U.S. patent application number 10/782521 was filed with the patent office on 2004-08-26 for method for preparing and using polyoxyethylated castor oil in pharmaceutical compositions.
This patent application is currently assigned to SuperGen, Inc.. Invention is credited to Gore, Ashok Y., Joshi-Hangal, Rajashree, Redkar, Sanjeev, Rubinfeld, Joseph.
Application Number | 20040167205 10/782521 |
Document ID | / |
Family ID | 23302886 |
Filed Date | 2004-08-26 |
United States Patent
Application |
20040167205 |
Kind Code |
A1 |
Joshi-Hangal, Rajashree ; et
al. |
August 26, 2004 |
Method for preparing and using polyoxyethylated castor oil in
pharmaceutical compositions
Abstract
A method is provided for preparing a pharmaceutical composition
comprising: taking polyoxyethylated castor oil which if diluted
1:10 in water has a pH greater than 5 and aging the
polyoxyethylated castor oil by exposing the polyoxyethylated castor
oil to a gas comprising oxygen for a period of time, the exposure
to the gas over the period of time causing an acidity of the
polyoxyethylated castor oil to increase; and forming a
pharmaceutical composition comprising the aged polyoxyethylated
castor oil and a pharmaceutically active agent such as paclitaxel;
wherein at least 80% of the potency of the pharmaceutically active
agent is retained by the pharmaceutical composition after the
pharmaceutical composition is stored for at least 7 days at
40.degree. C.
Inventors: |
Joshi-Hangal, Rajashree;
(Union City, CA) ; Rubinfeld, Joseph; (Danville,
CA) ; Redkar, Sanjeev; (Union City, CA) ;
Gore, Ashok Y.; (San Ramon, CA) |
Correspondence
Address: |
WILSON SONSINI GOODRICH & ROSATI
650 PAGE MILL ROAD
PALO ALTO
CA
943041050
|
Assignee: |
SuperGen, Inc.
Dublin
CA
|
Family ID: |
23302886 |
Appl. No.: |
10/782521 |
Filed: |
February 18, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10782521 |
Feb 18, 2004 |
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10306824 |
Nov 26, 2002 |
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6710195 |
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60333459 |
Nov 26, 2001 |
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Current U.S.
Class: |
514/449 ;
424/731 |
Current CPC
Class: |
A61P 35/00 20180101;
A61K 31/337 20130101; A61K 47/44 20130101; A61K 9/0019
20130101 |
Class at
Publication: |
514/449 ;
424/731 |
International
Class: |
A61K 031/337; A61K
035/78 |
Claims
What is claimed is:
1. A method for preparing a pharmaceutical composition comprising:
taking polyoxyethylated castor oil which if diluted 1:10 in water
has a pH greater than 6 and aging the polyoxyethylated castor oil
by exposing the polyoxyethylated castor oil to a gas comprising
oxygen for a period of time, the exposure to the gas over the
period of time causing an acidity of the polyoxyethylated castor
oil to increase; and forming a pharmaceutical composition
comprising the aged polyoxyethylated castor oil and paclitaxel;
wherein at least 80% of the paclitaxel potency is retained by the
pharmaceutical composition after the pharmaceutical composition is
stored for at least 7 days at 40.degree. C.
2. The method according to claim 1, further comprising adding an
antioxidant to the aged polyoxyethylated castor oil.
3. The method according to claim 1, further comprising adding a
pharmaceutically acceptable alcohol to the aged polyoxyethylated
castor oil.
4. The method according to claim 3, wherein the pharmaceutically
acceptable alcohol is ethanol.
5. The method according to claim 1, further comprising adding a
pharmaceutically acceptable glycol to the aged polyoxyethylated
castor oil.
6. The method according to claim 5, wherein the pharmaceutically
acceptable glycol is propylene glycol or polyethylene glycol.
7. The method according to claim 1, further comprising adding an
antioxidant to the pharmaceutical composition.
8. The method according to claim 7, wherein the antioxidant is
vitamin E, vitamin C or their derivatives.
9. The method according to claim 7, further comprising adding a
pharmaceutically acceptable alcohol to the aged polyoxyethylated
castor oil.
10. The method according to claim 1, wherein aging the
polyoxyethylated castor oil is performed for at least 30 minutes at
a temperature range between 0.degree. C. and 70.degree. C.
11. The method according to claim 1, wherein aging the
polyoxyethylated castor oil is performed for at least 30 minutes at
a temperature range between 30.degree. C. and 70.degree. C.
12. The method according to claim 1, wherein aging the
polyoxyethylated castor oil is performed for at least 30 minutes at
a temperature range between 40.degree. C. and 60.degree. C.
13. The method according to claim 1, wherein aging the
polyoxyethylated castor oil is performed for at least 7 days at a
temperature range between 40.degree. C. and 60.degree. C.
14. The method according to claim 1, wherein aging the
polyoxyethylated castor oil is performed for at least 30 minutes at
a temperature range between 0.degree. C. and 70.degree. C. by
sparging the polyoxyethylated castor oil with air.
15. The method according to claim 1, wherein aging the
polyoxyethylated castor oil is performed for at least 30 minutes at
a temperature range between 40.degree. C. and 60.degree. C. by
sparging the polyoxyethylated castor oil with air.
16. The method according to claim 1, wherein aging the
polyoxyethylated castor oil is performed for at least 30 minutes at
a temperature range between 0.degree. C. and 70.degree. C. by
pressurizing the polyoxyethylated castor oil to be at least 1.5
atmospheric pressure.
17. The method according to claim 1, wherein aging the
polyoxyethylated castor oil is performed for at least 30 minutes at
a temperature range between 0.degree. C. and 70.degree. C. by
pressurizing the polyoxyethylated castor oil to be at least 1.5
atmospheric pressure.
18. The method according to claim 1, wherein at least 90% of the
paclitaxel potency is retained by the pharmaceutical composition
after the pharmaceutical composition is stored for at least 7 days
at 40.degree. C.
19. The method according to claim 1, wherein at least 95% of the
paclitaxel potency is retained by the pharmaceutical composition
after the pharmaceutical composition is stored for at least 7 days
at 40.degree. C.
20. The method according to claim 1, wherein the polyoxyethylated
castor oil is selected from the group consisting of: Cremophor.RTM.
EL and Cremophor.RTM. ELP.
21. A method for preparing a pharmaceutical composition of
paclitaxel comprising: taking polyoxyethylated castor oil which if
diluted 1:10 in water has a pH greater than 6 and aging the
polyoxyethylated castor oil by exposing the polyoxyethylated castor
oil to a gas comprising oxygen until the aged polyoxyethylated
castor oil, if diluted 1:10 in water, has a pH equal to or less
than 5.9; and forming a pharmaceutical composition comprising the
aged polyoxyethylated castor oil and paclitaxel.
22. The method according to claim 21, wherein aging the
polyoxyethylated castor oil is performed until the aged
polyoxyethylated castor oil, if diluted 1:10 in water, has a pH
less than or equal to 5.5.
23. The method according to claim 21, wherein aging the
polyoxyethylated castor oil is performed until the aged
polyoxyethylated castor oil, if diluted 1:10 in water, has a pH
less than or equal to 5.
24. The method according to claim 21, wherein aging the
polyoxyethylated castor oil is performed until the aged
polyoxyethylated castor oil, if diluted 1:10 in water, has a pH
equal to or less than 4.8.
25. The method according to claim 21, wherein aging the
polyoxyethylated castor oil is performed until the aged
polyoxyethylated castor oil, if diluted 1:10 in water, has a pH
between 3.7 and 5.9.
26. The method according to claim 21, wherein aging the
polyoxyethylated castor oil is performed until the aged
polyoxyethylated castor oil, if diluted 1:10 in water, has a pH
between 3.8 and 5.5.
27. The method according to claim 21, wherein aging the
polyoxyethylated castor oil is performed until the aged
polyoxyethylated castor oil, if diluted 1:10 in water, has a pH
between 3.9 and 5.
