CA2149150C - Injectable taxol composition with improved stability - Google Patents

Injectable taxol composition with improved stability Download PDF

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Publication number
CA2149150C
CA2149150C CA002149150A CA2149150A CA2149150C CA 2149150 C CA2149150 C CA 2149150C CA 002149150 A CA002149150 A CA 002149150A CA 2149150 A CA2149150 A CA 2149150A CA 2149150 C CA2149150 C CA 2149150C
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acid
taxol
acidifying agent
pharmaceutical formulation
composition
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CA002149150A
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CA2149150A1 (en
Inventor
David R. Carver
Timothy R. Prout
Hernita Ewald
Robyn Elliott
Paul Handreck
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Mayne Pharma USA Inc
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Tapestry Pharmaceuticals Inc
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Application filed by Tapestry Pharmaceuticals Inc filed Critical Tapestry Pharmaceuticals Inc
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    • 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

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

A composition of taxol and polyethoxylated castor oil is pH balanced to have a pH less man 8.1 to improve stability. This composition can include an acid, preferably citric acid, to adjust the pH value. The invention includes a method of formulating a taxol solution for injection by mixing an acid with a carrier material, such as castor oil, to form a carrier solution after which taxol is mixed with the carrier solution to form the taxol solution at a pH of less than 8.1. The method may include the step of slurrying the taxol in alcohol before mixing with the carrier solution.

Description

INJECTABI~E COMPOSITION
This invention relates to a solution of taxol having improved stability.
Taxol 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, taxol 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.
Taxol 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. Taxol employs a different mechanism of action since it appears to shift the equilibrium of polymerization/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, taxol entered clinical trials in 1983.
Over the past few years, taxol has demonstrated good response rates in treating both ovarian and breast cancer patients who were not benefiting 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, Virginia USA on September 23-24, 1992.
It is a disadvantage of a known formulation that the taxol therein degrades, with the result that the shelf life of the formulation is unsatisfactory, and there is therefore a need for a taxol solution of improved stability.
In accordance with one aspect of the present invention, there is provided an improvement in a pharmaceutical formulation adapted for use in treating cancer comprising taxol and polyethoxylated castor oil, the improvement comprising an acidifying agent added to the pharmaceutical formulation in a proportion such that the composition has a resulting pH less than or equal to 7Ø
The present invention provides, in another aspect of the invention, an improvement in an anhydrous pharmaceutical formulation comprising taxol and polyethoxylated castor oil, the improvement comprising an acidifying agent mixed in a proportion such that said pharmaceutical formulation has a resulting pH of about 7 or less.
In accordance with an additional aspect of the invention, there is provided a pharmaceutical taxol composition comprising: taxol; polyethoxylated castor oil; and anhydrous citric acid in sufficient amounts to improve the stability of the taxol such that at least 95% of the taxol potency is retained when the composition is stored at 40°C for 7 days.
The present invention provides, in a yet further aspect of the invention, a pharmaceutical taxol composition comprising: taxol; polyethoxylated castor oil; and acetic acid in sufficient amounts to improve the stability of the taxol such that at least 95% of the taxol potency is retained when the composition is stored at 40°C for 7 days.
In an additional aspect of the invention, there is provided an article of manufacture comprising a container and a pharmaceutical formulation contained therein, the pharmaceutical formulation comprising a pharmaceutically-acceptable carrier, taxol, and an acidifying agent mixed in proportion such that the pharmaceutical formulation has a resulting pH of about 7 or less.
A further aspect of the present invention provides a method of formulating a taxol solution for injection in which the taxol does not readily degrade, comprising the following steps: mixing acid with a carrier material to form a first carrier solution; and mixing taxol with the first carrier solution to form a taxol solution whereby the taxol in the taxol solution does not readily degrade.
In a further aspect of the invention, there is provided a method for improving the stability of a pharmaceutical taxol solution over an extended period, comprising the steps of: providing a formulation comprising taxol, a pharmaceutically-acceptable carrier, and an acidifying agent; and storing the formulation in a container for at least 7 days.
The present invention, in a yet further aspect of the invention, provides a method of making a pharmaceutical carrier solution, useful in making a formulation comprising taxol, comprising the following steps: obtaining a pharmaceutical carrier material, and mixing an acid with the carrier material to yield a carrier solution.

