U.S. patent application number 10/835875 was filed with the patent office on 2004-10-14 for injectable composition.
Invention is credited to Carver, David, Elliott, Robyn, Ewald, Hernita, Handreck, Paul, Prout, Timothy.
Application Number | 20040204479 10/835875 |
Document ID | / |
Family ID | 25644377 |
Filed Date | 2004-10-14 |
United States Patent
Application |
20040204479 |
Kind Code |
A1 |
Carver, David ; et
al. |
October 14, 2004 |
Injectable composition
Abstract
A pharmaceutical formulation of paclitaxel and polyethoxylated
castor oil is disclosed to be relatively acidified to a pH of less
than 8.1 and preferably within a pH range of 5 to 7, inclusively.
Ethanol is optionally included in the formulation which is adapted
for use in a body for the treatment of cancer. A formulation method
is disclosed and includes the step of mixing an acid with a carrier
material, such as polyethoxylated castor oil, to form a carrier
solution after which paclitaxel is added in an amount such that the
resulting pH is less than 8.1 and preferably in a pH range of 5 to
7. Ethanol may optionally be slurried with the paclitaxel before
mixing with the carrier solution. A variety of acidifying agents, a
preferred one being anhydrous citric acid, are described.
Inventors: |
Carver, David; (Boulder,
CO) ; Prout, Timothy; (Erie, CO) ; Ewald,
Hernita; (Denver, CO) ; Elliott, Robyn;
(Langwarrin, AU) ; Handreck, Paul; (Glen Iris,
AU) |
Correspondence
Address: |
SALIWANCHIK LLOYD & SALIWANCHIK
A PROFESSIONAL ASSOCIATION
2421 N.W. 41ST STREET
SUITE A-1
GAINESVILLE
FL
32606-6669
US
|
Family ID: |
25644377 |
Appl. No.: |
10/835875 |
Filed: |
April 29, 2004 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10835875 |
Apr 29, 2004 |
|
|
|
09970558 |
Oct 4, 2001 |
|
|
|
6770670 |
|
|
|
|
09970558 |
Oct 4, 2001 |
|
|
|
09563969 |
May 3, 2000 |
|
|
|
6306894 |
|
|
|
|
09563969 |
May 3, 2000 |
|
|
|
09356158 |
Jul 19, 1999 |
|
|
|
6140359 |
|
|
|
|
09356158 |
Jul 19, 1999 |
|
|
|
09028906 |
Feb 24, 1998 |
|
|
|
5972992 |
|
|
|
|
09028906 |
Feb 24, 1998 |
|
|
|
08979836 |
Nov 26, 1997 |
|
|
|
5977164 |
|
|
|
|
08979836 |
Nov 26, 1997 |
|
|
|
08594478 |
Jan 31, 1996 |
|
|
|
5733888 |
|
|
|
|
08594478 |
Jan 31, 1996 |
|
|
|
07995501 |
Dec 22, 1992 |
|
|
|
Current U.S.
Class: |
514/449 |
Current CPC
Class: |
A61K 31/335 20130101;
A61K 47/12 20130101; A61K 47/14 20130101; A61K 47/44 20130101; A61K
9/0019 20130101; A61K 31/337 20130101; A61K 47/10 20130101 |
Class at
Publication: |
514/449 |
International
Class: |
A61K 031/337 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 27, 1992 |
AU |
6074 |
Claims
I claim:
1. A method for formulating a pharmaceutical paclitaxel composition
such that the paclitaxel does not readily degrade, comprising the
steps of: mixing an acid with a carrier material to form a first
carrier composition; and mixing paclitaxel with said first carrier
composition to form a pharmaceutical paclitaxel composition, such
that said pharmaceutical paclitaxel composition retains at least
96.6% of the original paclitaxel potency when said pharmaceutical
paclitaxel composition is stored at 40.degree. C. for seven
days.
2. The method of claim 1, wherein said first carrier composition
comprises polyethoxylated castor oil.
3. The method of claim 2, wherein said first carrier composition
further comprises ethanol.
