salt (NXL-104) and amorphous ceftaroline fosamil.
TABLE-US-00002 TABLE 2 NXL-104 and ceftaroline fosamil assay
Ceftaroline pH NXL-104 % fosamil % t-zero 5.68 104.2 94.3 1 month
at 40.degree. C./75% RH 5.67 99.5 80.3 3 months at 25.degree.
C./60% RH 5.71 101.9 87.0
TABLE-US-00003 TABLE 3 NXL-104 related impurities (%) Decarbonyl
Total Impurities t-zero ND 0.17 1 month at 0.23 1.32 40.degree.
C./75% RH 3 months at 0.23 0.91 25.degree. C./60% RH
TABLE-US-00004 TABLE 4 Ceftaroline related impurities (%) Total U1
Adduct U6 U4 U7 U3 U9 Impurities t-zero 1.01 0.57 0.10 0.03 0.02
2.59 0.03 4.52 1 month at 6.14 2.58 0.32 0.05 ND 3.62 0.09 14.88
40.degree. C./75% RH 3 months at 4.02 1.98 0.22 <0.05 0.02 3.00
<0.05 12.96 25.degree. C./60% RH
[0283] Amorphous NXL-104 and Amorphous Ceftaroline Fosamil with
Stabilizer
[0284] A solution was prepared by dissolving ceftaroline fosamil
monohydrate acetic acid solvate (668.4 mg/vial),
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (649.8 mg/vial), L-Arginine and/or suitable buffer or
other stabilizer in Water for Injection, USP. The concentration of
both ceftaroline fosamil (anhydrous and non-solvate) and
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
free acid was 120 mg/ml. Lyophilization cycle was designed based on
the glass transition temperatures of frozen solutions of
ceftaroline fosamil monohydrate acetic acid solvate,
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt and L-Arginine determined using Differential Scanning
Calorimetry as well as the glass transition temperatures of frozen
solutions of the buffer/other stabilizer. 5 ml of the solution was
filled into 20 cc Type I glass vial and lyophilized (Telstar
LyoBeta25) by freezing at -50.degree. C. for 1-5 hours, primary
drying at temperatures ranging from -40 to -10.degree. C. for 40-80
hours and pressures from 100 to 400 mTorr and secondary drying at
25.degree. C. for 10-20 hours. Depending on the formulation, an
annealing step was also included before primary drying in order to
allow complete ice crystallization or crystallization of
excipients. Annealing temperature was between -20.degree. C. and
0.degree. C. and annealing time was 4-12 hours. Intact lyophilized
cakes were obtained at the end of the process and the vials were
stored at different conditions to monitor stability. Packaging
components used were 20 ml Type I glass vial, Gray
chlorobutyl-isoprene stopper and Blue Aluminum tear-off seal.
[0285] Tables 5-7 show the stability data for a formulation
comprising lyophilized ceftaroline fosamil (668.4 mg), arginine
(434.3 mg), NXL-104 (649.8 mg) and Kollidon17 (93 mg).
TABLE-US-00005 TABLE 5 NXL-104 and ceftaroline fosamil assay pH
NXL-104 % Ceftaroline fosamil % t-zero 5.61 101.08 96.60 3 months
at 5.43 93.2 72.4 40.degree. C./75% RH
TABLE-US-00006 TABLE 6 NXL-104 related impurities (%) Decarbonyl
Total Impurities t-zero 0.61 0.76 3 months at 0.20 3.91 40.degree.
C./75% RH
TABLE-US-00007 TABLE 7 Ceftaroline fosamil related impurities (%)
Total U1 Adduct U6 U2 U3 U9 Impurities t-zero 1.37 0.76 0.19 0.11
3.28 0.25 6.72 3 months 10.20 4.57 0.90 0.21 5.04 0.22 22.76
40.degree. C./75% RH
[0286] Four formulations (1-4) comprising amorphous
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt and amorphous ceftaroline fosamil were prepared. Table
8 shows the stability data for lyophilized Formulations 1-4.
[0287] Formulation 1 (Per Vial)
[0288] Ceftaroline fosamil acetate=668.4 mg
[0289] NXL-104=649.8 mg
[0290] L-Arginine=434.3 mg
[0291] Citric acid monohydrate=1.1 mg
[0292] Trisodium citrate dihydrate=27.9 mg
[0293] Formulation 2 (Per Vial)
[0294] Ceftaroline fosamil acetate=668.4 mg
[0295] NXL-104=649.8 mg
[0296] L-Arginine=243.6 mg
[0297] Citric acid monohydrate=1.1 mg
[0298] Trisodium citrate dihydrate=27.9 mg
[0299] Formulation 3 (Per Vial)
[0300] Ceftaroline fosamil acetate=668.4 mg
[0301] NXL-104=649.8 mg
[0302] L-Arginine=243.6 mg
[0303] Citric acid monohydrate=2.2 mg
[0304] Trisodium citrate dihydrate=55.8 mg
[0305] Formulation 4 (Per Vial)
[0306] Ceftaroline fosamil acetate=668.4 mg
[0307] NXL-104=649.8 mg
[0308] L-Arginine=434.3 mg
[0309] Tartaric acid=37.5 mg
[0310] Sodium hydroxide=4 mg
TABLE-US-00008 TABLE 8 Assay and degradation profile of lyophilized
Formulations 1-4 NXL-104 related Ceftaroline Ceftaroline impurities
(%) related NXL-104 fosamil Total impurities (%) Formulation pH %
%* Decarbonyl impurities U1 U3 1 5.79 101.80 92.36 0.19 0.44 1.11
2.89 2 4.73 99.96 91.83 0.32 0.76 0.76 4.60 3 4.77 101.19 93.93
0.28 0.85 0.73 4.00 4 5.28 101.84 94.14 0.12 0.19 0.74 3.03 *Assay
values adjusted based on 95.5% assay of "as is" ceftaroline fosamil
acetate. Actual assay values were 88.20, 87.70, 89.70 and 89.90 for
Formulations 1, 2, 3 and 4 respectively.
[0311] Tables 9-12 show the assay and degradation profile of
lyophilized Formulation 1 stored at 40.degree. C./75% RH for 2
weeks.
TABLE-US-00009 TABLE 9 NXL-104 and ceftaroline fosamil assay
Ceftaroline fosamil Total NXL-104 impurities Total Assay (w/o U3)
Assay impurities pH (%)* U3 (%) (%) (%) 5.82 84.0 3.5 7.22 102.4
0.63 *Corrected value based on ceftaroline fosamil acetate potency
of 95.5%.
TABLE-US-00010 TABLE 10 Ceftaroline related substances (%) U1 U2 U4
U5 U6 U7 U8 U9 MPTT Adduct 2.47 0.11 0.05 ND 0.13 ND ND 0.10 0.37
2.63 ND = Not detectable
TABLE-US-00011 TABLE 11 Ceftaroline related substances (%) UNK* UNK
UNK UNK UNK UNK UNK UNK # 0.81 # 0.86 # 1.04 # 1.09 # 1.17 # 1.27 #
1.36 # 1.41 0.14 ND 0.59 0.14 0.12 ND ND ND UNK = unknown
impurities
TABLE-US-00012 TABLE 12 NXL-104 related substances (%) UNK UNK UNK
UNK Decarbonyl # 0.30 # 0.33 # 0.36 # 0.37 0.21 0.14 0.12 0.16
ND
[0312] Tables 13-16 show the assay and degradation profile of
lyophilized Formulation 2 stored at 40.degree. C./75% RH for 2
weeks.
TABLE-US-00013 TABLE 13 NXL-104 and ceftaroline fosamil assay
Ceftaroline fosamil Total NXL-104 impurities Total Assay (w/o U3)
Assay impurities pH (%)* U3 (%) (%) (%) 4.70 86.1 6.1 4.07 102.1
0.48 *Corrected value based on ceftaroline fosamil acetate potency
of 95.5%.
TABLE-US-00014 TABLE 14 Ceftaroline related substances (%) U1 U2 U4
U5 U6 U7 U8 U9 MPTT Adduct 1.76 0.46 0.09 ND 0.11 ND ND 0.11 0.32
0.77
TABLE-US-00015 TABLE 15 Ceftaroline related substances (%) UNK UNK
UNK UNK UNK UNK UNK UNK # 0.81 # 0.86 # 1.04 # 1.09 # 1.17 # 1.27 #
1.36 # 1.41 ND ND 0.13 ND 0.06 ND ND ND
TABLE-US-00016 TABLE 16 NXL-104 related substances (%) UNK UNK UNK
UNK Decarbonyl # 0.30 # 0.33 # 0.36 # 0.37 0.21 0.21 0.27 0.09
0.12
[0313] Tables 17-20 show the assay and degradation profile of
lyophilized Formulation 3 stored at 40.degree. C./75% RH for 2
weeks.
TABLE-US-00017 TABLE 17 NXL-104 and ceftaroline fosamil assay
Ceftaroline fosamil Total NXL-104 impurities Total Assay (w/o U3)
Assay impurities pH (%)* U3 (%) (%) (%) 4.82 87.4 5.6 3.85 103.4
0.44 *Corrected value based on ceftaroline fosamil acetate potency
of 95.5%.