28. The method according to claim 21, wherein aging the
polyoxyethylated castor oil is performed until the aged
polyoxyethylated castor oil, if diluted 1:10 in water, has a pH
between 4 and 4.8.
29. The method according to claim 21, further comprising adding an
antioxidant to the aged polyoxyethylated castor oil.
30. The method according to claim 21, further comprising adding a
pharmaceutically acceptable alcohol to the aged polyoxyethylated
castor oil.
31. The method according to claim 21, wherein aging the
polyoxyethylated castor oil is performed for at least 30 minutes at
a temperature range between 0 and 70.degree. C.
32. The method according to claim 21, wherein at least 80% of the
paclitaxel potency is retained by the pharmaceutical composition
after the pharmaceutical composition is stored for at least 7 days
at 40.degree. C.
33. The method according to claim 21, wherein at least 90% of the
paclitaxel potency is retained by the pharmaceutical composition
after the pharmaceutical composition is stored for at least 7 days
at 40.degree. C.
34. The method according to claim 21, wherein at least 95% of the
paclitaxel potency is retained by the pharmaceutical composition
after the pharmaceutical composition is stored for at least 7 days
at 40.degree. C.
35. The method according to claim 21, wherein aging causes the pH
of the polyoxyethylated castor oil, if diluted 1:10 in water, to
decrease without requiring an agent to be added that functions to
increase the acidity of the polyoxyethylated castor oil.
36. The method according to claim 21, wherein the polyoxyethylated
castor oil is selected from the group consisting of: Cremophor.RTM.
EL and Cremophor.RTM. ELP.
37. A method for preparing a pharmaceutical composition comprising:
taking polyoxyethylated castor oil which if diluted 1:10 in water
has a pH greater than 6 and aging the polyoxyethylated castor oil
by exposing the polyoxyethylated castor oil to a gas comprising
oxygen for a period of time, the exposure to the gas over the
period of time causing an acidity of the polyoxyethylated castor
oil to increase; and forming a pharmaceutical composition
comprising the aged polyoxyethylated castor oil, ethanol and
paclitaxel; wherein at least 80% of the paclitaxel potency is
retained by the pharmaceutical composition after the pharmaceutical
composition is stored for at least 7 days at 40.degree. C.
38. The method according to claim 37, wherein at least 80% of the
paclitaxel potency is retained by the pharmaceutical composition
after the pharmaceutical composition is stored for at least 7 days
at 40.degree. C.
39. The method according to claim 37, wherein at least 90% of the
paclitaxel potency is retained by the pharmaceutical composition
after the pharmaceutical composition is stored for at least 7 days
at 40.degree. C.
40. The method according to claim 37, wherein at least 95% of the
paclitaxel potency is retained by the pharmaceutical composition
after the pharmaceutical composition is stored for at least 7 days
at 40.degree. C.
41. The method according to claim 37, wherein the pharmaceutical
composition comprises 500-550 mg/mL of polyoxyethylated castor oil,
and 40-60% of ethanol vol/vol.
42. The method according to claim 37, wherein the pharmaceutical
composition comprises 527 mg/mL of polyoxyethylated castor oil, and
49.7% of ethanol vol/vol.
43. A method for preparing a pharmaceutical composition of
paclitaxel comprising: taking polyoxyethylated castor oil which if
diluted 1:10 in water has a pH greater than 5 and aging the
polyoxyethylated castor oil by exposing the polyoxyethylated castor
oil to a gas comprising oxygen until the aged polyoxyethylated
castor oil, if diluted 1:10 in water, has a pH equal to or less
than 4.9; and forming a pharmaceutical composition comprising the
aged polyoxyethylated castor oil, ethanol and paclitaxel; wherein
at least 80% of the paclitaxel potency is retained by the
pharmaceutical composition after the pharmaceutical composition is
stored for at least 7 days at 40.degree. C.
44. The method according to claim 43, wherein aging the
polyoxyethylated castor oil is performed until the aged
polyoxyethylated castor oil, if diluted 1:10 in water, has a pH
equal to or less than 4.7.
45. The method according to claim 43, wherein aging the
polyoxyethylated castor oil is performed until the aged
polyoxyethylated castor oil, if diluted 1:10 in water, has a pH
between 3.7 and 4.9.
46. The method according to claim 43, wherein aging the
polyoxyethylated castor oil is performed until the aged
polyoxyethylated castor oil, if diluted 1:10 in water, has a pH
between 3.9 and 4.3.
47. The method according to claim 43, wherein at least 90% of the
paclitaxel potency is retained by the pharmaceutical composition
after the pharmaceutical composition is stored for at least 7 days
at 40.degree. C.
48. The method according to claim 43, wherein at least 95% of the
paclitaxel potency is retained by the pharmaceutical composition
after the pharmaceutical composition is stored for at least 7 days
at 40.degree. C.
49. The method according to claim 43, wherein the pharmaceutical
composition comprises 500-550 mg/mL of polyoxyethylated castor oil,
and 40-60% of ethanol vol/vol.
50. The method according to claim 43, wherein the pharmaceutical
composition comprises 527 mg/mL of polyoxyethylated castor oil, and
49.7% of ethanol vol/vol.
51. A pharmaceutical composition comprising: polyoxyethylated
castor oil that has been modified by taking polyoxyethylated castor
oil which if diluted 1:10 in water has a pH greater than 6 and
aging the polyoxyethylated castor oil by exposing the
polyoxyethylated castor oil to a gas comprising oxygen until the
aged polyoxyethylated castor oil, if diluted 1:10 in water, has a
pH equal to or less than 5.9; and paclitaxel; wherein the
pharmaceutical composition does not comprise an agent added to the
polyoxyethylated castor oil that functions to increase the acidity
of the polyoxyethylated castor oil.
52. The pharmaceutical composition according to claim 51, wherein
at least 80% of the paclitaxel potency is retained by the
pharmaceutical composition after the pharmaceutical composition is
stored for at least 7 days at 40.degree. C.
53. The pharmaceutical composition according to claim 51, wherein
at least 90% of the paclitaxel potency is retained by the
pharmaceutical composition after the pharmaceutical composition is
stored for at least 7 days at 40.degree. C.
54. The pharmaceutical composition according to claim 51, wherein
at least 95% of the paclitaxel potency is retained by the
pharmaceutical composition after the pharmaceutical composition is
stored for at least 7 days at 40.degree. C.
55. The pharmaceutical composition according to claim 51, wherein
the pharmaceutical composition further comprises ethanol.
56. The pharmaceutical composition according to claim 55, wherein
the pharmaceutical composition comprises 500-550 mg/mL of
polyoxyethylated castor oil, and 40-60% of ethanol vol/vol.
57. The pharmaceutical composition according to claim 55, wherein
the pharmaceutical composition comprises 527 mg/mL of
polyoxyethylated castor oil, and 49.7% of ethanol vol/vol.
58. A pharmaceutical composition comprising: polyoxyethylated
castor oil that has been modified by taking polyoxyethylated castor
oil which if diluted 1:10 in water has a pH greater than 5 and
aging the polyoxyethylated castor oil by exposing the
polyoxyethylated castor oil to a gas comprising oxygen until the
aged polyoxyethylated castor oil, if diluted 1:10 in water, has a
pH equal to or less than 4.9; and paclitaxel; wherein at least 80%
of the paclitaxel potency is retained by the pharmaceutical
composition after the pharmaceutical composition is stored for at
least 7 days at 40.degree. C.
59. The pharmaceutical composition according to claim 58, wherein
at least 90% of the paclitaxel potency is retained by the
pharmaceutical composition after the pharmaceutical composition is
stored for at least 7 days at 40.degree. C.
60. The pharmaceutical composition according to claim 58, wherein
at least 95% of the paclitaxel potency is retained by the
pharmaceutical composition after the pharmaceutical composition is
stored for at least 7 days at 40.degree. C.