4. The method of claim 1, wherein said acid is an organic acid.
5. The method of claim 1, wherein said acid is a mineral acid.
6. The method of claim 4, wherein said acid is acetic acid.
7. The method of claim 4, wherein said acid is citric acid.
8. The method of claim 7, wherein said citric acid is
anhydrous.
9. The method of claim 7, wherein said citric acid is
monohydrous.
10. The method of claim 7, wherein said citric acid is hydrous.
11. The method of claim 2, wherein said acid is an organic
acid.
12. The method of claim 2, wherein said acid is a mineral acid.
13. The method of claim 11, wherein said acid is acetic acid.
14. The method of claim 11, wherein said acid is citric acid.
15. The method of claim 14, wherein said citric acid is
anhydrous.
16. The method of claim 14, wherein said citric acid is
monohydrous.
17. The method of claim 14, wherein said citric acid is
hydrous.
18. The method of claim 3, wherein said acid is an organic
acid.
19. The method of claim 3, wherein said acid is a mineral acid.
20. The method of claim 18, wherein said acid is acetic acid.
21. The method of claim 18, wherein said acid is citric acid.
22. The method of claim 21, wherein said citric acid is
anhydrous.
23. The method of claim 21, wherein said citric acid is
monohydrous.
24. The method of claim 21, wherein said citric acid is
hydrous.
25. A method for formulating a pharmaceutical paclitaxel
composition such that the paclitaxel does not readily degrade,
comprising the steps of: mixing an acid with a carrier material to
form a first carrier composition; and mixing paclitaxel with said
first carrier composition to form a pharmaceutical paclitaxel
composition, such that said pharmaceutical paclitaxel composition
comprises no more than 2.3% total impurities when stored at
40.degree. C. for seven days.
26. The method of claim 25, wherein said first carrier composition
comprises polyethoxylated castor oil.
27. The method of claim 26, wherein said first carrier composition
further comprises ethanol.
28. The method of claim 25, wherein said acid is an organic
acid.
29. The method of claim 25, wherein said acid is a mineral
acid.
30. The method of claim 28, wherein said acid is acetic acid.
31. The method of claim 28, wherein said acid is citric acid.
32. The method of claim 31, wherein said citric acid is
anhydrous.
33. The method of claim 31, wherein said citric acid is
monohydrous.
34. The method of claim 31, wherein said citric acid is
hydrous.
35. The method of claim 26, wherein said acid is an organic
acid.
36. The method of claim 26, wherein said acid is a mineral
acid.
37. The method of claim 35 wherein said acid is acetic acid.
38. The method of claim 35, wherein said acid is citric acid.
39. The method of claim 38, wherein said citric acid is
anhydrous.
40. The method of claim 38, wherein said citric acid is
monohydrous.
41. The method of claim 38, wherein said citric acid is
hydrous.
42. The method of claim 27, wherein said acid is an organic
acid.
43. The method of claim 27, wherein said acid is a mineral
acid.
44. The method of claim 42, wherein said acid is acetic acid.
45. The method of claim 42, wherein said acid is citric acid.
46. The method of claim 45, wherein said citric acid is
anhydrous.
47. The method of claim 45, wherein said citric acid is
monohydrous.
48. The method of claim 45, wherein said citric acid is
hydrous.
49. A method of making an article of manufacture comprising a
sealed container and a pharmaceutical paclitaxel formulation
contained therein, said method comprising the steps of: (a)
obtaining a sealable container; (b) obtaining a pharmaceutical
formulation comprising paclitaxel, a pharmaceutically-acceptable
carrier, and an acid; said formulation being such that at least
96.6% of the paclitaxel potency is retained when the formulation is
stored at 40.degree. C. for seven days; (c) placing said
pharmaceutical formulation in said sealable container; (d) sealing
said sealable container; and (e) storing said pharmaceutical
formulation in said sealed container for at least seven days.
50. The method of claim 49, wherein said first carrier composition
comprises polyethoxylated castor oil.
51. The method of claim 50, wherein said first carrier composition
further comprises ethanol.
52. The method of claim 49, wherein said acid is an organic
acid.
53. The method of claim 49, wherein said acid is a mineral
acid.