TABLE-US-00018 TABLE 18 Ceftaroline related substances (%) U1 U2 U4
U5 U6 U7 U8 U9 MPTT Adduct 1.53 0.45 0.08 ND 0.10 ND ND 0.11 0.31
0.84
TABLE-US-00019 TABLE 19 Ceftaroline related substances (%) UNK UNK
UNK UNK UNK UNK UNK UNK # 0.81 # 0.86 # 1.04 # 1.09 # 1.17 # 1.27 #
1.36 # 1.41 ND ND 0.14 ND 0.06 ND ND ND
TABLE-US-00020 TABLE 20 NXL-104 related substances (%) UNK UNK UNK
UNK Decarbonyl # 0.30 # 0.33 # 0.36 # 0.37 0.20 0.22 0.10 0.12
ND
[0314] Table 21-24 show the assay and degradation profile of
lyophilized Formulation 4 stored at 40.degree. C./75% RH for 2
weeks.
TABLE-US-00021 TABLE 21 NXL-104 and ceftaroline fosamil assay
Ceftaroline fosamil Total NXL-104 impurities Total Assay (w/o U3)
Assay impurities pH (%)* U3 (%) (%) (%) 5.26 87.1 3.8 5.44 103.6
0.59 *Corrected value based on ceftaroline fosamil acetate potency
of 95.5%.
TABLE-US-00022 TABLE 22 Ceftaroline related substances (%) U1 U2 U4
U5 U6 U7 U8 U9 MPTT Adduct 1.83 0.13 0.06 ND 0.13 ND ND 0.10 0.33
1.97
TABLE-US-00023 TABLE 23 Ceftaroline related substances (%) UNK UNK
UNK UNK UNK UNK UNK UNK # 0.81 # 0.86 # 1.04 # 1.09 # 1.17 # 1.27 #
1.36 # 1.41 0.06 ND 0.36 0.09 0.09 ND ND ND
TABLE-US-00024 TABLE 24 NXL-104 related substances (%) UNK UNK UNK
UNK Decarbonyl # 0.30 # 0.33 # 0.36 # 0.37 0.18 0.16 0.11 0.14
ND
[0315] Formulation 5 was prepared with the following
composition:
[0316] Ceftaroline fosamil=600 mg
[0317] NXL-104 (free acid)=600 mg
[0318] L-Arginine=434.3 mg
[0319] Citric acid monohydrate=1.08 mg
[0320] Trisodium citrate dihydrate=27.90 mg
[0321] Pluronic F127=18.00 mg (equivalent to approximately 5% w/w
of final lyophile)
[0322] Tables 25-27 show the assay and degradation profile of
lyophilized Formulation 5 stored at 40.degree. C./75% RH for 0 and
2 weeks.
TABLE-US-00025 TABLE 25 NXL-104 and ceftaroline fosamil assay
Ceftaroline fosamil Total NXL-104 impurities Total Assay (w/o U3)
Assay impurities pH (%)* U3 (%) (%) (%) t-zero 6.01 92.8 3.0 1.62
103.9 0.33 2 weeks 5.76 83.5 3.6 8.75 104.2 1.45 *Corrected value
based on ceftaroline fosamil acetate potency of 95.5%.
TABLE-US-00026 TABLE 26 Ceftaroline related substances (%) U1 U2 U4
U5 U6 U7 U8 U9 MPTT Adduct t-zero 0.45 0.05 0.08 ND 0.05 0.05 ND
0.12 <0.05 0.61 2 weeks 3.90 0.12 0.18 <0.05 0.24 0.04 ND
0.11 0.38 3.05
TABLE-US-00027 TABLE 27 NXL-104 related substances (%) UNK UNK UNK
UNK UNK Decarbonyl # 0.36 # 0.47 # 0.55 # 0.95 # 0.97 t-zero 0.11
0.22 ND ND ND ND 2 weeks 0.10 0.21 0.49 0.17 0.36 0.12
[0323] Formulation 6 was prepared with the following
composition:
[0324] Ceftaroline fosamil=600 mg
[0325] NXL-104 (free acid)=600 mg
[0326] L-Arginine=434.3 mg
[0327] Hydroxy propyl .beta. cyclodextrin (HP.beta.CD)=1300 mg
[0328] Table 28-30 show the assay and degradation profile of
lyophilized Formulation 6 stored at 40.degree. C./75% RH for 0 and
2 weeks.
TABLE-US-00028 TABLE 28 NXL-104 and ceftaroline fosamil assay
Ceftaroline fosamil Total NXL-104 impurities Total Assay (w/o U3)
Assay impurities pH (%)* U3 (%) (%) (%) t-zero 6.00 91.5 2.9 1.82
103.3 0.66 2 weeks 5.73 79.1 3.8 10.36 104.3 1.20 *Corrected value
based on ceftaroline fosamil acetate potency of 95.5%.
TABLE-US-00029 TABLE 29 Ceftaroline related substances (%) U1 U2 U4
U5 U6 U7 U8 U9 MPTT Adduct t-zero 0.41 <0.05 0.06 ND 0.05 0.06
ND 0.11 0.21 0.92 2 weeks 3.19 0.08 0.34 0.07 0.22 0.07 ND 0.09
0.41 4.71
TABLE-US-00030 TABLE 30 NXL-104 related substances (%) UNK UNK UNK
UNK UNK Decarbonyl # 0.36 # 0.47 # 0.84 # 0.95 # 0.97 t-zero 0.05
0.21 ND 0.40 ND ND 2 weeks <0.05 0.18 0.32 ND 0.60 0.10
[0329] Formulation 7 was prepared with the following
composition:
[0330] Ceftaroline fosamil=600 mg
[0331] NXL-104 (free acid)=600 mg
[0332] Citric acid monohydrate=10.8 mg
[0333] Trisodium citrate dihydrate=279.0 mg
[0334] Table 31 shows the assay for lyophilized Formulation 7
stored at 40.degree. C./75% RH for 0 and 2 weeks.
TABLE-US-00031 TABLE 31 NXL-104 and ceftaroline fosamil assay
NXL-104 Ceftaroline fosamil Total Assay Assay impurities pH (%)* U3
(%) (%) t-zero 4.58 96.6 3.9 105.4 2.51 2 weeks 4.58 87.3 7.6 104.4
2.85 *Corrected value based on ceftaroline fosamil acetate potency
of 95.5%.
[0335] Formulation 8 was prepared with the following
composition:
[0336] Ceftaroline fosamil=450 mg
[0337] NXL-104 (free acid)=450 mg
[0338] L-Arginine=182.7 mg
[0339] Citric acid monohydrate=8.1 mg
[0340] Trisodium citrate dihydrate=209.3 mg
[0341] Table 32 shows the assay for lyophilized CXL Formulation 8
stored at 40.degree. C./75% RH for 0 and 2 weeks.
TABLE-US-00032 TABLE 32 NXL-104 and ceftaroline fosamil assay
NXL-104 Ceftaroline fosamil Total Assay Assay impurities pH (%)* U3
(%) (%) t-zero 5.40 94.7 3.2 106.1 2.29 2 weeks 5.38 87.7 5.0 105.0
2.34 *Corrected value based on ceftaroline fosamil acetate potency
of 95.5%.
[0342] Formulation 9 was prepared with the following
composition:
[0343] Ceftaroline fosamil acetate=668.4 mg
[0344] NXL-104=649.8 mg
[0345] Citric acid monohydrate=87.8 mg
[0346] Trisodium citrate dihydrate=171.3 mg
[0347] (Citrate concentration.times.0.2M corresponding to pH
4.8)
[0348] Tables 33-35 show the assay and degradation profile of
lyophilized CXL Formulation 9 stored at 40.degree. C./75% RH for 0
and 1 month.
TABLE-US-00033 TABLE 33 NXL-104 and ceftaroline fosamil assay
Ceftaroline fosamil Total NXL-104 impurities Total Assay (w/o U3)
Assay impurities pH (%)* U3 (%) (%) (%) t-zero 3.54 95.5 3.8 0.92
103.6 1.18 1 month 3.62 82.4 10.39 3.96 101.9 2.06 *Corrected value
based on ceftaroline fosamil acetate potency of 95.5%.
TABLE-US-00034 TABLE 34 Ceftaroline related substances (%) U1 U2 U4
U5 U6 U7 U8 U9 MPTT Adduct t-zero 0.37 0.09 <0.05 <0.05 0.12
ND ND 0.06 0.28 ND 1 month 1.20 1.42 0.05 0.10 0.25 ND ND 0.08 0.45
ND
TABLE-US-00035 TABLE 35 NXL-104 related substances (%) Decarbonyl
t-zero 0.94 1 month 1.77
[0349] Formulation 10 was prepared with the following
composition:
[0350] Ceftaroline fosamil acetate=668.4 mg
[0351] NXL-104=649.8 mg
[0352] Tartaric acid=150.0 mg (equivalent to 60 ml of 0.2M tartrate
solution)
[0353] Sodium hydroxide=16.0 mg
[0354] L-Arginine=171.7 mg
[0355] Tables 36-38 show the assay and degradation profile of
lyophilized Formulation 10 stored at 40.degree. C./75% RH for 0 and
1 month.
TABLE-US-00036 TABLE 36 NXL-104 and ceftaroline fosamil assay
Ceftaroline fosamil Total NXL-104 impurities Total Assay (w/o U3)
Assay impurities pH (%)* U3 (%) (%) (%) t-zero 3.42 94.9 3.7 1.10
104.2 1.05 1 month 3.49 85.2 8.80 3.67 102.6 2.28 *Corrected value
based on ceftaroline fosamil acetate potency of 95.5%.