3a An additional aspect of the present invention provides an improvement in a pharmaceutical carrier composition useful for combining with taxol to yield a taxol formulation, the improvement comprising mixing an acid with the carrier composition.
Accordingly, in a general aspect the invention provides a solution containing taxol, 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, 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 Malefic acid Succinic acid 3b Due to its limited solubility in water, Taxol is usually prepared and administered in a vehicle containing cremophor ELTM (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 taxol formulation to adjust its pH into the range 1 to 8, preferably 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 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 weighted 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 taxol was weighed out and slurried using absolute alcohol, using a ratio of 8 ml of absolute alcohol to 1 gm of taxol. The slurried taxol was added to solution 3 and the slurrying vessel was washed with a minimum quantity of absolute alcohol. Solution 3 was adjusted to 750 of required volume using absolute alcohol, and thoroughly stirred for at least 45 minutes until 3c completely dissolved. Once completely dissolved, the volume was checked and made up as necessary with absolute alcohol and the final solution stirred for 5 minutes.
Example 1 A solution was prepared with the following formulation:
Formulation: (Sample 1):
Cremophor EL 0.5 mL
Citric Acid (Anhydrous) 2.0 mg Taxol 6.0 mg Absolute Alcohol to 1.0 mL

W~ 94/12031 ~ ~ '~ '~. ~ 0 PCT/ZJS931i1209 The gH 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 ICI Taxol Clinical brochure (as follows) which had a pH of 9.1. (Sample 2) Sample 2 per mL
Taxol 6 mg ~remophor EL 0.5 mL
Absolute Alcohol to ~. 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 resul~cs are shown in Table 1.
S~mp~.e 1 Samola ~
PH 6.2 9:0 Potency 95.6 X6.7 Major individual 003% 5.1% impurity Total impurities 2.0% 12.2%
Clearly Sample 1 shored significantly increased stability over Sample 2.
lExam~ple 2 A solution was prepared with the follo~nring formulation:
Formulae.on° (Sample 3~
Cremophor HL 0.5 mL
Tax.ol 6.0 mg Absolute Hthanol to 1 mL
pH adjusted to 6.6 with 1: OM Acetic Acid.
The so3.ution was filled into clear type z glass 5 mL
~I vials and sealed with rubber bungs.
The solution was stored at 40°C for 7 days.
The stab3.lity results obtained are compared to those seen . with Sample 2.
Sam S amt~l a 2 ~H 6.7 ~.0 Fotency 97.5 X6.7 Major individual 0.3% 5.1% impurity . , ,.. .:: ., . : :.,. ". , . . . : ,,. . .,.:- . ; . . . ; -: :- . . :: ; ;
«-- ~ . .. . ; ; :: . . . ~, ~ ~ : ,:.
a. ',.....: . .. .. -... ...... . .. ...... ~ . :., . ..:....... .,...... ..
.....:.. ,. . . . . .. . ,:... . ; ...
t .. : - :... ,..:.,.~. :. ...~.. :. ~.~. ...,.', ,~.:..:; ".....w... ~.,~.r.
. ~ .,..,,.,.. .... , . ,:...,:..., . .....:..~ ;..~..._ ~. ~.;...., . ......
~i ........:~.~ '~ ..~~-...... ;,.... ..
r .:
i a..~;<... ;;~;. ,.,..,.. ' '.~ ....;-~.'. .:,..... .::,..~, ,:'.'-;', .
~,.:...w . , ,... ~..:::... ..;.~;:.; , .,~,,.,.,,..,. ...~; ,..:
,r a l... ::' ~,~.....: ".:,._.:.. :,::.: . ';~.;~.; _...;,.:..., , :..,.,: ,.
,:.;. . ~.:,::~..~ , ,:..,";.,.. ..;~.,~ .:',~....,.. n,...~v,,.'.,..; ,~ , .t~.4.....?:., ..~ ., ~.,-~:, . ~...., .. .: ...,~... ~-.... ;-..: ~,.. ~ .
,........ .. . . .... .". ~... :..:....~. n .. . ..... ..., ..:.~ ~..,... .
..,:.. ... ._ .....,., ..~~. .. .. ..,. . .,.