61. The pharmaceutical composition according to claim 58, wherein
the pharmaceutical composition further comprises ethanol.
62. The pharmaceutical composition according to claim 61, wherein
the pharmaceutical composition comprises 500-550 mg/mL of
polyoxyethylated castor oil, and 40-60% of ethanol vol/vol.
63. The pharmaceutical composition according to claim 61, wherein
the pharmaceutical composition comprises 527 mg/mL of
polyoxyethylated castor oil, and 49.7% of ethanol vol/vol.
64. The pharmaceutical according to claim 61, wherein the
concentration of paclitaxel in the pharmaceutical composition is
about 1-20 mg/g.
65. A pharmaceutical comprising: a sealed vial comprising:
polyoxyethylated castor oil that has been modified by taking
polyoxyethylated castor oil which if diluted 1:10 in water has a pH
greater than 6 and aging the polyoxyethylated castor oil by
exposing the polyoxyethylated castor oil to a gas comprising oxygen
until the aged polyoxyethylated castor oil, if diluted 1:10 in
water, has a pH equal to or less than 5.9; and paclitaxel; wherein
the pharmaceutical does not comprise an agent added to the
polyoxyethylated castor oil that functions to increase the acidity
of the polyoxyethylated castor oil.
66. The pharmaceutical according to claim 65, wherein the vial
further comprises ethanol.
67. A pharmaceutical comprising: a sealed vial comprising
polyoxyethylated castor oil that has been modified by taking
polyoxyethylated castor oil which if diluted 1:10 in water has a pH
greater than 6 and aging the polyoxyethylated castor oil by
exposing the polyoxyethylated castor oil to a gas comprising oxygen
until the aged polyoxyethylated castor oil, if diluted 1:10 in
water, has a pH equal to or less than 5.9; and paclitaxel; wherein
at least 80% of the paclitaxel potency is retained by the
pharmaceutical after the pharmaceutical is stored for at least 7
days at 40.degree. C.
68. The pharmaceutical according to claim 67, wherein the vial
further comprises ethanol.
69. A pharmaceutical comprising: a sealed vial comprising
polyoxyethylated castor oil that has been modified by taking
polyoxyethylated castor oil which if diluted 1:10 in water has a pH
greater than 5 and aging the polyoxyethylated castor oil by
exposing the polyoxyethylated castor oil to a gas comprising oxygen
until the aged polyoxyethylated castor oil, if diluted 1:10 in
water, has a pH equal to or less than 4.9; and paclitaxel; wherein
at least 80% of the paclitaxel potency is retained by the
pharmaceutical after the pharmaceutical is stored for at least 7
days at 40.degree. C.
70. The pharmaceutical according to claim 69, wherein the vial
further comprises ethanol.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. application Ser.
No. 10/306,824 filed Nov. 26, 2002, which claims the benefit of
U.S. Provisional Application No. 60/333,459, filed Nov. 26, 2001,
entitled "Method For Preparing And Using Polyoxyethylated Castor
Oil In Pharmaceutical Compositions." These applications are
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates generally to the formulation
of pharmaceutical compositions. More particularly, the invention
relates to the preparation and use of polyoxyethylated castor oil
in pharmaceutical compositions.
DESCRIPTION OF RELATED ART
[0003] Paclitaxel has proven to be a highly sucessful
antineoplastic agent. It is currently administered to patients in a
formulation that comprises paclitaxel, Cremophor.RTM.
(polyoxyethylated castor oil), and ethanol.
[0004] Paclitaxel is a unique diterpene derived from the bark of
the Taxus brevifolia (Pacific yew) tree. A crude extract of the
bark demonstrated antineoplastic activity in preclinical tumor
screening 30 years ago as part of the National Cancer Institute's
(NCI's) large-scale screening program. The active component of the
extract, paclitaxel, was isolated and described by M. C. Wani et
al, Plant antitumor agents. VI: The isolation and structure of
Paclitaxel. a novel antileukemic and antitumor agent from Taxus
brevifolia, J. Am. Chem. Soc. 93:2325-2327 (1971). This document,
and all others referred to herein, are incorporated by reference as
if reproduced fully below.
[0005] Unfortunately, paclitaxel is poorly soluble in water (less
than 0.01 mg/mL) and other common vehicles used for the parenteral
administration of drugs. Certain organic solvents, however, may at
least partially dissolve paclitaxel. However, when a watermiscible
organic solvent containing paclitaxel at near its saturation
solubility is diluted with aqueous infusion fluid, the drug may
precipitate.
[0006] Solubilization of paclitaxel with surfactants allows for
dilution of saturated or near-saturated formulations of paclitaxel.
Specifically, paclitaxel has been formulated using 50%
Cremophor.RTM. EL 50% dehydrated alcohol (USP, United States
Pharmacopoeia), diluted in NS normal saline or D5W (5% dextrose in
water) to a final concentration of 5% Cremophor.RTM. EL and 5%
dehydrated alcohol or less, for the intravenous administration of
the drug to humans in early clinical trials. (Cremophor.RTM. EL;
Badische Anilin und Soda Fabrik AG (BASF), Ludwigshafen, Federal
Republic of Germany). A concentrate of paclitaxel for injection is
currently available from Bristol-Myers Squibb Co. (New York, N.Y.)
in vials where each milliliter of formulation contains
approximately 6 mg Paclitaxel, 527 mg of Cremophor.RTM. EL, and
49.7% (vol/vol) dehydrated alcohol. This concentrated formulation
must be further diluted with NS, D5W, D5NS (normal saline, 5%
dextrose in water and 5% dextrose in normal saline) or D5W-R
(Ringer's solution with 5% dextrose in water) prior to
administration. It has been noted that the Cremophor.RTM./ethanol
formulation of paclitaxel precipitates upon dilution with infusion
fluid, and fibrous precipitates formed in some compositions during
storage for extended periods of time. Additional information
regarding Cremophor.RTM. formulations of paclitaxel may be found in
Agharkar et al., U.S. Pat. No. 5,504,102.
[0007] It was discovered that commercial grade Cremophor.RTM. EL
with ethanol as a co-solvent, although effective in solubilizing
pharmaceutical agents, produces injection compositions that exhibit
instability over extended periods of time. In particular,
concentrated formulations of paclitaxel in a co-solvent of 50:50 by
volume of dehydrated ethyl alcohol and commercial grade
Cremophor.RTM. EL exhibit a loss of potency of greater than 60%
after storage for 12 weeks at 50.degree. C. The loss of potency is
attributed to the decomposition of paclitaxel during storage.
[0008] Various methods of stabilizing paclitaxel solubilized in
polyoxyethylated castor oil and ethanol during storage have been
developed. For example, U.S. Pat. Nos. 5,504,102, 5,733,888,
5,972,992, 5,977,164, 6,071,952, 6,140,359 each teach adding an
agent to modify the pH of the concentrated formulation in order to
stabilize paclitaxel.
[0009] Other concentrated formulations of taxoid compounds have
been developed. For example, several U.S. patents assigned to
Rhone-Poulenc Rorer (U.S. Pat. Nos. 5,403,858, 5,438,072,
5,670,536, 5,698,582, 5,714,512) provide a formulation composed of
a taxane compound dissolved in a surfactant selected from a group
consisting of polysorbate, polyoxyethylene glycol, or hydrogenated
castor oil, and essentially free of ethanol.
[0010] U.S. Pat. No. 6,071,952 to Owens et al discloses a human
administration comprising an anti-neoplastic taxol compound, a
solubilizing/dispersing agent, and a stabilizing amount of an
anti-oxidant.
[0011] It is important for concentrated formulations of paclitaxel
to have prolonged shelf lives since product instability increases
manufacturing costs due to extensive consumption of raw materials
and yields a product of inferior quality, both translating into
higher patient cost. Additional stabilization strategies for
paclitaxel and other pharmaceutically active agents are therefore
needed, one of which is provided by the present invention.