54. The method of claim 52, wherein said acid is acetic acid.
55. The method of claim 52, wherein said acid is citric acid.
56. The method of claim 55, wherein said citric acid is
anhydrous.
57. The method of claim 55, wherein said citric acid is
monohydrous.
58. The method of claim 55, wherein said citric acid is
hydrous.
59. The method of claim 50, wherein said acid is an organic
acid.
60. The method of claim 50, wherein said acid is a mineral
acid.
61. The method of claim 59, wherein said acid is acetic acid.
62. The method of claim 59, wherein said acid is citric acid.
63. The method of claim 62, wherein said citric acid is
anhydrous.
64. The method of claim 62, wherein said citric acid is
monohydrous.
65. The method of claim 62, wherein said citric acid is
hydrous.
66. The method of claim 51, wherein said acid is an organic
acid.
67. The method of claim 51, wherein said acid is a mineral
acid.
68. The method of claim 66, wherein said acid is acetic acid.
69. The method of claim 66, wherein said acid is citric acid.
70. The method of claim 69, wherein said citric acid is
anhydrous.
71. The method of claim 69, wherein said citric acid is
monohydrous.
72. The method of claim 69, wherein said citric acid is
hydrous.
73. A method of making an article of manufacture comprising a
sealed container and a pharmaceutical paclitaxel formulation
contained therein, said method comprising the steps of: (a)
obtaining a sealable container; (b) obtaining a pharmaceutical
formulation comprising paclitaxel, a pharmaceutically-acceptable
carrier, and an acid; said formulation being such that the
formulation comprises no more than 2.3% total impurities when said
formulation is stored at 40.degree. C. for seven days; (c) placing
said pharmaceutical formulation in said sealable container; (d)
sealing said sealable container; and (e) storing said
pharmaceutical formulation in said sealed container for at least
seven days.
74. The method of claim 73, wherein said first carrier composition
comprises polyethoxylated castor oil.
75. The method of claim 74, wherein said first carrier composition
further comprises ethanol.
76. The method of claim 73, wherein said acid is an organic
acid.
77. The method of claim 73, wherein said acid is a mineral
acid.
78. The method of claim 76, wherein said acid is acetic acid.
79. The method of claim 76, wherein said acid is citric acid.
80. The method of claim 79, wherein said citric acid is
anhydrous.
81. The method of claim 79, wherein said citric acid is
monohydrous.
82. The method of claim 79, wherein said citric acid is
hydrous.
83. The method of claim 74, wherein said acid is an organic
acid.
84. The method of claim 74, wherein said acid is a mineral
acid.
85. The method of claim 83, wherein said acid is acetic acid.
86. The method of claim 83, wherein said acid is citric acid.
87. The method of claim 86, wherein said citric acid is
anhydrous.
88. The method of claim 86, wherein said citric acid is
monohydrous.
89. The method of claim 86, wherein said citric acid is
hydrous.
90. The method of claim 75, wherein said acid is an organic
acid.
91. The method of claim 75, wherein said acid is a mineral
acid.
92. The method of claim 90, wherein said acid is acetic acid.
93. The method of claim 90, wherein said acid is citric acid.
94. The method of claim 93, wherein said citric acid is
anhydrous.
95. The method of claim 93, wherein said citric acid is
monohydrous.
96. The method of claim 93, wherein said citric acid is
hydrous.
97. A method for formulating a pharmaceutical paclitaxel
composition such that the paclitaxel does not readily degrade,
comprising obtaining a composition consisting essentially of
paclitaxel, polyethoxylated castor oil, ethanol, and an acid, said
acid being in sufficient amount such that the paclitaxel stability
of said composition is improved as compared to the paclitaxel
stability of an identical composition without said acid; and
sealing said acid-containing paclitaxel composition in a container,
wherein said pharmaceutical acid-containing paclitaxel composition
retains at least 97.5% of the original paclitaxel potency when
stored at 40.degree. C. for 7 days.
98. The method of claim 97, wherein said acid is an organic
acid.
99. The method of claim 97, wherein said acid is a mineral
acid.