TABLE-US-00037 TABLE 37 Ceftaroline related substances (%) U1 U2 U4
U5 U6 U7 U8 U9 MPTT Adduct t-zero 0.43 0.06 <0.05 <0.05 0.12
ND ND 0.06 0.30 0.13 1 month 1.38 0.89 <0.05 0.07 0.24 0.01 ND
0.07 0.46 0.19
TABLE-US-00038 TABLE 38 NXL-104 related substances (%) Decarbonyl
t-zero 0.81 1 month 1.54
Example 8
Stability of Amorphous NXL-104 and Crystalline Ceftaroline
Fosamil
[0356] A formulation containing amorphous NXL-104 and crystalline
ceftaroline fosamil was prepared with the following composition per
vial:
TABLE-US-00039 Ceftaroline fosamil (monohydrate, 668.4 mg acetic
acid solvate) (equivalent to 600 mg of ceftaroline fosamil)
L-Arginine 434.3 mg NXL-104 649.8 mg (equivalent to 600 mg of
NXL-104 free acid)
[0357] Amorphous NXL-104 was weighed into vials pre-filled with
ceftaroline fosamil-Arginine blend. The vials were flushed with
nitrogen, stoppered, sealed and stored at different conditions to
monitor stability. Packaging components used were 20 ml Type I
glass vial, Gray chlorobutyl-isoprene stopper and Blue Aluminum
tear-off seal.
[0358] Tables 39.41 show the stability data for the formulation at
t-zero.
TABLE-US-00040 TABLE 39 NXL-104 and ceftaroline fosamil assay
Ceftaroline fosamil Total NXL-104 impurities Total Assay (w/o U3)
Assay impurities pH (%) U3 (%) (%) (%) Initial 5.49 100.45 2.74
0.92 101.21 0.72 3 hours 5.44 99.93 2.97 0.10 101.35 0.74 6 hours
5.46 99.74 3.19 0.98 101.30 0.75
TABLE-US-00041 TABLE 40 Decarbonyl and unknown impurities
Decarbonyl UNK # 0.43 Initial 0.56 0.16 3 hours 0.58 0.16 6 hours
0.59 0.16
TABLE-US-00042 TABLE 41 Ceftaroline related impurities UNK U1 U2 U4
U5 U6 U7 U8 U9 MPTT Adduct # 1.55 Initial 0.47 0.04 ND ND 0.10 0.06
ND 0.08 0.04 0.13 0.00 3 hours 0.53 0.05 ND ND 0.09 0.05 ND 0.08
0.04 0.12 0.04 6 hours 0.51 0.05 ND ND 0.09 0.05 ND 0.07 0.04 0.12
0.05
[0359] Tables 42-44 show the stability data for the formulation
stored for 3 months at 40.degree. C./75% RH.
TABLE-US-00043 TABLE 42 NXL-104 and ceftaroline fosamil assay
Ceftaroline fosamil Total NXL-104 impurities Total Assay (w/o U3)
Assay impurities pH (%) U3 (%) (%) (%) Initial 5.71 96.13 3.66 1.58
93.30 1.04 3 hours 5.62 95.38 3.87 1.55 92.98 1.16 6 hours 5.67
95.03 4.11 1.75 93.12 1.09
TABLE-US-00044 TABLE 43 Decarbonyl and unknown impurities UNK # UNK
# Decarbonyl UNK # 0.35 0.38 UNK # 0.39 0.53 Initial 0.73 0.03 0.05
0.03 0.21 3 hours 0.76 0.02 0.19 0.03 0.18 6 hours 0.77 0.03 0.19
0.03 0.15
TABLE-US-00045 TABLE 44 Ceftaroline related impurities UNK U1 U2 U4
U5 U6 U7 U8 U9 MPTT Adduct # 1.56 Initial 0.50 0.13 ND ND 0.30 ND
ND 0.08 0.22 0.27 0.08 3 hours 0.56 0.14 ND ND 0.27 ND ND 0.08 0.23
0.27 ND 6 hours 0.62 0.14 ND ND 0.24 0.05 ND 0.08 0.24 0.26
0.12
[0360] Tables 45-48 show the stability data for the formulation
stored for 6 months at 40.degree. C./75% RH.
TABLE-US-00046 TABLE 45 NXL-104 and ceftaroline fosamil assay
Ceftaroline fosamil Total NXL-104 impurities Total Assay (w/o U3)
Assay impurities pH (%) U3 (%) (%) (%) Initial 5.69 96.80 3.83 1.77
90.34 1.49 3 hours 5.85 97.20 4.05 1.77 90.53 1.45 6 hours 5.77
95.80 4.31 1.74 90.40 1.43
TABLE-US-00047 TABLE 46 NXL-104 related impurities Decarbonyl UNK #
0.38 UNK # 0.55 Initial 0.99 0.24 0.26 3 hours 0.98 0.24 0.23 6
hours 0.98 0.25 0.20
TABLE-US-00048 TABLE 47 Ceftaroline related impurities U1 U2 U4 U5
U6 U7 U8 U9 MPTT Adduct Initial 0.38 0.10 <0.05 <0.05 0.34
0.06 ND 0.10 0.30 0.38 3 hours 0.39 0.11 <0.05 <0.05 0.31
0.05 ND 0.09 0.30 0.37 6 hours 0.42 0.11 <0.05 <0.05 0.29
0.05 ND 0.09 0.31 0.36
TABLE-US-00049 TABLE 48 Unknown impurities UNK UNK UNK UNK UNK UNK
UNK # 0.18 # 0.24 # 0.42 # 0.48 # 1.55 # 1.72 # 1.82 Initial
<0.05 <0.05 <0.05 0.05 0.06 <0.05 <0.05 3 hours 0.05
<0.05 <0.05 0.05 0.05 <0.05 <0.05 6 hours 0.05 <0.05
<0.05 0.06 <0.05 <0.05 <0.05
[0361] Table 49-52 show the stability data for the formulation
containing amorphous NXL-104 and crystalline ceftaroline fosamil
stored for 9 months at 40.degree. C./75% RH.
TABLE-US-00050 TABLE 49 NXL-104 and ceftaroline fosamil assay
Ceftaroline fosamil Total NXL-104 impurities Total Assay (w/o U3)
Assay impurities pH (%) U3 (%) (%) (%) Initial 5.59 96.4 4.22 1.49
90.3 1.68 3 hours 5.61 97.0 4.28 1.47 90.0 1.66 6 hours 5.66 94.9
4.56 1.45 89.1 1.61
TABLE-US-00051 TABLE 50 Decarbonyl and unknown impurities
Decarbonyl UNK # 0.38 UNK # 0.40 UNK # 0.60 Initial 1.09 0.11 0.27
0.21 3 hours 1.08 0.11 0.27 0.20 6 hours 1.07 0.11 0.27 0.16
TABLE-US-00052 TABLE 51 Ceftaroline related impurities U1 U2 U4 U5
U6 U7 U8 U9 MPTT Adduct Initial 0.33 0.11 <0.05 <0.05 0.22
0.04 ND 0.11 0.35 0.09 3 hours 0.32 0.11 ND ND 0.21 0.04 ND 0.11
0.35 0.09 6 hours 0.33 0.11 <0.05 <0.05 0.18 0.04 ND 0.10
0.36 0.09
TABLE-US-00053 TABLE 52 Unknown impurities UNK # UNK # UNK # UNK #
0.12 0.19 0.47 1.52 Initial 0.12 ND 0.06 0.06 3 hours 0.12 ND 0.06
0.06 6 hours 0.13 0.05 0.06 <0.05
[0362] Table 53-56 show the stability data for the formulation
containing amorphous NXL-104 and crystalline ceftaroline fosamil
stored for 9 months at 25.degree. C./60% RH
TABLE-US-00054 TABLE 53 NXL-104 and ceftaroline fosamil assay
Ceftaroline fosamil Total NXL-104 impurities Total Assay (w/o U3)
Assay impurities pH (%) U3 (%) (%) (%) Initial 5.65 97.9 3.40 1.19
93.1 1.44 3 hours 5.57 97.1 3.47 1.11 92.5 1.40 6 hours 5.64 96.4
3.74 1.09 92.7 1.39
TABLE-US-00055 TABLE 54 Decarbonyl and unknown impurities
Decarbonyl UNK # 0.38 UNK # 0.40 UNK # 0.60 Initial 1.08 <0.05
0.25 0.11 3 hours 1.05 <0.05 0.25 0.10 6 hours 1.05 <0.05
0.25 0.09
TABLE-US-00056 TABLE 55 Ceftaroline related impurities U1 U2 U4 U5
U6 U7 U8 U9 MPTT Adduct Initial 0.50 0.13 <0.05 <0.05 0.17
0.05 ND 0.14 0.11 0.09 3 hours 0.43 0.13 <0.05 <0.05 0.16
0.04 ND 0.14 0.12 0.09 6 hours 0.44 0.14 <0.05 <0.05 0.14
0.04 ND 0.13 0.12 0.08
TABLE-US-00057 TABLE 56 Unknown impurities UNK # UNK # UNK # UNK #
0.12 0.19 0.47 1.52 Initial <0.05 <0.05 <0.05 <0.05 3
hours <0.05 <0.05 <0.05 <0.05 6 hours <0.05 <0.05
<0.05 <0.05
[0363] Table 57-60 show the stability data for the formulation
containing amorphous NXL-104 and crystalline ceftaroline fosamil
stored for 9 months at 2-8.degree. C.