SUMMARY OF THE INVENTION
[0012] The present invention provides novel methods of preparing
pharmaceutical formulations containing polyoxyethylated castor oil
as excipient. In particular, methods are provided for preparing
pharmaceutical compositions containing paclitaxel formulated with
polyoxyethylated castor oil that has been aged to a reduced pH
value relative to that of polyoxyethylated castor oil freshly
synthesized. Aging can be performed by varying the time and
condition of storage, such as by heating, pressurization,
air-sparging or combinations thereof, without substantially
changing physical and chemical characteristics of polyoxyethylated
castor oil except its pH value. Such aged polyoxyethylated castor
oil is then mixed with a pharmaceutically active agent such as
paclitaxel. Pharmaceutical compositions comprising the aged
polyoxyethylated castor oil and a pharmaceutically active agent are
also provided. Paclitaxel formulations containing the aged
polyoxyethylated castor oil that is acidified without addition of
an acidifying chemical are believed to be physically and chemically
more stable than those formulated with polyoxyethylated castor oil
freshly synthesized or at higher pH.
[0013] In one aspect of the invention, a method is provided for
preparing a pharmaceutical composition.
[0014] In one embodiment, the method comprises:
[0015] taking polyoxyethylated castor oil which if diluted 1:10 in
water has a pH greater than 6 and aging the polyoxyethylated castor
oil by exposing the polyoxyethylated castor oil to a gas comprising
oxygen for a period of time, the exposure to the gas over the
period of time causing an acidity of the polyoxyethylated castor
oil to increase; and
[0016] forming a pharmaceutical composition comprising the aged
polyoxyethylated castor oil and a pharmaceutically active agent
such as paclitaxel and docetaxel, wherein at least 80% of the
potency of the pharmaceutically active agent is retained by the
pharmaceutical composition after the pharmaceutical composition is
stored for at least 7 days at 40.degree. C.
[0017] In another embodiment, the method comprises:
[0018] taking polyoxyethylated castor oil which if diluted 1:10 in
water has a pH greater than 6 and aging the polyoxyethylated castor
oil by exposing the polyoxyethylated castor oil to a gas comprising
oxygen until the aged polyoxyethylated castor oil, if diluted 1:10
in water, has a pH equal to or less than 5.9; and
[0019] forming a pharmaceutical composition comprising the aged
polyoxyethylated castor oil and a pharmaceutically active agent
such as paclitaxel and docetaxel.
[0020] Optionally, aging the polyoxyethylated castor oil is
performed until the aged polyoxyethylated castor oil, if diluted
1:10 in water, has a pH equal to or lower than 5.5, optionally
equal to or lower than 5, optionally equal to or lower than
4.8.
[0021] Optionally, aging the polyoxyethylated castor oil is
performed until the aged polyoxyethylated castor oil, if diluted
1:10 in water, has a pH between 3.7 and 5.9, optionally between 3.8
and 5.5, optionally between 3.9 and 5, and optionally between 4 and
4.8.
[0022] In yet another embodiment, the method comprises:
[0023] taking polyoxyethylated castor oil which if diluted 1:10 in
water has a pH greater than 6 and aging the polyoxyethylated castor
oil by exposing the polyoxyethylated castor oil to a gas comprising
oxygen for a period of time, the exposure to the gas over the
period of time causing an acidity of the polyoxyethylated castor
oil to increase; and
[0024] forming a pharmaceutical composition comprising the aged
polyoxyethylated castor oil, ethanol and paclitaxel; wherein at
least 80% of the paclitaxel potency is retained by the
pharmaceutical composition after the pharmaceutical composition is
stored for at least 7 days at 40.degree. C.
[0025] In yet another embodiment, the method comprises:
[0026] taking polyoxyethylated castor oil which if diluted 1:10 in
water has a pH greater than 6 and aging the polyoxyethylated castor
oil by exposing the polyoxyethylated castor oil to a gas comprising
oxygen until the aged polyoxyethylated castor oil, if diluted 1:10
in water, has a pH equal to or less than 5.9; and
[0027] forming a pharmaceutical composition comprising the aged
polyoxyethylated castor oil, ethanol and paclitaxel; wherein at
least 80% of the paclitaxel potency is retained by the
pharmaceutical composition after the pharmaceutical composition is
stored for at least 7 days at 40.degree. C.
[0028] In yet another embodiment, the method comprises:
[0029] taking polyoxyethylated castor oil which if diluted 1:10 in
water has a pH greater than 5 and aging the polyoxyethylated castor
oil by exposing the polyoxyethylated castor oil to a gas comprising
oxygen until the aged polyoxyethylated castor oil, if diluted 1:10
in water, has a pH equal to or less than 4.9; and
[0030] forming a pharmaceutical composition comprising the aged
polyoxyethylated castor oil, ethanol and paclitaxel, wherein at
least 80% of the paclitaxel potency is retained by the
pharmaceutical composition after the pharmaceutical composition is
stored for at least 7 days at 40.degree. C.
[0031] Optionally, aging the polyoxyethylated castor oil is
performed until the aged polyoxyethylated castor oil, if diluted
1:10 in water, has a pH less than or equal to 4.7, optionally equal
to or lower than 4.5, optionally equal to or lower than 4.2.
[0032] Optionally, aging the polyoxyethylated castor oil is
performed until the aged polyoxyethylated castor oil, if diluted
1:10 in water, has a pH between 3.7 and 4.9, optionally between 3.8
and 4.5, optionally between 3.9 and 4.3, and optionally between 4.0
and 4.5.
[0033] According to any of the above methods, the pharmaceutical
composition optionally comprises 500-550 mg/mL of polyoxyethylated
castor oil, and 40-60% of ethanol vol/vol. Optionally, the
pharmaceutical composition comprises 527 mg/mL of polyoxyethylated
castor oil, and 49.7% of ethanol vol/vol.
[0034] In regard to any of the above methods, an antioxidant or a
pharmaceutically acceptable alcohol such as ethanol may optionally
be added to the aged polyoxyethylated castor oil or the
pharmaceutical composition.
[0035] Aging of the polyoxyethylated castor oil may be performed
over a variety of time periods and under various conditions before
mixing the aged polyoxyethylated castor oil with the
pharmaceutically active agent such as paclitaxel.
[0036] In one variation, aging the polyoxyethylated castor oil is
performed for at least 30 minutes at a temperature range between
0.degree. C. and 70.degree. C. Preferably, aging the
polyoxyethylated castor oil is performed for at least 3 day,
optionally for at least 7 days, and optionally for at least 14
days, at a temperature range between 30.degree. C. and 70.degree.
C., optionally between 40.degree. C. and 60.degree. C., and
optionally between 45.degree. C. and 55.degree. C. As demonstrated
in the present invention, acidification of polyoxyethylated castor
oil is significantly accelerated by aging at a temperature higher
than the ambient temperature (about 20-25.degree. C.) and/or by
sparging air into the polyoxyethylated castor oil.
[0037] In another variation, aging the polyoxyethylated castor oil
is performed for at least 30 minutes at a temperature range between
0.degree. C. and 70.degree. C. by sparging the polyoxyethylated
castor oil with air.
[0038] In yet another variation, aging the polyoxyethylated castor
oil is performed for at least 30 minutes at a temperature range
between 0.degree. C. and 70.degree. C. by pressurizing the
polyoxyethylated castor oil to be at least 1.2 atmospheric
pressure, optionally at least 1.5 atmospheric pressure, optionally
at least 2.0 atmospheric pressure, and optionally at least 3.0
atmospheric pressure.
[0039] In regard to any of the above methods, optionally, at least
80%, at least 90% or at least 95% of the potency of paclitaxel is
retained by the pharmaceutical composition after the pharmaceutical
composition is stored for at least 7 days at 40.degree. C.