100. The method of claim 98, wherein said acid is acetic acid.
101. The method of claim 98, wherein said acid is citric acid.
102. The method of claim 101, wherein said citric acid is
anhydrous.
103. The method of claim 101, wherein said citric acid is
monohydrous.
104. The method of claim 101, wherein said citric acid is hydrous.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. Ser. No.
09/970,558; filed Oct. 4, 2001; which is a continuation of U.S.
Ser. No. 09/563,969, filed May 3, 2000 (now U.S. Pat. No.
6,306,894); which is a continuation of U.S. Ser. No. 09/356,158,
filed Jul. 19, 1999 (now U.S. Pat. No. 6,140,359); which is a
continuation of U.S. Ser. No. 09/028,906, filed Feb. 24, 1998 (now
U.S. Pat. No. 5,972,992); which is a continuation of U.S. Ser. No.
08/979,836, filed Nov. 26, 1997 (now U.S. Pat. No. 5,977,164);
which is a divisional of U.S. Ser. No. 08/594,478, filed Jan. 31,
1996 (now U.S. Pat. No. 5,733,888), and which is a continuation of
U.S. Ser. No. 07/995,501, filed Dec. 22, 1992, (now abandoned); all
of which are hereby incorporated by reference herein in their
entirety.
BACKGROUND OF THE INVENTION
[0002] Paclitaxel is a compound extracted from the bark of a
western yew, Taxus brevifolia and known for its antineoplastic
activity. It is described for example in The Merck Index, Eleventh
Edition 1989, monograph 9049.
[0003] In 1977, paclitaxel was chosen for development as an
antineoplastic agent because of its unique mechanism of action and
good cytotoxic activity against IP implanted D16 melanoma and the
human X-1 mammary tumor xenograft. Paclitaxel is believed to
function as a mitotic spindle poison and as a potent inhibitor of
cell replication in vitro. Other mitotic spindle points (colchicine
and podophyllotoxin) inhibit microtubule assembly. Paclitaxel
employs a different mechanism of action since it appears to shift
the equilibrium of polymerimization/depolymeriz- ation toward
polymer assembly and to stabilize microtubules against
depolymerization under conditions which would cause rapid
disaggregation of microtubules. The interference with the
polymerization/depolymerizatio- n cycle in cells appears to
interfere with both the replication and migration of cells.
[0004] After extensive preclinical screening in mouse tumor models,
paclitaxel entered clinical trials in 1983. Over the past few
years, paclitaxel has demonstrated good response rates in treating
both ovarian and breast cancer patients who were not benefitting
from vinca alkaloid or cisplatin therapy. It has also shown
encouraging results in patients with other types of cancer
including lung, melanoma, lymphoma, head and neck.
[0005] For further information, reference may be made to the U.S.
National Cancer Institute's Clinical Brochure for Taxol, revised
July 1991, and papers presented at the Second National Cancer
Institute Workshop on Taxol and Taxus held in Alexandria, Va. USA
on Sep. 23-24, 1992.
BRIEF DESCRIPTION OF THE INVENTION
[0006] It is a disadvantage of the known formulation that the
paclitaxel therein degrades, with the result that the shelf life of
the formulation is unsatisfactory, and there is therefore a need
for a paclitaxel solution of improved stability.
[0007] Accordingly, in a general aspect the invention provides a
solution containing paclitaxel, cremophor EL.TM. and ethanol,
characterized in that the pH of the solution has been adjusted into
the range 1 to 8 by addition of an acid.