TABLE-US-00058 TABLE 57 NXL-104 and ceftaroline fosamil assay
Ceftaroline fosamil Total NXL-104 impurities Total Assay (w/o U3)
Assay impurities pH (%) U3 (%) (%) (%) Initial 5.43 100.5 3.02 0.89
96.8 1.11 3 hours 5.50 100.6 3.07 0.87 97.0 1.11 6 hours 5.65 100.1
3.35 0.91 96.9 1.08
TABLE-US-00059 TABLE 58 Decarbonyl and unknown impurities
Decarbonyl UNK # 0.38 UNK # 0.40 UNK # 0.60 Initial 0.87 <0.05
0.24 ND 3 hours 0.84 <0.05 0.27 ND 6 hours 0.84 <0.05 0.24
ND
TABLE-US-00060 TABLE 59 Ceftaroline related impurities U1 U2 U4 U5
U6 U7 U8 U9 MPTT Adduct Initial 0.45 0.11 <0.05 <0.05 0.09
0.05 ND 0.11 <0.05 0.08 3 hours 0.43 0.11 <0.05 <0.05 0.09
0.05 ND 0.11 <0.05 0.08 6 hours 0.42 0.12 <0.05 <0.05 0.08
0.05 ND 0.11 0.05 0.08
TABLE-US-00061 TABLE 60 Unknown impurities UNK # UNK # UNK # UNK #
0.12 0.19 0.47 1.52 Initial <0.05 <0.05 <0.05 <0.05 3
hours <0.05 ND ND ND 6 hours <0.05 <0.05 <0.05 ND
Example 9
Stability of Crystalline Form I of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
Sodium Salt and Crystalline Ceftaroline Fosamil
[0364] A formulation containing Form I NXL-104 and crystalline
ceftaroline fosamil was prepared with the following composition per
vial:
TABLE-US-00062 Ceftaroline fosamil (monohydrate, 668.4 mg acetic
acid solvate) (equivalent to 600 mg of ceftaroline fosamil)
L-Arginine 434.3 mg NXL-104 649.8 mg (equivalent to 600 mg of
NXL-104 free acid)
[0365] Ceftaroline fosamil,
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (Form I) and L-Arginine were blended in a twin shell
blender (Patterson-Kelly) for times ranging from 15 to 60 minutes.
The blend was subsequently weighed into vials and the vials were
stoppered (with or without nitrogen), sealed and stored at
different conditions to monitor stability. Packaging components
used were 20 ml Type I glass vial, Gray chlorobutyl-isoprene
stopper and Blue Aluminum tear-off seal. [0366] Ceftaroline fosamil
median particle diameter=10 .mu.m [0367]
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt (Form I) median particle diameter=145 .mu.m [0368]
L-Arginine median particle diameter=Variable
[0369] Surprisingly and unexpectedly, the formulation comprising
crystalline NXL-104 and ceftaroline fosamil was found to be more
stable than formulations comprising amorphous NXL-104 and
ceftaroline fosamil.
[0370] Table 61-62 provide the stability data for the formulation
comprising Form I containing nitrogen in vial headspace. The median
diameter of L-Arginine was 290 .mu.m.
TABLE-US-00063 TABLE 61 NXL-104 and ceftaroline fosamil assay
Ceftaroline NXL-104 Total NXL-104 Total Ceftaroline Impurities
Water Assay Decarbonyl Impurities Assay U3 (w/o U3) Content pH (%)
(%) (%) (%)* (%) (%) (%) t-zero 5.72 104.8 0.21 0.45 97.4 2.5 0.74
-- 2 weeks 5.67 108.4 ND 0.33 100.7 2.6 0.70 -- 2-8.degree. C. 2
weeks 5.56 108.5 ND 0.38 99.9 2.8 0.90 -- 25.degree. C./60% RH 2
weeks 5.59 108.7 ND 0.45 97.5 3.4 1.01 -- 40.degree. C./75% RH 1
month 5.79 106.4 <0.05 <0.05 97.4 2.6 0.64 -- 2-8.degree. C.
1 month 5.63 104.3 <0.05 0.21 94.7 3.1 0.74 -- 25.degree. C./60%
RH 1 month 5.71 104.6 <0.05 0.22 93.2 3.7 1.10 -- 40.degree.
C./75% RH 3 months 5.76 104.7 0.02 0.02 95.9 3.31 1.14 1.11
25.degree. C./60% RH 3 months 5.87 104.6 0.02 0.02 94.6 3.97 1.52
1.10 40.degree. C./75% RH
TABLE-US-00064 TABLE 62 Ceftaroline related substances (%) U1 U2 U6
U7 U9 MPTT Adduct t-zero 0.32 ND 0.04 ND 0.10 0.23 ND 2 weeks 0.32
ND 0.06 0.01 0.05 0.19 0.07 2-8.degree. C. 2 weeks 0.41 0.05 0.10
0.01 0.05 0.21 0.08 25.degree. C./60% RH 2 weeks 0.31 0.06 0.13
0.01 0.05 0.32 0.13 40.degree. C./75% RH 1 month 0.24 <0.05 0.09
0.01 0.05 0.20 0.05 2-8.degree. C. 1 month 0.30 <0.05 0.17 ND
<0.05 0.27 <0.05 25.degree. C./60% RH 1 month 0.22 <0.05
0.20 ND 0.05 0.53 <0.05 40.degree. C./75% RH 3 months 0.52
<0.05 0.19 <0.05 <0.05 0.37 0.06 25.degree. C./60% RH 3
months 0.38 <0.05 0.18 <0.05 <0.05 0.70 0.05 40.degree.
C./75% RH
[0371] Table 63-64 provide the stability data for the formulation
comprising Form I without nitrogen in vial headspace. The median
diameter of L-Arginine was 290 .mu.m.
TABLE-US-00065 TABLE 63 NXL-104 and ceftaroline fosamil assay
NXL-104 Ceftaroline Ceftaroline NXL-104 Total fosamil Total Water
Assay Decarbonyl Impurities Assay U3 Impurities Content pH (%) (%)
(%) (%)* (%) (w/o U3) (%) (%) t-zero 5.76 104.8 0.21 0.45 98.0 2.50
0.71 -- 3 months 5.81 104.7 0.03 0.03 94.4 4.04 1.67 0.98
40.degree. C./75% RH 3 months 5.72 105.2 0.02 0.02 97.6 3.36 1.18
1.37 25.degree. C./60% RH
TABLE-US-00066 TABLE 64 Ceftaroline related substances (%) U1 U2 U6
U7 U9 MPTT Adduct t-zero 0.29 ND 0.04 ND 0.01 0.23 ND 3 months 0.41
<0.05 0.18 <0.05 <0.05 0.71 0.10 40.degree. C./75% RH 3
months 0.53 <0.05 0.19 <0.05 0.05 0.36 0.10 25.degree. C./60%
RH
[0372] Table 65-66 provide the stability data for the formulation
comprising Form I containing nitrogen in vial headspace. The median
diameter of L-Arginine was 20 .mu.m,
TABLE-US-00067 TABLE 65 NXL-104 and ceftaroline fosamil assay
NXL-104 Ceftaroline NXL-104 Total Ceftaroline Total Water Assay
Decarbonyl Impurities Assay U3 Impurities Content pH (%) (%) (%)
(%)* (%) (w/o U3) (%) (%) t-zero 5.76 104.9 0.22 0.41 97.0 2.7 0.78
-- 1 month 5.72 102.8 <0.05 0.26 97.3 3.0 0.43 -- 2-8.degree. C.
1 month 6.53 101.1 <0.05 0.25 93.0 3.3 0.43 -- 25.degree. C./60%
RH 1 month 5.56 105.1 <0.05 1.19 94.5 4.1 0.82 -- 40.degree.
C./75% RH 3 months 5.81 107.3 ND ND 94.5 3.55 1.39 1.54 25.degree.
C./60% RH 3 months 6.79 109.3 0.06 0.06 84.5 4.15 2.48 1.41
40.degree. C./75% RH
TABLE-US-00068 TABLE 66 Ceftaroline related substances (%) U1 U2 U6
U7 U9 MPTT Adduct t-zero 0.27 <0.05 0.10 ND 0.10 0.15 0.10 1
month 0.05 0.05 0.04 0.03 0.09 <0.05 0.10 2-8.degree. C. 1 month
0.08 0.06 0.10 0.02 0.07 <0.05 0.05 25.degree. C./60% RH 1 month
0.07 0.07 0.25 0.01 0.07 <0.05 0.05 40.degree. C./75% RH 3
months 0.64 <0.05 0.24 <0.05 <0.05 0.28 0.15 25.degree.
C./60% RH 3 months 0.51 <0.05 0.39 0.05 <0.05 0.85 0.23
40.degree. C./75% RH
[0373] Table 67-68 provide the stability data for the formulation
comprising Form I containing nitrogen in vial headspace. The median
diameter of L-Arginine was 290 .mu.m.
TABLE-US-00069 TABLE 67 NXL-104 and ceftaroline fosamil assay
NXL-104 Ceftaroline NXL-104 Total Ceftaroline Total Water Assay
Decarbonyl Impurities Assay U3 Impurities Content pH (%) (%) (%)
(%)* (%) (w/o U3) (%) (%) t-zero 6.33 102.9 <0.05 <0.05 97.0
2.50 0.85 -- 3 months 6.46 96.3 <0.05 <0.05 95.9 3.24 0.97
1.45 25.degree. C./60% RH 3 months 5.40 105.1 <0.05 <0.05
93.8 4.02 1.53 1.38 40.degree. C./75% RH
TABLE-US-00070 TABLE 68 Ceftaroline related substances (%) U1 U2 U6
U7 U9 MPTT Adduct t-zero 0.28 <0.05 0.08 0.03 0.05 0.24 0.17 3
months 0.29 <0.05 0.17 ND 0.05 0.35 0.06 25.degree. C./60% RH 3
months 0.20 <0.05 0.23 ND <0.05 0.84 0.07 40.degree. C./75%
RH
[0374] Table 69-70 provide the stability data for the formulation
comprising Form I containing nitrogen in vial headspace. The median
diameter of L-Arginine was 181 .mu.m.