[0040] Also in regard to any of the above methods, it is preferred
that no agent is added that functions to increase the acidity of
the polyoxyethylated castor oil. However, a chemical acidifying
agent may optionally be added to the polyoxyethylated castor oil
before, during or after the aging process to further increase the
acidity of the polyoxyethylated castor oil. The acidifying agent
may be an organic acid. Examples of organic acid include, but are
not limited to, ascorbic acid, citric acid, tartaric acid, lactic
acid, oxalic acid, formic acid, benzene sulphonic acid, benzoic
acid, maleic acid, glutamic acid, succinic acid, aspartic acid,
diatrizoic acid, and acetic acid. The acidifying agent may also be
an inorganic acid, such as hydrochloric acid, sulphuric acid,
phosphoric acid, and nitric acid.
[0041] In another aspect of the invention, a pharmaceutical
composition is provided.
[0042] In one embodiment, the pharmaceutical composition comprises:
polyoxyethylated castor oil that has been modified by taking
polyoxyethylated castor oil which if diluted 1:10 in water has a pH
greater than 6 and aging the polyoxyethylated castor oil by
exposing the polyoxyethylated castor oil to a gas comprising oxygen
until the aged polyoxyethylated castor oil, if diluted 1:10 in
water, has a pH equal to or less than 5.9; and a pharmaceutically
active agent such as paclitaxel; wherein the pharmaceutical
composition does not comprise an agent added to the
polyoxyethylated castor oil that functions to increase the acidity
of the polyoxyethylated castor oil.
[0043] In another embodiment, the pharmaceutical composition
comprises: polyoxyethylated castor oil that has been modified by
taking polyoxyethylated castor oil which if diluted 1:10 in water
has a pH greater than 6 and aging the polyoxyethylated castor oil
by exposing the polyoxyethylated castor oil to a gas comprising
oxygen until the aged polyoxyethylated castor oil, if diluted 1:10
in water, has a pH equal to or less than 5.9; and a
pharmaceutically active agent such as paclitaxel; wherein at least
80% of the potency of the pharmaceutically active agent is retained
by the pharmaceutical composition after the pharmaceutical
composition is stored for at least 7 days at 40.degree. C.
[0044] In yet another embodiment, the pharmaceutical composition
comprises: polyoxyethylated castor oil that has been modified by
taking polyoxyethylated castor oil which if diluted 1:10 in water
has a pH greater than 5 and aging the polyoxyethylated castor oil
by exposing the polyoxyethylated castor oil to a gas comprising
oxygen until the aged polyoxyethylated castor oil, if diluted 1:10
in water, has a pH equal to or less than 4.9; and a
pharmaceutically active agent such as paclitaxel; wherein at least
80% of the potency of the pharmaceutically active agent is retained
by the pharmaceutical composition after the pharmaceutical
composition is stored for at least 7 days at 40.degree. C.
[0045] In yet another aspect of the invention, a pharmaceutical is
provided.
[0046] In one embodiment, the pharmaceutical comprises: a sealed
vial comprising polyoxyethylated castor oil that has been modified
by taking polyoxyethylated castor oil which if diluted 1:10 in
water has a pH greater than 6 and aging the polyoxyethylated castor
oil by exposing the polyoxyethylated castor oil to a gas comprising
oxygen until the aged polyoxyethylated castor oil, if diluted 1:10
in water, has a pH equal to or less than 5.9; and a
pharmaceutically active agent such as paclitaxel, wherein the
pharmaceutical does not comprise an agent added to the
polyoxyethylated castor oil that functions to increase the acidity
of the polyoxyethylated castor oil.
[0047] In another embodiment, the pharmaceutical comprises: a
sealed vial comprising polyoxyethylated castor oil that has been
modified by taking polyoxyethylated castor oil which if diluted
1:10 in water has a pH greater than 6 and aging the
polyoxyethylated castor oil by exposing the polyoxyethylated castor
oil to a gas comprising oxygen until the aged polyoxyethylated
castor oil, if diluted 1:10 in water, has a pH equal to or less
than 5.9; and a pharmaceutically active agent such as paclitaxel,
wherein at least 80% of the potency of the pharmaceutically active
agent is retained by the pharmaceutical after the pharmaceutical is
stored for at least 7 days at 40.degree. C.
[0048] In yet another embodiment, the pharmaceutical comprises: a
sealed vial comprising polyoxyethylated castor oil that has been
modified by taking polyoxyethylated castor oil which if diluted
1:10 in water has a pH greater than 5 and aging the
polyoxyethylated castor oil by exposing the polyoxyethylated castor
oil to a gas comprising oxygen until the aged polyoxyethylated
castor oil, if diluted 1:10 in water, has a pH equal to or less
than 4.9; and a pharmaceutically active agent such as paclitaxel,
wherein at least 80% of the potency of the pharmaceutically active
agent is retained by the pharmaceutical after the pharmaceutical is
stored for at least 7 days at 40.degree. C.
[0049] In regard to any embodiment of the above pharmaceutical
compositions or pharmaceuticals, an antioxidant or a
pharmaceutically acceptable alcohol such as ethanol may optionally
be added to the aged polyoxyethylated castor oil or the
pharmaceutical composition. For example, the pharmaceutical
composition or pharmaceutical may comprise 500-550 mg/mL of
polyoxyethylated castor oil, and 40-60% of ethanol vol/vol and
optionally comprises 527 mg/mL of polyoxyethylated castor oil, and
49.7% of ethanol vol/vol.
[0050] In regard to any embodiment of the above pharmaceutical
compositions or pharmaceuticals, a pharmaceutically acceptable
glycol such as propylene glycol and polyethylene glycol (PEG) or
amide such as 2-pyrrolidone, N-methyl-pyrrolidone and N,N-dimethyl
acetamide may optionally be added to the aged polyoxyethylated
castor oil or the pharmaceutical composition.
[0051] In regard to any embodiment of the above pharmaceutical
compositions or pharmaceuticals, the concentration of paclitaxel in
the pharmaceutical composition is optionally about 1-20 mg/g,
optionally about 3-15 mg/g, and optionally about 5-8 mg/g.
[0052] In regard to any embodiment of the above pharmaceutical
compositions or pharmaceuticals, optionally at least 80%, at least
90% or at least 95% of the potency is retained by the
pharmaceutical composition after the pharmaceutical composition is
stored for at least 7 days at 40.degree. C.
[0053] Also in regard to any embodiment of the above pharmaceutical
compositions or pharmaceuticals, preferably no acidifying chemical
agent is added that functions to increase the acidity of the
polyoxyethylated castor oil. However, an inorganic or organic acid
may be added to the polyoxyethylated castor oil before, during or
after the aging process to further reduce the pH of the
polyoxyethylated castor oil.
BRIEF DESCRIPTION OF FIGURES
[0054] The various features and aspects of the instant invention
may be more readily understood, in conjunction with the description
to follow, by reference to the following drawings:
[0055] FIG. 1 is a plot over time of the pH of samples of
Cremophor.RTM. ELP (after having been diluted 1/10 (vol/vol) with
H.sub.2O) that have been stored under ambient conditions.
[0056] FIG. 2 is a plot over time of the pH of samples of
Cremophor.RTM. ELP (after having been diluted 1/10 (vol/vol) with
H.sub.2O) that have been stored at 50.degree. C. at ambient
atmospheric pressure.
[0057] FIG. 3 is a plot over time of the pH of samples of
Cremophor.RTM. ELP (after having been diluted 1/10 (vol/vol) with
H.sub.2O) that have been stored at 70.degree. C. at ambient
atmospheric pressure.
DEFINITIONS
[0058] The term "polyoxyethylated castor oil" (also sometimes
referred to elsewhere as polyethoxylated castor oil) refers to
products resulting from the condensation of castor oil with
ethylene oxide. Polyoxyethylated castor oil is commercially
available and has been used to solubilize and disperse
anti-neoplastic compounds such as paclitaxel. For example,
polyoxyethylated castor oil products are available under the trade
names Cremophor.RTM. EL and Cremophor.RTM. ELP. These products are
readily available through BASF Germany. The preparation of
Cremophor.RTM. EL is described in U.S. Pat. No. 3,070,499. A low
cation version of polyoxyethylated castor oil, Cremophor.RTM. EL
and its preparation is described in U.S. Pat. No. 5,925,776.
