US20040204479A1 - Injectable composition - Google Patents
Injectable composition Download PDFInfo
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- US20040204479A1 US20040204479A1 US10/835,875 US83587504A US2004204479A1 US 20040204479 A1 US20040204479 A1 US 20040204479A1 US 83587504 A US83587504 A US 83587504A US 2004204479 A1 US2004204479 A1 US 2004204479A1
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- United States
- Prior art keywords
- acid
- citric acid
- paclitaxel
- citric
- composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
Definitions
- 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.
- 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/depolymerization toward polymer assembly and to stabilize microtubules against depolymerization under conditions which would cause rapid disaggregation of microtubules.
- the interference with the polymerization/depolymerization cycle in cells appears to interfere with both the replication and migration of cells.
- paclitaxel 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.
- the invention provides a solution containing paclitaxel, cremophor ELTM and ethanol, characterized in that the pH of the solution has been adjusted into the range 1 to 8 by addition of an acid.
- Acids in the form of powders for example citric acid
- 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:
- Citric acid monohydrous
- Paclitaxel is usually prepared and administered in a vehicle containing cremophor ELTM (a polyethoxylated castor oil which acts as a solubilizer) and ethanol.
- cremophor ELTM a polyethoxylated castor oil which acts as a solubilizer
- BMS Bristol-Myers Squibb
- 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.
- 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.
- Cremophor EL was weighed out into the main mixing vessel.
- 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.
- a solution was prepared with the following formulation: 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.
- a solution was prepared with the following formulation: 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.
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.
Description
- 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.
- 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.
- 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/depolymerization toward polymer assembly and to stabilize microtubules against depolymerization under conditions which would cause rapid disaggregation of microtubules. The interference with the polymerization/depolymerization cycle in cells appears to interfere with both the replication and migration of cells.
- 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.
- 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.
- 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.
- Accordingly, in a general aspect the invention provides a solution containing paclitaxel, cremophor EL™ and ethanol, characterized in that the pH of the solution has been adjusted into the range 1 to 8 by addition of an acid.
- 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:
- Citric acid—monohydrous
- Citric acid—anhydrous
- Citric acid—hydrous
- Acetic acid
- Formic acid
- Ascorbic acid
- Aspartic acid
- Benzene sulphonic acid
- Benzoic acid
- Hydrochloric acid
- Sulphuric acid
- Phosphoric acid
- Nitric acid
- Tartaric acid
- Diatrizoic acid
- Glutamic acid
- Lactic acid
- Maleic acid
- Succinic acid
- Due to its limited solubility in water, Paclitaxel is usually prepared and administered in a vehicle containing cremophor EL™ (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.
- 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.
- In a preferred procedure adopted by the applicant, which it will be clearly understood is non-limiting, the following steps were carried out:
- Mixing Instructions
- Solution 1
- 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.
- Solution 2
- Cremophor EL was weighed out into the main mixing vessel.
- Solution 3
- 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.
- A solution was prepared with the following formulation:
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. - 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)
Sample 2 per mL Paclitaxel 6 mg Cremophor EL 0.5 mL Absolute Alcohol to 1 mL - The solutions were filled into clear type 1 glass 5 mL vials and sealed with rubber bungs.
- The solutions were stored at 40° C. for 7 (seven) days and the stability results are shown in Table 1.
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. - A solution was prepared with the following formulation:
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. - The solution was filled into clear type I glass 5 mL vials and sealed with rubber bungs.
- The solution was stored at 40° C. for 7 days.
- The stability results obtained are compared to those seen with Sample 2.
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% - Again the significantly superior stability of the formulation according to the invention (Sample 3) is evident.
- It will be clearly understood that the invention in its general aspects is not limited to the specific details referred to hereinabove.