[0008] Acids in the form of powders, for example citric acid, are
preferred over those which contain water, for example sulfuric
acid. The most preferred acid for use in accordance with the
present invention is citric acid, but a wide range of acids may be
used including the following:
[0009] Citric acid--monohydrous
[0010] Citric acid--anhydrous
[0011] Citric acid--hydrous
[0012] Acetic acid
[0013] Formic acid
[0014] Ascorbic acid
[0015] Aspartic acid
[0016] Benzene sulphonic acid
[0017] Benzoic acid
[0018] Hydrochloric acid
[0019] Sulphuric acid
[0020] Phosphoric acid
[0021] Nitric acid
[0022] Tartaric acid
[0023] Diatrizoic acid
[0024] Glutamic acid
[0025] Lactic acid
[0026] Maleic acid
[0027] Succinic acid
DETAILED DESCRIPTION OF THE ILLUSTRATED EMBODIMENTS
[0028] Due to its limited solubility in water, Paclitaxel is
usually prepared and administered in a vehicle containing cremophor
EL.TM. (a polyethoxylated castor oil which acts as a solubilizer)
and ethanol. A commercially available solution supplied by
Bristol-Myers Squibb (BMS) is formulated with these components and
has a pH of 9.1.
[0029] As indicated above, the invention essentially teaches
addition of an acid to a paclitaxel formulation to adjust its pH
into the range 1 to 8, preferable 5 to 7.
[0030] In a preferred procedure adopted by the applicant, which it
will be clearly understood is non-limiting, the following steps
were carried out:
[0031] Mixing Instructions
[0032] Solution 1
[0033] Citric acid was dissolved in absolute alcohol, using a ratio
of 8 mls of absolute alcohol to 1 gram of citric acid, and the
solution was stirred for fifteen (15) minutes.
[0034] Solution 2
[0035] Cremophor EL was weighed out into the main mixing
vessel.
[0036] Solution 3
[0037] Solution 1 was added to solution 2, and the container used
for solution 2 was washed with a minimum quantity of absolute
alcohol to ensure complete transfer of the citric acid. Solution 3
was mixed and bubbled with nitrogen for at least 15 minutes. The
paclitaxel was weighed out and slurried using absolute alcohol,
using a ratio of 8 ml of absolute alcohol to 1 gm of paclitaxel.
The slurried paclitaxel was added to solution 3 and the slurrying
vessel was washed with a minimum quantity of absolute alcohol.
Solution 3 was adjusted to 75% of required volume using absolute
alcohol, and thoroughly stirred for at least 45 minutes until
completely dissolved. Once completely dissolved, the volume was
checked and made up as necessary with absolute alcohol and the
final solution stirred for 5 minutes.
EXAMPLE 1
[0038] A solution was prepared with the following formulation:
1 Formulation: (Sample 1) Cremophor EL 0.5 mL Citric Acid
(Anhydrous) 2.0 mg Paclitaxel 6.0 mg Absolute Alcohol to 1.0 mL The
pH of this solution was determined as 6.1.
[0039] The stability of this sample was compared with a sample
prepared by the formulation stated in the NCI Taxol Clinical
brochure (as follows) which had a pH of 9.1. (Sample 2)
2 Sample 2 per mL Paclitaxel 6 mg Cremophor EL 0.5 mL Absolute
Alcohol to 1 mL
[0040] The solutions were filled into clear type 1 glass 5 mL vials
and sealed with rubber bungs.
[0041] The solutions were stored at 40.degree. C. for 7 (seven)
days and the stability results are shown in Table 1.
3 Sample 1 Sample 2 pH 6.2 9.0 Potency 96.6 86.7 Major individual
impurity 0.3% 5.1% Total impurities 1.0% 12.2% Clearly Sample 1
showed significantly increased stability over Sample 2.
EXAMPLE 2
[0042] A solution was prepared with the following formulation:
4 Formulation: (Sample 3) Cremophor EL 0.5 mL Paclitaxel 6.0 mg
Absolute Ethanol to 1.0 mL pH adjusted to 6.6 with 1.0 M Acetic
Acid.
[0043] The solution was filled into clear type I glass 5 mL vials
and sealed with rubber bungs.
[0044] The solution was stored at 40.degree. C. for 7 days.
[0045] The stability results obtained are compared to those seen
with Sample 2.
5 Sample 3 Sample 2 pH 6.7 9.0 Potency 97.5 86.7 Major individual
impurity 0.3% 5.1% Total impurities 2.3% 12.2%
[0046] Again the significantly superior stability of the
formulation according to the invention (Sample 3) is evident.
[0047] It will be clearly understood that the invention in its
general aspects is not limited to the specific details referred to
hereinabove.
* * * * *