[0059] The term "paclitaxel" is intended to include paclitaxel,
taxoid, taxane, or any derivatives and analogs of paclitaxel, such
as the semi-synthetic drug derived from precursor extracted from
the needles of the European yew tree Taxus baccata, docetaxel or
Taxotere.RTM..
[0060] The term "therapeutic" refers to prophylaxis and to
amelioration and cure of a disease or pathology, and/or the
symptoms and/or sequelae thereof. Therapeutic agents may exert
their effects, for example, by preventing or halting the
pathogenesis, reducing the rate or extent of pathophysiologic
progression, or alleviating the symptomatology of a disease or
pathologic condition.
[0061] The phrase "therapeutically acceptable" in the context of a
describing a pharmacologic or pharmaceutical composition,
encompasses the concept of therapeutic index of a dosing unit as
commonly defined in terms of a ratio of LD.sub.50 (lethal dose to
50% of population) to ED.sub.50 (effective dose to 50% of
population) in the context of the severity of a disease process as
described, for example in Hardman & Limbird, Eds., Goodman
& Gilman's Pharmacologic Basis of Therapeutics, 10.sup.th Ed,
McGraw-Hill Co., Inc. (2001).
[0062] Additionally encompassed by therapeutic acceptability are
concepts of long term or cumulative toxicity, as for example when a
composition or impurity thereof can cause pathology over a long
period of administration without there being a lethal dose for
acute administration. Also encompassed infectious pathogenic
impurities, including eukaryotic, prokaryotic, viral and
proteinacious infectious agents.
[0063] The population is typically a human population, but
therapeutically acceptable for humans ipso facto encompasses
therapeutic acceptability for other members of Kingdom animalia.
Thus any factor that affects efficacy and/or acute or long-term
toxicity of a dosing unit is encompassed by the phrase
therapeutically acceptable. Therapeutically acceptable incorporates
suitability for administration in terms of acceptable toxicity for
the disease process treated. A therapeutically acceptable
formulation must have both acceptable efficacy and acute and
chronic toxicity. In the case of a pharmacologic agent that
decomposes into a biologically or pharmacologically inactive
decomposition product that is relatively non-toxic compared to the
pharmacologic agent, therapeutic acceptability is in terms of an
acceptable level of the active agent.
[0064] The term "pH" refers to or describes a measurement made of
the--log.sub.10 of [H.sup.+] (concentration in units M=moles/liter)
of a solution. Because pH measurements are preferably made in an
aqueous environment and polyoxyethylated castor oil is anhydrous,
polyoxyethylated castor oil is diluted 1:10 using deionized or
distilled water prior to measuring its pH. For example, a sample
volume, V, of polyoxyethylated castor oil is taken and diluted in a
volume, 10*V, of water prior. After dilution, the pH of the
resulting solution is measured.
DETAILED DESCRIPTION OF THE INVENTION
[0065] The present invention is directed to pharmaceutical
compositions that comprise polyoxyethylated castor oil that have
been aged by exposing the polyoxyethylated castor oil to a gas
comprising oxygen for a period of time, the exposure to the gas
over the period of time causes an acidity of the polyoxyethylated
castor oil to increase. The present invention is also related to
methods for aging polyoxyethylated castor oil and for preparing
these pharmaceutical compositions.
[0066] The present invention arises from the inventors' discovery
that exposing polyoxyethylated castor oil to a gas comprising
oxygen causes the acidity of the polyoxyethylated castor oil to
increase. This discovery is evidenced by the observation that the
pH of 1:10 water diluted solutions made from samples of
polyoxyethylated castor oil aged for different periods of time
decrease as a function of time.
[0067] U.S. Pat. Nos. 5,504,102, 5,733,888, 5,972,992, 5,977,164,
6,071,952, 6,140,359 teach that extraneous acidifying agents need
to be added to paclitaxel polyoxyethylated castor oil--ethanol
formulations in order to stabilize the paclitaxel. By aging the
polyoxyethylated castor oil by exposing it to oxygen, the
polyoxyethylated castor oil is acidified without having to add an
acidifying agent to the polyoxyethylated castor oil.
[0068] The acidification of the polyoxyethylated castor oil
achieved by aging the polyoxyethylated castor oil according to the
present invention is believed to provide several advantages over
acidifying the polyoxyethylated castor oil by the addition of an
acidifying agent, such as mineral acid. For example, titration with
an acidifying agent may be imprecise. Furthermore, when the native
acidity of the polyoxyethylated castor oil changes via aging
according to the present invention, it is likely to be as a result
of the formation of carboxylic acids. This higher concentration of
carboxylic acids serves as a more stable buffer for the protonation
of the paclitaxel molecules that impedes paclitaxel's
decomposition.
[0069] While the present invention is largely described herein in
relation to pharmaceutical compositions comprising paclitaxel, it
is noted that the invention is intended to encompass any
pharmaceutical compositions comprising a pharmaceutically active
agent in combination with polyoxyethylated castor oil aged
according to the present invention. Numerous different
pharmaceutically active agents may be formulated with
polyoxyethylated castor oil. For example, U.S. Pat. No. 5,504,102
to Agharkar, et al. teaches formulating paclitaxel, teniposide,
camptothecin and other antineoplastic agents with polyoxyethylated
castor oil.
[0070] In one embodiment, the pharmaceutical composition comprises
a taxane or analog or derivative of a taxane as the
pharmaceutically active agent such as docetaxel. In a particular
embodiment, the taxane is paclitaxel. Given the success of
paclitaxel as an antineoplastic agent, a great deal of research has
been performed to identify pharmaceutically active taxanes as well
as analogs and derivatives of taxanes, all of which may be
formulated with polyoxyethylated castor oil aged according to the
present invention.
[0071] Given the significance of paclitaxel, a particular
embodiment of the present invention comprises polyoxyethylated
castor oil aged according to the present invention, paclitaxel, and
ethanol. Optionally, the pharmaceutical composition comprises
500-550 mg/mL of polyoxyethylated castor oil and 40-60% of ethanol
vol/vol. For example, in a very particular embodiment, the
pharmaceutical composition comprises 527 mg/mL of polyoxyethylated
castor oil and 49.7% of ethanol vol/vol.
[0072] Pharmaceutical compositions according to the present
invention are typically supplied as a nonaqueous solution intended
for dilution with a suitable aqueous parenteral fluid prior to
intravenous infusion. The pharmaceuticals are generally available
in different sized single dose or multidose sealed vials. For
example, 30 mg (5 ml), 100 mg (16.7 ml), and 300 mg (50 ml) vials
of paclitaxel/Cremophor/ethanol are currently produced.
[0073] In order to administer the pharmaceutical compositions from
these vials, the compositions are diluted with an aqueous solution
so that intravenous infusions which typically have 135 to 175
mg/m.sup.2 paclitaxel may be delivered over a period of 3 to 24
hours.
[0074] Aging the polyoxyethylated castor oil by exposing it to a
gas comprising oxygen may be performed over a wide range of
temperatures, pressures and times. For example, aging may
optionally be performed at a temperature range between 0oC and
70oC. Preferably, aging the polyoxyethylated castor oil is
performed for at least 1 day, more preferably for at least 3 days,
and most preferably for at least 7 days, at a temperature range
between 30.degree. C. and 70.degree. C., more preferably between
40oC and 60.degree. C., and most preferably between 45.degree. C.
and 55.degree. C.
[0075] As shown in Examples 1-3 herein and FIGS. 1-3, acidification
of polyoxyethylated castor oil is accelerated with elevated
temperatures, although the rate of acceleration appears to decrease
at temperatures above 50.degree. C. Nevertheless, aging
polyoxyethylated castor oil at temperatures higher than 70.degree.