TABLE-US-00071 TABLE 69 NXL-104 and ceftaroline fosamil assay
Ceftaroline NXL- NXL-104 Total 104 Total Impurities Water Assay
Decarbonyl Impurities Ceftaroline U3 (w/o U3) Content pH (%) (%)
(%) Assay (%)* (%) (%) (%) t-zero 5.65 105.4 <0.05 0.25 98.8
2.44 0.71 1.62 1 month 5.85 105.7 <0.05 <0.05 93.8 3.56 1.47
-- 25.degree. C./60% RH 1 month 5.65 107.9 <0.05 <0.05 97.0
3.02 1.18 -- 40.degree. C./75% RH
TABLE-US-00072 TABLE 70 Ceftaroline related substances (%) U1 U2 U6
U7 U9 MPTT Adduct t-zero 0.27 <0.05 0.09 ND 0.06 0.29 <0.05 1
month 0.42 <0.05 0.18 0.02 0.05 0.64 0.10 25.degree. C./60% RH 1
month 0.47 <0.05 0.13 0.02 0.05 0.42 0.08 40.degree. C./75%
RH
[0375] Thus, the present example demonstrates that surprisingly and
unexpectedly, formulations comprising Form I and ceftaroline
fosamil are more stable than formulations comprising amorphous
NXL-104 and ceftaroline fosamil.
[0376] Tables 71-72 provide the stability data for formulation
comprising Form I that was irradiated by .gamma.-radiation (45 KGy)
containing nitrogen in vial.
TABLE-US-00073 TABLE 71 NXL-104 and ceftaroline fosamil assay NXL-
NXL-104 Ceftaroline 104 Total Ceftaroline Total Assay Decarbonyl
Impurities Assay U3 Impurities (%) pH (%) (%) (%) (%)* (%) w/o U3
t-zero 5.88 108.2 <0.05 <0.05 99.3 2.44 0.84 After 5.55 101.1
<0.05 0.35 95.6 2.61 1.17 irradiation *Adjusted by ceftaroline
fosamil acetate potency
TABLE-US-00074 TABLE 72 Ceftaroline related substances (%) U1 U2 U4
U6 U7 U9 MPTT Adduct t-zero 0.26 ND <0.05 0.08 ND 0.05 0.33 0.12
After 0.28 0.05 <0.05 0.20 0.05 0.06 0.37 0.14 irradiation
[0377] Tables 73-74 provide the stability data for formulation
comprising Form I that was irradiated by .gamma.-radiation (45 KGy)
without nitrogen in vial.
TABLE-US-00075 TABLE 73 NXL-104 and ceftaroline fosamil assay NXL-
NXL-104 Ceftaroline 104 Total Total Assay Decarbonyl Impurities
Ceftaroline U3 Impurities pH (%) (%) (%) Assay (%)* (%) (%) w/o U3
t-zero 5.97 106.5 <0.05 <0.05 97.6 2.41 0.77 After 5.47 100.6
<0.05 0.35 94.8 2.60 1.35 irradiation *Adjusted by ceftaroline
fosamil acetate potency
TABLE-US-00076 TABLE 74 Ceftaroline related substances (%) U1 U2 U4
U6 U7 U9 MPTT Adduct t-zero 0.25 ND <0.05 0.08 ND 0.05 0.33 0.06
After 0.24 0.05 <0.05 0.19 0.05 0.06 0.50 0.12 irradiation
[0378] Tables 75-76 provide the stability data for formulation
comprising Form I that was irradiated by e-beam (45 KGy) containing
nitrogen in vial.
TABLE-US-00077 TABLE 75 NXL-104 and ceftaroline fosamil assay NXL-
NXL-104 Ceftaroline 104 Total Total Assay Decarbonyl Impurities
Ceftaroline U3 Impurities pH (%) (%) (%) Assay (%)* (%) (%) w/o U3
t-zero 5.88 108.2 <0.05 <0.05 99.3 2.44 0.84 After 6.40 96.6
<0.05 0.32 94.3 2.45 1.12 irradiation *Adjusted by ceftaroline
fosamil acetate potency
TABLE-US-00078 TABLE 76 Ceftaroline related substances (%) U1 U2 U4
U6 U7 U9 MPTT Adduct t-zero 0.26 ND <0.05 0.08 ND 0.05 0.33 0.12
After 0.23 <0.05 <0.05 0.20 0.06 0.06 0.42 0.13
irradiation
[0379] Tables 77-78 provide the stability data for formulation
comprising Form I that was irradiated by e-beam (45 KGy) without
nitrogen in vial.
TABLE-US-00079 TABLE 77 NXL-104 and ceftaroline fosamil assay
NXL-104 Ceftaroline Total Total NXL-104 Decarbonyl Impurities
Ceftaroline U3 Impurities pH Assay (%) (%) (%) Assay (%)* (%) (%)
w/o U3 t-zero 5.97 106.5 <0.05 <0.05 97.6 2.41 0.77 After
5.80 97.9 <0.05 0.31 94.9 2.50 1.17 irradiation *Adjusted by
ceftaroline fosamil acetate potency
TABLE-US-00080 TABLE 78 Ceftaroline related substances (%) U1 U2 U4
U6 U7 U9 MPTT Adduct t-zero 0.25 ND <0.05 0.08 ND 0.05 0.33 0.06
After 0.22 <0.05 <0.05 0.19 0.06 0.06 0.39 0.23
irradiation
Example 10
Stability of Form II of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
Sodium Salt and Crystalline Ceftaroline Fosamil
[0380] Formulation comprising Form II of NXL-104 and ceftaroline
fosamil was prepared with the following composition per vial:
TABLE-US-00081 Ceftaroline fosamil (monohydrate, 668.4 mg
(equivalent to acetic acid solvate) 600 mg of ceftaroline fosamil)
L-Arginine 434.3 mg NXL-104 690.4 mg (equivalent to 600 mg of
NXL-104 free acid)
[0381] Ceftaroline fosamil monohydrate, acetic acid solvate,
NXL-104 (Form II) and L-Arginine were blended in a twin shell
blender (Patterson-Kelly) for times ranging from 15 to 60 minutes.
The blend was subsequently weighed into vials and the vials were
stoppered (with or without nitrogen), sealed and stored at
different conditions to monitor stability. Packaging components
used were 20 ml Type I glass vial, Gray bromobutyl Omni stopper and
Blue Aluminum tear-offseal.
[0382] Tables 79-80 show the stability data for the formulation in
a vial without nitrogen. The median diameter of L-Arginine was 20
.mu.m.
TABLE-US-00082 TABLE 79 NXL-404 and ceftaroline fosamil assay
Ceftaroline NXL- NXL-104 Total 104 Total Ceftaroline Impurities
Assay Decarbonyl Impurities fosamil Assay U3 (%) pH (%) (%) (%)
(%)* (%) w/o U3 t-zero 4.80 113.8 0.10 0.10 102.2 2.89 1.15 3
months 5.90 99.9 0.17 0.33 91.2 4.32 1.97 40.degree. C./75% RH
*Corrected by ceftaroline fosamil acetate potency
TABLE-US-00083 TABLE 80 Ceftaroline related substances (%) U1 U2 U6
U7 U9 MPTT Adduct Total unknown t-zero 0.39 <0.05 0.08 <0.05
0.06 0.41 0.17 <0.05 3 months <0.05 <0.05 0.17 0.05
<0.05 1.14 0.05 0.30 40.degree. C./75% RH
[0383] Tables 81-82 show the stability data for the formulation
comprising Form II and ceftaroline fosamil in a vial containing
nitrogen. The median diameter of L-Arginine was 20 .mu.m.
TABLE-US-00084 TABLE 81 NXL-104 and ceftaroline fosamil assay NXL-
NXL-104 Ceftaroline 104 Total Ceftaroline Total Assay Decarbonyl
Impurities fosamil U3 Impurities pH (%) (%) (%) Assay (%)* (%) (%)
w/o U3 t-zero 6.77 102.3 0.08 0.08 92.3 2.30 1.49 3 months 5.80
98.3 0.25 0.49 87.2 4.17 2.11 40.degree. C./75% RH *Corrected by
ceftaroline fosamil acetate potency
TABLE-US-00085 TABLE 82 Ceftaroline related substances (%) U1 U2 U6
U7 U9 MPTT Adduct Total unknown t-zero 0.50 <0.05 0.08 0.11 0.05
0.47 0.24 <0.05 3 months 0.09 <0.05 0.17 0.06 <0.05 1.25
<0.05 0.33 40.degree. C./75% RH
Example 11
Pharmacokinetic Data
[0384] A single center, two-part randomized Phase I Study was
conducted to evaluate the safety, tolerability, and
pharmacokinetics of single and multiple intravenous doses of
ceftaroline fosamil and NXL-104 in healthy male and female
subjects, aged 18 through 45 years.
[0385] Study Drugs
[0386] Ceftaroline fosamil for injection was supplied as a sterile
powder containing a dry mixture of ceftaroline fosamil and
L-arginine in single-dose, clear vials containing 600 mg of
ceftaroline fosamil (on a corrected basis, anhydrous acetate
free).
[0387] NXL-104 for Injection
(trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide
sodium salt) was supplied as a sterile powder in single-dose, clear
vials containing 600 mg of NXL-104 (on a free-acid basis).