Claims (104)
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° 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° 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° 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° 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° 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.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/835,875 US20040204479A1 (en) | 1992-11-27 | 2004-04-29 | Injectable composition |
Applications Claiming Priority (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU6074 | 1984-07-18 | ||
AUPL607492 | 1992-11-27 | ||
US99550192A | 1992-12-22 | 1992-12-22 | |
US08/594,478 US5733888A (en) | 1992-11-27 | 1996-01-31 | Injectable composition |
US08/979,836 US5977164A (en) | 1992-11-27 | 1997-11-26 | Stabilized pharmaceutical composition |
US09/028,906 US5972992A (en) | 1992-11-27 | 1998-02-24 | Injectable composition |
US09/356,158 US6140359A (en) | 1992-11-27 | 1999-07-19 | Injectable composition |
US09/563,969 US6306894B1 (en) | 1992-11-27 | 2000-05-03 | Injectable composition |
US09/970,558 US6770670B2 (en) | 1992-11-27 | 2001-10-04 | Injectable composition |
US10/835,875 US20040204479A1 (en) | 1992-11-27 | 2004-04-29 | Injectable composition |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/970,558 Continuation US6770670B2 (en) | 1992-11-27 | 2001-10-04 | Injectable composition |
Publications (1)
Publication Number | Publication Date |
---|---|
US20040204479A1 true US20040204479A1 (en) | 2004-10-14 |
Family
ID=25644377
Family Applications (7)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/594,478 Expired - Lifetime US5733888A (en) | 1992-11-27 | 1996-01-31 | Injectable composition |
US08/979,836 Expired - Lifetime US5977164A (en) | 1992-11-27 | 1997-11-26 | Stabilized pharmaceutical composition |
US09/028,906 Expired - Lifetime US5972992A (en) | 1992-11-27 | 1998-02-24 | Injectable composition |
US09/356,158 Expired - Fee Related US6140359A (en) | 1992-11-27 | 1999-07-19 | Injectable composition |
US09/563,969 Expired - Fee Related US6306894B1 (en) | 1992-11-27 | 2000-05-03 | Injectable composition |
US09/970,558 Expired - Fee Related US6770670B2 (en) | 1992-11-27 | 2001-10-04 | Injectable composition |
US10/835,875 Abandoned US20040204479A1 (en) | 1992-11-27 | 2004-04-29 | Injectable composition |
Family Applications Before (6)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/594,478 Expired - Lifetime US5733888A (en) | 1992-11-27 | 1996-01-31 | Injectable composition |
US08/979,836 Expired - Lifetime US5977164A (en) | 1992-11-27 | 1997-11-26 | Stabilized pharmaceutical composition |
US09/028,906 Expired - Lifetime US5972992A (en) | 1992-11-27 | 1998-02-24 | Injectable composition |
US09/356,158 Expired - Fee Related US6140359A (en) | 1992-11-27 | 1999-07-19 | Injectable composition |
US09/563,969 Expired - Fee Related US6306894B1 (en) | 1992-11-27 | 2000-05-03 | Injectable composition |
US09/970,558 Expired - Fee Related US6770670B2 (en) | 1992-11-27 | 2001-10-04 | Injectable composition |
Country Status (12)
Country | Link |
---|---|
US (7) | US5733888A (en) |
EP (4) | EP1384474A1 (en) |
JP (1) | JP2880292B2 (en) |
AT (2) | ATE274347T1 (en) |
AU (1) | AU5612694A (en) |
CA (2) | CA2308082A1 (en) |
DE (2) | DE69333605T2 (en) |
DK (2) | DK0835657T3 (en) |
ES (2) | ES2224200T3 (en) |
GR (1) | GR3027724T3 (en) |
PT (1) | PT835657E (en) |
WO (2) | WO1994012030A1 (en) |
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WO2014152562A1 (en) * | 2013-03-15 | 2014-09-25 | Epizyme, Inc. | Injectable formulations for treating cancer |
US20210353661A1 (en) * | 2013-03-15 | 2021-11-18 | Epizyme, Inc. | Injectable formulations for treating cancer |
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Also Published As
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EP0674510A4 (en) | 1995-08-12 |
EP0835657A1 (en) | 1998-04-15 |
AU5612694A (en) | 1994-06-22 |
DK0835657T3 (en) | 2005-01-10 |
DE69333605D1 (en) | 2004-09-30 |
DE69320206D1 (en) | 1998-09-10 |
CA2149150C (en) | 2000-08-01 |
CA2308082A1 (en) | 1994-06-09 |
GR3027724T3 (en) | 1998-11-30 |
JPH08503945A (en) | 1996-04-30 |
ATE274347T1 (en) | 2004-09-15 |
PT835657E (en) | 2004-11-30 |
DE69333605T2 (en) | 2005-02-03 |
WO1994012030A1 (en) | 1994-06-09 |
DK0674510T3 (en) | 1999-05-10 |
US5977164A (en) | 1999-11-02 |
EP1384474A1 (en) | 2004-01-28 |
EP1500393A1 (en) | 2005-01-26 |
US6306894B1 (en) | 2001-10-23 |
EP0674510B1 (en) | 1998-08-05 |
US20030065022A1 (en) | 2003-04-03 |
ES2119996T3 (en) | 1998-10-16 |
US5972992A (en) | 1999-10-26 |
ATE169216T1 (en) | 1998-08-15 |
US5733888A (en) | 1998-03-31 |
DE69320206T2 (en) | 1999-02-11 |
JP2880292B2 (en) | 1999-04-05 |
EP0835657B1 (en) | 2004-08-25 |
US6140359A (en) | 2000-10-31 |
ES2224200T3 (en) | 2005-03-01 |
WO1994012031A1 (en) | 1994-06-09 |
US6770670B2 (en) | 2004-08-03 |
EP0674510A1 (en) | 1995-10-04 |
CA2149150A1 (en) | 1994-06-09 |
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