C. is still intended to fall within the scope of the present
invention.
[0076] As described herein with regard to Example 4, sparging
polyoxyethylated castor oil with air can be used to accelerate the
acidification of polyoxyethylated castor oil. Sparging functions to
agitate the polyoxyethylated castor oil. More importantly, sparging
improves mixing between the sparged air and the polyoxyethylated
castor oil.
[0077] One of skill in the art will also appreciate that increasing
the pressure of an atmospheric gas mixture over the
polyoxyethylated castor oil could accelerate the aging of the
polyoxyethylated castor oil. Increasing the pressure could also
allow higher temperatures to be used for incubating the
polyoxyethylated castor oil. For example, aging the
polyoxyethylated castor oil can be performed for at least 30
minutes at a temperature range between 0.degree. C. and 70.degree.
C. by pressurizing the polyoxyethylated castor oil to be at least
1.2 atmospheric pressure, optionally at least 1.5 atmospheric
pressure, optionally at least 2.0 atmospheric pressure, and
optionally at least 3.0 atmospheric pressure.
[0078] Aging may be performed for a variety of periods of time. How
long the polyoxyethylated castor oil needs to be aged is dependent
upon the aging conditions, for example the temperature, the
pressure, and how the polyoxyethylated castor oil is exposed to
oxygen. As described herein with regard to Examples 1-3 and FIGS.
1-3, aging of polyoxyethylated castor oil can be accelerated when
aging is performed at higher temperatures and/or with sparging. In
one variation, aging is performed for at least 30 minutes,
preferably for at least 1 day, more preferably for at least 3 days,
and most preferably for at least 7 days.
[0079] It should be recognized that wide variations of temperature,
pressure, and time condition(s), including conditions not
exemplified herein, are intended within the scope of the instant
invention, so long as a desired level of aging is achieved.
[0080] The acidity of polyoxyethylated castor oil can be readily
monitored by monitoring the pH of a solution comprising a sample of
the polyoxyethylated castor oil which has been diluted 1:10 with
water. This allows the aging of the polyoxyethylated castor oil to
be efficiently monitored. As a result, the aging process may be
monitored and discontinued when the pH of the diluted solution
reaches a desired pH. Accordingly, different aging conditions may
be employed without losing track of the acidification of the
polyoxyethylated castor oil.
[0081] When obtained from commercial suppliers, polyoxyethylated
castor oil, prior to aging, typically has a pH greater than 6 when
diluted with 1:10 with water. According to the present invention,
the desired pH to which the polyoxyethylated castor oil should be
aged is less than 5.9, optionally less than 5.5, optionally less
than 5 and optionally less than 4.8. Optionally, the pH of the
diluted solution of the aged polyoxyethylated castor oil may be
between 3.7 and 5.9, 3.8 and 5.5, 3.9 and 5, or 4 and 4.8.
[0082] Sometimes, the commercially available polyoxyethylated
castor oil, for example, Cremophor.RTM. ELP supplied by BASF, is
within a pH range of 5.0-7.0. If the polyoxyethylated castor oil is
at pH lower than 6 but higher than 5.0, it may also be aged
according to the present invention to reach a pH equal to or lower
than 4.9, optionally equal to or lower than 4.7, optionally equal
to or lower than 4.5, and optionally equal to or lower than
4.2.
[0083] Optionally, aging the polyoxyethylated castor oil is
performed until the aged polyoxyethylated castor oil, if diluted
1:10 in water, has a pH between 3.7 and 4.9, optionally between 3.8
and 4.5, optionally between 3.9 and 4.3, and optionally between 4.0
and 4.5.
[0084] The polyoxyethylated castor oil used in the pharmaceutical
compositions of the present invention should be aged sufficiently
so that the pharmaceutically active agent comprised in the
pharmaceutical composition is stable. For example, in one
variation, at least 80% of the potency of the pharmaceutically
active agent is retained by the pharmaceutical composition after
the pharmaceutical composition is stored for at least 7 days at
40.degree. C. Preferably, at least 90%, 95% or more of the potency
of the pharmaceutically active agent is retained. For the purposes
of this application, storage for at least 7 days at 40.degree. C.
is used as a benchmark.
[0085] Optionally, the pharmaceutical composition may further
comprise additional constituents including any additives that are
appropriate for the intravenous administration route used for
paclitaxel. Thus, any additive that is soluble, suspendable or
emulsifiable in aged polyoxyethylated castor oil may be employed.
Such additives may include microcrystalline and ground amorphous
solids, in suspension, soluble solids and miscible liquids in
solution, and emulsified immiscible liquids, typically with an
emulsifying agent such as lecithin and surfactants including
detergents.
[0086] Pharmaceutically acceptable alcohols may also be added to
the pharmaceutical composition. For example, ethanol is commonly
used in on combination with polyoxyethylated castor oil for the
formulation of paclitaxel. Optionally, a pharmaceutically
acceptable glycol such as propylene glycol and polyethylene glycol
(PEG) or amide such as 2-pyrrolidone, N-methyl-pyrrolidone and
N,N-dimethyl acetamide may be added to the aged polyoxyethylated
castor oil or the pharmaceutical composition.
[0087] Antioxidants may also be added to the pharmaceutical
composition. Antioxidants have previously been used to stabilize
paclitaxel in pharmaceutical compositions for example as disclosed
in U.S. Pat. Nos. 6,153,644 and 6,071,952 to Owens et al., and may
be added to formulations according to the instant invention.
[0088] It is preferred that no agent is added that functions to
increase the acidity of the polyoxyethylated castor oil. However, a
chemical acidifying agent may optionally be added to the
polyoxyethylated castor oil before, during or after the aging
process to further increase the acidity of the polyoxyethylated
castor oil. The acidifying agent may be an organic acid. Examples
of organic acid include, but are not limited to, ascorbic acid,
citric acid, tartaric acid, lactic acid, oxalic acid, formic acid,
benzene sulphonic acid, benzoic acid, maleic acid, glutamic acid,
succinic acid, aspartic acid, diatrizoic acid, and acetic acid. The
acidifying agent may also be an inorganic acid, such as
hydrochloric acid, sulphuric acid, phosphoric acid, and nitric
acid.
EXAMPLES
[0089] The following examples further illustrate the invention and
are not to be construed to limit the claims in any manner.
Example 1
[0090] Three different lots of Cremophor.RTM. ELP were stored in
original plastic containers under ambient conditions. Samples from
these lots were taken at different times. The pH of these samples,
after being diluted 1:10 with water, was measured. Table 1 provides
the pH measurements for the samples. The pH measurements are also
plotted in FIG. 1. As can be seen from both Table 1 and FIG. 1,
Cremophor.RTM. ELP becomes more acidic over time. Without being
bound by theory, it appears from FIG. 1 that the acidification of
the Cremophor.RTM. ELP decelerates over time under ambient
conditions such that the resulting pH may plateau around pH 3.6 and
4.0.
1TABLE 1 pH of different lots of Cremophor ELP measured at
predetermined time intervals. Lot # 14-3441 42-3489 94-3817 pH on
Certificate of Analysis provided by BASF TTime (Months) 6.4 6.1 6.1
Initial 4.1 5.1 6.1 1 4.2 5.3 6.2 2 4.0 4.7 6.0 3 3.6 4.1 5.6 4 3.6
4.0 5.0
Example 2
[0091] Twenty (20) mL aliquots obtained from two lots of
Cremophor.RTM. ELP were stored in glass vials at 50.degree. C.
Samples from these aliquots were taken at different times. The pH
of these samples, after being diluted 1:10 with water, was
measured. Table 2 provides the pH measurements for the samples. The
pH measurements are also plotted in FIG. 2.