[0388] Inclusion Criteria
[0389] To be eligible to participate in the study, subjects were
required to meet the following criteria: [0390] 1. Sign a written
informed consent before any study procedures were performed [0391]
2. Be healthy males or females, 18 through 45 years of age,
inclusive [0392] 3. If female, have a negative serum pregnancy test
(.beta.-human chorionic gonadotropin [HCG]) at screening and a
negative serum or urine pregnancy test on Day -1 [0393] 4. If
female of child-bearing potential or female <2 years
postmenopausal, agree to and comply with using highly effective
double-barrier methods of birth control (eg, condom plus diaphragm)
while participating in this study [0394] 5. Have normal, or
abnormal but not clinically significant, results on the hematology
evaluation, serum chemistry evaluation, UA, vital sign evaluation,
ECG, or physical examination [0395] 6. Have negative test results
for hepatitis B surface antigen, anti-hepatitis B core antibody
immunoglobulin M, anti-hepatitis C virus antibody, rapid plasma
reagin/VDRL values, and anti-human immunodeficiency virus types 1
[0396] 7. Be a nonsmoker (never smoked or have not smoked within
the previous 2 years) [0397] 8. Have a body mass index (BMI)
.gtoreq.18 kg/m.sup.2 and .ltoreq.30 kg/m.sup.2 [0398] 9. Have a
supine pulse rate of not more than 100 bpm and not less than 50 bpm
during the vital sign assessment at screening
[0399] Exclusion Criteria
[0400] Subjects who met any of the following criteria were not
eligible to participate in the study: [0401] 1. Any
hypersensitivity or allergic reaction to any .beta.-lactam
antibiotic or .beta.-lactamase inhibitor [0402] 2. Clinically
significant disease state in any body system that, in the opinion
of the examining physician, would place the subject at risk or
compromise the quality of the data [0403] 3. CrCl levels less than
80 mL/min (Cockcroft-Gault formula estimate) [0404] 4. Supine
systolic blood pressure (BP) .gtoreq.140 mm Hg or .ltoreq.90 mm Hg
at screening [0405] 5. Supine diastolic BP .gtoreq.90 mm Hg or
.ltoreq.50 mm Hg at screening [0406] 6. Clinically significant ECG
abnormalities based on PI interpretation, such as a PR interval
.gtoreq.220 msec or .ltoreq.100 msec; QTc interval .gtoreq.450 msec
for male and female subjects; sinus bradycardia (.ltoreq.50 bpm);
sick sinus syndrome; first-, second-, or third-degree
atrioventricular block; any type of tachycardia; more than 1 PVC on
a 12-lead ECG; incomplete or complete left bundle-branch block;
nonsinus rhythm; or evidence of myocardial ischemia/infarction
(either changes suggesting acute ischemia/infarction or changes
from previous tracings compatible with the infarction during the
preceding 6 months) [0407] 7. History of alcohol or substance abuse
within the previous 5 years [0408] 8. Positive urine test results
for any drug of abuse, including cotinine or alcohol [0409] 9.
Participation in any other clinical investigation using an
experimental drug requiring repeated blood draws within 30 days of
Day 1 of this study or participation in a blood donation program
within the preceding 60 days [0410] 10. Consumption of caffeine,
cruciferous vegetables, or orange or grapefruit-containing products
within 48 hours before Day 1 or consumption of alcohol within 72
hours before Day 1 [0411] 11. Any clinical condition that might
affect the absorption, distribution, biotransformation, or
excretion of ceftaroline or NXL-104 [0412] 12. Employee or family
member of an employee of the clinical research organization at
which the study was conducted [0413] 13. Any concomitant
medications, including over-the-counter medications and vitamin or
herbal supplements (eg, St. Johns wort), taken within 14 days or 5
half-lives (whichever is longer) before Day 1 of study drug
administration. (Hormonal drug products are prohibited from 30 days
before Day 1, including oral contraceptives) [0414] 14. Previous
use of ceftaroline or NXL-104 or previous participation in an
investigational study of ceftaroline or NXL-104 [0415] 15. Female
subjects who were pregnant and/or breast-feeding [0416] 16.
Inability or unwillingness to adhere to the study-specific
procedures and restrictions [0417] 17. Any hypersensitivity or
allergic reaction to heparin [0418] 18. History of recent
vaccination within 14 days of first dose of study medication [0419]
19. History of a recent viral illness within 14 days of first dose
of study medication
[0420] Part A
[0421] Part A was an open-label, 3-way crossover, single-dose study
to evaluate the safety, tolerability, and pharmacokinetics of
ceftaroline and NXL-104 following co-administration of a single
intravenous (IV) dose of ceftaroline fosamil and NXL-104 in 12
healthy subjects.
[0422] The subjects were randomized (1:1:1) to receive three
treatment sequences A, B and C as shown in Table 83.
[0423] Treatment A: single dose of 600 mg ceftaroline fosamil via
IV infusion over one hour.
[0424] Treatment B: single dose of 600 mg NXL-104 via IV infusion
over one hour.
[0425] Treatment C: single dose of 600 mg ceftaroline fosamil and
600 mg NXL-104 via concomitant IV infusion over one hour.
TABLE-US-00086 TABLE 83 Part A - Treatment Sequence Treatment
Sequence Period I Period II Period III (No. of Subjects) Treatment
Treatment Treatment I A B C (4 subjects) II C A B (4 subjects) III
B C A (4 subjects)
There was a 5-day washout period after the study drug
administration.
[0426] Selection and Timing of Dose for Each Subject
[0427] Subjects in part A were randomized to receive study drug
between 0800 and 1000 hours following a standard breakfast given at
0700 hours on Days 1, 6, and 11. Following each dose
administration, were to remain semirecumbent (excluding time when
study procedures require otherwise) and awake for 1 hours.
[0428] No concomitant medications were permitted during the study
unless needed to treat an AE. Subjects were instructed not to take
any drugs for at least 14 days or 5 half-lives (whichever was
longer) before the first day of dosing and during the course of the
study. Subjects were to be specifically reminded that this includes
over-the-counter medications such as aspirin, acetaminophen,
ibuprofen, vitamin preparations, herbal and dietary supplements,
and cough syrup, as well as medicines requiring a prescription. No
hormonal drug products (including oral contraceptives) were to be
allowed 30 days before Day 1 and throughout the study.
Screening
[0429] Part A (Day -21 to Day -2)
[0430] Screening was to be performed within 21 days before the
first dose. At screening, a review of inclusion and exclusion
criteria was conducted to determine the subject's eligibility for
enrollment. Study procedures were reviewed with the subject, and
documentation of informed consent was obtained before any study
procedures are performed.
[0431] The following procedures were performed and recorded at
screening: [0432] Collect blood samples for serology testing,
hematology evaluation (including CBC, prothrombin time and
international normalized ratio [PT/INR], partial thromboplastin
time [PTT], free hemoglobin, haptoglobin, and reticulocyte count),
and comprehensive metabolic panel [0433] Collect urine for UA
(including urine microscopy) and for drugs-of-abuse screen [0434]
Perform .beta.-HCG serum pregnancy test (female subjects only)
[0435] Calculate CrCl and BMI [0436] Assess vital signs [0437]
Perform 12-lead ECG [0438] Perform complete physical examination
[0439] Assess prior medications [0440] Record medical and surgical
history [0441] Record any spontaneously reported AE or SAE between
signing of informed consent and Day -1 for subjects who comply with
all screening processes
[0442] Study Days
[0443] Subjects were admitted into a nonsmoking environment on Day
-1 and were to remain in the clinic until 48 hours following Day 11
dose administration (Day 13), for a total of 13 overnight stays per
subject (overnight stays Days -1 to 12).
[0444] The following protocol was used during the study days:
[0445] Day -1 (Period I) [0446] Admit subjects to a nonsmoking
environment [0447] Collect any updated medical and surgical history
not reported at screening [0448] Collect urine for UA (including
urine microscopy) [0449] Collect urine for drugs-of-abuse screen
[0450] Conduct serum or urine pregnancy test (female subjects only)
[0451] Perform a complete physical examination [0452] Record weight
[0453] Calculate CrCl [0454] Collect blood sample for Coombs test
(direct and indirect antiglobulin) [0455] Collect blood samples for
hematology evaluation (including CBC, PT/INR, PTT, free hemoglobin,
haptoglobin, and reticulocyte count) and comprehensive metabolic
panel [0456] Assess AEs, SAEs, and prior medications [0457] Provide
dinner and snack at approximately 1800 and 2100 hours,
respectively
[0458] Day 1 (Period I) [0459] Randomize each subject before the
start of infusion [0460] Administer study drug at 0800 hour via 1V
infusion over 1 hour (.+-.5 minutes) according to the treatment
sequence assigned (per Table 9.4.1-1) [0461] Assess vital signs at
0.0 hour (within 4 hours before the start of infusion) and 0.5, 1,
2, 4, and 8 hours (.+-.15 minutes) after the start of dose infusion
[0462] Collect PK blood samples at 0.0 hour (within 15 minutes
before the start of infusion) predose and after the start of
infusion at 20, 40, 60 (immediately before the end of study-drug
infusion), 65, and 75 minutes and 1.5, 2, 3, 4, 6, 8, 12, and 18
hours [0463] Collect PK urine samples from -2 to 0 hours predose
and over the following continuous time intervals: 0 to 2, 2 to 4, 4
to 8, 8 to 12, and 12 to 24 hours after the start of infusion
[0464] Perform ECGs at 0.0 hour (within 20 minutes before the start
of infusion) predose and at 1, 2, and 4 hours (.+-.20 minutes)
after the start of infusion [0465] Assess AEs, SAEs, and
concomitant medication use [0466] Provide breakfast, lunch, dinner,
and snack at approximately 0700, 1200, 1800, and 2100 hours,
respectively
[0467] Day 2 (Period I), Day 7 (Period II), and Day 12 (Period III)
[0468] Assess vital signs at 24 hours (.+-.15 minutes) after the
start of infusion in each period [0469] Perform a 12-lead ECG 24
hours (.+-.20 minutes) after the start of study drug infusion in
each period [0470] Collect PK blood samples from 24 through 36
hours after the start of study drug infusion in each period [0471]
Collect PK urine sample for 24-48 hours after the start of infusion
in each period [0472] Assess AEs, SAEs, and concomitant medication
use [0473] Begin the washout period (applicable to period I and II
only) [0474] Provide breakfast, lunch, dinner, and snack at
approximately 0700, 1200, 1800, and 2100 hours, respectively
[0475] Day 3 (Period I) and Day 8 (Period II) [0476] Continue the
washout period [0477] Assess AEs, SAEs, and concomitant medication
use [0478] Complete the collection of PK urine sample from 24 to 48
hours after the start of infusion in each period [0479] Collect PK
blood sample at 48 hours after the start of infusion in each period
[0480] Provide breakfast, lunch, dinner, and snack at approximately
0700, 1200, 1800, and 2100 hours, respectively
[0481] Day 4 (Period I) and Day 9 (Period II) [0482] Continue the
washout period [0483] Assess AEs, SAEs, and concomitant medication
use [0484] Provide breakfast, lunch, dinner, and snack at
approximately 0700, 1200, 1800, and 2100 hours, respectively
[0485] Day 5 (Period II) and Day 10 (Period III) [0486] Continue
the washout period [0487] Collect blood samples for hematology
evaluation (including CBC, PT/INR, PTT, free hemoglobin,
haptoglobin, and reticulocyte count) and comprehensive metabolic
panel [0488] Collect urine for UA (including urine microscopy)
[0489] Assess AEs, SAEs, and concomitant medication use [0490]
Provide breakfast, lunch, dinner, and snack at approximately 0700,
1200, 1800, and 2100 hours, respectively
[0491] Day 6 (Period II) and Day 11 (Period III) [0492] Administer
study drug at 0800 hour via IV infusion over 1 hour (5 minutes)
according to the treatment sequence assigned (per Table 9.4.1-1)
[0493] Assess vital signs at 0.0 hour (within 4 hours before the
start of infusion) and 0.5, 1, 2, 4, and 8 hours (.+-.15 minutes)
after the start of dose infusion [0494] Collect PK blood samples at
0.0 hour (within 15 minutes before the start of infusion) predose
and after the start of infusion at 20, 40, 60 (immediately before
the end of study-drug infusion), 65, and 75 minutes and 1.5, 2, 3,
4, 6, 8, 12, and 18 hours [0495] Collect PK urine samples at -2 to
0 hours predose and after the start of infusion over the following
continuous time intervals: 0 to 2, 2 to 4, 4 to 8, 8 to 12, and 12
to 24 hours [0496] Perform ECGs at 0.0 hour (within 20 minutes
before the start of infusion) predose and at 1, 2, and 4 hours
(.+-.20 minutes) after the start of infusion [0497] Assess AEs,
SAEs, and concomitant medication use [0498] Provide breakfast,
lunch, dinner, and snack at approximately 0700, 1200, 1800, and
2100 hours, respectively
[0499] Day 13 (Period III) [0500] Assess AEs, SAEs, and concomitant
medication use [0501] Complete the collection of PK urine sample
from 24 to 48 hours after the start of infusion [0502] Collect PK
blood sample at 48 hours after the start of infusion [0503] Provide
breakfast at approximately 0700 hours [0504] Perform a complete
physical examination [0505] Discharge subjects
[0506] End of Study (EOS)
[0507] EOS evaluations were completed within 7 to 10 days from Day
11 or at the time of early discontinuation
[0508] Drug Concentration Measurements
[0509] Blood Sampling
[0510] Blood samples were collected at the following times to
determine ceftaroline, ceftaroline fosamil, ceftaroline M-1
(metabolite of ceftaroline fosamil), and NXL-104 free-acid plasma
concentrations.
[0511] Days 1 (Period I), 6 (Period II), and II (Period III): in
each study period immediately before (within 15 minutes) the start
of infusion and after the start of study drug infusion at 20, 40,
60 (immediately before the end of study-drug infusion), 65, and 75
minutes and at 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, and 48 hours
[0512] Urine Sampling
[0513] Urine was collected during the following time intervals in
each part of study.
[0514] Part A
[0515] Urine was collected from -2 to 0 hours predose and from 0 to
2, 2 to 4, 4 to 8, 8 to 12, 12 to 24, and 24 to 48 hours after the
start of infusion in each period.
[0516] Pharmacokinetic Analyses
[0517] The principal parameters describing the pharmacokinetics of
ceftaroline, ceftaroline fosamil, ceftaroline M-1 (metabolite of
ceftaroline fosamil), and NXL-104 were derived from plasma
concentrations using noncompartmental analysis with the software
program WinNonlin. Plasma concentrations below the limit of
quantification were treated as zero for all PK calculations. The
actual sampling times were used in the calculations of PK
parameters.
[0518] Plasma Data
[0519] The following PK parameters were determined for ceftaroline,
ceftaroline fosamil, ceftaroline M-1, and NXL-104 free acid:
AUC.sub.0-t and area under the plasma concentration versus time
curve from time zero to infinity (AUC.sub.0-.infin.), C.sub.max,
time of maximum plasma concentration (T.sub.max), T.sub.1/2, CL,
volume of distribution (V.sub.z), and steady-state volume of
distribution (V.sub.ss). Minimum plasma concentration (C.sub.min),
accumulation ratio (R.sub.ac), and area under the plasma
concentration versus time curve during the dosing interval, .tau.,
(AUC.sub.0-.tau.) will be determined following multiple-dose
administration.
[0520] Because all doses of ceftaroline are expressed in terms of
anhydrous, acetate-free ceftaroline fosamil (ceftaroline prodrug,
molecular weight=684.68), the following corrections were made to
the dose when calculating PK parameters that include doses for
ceftaroline (molecular weight=604.70) and ceftaroline M-1
(molecular weight=622.72):
[0521] Ceftaroline dose=0.883.times.ceftaroline fosamil dose
[0522] Ceftaroline M-1 dose=0.909.times.ceftaroline fosamil
dose
[0523] The C.sub.max of ceftaroline, ceftaroline fosamil,
ceftaroline M-1, and NXL-104 free acid was determined
observationally as the peak concentration for each subject.
T.sub.max was determined as the time corresponding to
C.sub.max.
[0524] Area under the plasma concentration versus time curve up to
the time corresponding to the last measurable concentration
(AUC.sub.0-t) was calculated by numeric integration using the
linear trapezoidal rule as follows:
AUC 0 - t = i = 2 n 0.5 .times. ( C i + C i - 1 ) .times. ( t i - t
i - 1 ) ##EQU00001##
[0525] in which C.sub.i is the plasma ceftaroline, ceftaroline
fosamil, ceftaroline M-1, and NXL-104 free-acid concentrations at
the corresponding sampling time point t.sub.i and n is the number
of time points up to and including the last quantifiable
concentration.
[0526] Estimates of T.sub.1/2 were calculated using the following
equation:
T.sub.1/2=0.693/.lamda..sub.z
[0527] in which .lamda..sub.z is the terminal elimination rate
constant and was determined by noncompartmental analysis using
WinNonlin. Briefly described, a regression analysis was performed
on the terminal linear phase of semilogarithmic plots of individual
ceftaroline, ceftaroline fosamil, ceftaroline M-1, and NXL-104 free
acid concentration-time data.
[0528] The AUC.sub.0-.infin. was calculated according to the
following equation:
AUC.sub.0-.infin.=AUC.sub.0-t+C.sub.last/.lamda..sub.z
in which C.sub.last is the last measurable concentration.
[0529] CL was calculated with the following equation:
CL=Dose.sub.iv/AUC.sub.0-.infin.
[0530] V.sub.z based on the terminal phase was determined as:
V.sub.z=Dose.sub.iv/.lamda..sub.z.times.AUC.sub.0-.infin.
[0531] C.sub.min was determined observationally as the drug
concentration at the end of the dosing interval at
steady-state.
[0532] V.sub.ss following multiple-dose administration was
determined using the following equations:
V ss = CL .times. AUMC AUC - Tdur 2 ##EQU00002##
[0533] in which with Tdur is the infusion duration
AUMC 0 - .infin. = AUMC 0 - t + C last t last .lamda. z + C last
.lamda. z .lamda. z ##EQU00003##
[0534] in which AUMC.sub.0-.infin. is the area under the first
moment of the plasma concentration-versus-time curve from time zero
to infinity with extrapolation of the terminal phase.
[0535] Area under the first moment of the plasma
concentration-versus-time curve up to the time corresponding to the
last measurable concentration (AUMC.sub.0-t) was calculated by
numeric integration using the linear trapezoidal rule as
follows:
AUMC 0 - t = i = 2 n 0.5 .times. ( C i t i + C i - 1 t i - 1 )
.times. ( t i - t i - 1 ) ##EQU00004##
[0536] R.sub.ac was calculated using the following equation:
R ac = AUC 0 - t ( Day 7 ) AUC 0 - t ( Day 1 ) ##EQU00005##
[0537] Urine Data
[0538] The PK parameters to be determined from the urine excretion
data included the cumulative amount of ceftaroline, ceftaroline
fosamil, ceftaroline M-1, and NXL-104 free acid excreted during the
entire urine collection period from time 0 to time t (Ae.sub.0-t),
renal clearance (CL.sub.r) and the percent of dose excreted (%
Dose). These parameters were determined using noncompartmental
analysis.