[0092] As can be seen from both the table and FIG. 2, increasing
the storage temperature from ambient to 50.degree. C. accelerates
the rate at which the acidity of the Cremophor increases. For
example, the pH of samples from Lot 94-3817 stored at 50.degree. C.
dropped from 6.1 to 4.4 in four weeks whereas it took samples from
Lot 94-3817 stored at ambient conditions to drop from pH 6.1 to pH
5.0 in four months (see Table 1 for results).
2TABLE 2 pH measurements of different lots of Cremophor .RTM. ELP
at predetermined time intervals following storage at 50.degree. C.
42-3489 94-3817 pH on Certificate of Analysis provided by BASF Time
(weeks) 6.1 6.1 Initial 4.6 6.1 2 4.6 5.7 4 3.9 4.4 8 3.8 4.0
Example 3
[0093] Twenty (20) mL aliquots obtained from three lots of
Cremophor.RTM. ELP were stored in glass vials and in plastic
containers at 70.degree. C. Samples from these aliquots were taken
at different times. The pH of these samples, after being diluted
1:10 with water, was measured. Table 3 provides the pH measurements
for the samples. The pH measurements are also plotted in FIG.
3.
[0094] Increasing the storage temperature from 50.degree. C. to 70
.degree. C. does not greatly accelerate the rate at which the
acidity of the Cremophor increases when results for different lots
of Cremophor ELP in Table 2 are compared with corresponding results
in Table 3.
[0095] The type of container used to age Cremophor.RTM. ELP did not
appear to be critical. For example, the pH of samples from Lot
94-3817 stored at 70.degree. C. dropped from pH 6.1 to 4.1 in four
weeks in plastic container and pH 4.2 in the same time when stored
in glass container. However, the pH data from Lot #37-3442 suggests
some vulnerability of plastic to pH drop over glass and may be
attributed to high permeability of plastic to air. A larger sample
size may be required to confirm this observation. A strong linear
relationship between pH drop and time over the entire range of pH
3.5 to 6.0 is not evidenced based on the r.sup.2 values except for
lot 37-3442 contained in a glass vial in which case the pH
measurements were limited to the range of 6.1-4.4. It appears that
due to deceleration in the pH drop around pH of 4, the slope beyond
this point changes thereby deviating from linearity.
[0096] Lot #94-3817 and 37-3442 have similar slopes and differ from
that of Lot #42-3489. Decrease in the slope in the latter case is
probably due to deceleration in the pH drop beyond pH of 4.4.
3 TABLE 3 Lot # 42-3489 94-3817 37-3442 pH on Certificate of
Analysis provided by BASF Time (weeks) 6.1 6.1 6.8 Initial 4.9 5.7
6.1 Container Type Plastic Glass Plastic Glass Plastic Glass Bottle
Vial Bottle Vial Bottle Vial 1 4.4 4.4 4.7 4.9 5.2 5.6 2 4.2 4.3
4.4 4.6 4.7 5.3 3 4.1 4.2 4.2 4.3 4.4 5.0 4 4.0 4.1 4.1 4.2 4.3 4.8
5 3.9 3.9 3.9 4.0 4.0 4.4 Slopes -0.18 -0.17 -0.31 -0.31 -0.39
-0.32 r.sup.2 0.86 0.89 0.82 0.89 0.89 0.98
Example 4
[0097] This experiment was performed in order to evaluate whether
sparging with air affects the rate at which the polyoxyethylated
castor oil acidifies. It is noted that this experiment was
performed on larger volumes (4 L) than the volumes used in Examples
1-3.
[0098] A temperature controlled stainless steel jacketed vessel was
charged twice, each time with 4 L of polyoxyethylated castor oil
from the same lot, Lot #63-4693. While the first time, the vessel
was fitted with an air sparger (flow rate of 4.65 Standard Liters
Per Minute) and sparged with compressed air (treatment A); sparging
was eliminated the second time (treatment B). In both treatment A
and B the polyoxyethylated castor oil contained in the vessel was
incubated at 50.degree. C. to 60.degree. C. No additional agitation
was provided other than the agitation caused by sparging. The
temperature of the polyoxyethylated castor oil was measured
periodically.
[0099] Samples from the vessel were taken at different times during
treatment A and B. The pH of these samples, after being diluted
1:10 with water, was measured. Table 4 provides the pH measurements
for the samples. The experiment was conducted until samples from
the vessel with sparging were found to have a pH between 4.0-4.8.
The experiment was continued a few additional days in treatment B
(without sparging) and was discontinued thereafter.
4TABLE 4 Temperature Treatment A Treatment B Day of the contents
(.degree. C.) Sparged w/air Without air pH 6.4 (BASF, Cert. of
Analysis) 0 -- 6.6 6.6 1 52 6.4 6.6 2 56 6.6 6.6 3 -- 6.3 6.6 4 62
6.0 -- 5 -- -- -- 6 -- -- 6.5 7 60 4.4 6.4 8 -- 6.3 9 -- 6.3 13 --
5.9
[0100] As can be seen from Table 4, air sparging was found to
significantly accelerate the acidification of polyoxyethylated
castor oil. For example, diluted samples of sparged
polyoxyethylated castor oil had a pH of 4.4 after one week.
Meanwhile, diluted samples of polyoxethylated castor oil that was
not sparged had a pH of 5.9 after 13 days.
[0101] The observed increased rate of acidification as a result of
sparging may be due to mixing of the polyoxyethylated castor oil
itself caused by sparging or mixing between the polyoxyethylated
castor oil and sparged air.
[0102] The observation from Example 3 that acidification is faster
in a more air permeable container (i.e., plastic) is consistent
with sparging enhances the acidification kinetics by a combination
of mixing and the delivery of air to the polyoxyethylated castor
oil.
Example 5
[0103] 8024 grams of Cremophor.RTM. ELP was aged in four separate
containers (2006 g/container) at 50.degree. C. at ambient pressure
with sparging. Aging was performed in the temperature controlled
stainless steel jacketed vessel, fitted with an air sparger (Flow
rate of 4.65 Standard Liters Per Minute) used in Example 4. After
aging for 7 days, the pH of a diluted sample of the
polyoxyethylated castor oil was below 4.8 for all the containers,
the pH measurements varying from 4.3 to 4.5 between the
containers.
Example 6
[0104] 8024 grams of Cremophor.RTM. ELP was aged in four separate
containers (2006 g/container) at 60.degree. C. at ambient pressure
with sparging. Aging was performed in the temperature controlled
stainless steel jacketed vessel, fitted with an air sparger (Flow
rate of 4.65 Standard Liters Per Minute) used in Example 4. After
aging for 7 days, the pH of a diluted sample of the
polyoxyethylated castor oil was below 4.8 for all the containers,
the pH measurements varying from 4.3 to 4.5 between the
containers.
Example 7
[0105] A large batch of pharmaceutical compositions according to
the present invention may be formed as follows. 750 grams of a
polyoxyethylated castor oil aged according to the present invention
may be placed into a 2 liter glass carboy. 560 grams of Dehydrated
Ethanol, USP may then be added to the aged polyoxyethylated castor
oil and mixed for a minimum of 10 minutes or until homogeneously
dispersed. The headspace of the carboy is flushed with filtered
nitrogen while mixing. Nitrogen flushing of the carboy headspace is
continued as 8.5 grams of paclitaxel are added and mixed until
completely dissolved.
[0106] The final solution weight is adjusted to 1,325 grams with
dehydrated ethanol, flushed with filtered nitrogen and mixed
thoroughly. This final solution is aseptically filled into 5 ml
unit vials.
[0107] While the instant invention is disclosed with reference to
preferred embodiments detailed above, it is to be understood that
these embodiments are intended in an illustrative or exemplary
rather than in a limiting sense, as it is contemplated that
modifications will readily occur to those skilled in the art,
modifications which will be within the spirit of the invention and
the scope of the appended claims. All patents, papers, articles,
references and books cited herein are incorporated by reference in
their entirety.
* * * * *