[0539] The cumulative amount of ceftaroline, ceftaroline fosamil,
ceftaroline M-1, and NXL-104 excreted over all collection
intervals, Ae.sub.0-t, was calculated as
Ae 0 - t = i = 1 n Ae i ##EQU00006##
[0540] in which Ae.sub.1 is the amount of drug excreted per
collection interval calculated as
Ae.sub.1=Concentration.times.Volume
[0541] CL.sub.r of ceftaroline, ceftaroline fosamil, ceftaroline
M-1, and NXL-104 was determined according to the following
equation:
CL r - = Ae 0 - t AUC 0 - t ##EQU00007##
Percent dose excreted in urine was determined according to the
following equation:
[0542] Statistical Analyses of Pharmacokinetic Parameters
[0543] In part A, PK parameters were compared by analysis of
variance using SAS version 9.1.3 on a UNIX operating system. A
general linear model with sequence, subject within sequence,
treatment, and period as factors was used as the basis for the
analysis. The PK parameters for ceftaroline, ceftaroline fosamil,
and ceftaroline M-1 following administration of ceftaroline fosamil
concomitantly with NXL-104 (test) were compared with the PK
parameters for these analytes following administration of
ceftaroline fosamil alone (reference), in addition, the PK
parameters for NXL-104 following administration of NXL-104
concomitantly with ceftaroline fosamil (test) were compared with
the PK parameters for NXL-104 following administration of NXL-104
alone (reference). Statistical inference was based on
log-transformed values for the C.sub.max and AUC parameters. The
2-sided 90% CI for the ratio of geometric means of C.sub.max and
AUC between the test and reference treatments was constructed.
T.sub.max for test and reference was compared using the Wilcoxon
signed rank test.
[0544] There were no safety concerns and no pharmacokinetic
interactions were found between ceftaroline fosamil and
NXL-104.
[0545] Table 84 provides the pharmacokinetic data for Part A of the
study.
TABLE-US-00087 TABLE 84 Pharmacokinetic data for Part A
AUC.sub.0-inf C.sub.max (.mu.g * hr/ T.sub.1/2 Treatment (.mu.g/mL)
T.sub.max (hr) mL) (hr) Ceftaroline 600 mg Geo mean 24.77 1.00
60.97 2.51 Ceftaroline CV (%) 27.55 (1.00-4.00)* 13.70 13.88
fosamil 600 mg NXL- Geo mean 26.71 1.00 60.02 2.47 104 + CV (%)
12.06 (1.00-1.08)* 10.83 16.17 Ceftaroline fosamil 600 mg
Ceftaroline 600 mg Geo mean 2.11 0.67 2.17 0.084 fosamil
Ceftaroline CV (%) 30.73 (0.33-1.50)* 15.59 222.8 fosamil 600 mg
NXL- Geo mean 2.37 0.67 2.16 0.055 104 + CV (%) 21.98 (0.33-1.00)*
11.97 12.34 Ceftaroline fosamil 600 mg Ceftaroline 600 mg Geo mean
3.29 1.08 16.42 3.75 M-1 Ceftaroline CV (%) 43.02 (1.00-.6.00)*
18.72 11.26 fosamil 600 mg NXL- Geo mean 3.21 1.04 15.78 3.78 104 +
CV (%) 42.64 (0.67-2.00)* 21.67 14.01 Ceftaroline fosamil 600 mg
NXL-104 600 mg NXL- Geo mean 29.48 1.00 51.90 1.64 104 CV (%) 12.97
(1.00-1.08)* 11.60 26.32 600 mg NXL- Geo mean 29.06 1.00 51.21 1.63
104 + CV (%) 11.65 (1.00-1.08)* 13.52 19.97 Ceftaroline fosamil 600
mg *Median (Min-Max)
[0546] Part B
[0547] Part B is a randomized, double-blind, placebo-controlled,
10-day multiple dose study to evaluate the safety, tolerability,
and pharmacokinetics of ceftaroline and NXL-104 following
co-administration of multiple IV doses of ceftaroline fosamil and
NXL-104 over 10 days to 48 healthy subjects. The treatment groups
for Part B are as follows:
[0548] Treatment group I: multiple doses of 600 mg ceftaroline
fosamil and 600 mg NXL04 co-administered every 12 hours (q12 h) via
IV infusion over 1 hour
[0549] Treatment group II: multiple doses of 400 mg ceftaroline
fosamil and 400 mg NXL-104 co-administered every 8 hours (q8 h) via
IV infusion over 1 hour
[0550] Treatment group III: multiple doses of 900 mg ceftaroline
fosamil and 900 mg NXL-104 co-administered q12 h via IV infusion
over 1 hour
[0551] Treatment group IV: multiple doses of 600 mg ceftaroline
fosamil and 600 mg NXL-104 co-administered q8 h via IV infusion
over 1 hour
[0552] Treatment group V: multiple doses of placebo (normal saline)
administered q12 h via IV infusion over 1 hour
[0553] Treatment group VI: multiple doses of placebo (normal
saline) administered q8 h via IV infusion over 1 hour
[0554] Subject participation will require a commitment of up to 21
days, not including the Screening Visit, which may occur up to 21
days before study drug administration.
[0555] Treatment duration in each cohort for part B is 10 days.
Subjects will be confined to the clinical research unit from Day -1
through Day 12.
[0556] The following PK parameters for ceftaroline, ceftaroline
fosamil, ceftaroline M-1 (metabolite of ceftaroline fosamil), and
NXL-104 free acid will be calculated following multiple-dose
administration: minimum plasma concentration (Cmin), accumulation
ration (Rac), area under the plasma concentration versus time curve
during the dosing interval, .tau., (AUC0 .tau.), Cmax, Tmax, CL,
T1/2, Ae0-t, CLr, and % Dose.
[0557] Table 85 gives the expected mean pharmacokinetic parameters
for a single dose of 400 mg dose of ceftaroline fosamil, NXL-104 or
a combination of 400 mg ceftaroline fosamil and 400 mg NXL-104
TABLE-US-00088 TABLE 85 Expected pharmacokinetic parameters for a
single 400 mg dose of ceftaroline fosamil, NXL-104 or 400 mg
NXL-104 + ceftaroline fosamil 400 mg C.sub.max T.sub.max
AUC.sub.0-inf T.sub.1/2 Treatment (.mu.g/mL) (hr) (.mu.g * hr/mL)
(hr) Ceftaroline 400 mg Ceftaroline 16.51 0.67 40.65 1.67 fosamil
400 mg NXL-104 + 17.81 0.67 40.01 1.65 Ceftaroline fosamil 400 mg
Ceftaroline 400 mg Ceftaroline 1.41 0.45 1.45 0.06 fosamil fosamil
400 mg NXL-104 + 1.58 0.45 1.44 0.04 Ceftaroline fosamil 400 mg
Ceftaroline 400 mg Ceftaroline 2.19 0.72 10.95 2.5 M-1 fosamil 400
mg NXL-104 + 2.14 0.69 10.52 2.52 Ceftaroline fosamil 400 mg
NXL-104 400 mg NXL-104 19.65 0.67 34.6 1.09 400 mg NXL-104 + 19.37
0.67 34.14 1.09 Ceftaroline fosamil 400 mg
[0558] Table 86 gives the expected mean pharmacokinetic parameters
for a single dose of 900 mg dose of ceftaroline fosamil, NXL-104 or
a combination of 900 mg ceftaroline fosamil and 900 mg NXL-104
TABLE-US-00089 TABLE 86 Expected pharmacokinetic parameters for a
single 900 mg dose of ceftaroline fosamil, NXL-104 or 900 mg
NXL-104 + ceftaroline fosamil 900 mg C.sub.max T.sub.max
AUC.sub.0-inf T.sub.1/2 Treatment (.mu.g/mL) (hr) (.mu.g * hr/mL)
(hr) Ceftaroline 900 mg Ceftaroline 37.16 1.5 91.46 3.77 fosamil
900 mg NXL-104 + 40.07 1.5 90.03 3.71 Ceftaroline fosamil 900 mg
Ceftaroline 900 mg Ceftaroline 3.17 1.01 3.26 0.13 fosamil fosamil
900 mg NXL-104 + 3.56 1.01 3.24 0.08 Ceftaroline fosamil 900 mg
Ceftaroline 900 mg Ceftaroline 4.94 1.62 24.63 5.63 M-1 fosamil 900
mg NXL-104 + 4.82 1.56 23.67 5.67 Ceftaroline fosamil 900 mg
NXL-104 900 mg NXL-104 44.22 1.5 77.85 2.46 900 mg NXL-104 + 43.59
1.5 76.82 2.45 Ceftaroline fosamil 900 mg
[0559] The present invention is not to be limited in scope by the
specific embodiments described herein. Indeed, various
modifications of the invention in addition to those described
herein will become apparent to those skilled in the art from the
foregoing description and the accompanying figures. Such
modifications are intended to fall within the scope of the appended
claims. It is further to be understood that all values are
approximate, and are provided for description.
[0560] All patents, patent applications, publications, product
descriptions, and protocols are cited throughout this application,
the disclosures of which are incorporated herein by reference in
their entireties for all purposes.
* * * * *