V6~0 94112031 ~ PCT/US93/11209 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 (56)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
1. In a pharmaceutical formulation adapted for use in treating cancer comprising taxol and polyethoxylated castor oil, the improvement comprising an acidifying agent added to said pharmaceutical formulation in a proportion such that said composition has a resulting pH less than or equal to 7Ø
2. The improved pharmaceutical formulation of claim 1 wherein said composition has a pH of between 5 and 7, inclusively.
3. The improved pharmaceutical formulation of claim 1 including ethanol as a constituent thereof.
4. The improved pharmaceutical formulation of claim 3 wherein said composition has a pH of between 5 and 7, inclusively.
5. The improved pharmaceutical formulation of any one of claims 1 to 4, wherein said acidifying agent is a mineral acid.
6. The improved pharmaceutical formulation of any one of claims 1 to 4, wherein said acidifying agent is an organic acid.
7. The improved pharmaceutical formulation of any one of claims 1 to 9, wherein said acidifying agent is acetic acid.
8. The improved pharmaceutical formulation of any one of claims 1 to 4, wherein said acidifying agent is citric acid.
9. The improved pharmaceutical formulation claimed in claim 8, wherein said citric acid is anhydrous.
10. In an anhydrous pharmaceutical formulation comprising taxol and polyethoxylated castor oil, the improvement comprising an acidifying agent mixed in a proportion such that said pharmaceutical formulation has a resulting pH of about 7 or less.
11. The improved pharmaceutical formulation of claim 10, wherein the pH is from about 7 to about 5.
12. The improved pharmaceutical formulation of claim 10 or 11, wherein said acidifying agent is a mineral acid.
13. The improved pharmaceutical formulation of claim 10 or 11, wherein said acidifying agent is an organic acid.
14. The improved pharmaceutical formulation of claim 10 or 11, wherein said acidifying agent is acetic acid.
15. The improved pharmaceutical formulation of claim 10 or 11, wherein said acidifying agent is citric acid.
16. The improved pharmaceutical formulation of claim 15, wherein said citric acid is anhydrous.
17. A pharmaceutical taxol composition comprising:
taxol;
polyethoxylated castor oil; and anhydrous citric acid in sufficient amounts to improve the stability of the taxol such that at least 95% of the taxol potency is retained when the composition is stored at 40°C for 7 days.
18. A pharmaceutical taxol composition comprising taxol;
polyethoxylated castor oil; and acetic acid in sufficient amounts to improve the stability of the taxol such that at least 95% of the taxol potency is retained when the composition is stored at 40°C for 7 days.
19. An article of manufacture comprising a container and a pharmaceutical formulation contained therein, said pharmaceutical formulation comprising a pharmaceutically-acceptable carrier which is a polyethoxylated castor oil, taxol, and an acidifying agent mixed in proportion such that said pharmaceutical formulation has a resulting pH of about 7 or less.
20. The article of manufacture of claim 19 further comprising instructions for administering said pharmaceutical formulation to a patient.
21. The article of manufacture of claim 20, wherein said acidifying agent is a mineral acid.
22. The article of manufacture of claim 20, wherein said acidifying agent is an organic acid.
23. The article of manufacture of claim 20, wherein said acidifying agent is acetic acid.
24. The article of manufacture of claim 20, wherein said acidifying agent is citric acid.
25. The article of manufacture of claim 24, wherein said citric acid is anhydrous.
26. A method of formulating a taxol solution for injection in which the taxol does not readily degrade, comprising the following steps:
mixing acid with a carrier material which is a polyethoxylated castor oil to form a first carrier solution; and mixing taxol with the first carrier solution to form a taxol solution having a pH of less than or equal to 7.0 whereby the taxol in the taxol solution does not readily degrade.
27. The method of claim 26, wherein said acid is a mineral acid.
28. The method of claim 26, wherein said acid is an organic acid.
29. The method of claim 26 wherein said acid is acetic acid.
30. The method of claim 26 wherein said acid is citric acid.
31. The method of claim 30 wherein said citric acid is anhydrous.
32. The method of any one of claims 27 to 31 including the step of slurrying said taxol in alcohol before mixing said taxol with the first carrier solution.
33. The method of any one of claims 26 to 32, wherein said taxol solution has a pH of between 5 and 7, inclusively.
34. A method for improving the stability of a pharmaceutical taxol solution over an extended period, comprising the steps of:
providing a formulation comprising taxol, a pharmaceutically-acceptable carrier which is a polyethoxylated castor oil, and an acidifying agent conferring to the solution a pH of less than or equal to 7.0; and storing said formulation in a container for at least 7 days.
35. The method of claim 34, wherein said formulation is anhydrous.
36. The method of claim 34 or 35, wherein said acidifying agent is a mineral acid.
37. The method of claim 34 or 35, wherein said acidifying agent is an organic acid.
38. The method of claim 34 or 35, wherein said acidifying agent is citric acid.
39. The method of claim 34 or 35, wherein said acidifying agent is acetic acid.
40. The method of claim 38, wherein said citric acid is anhydrous.
41. A method of making a pharmaceutical carrier solution, useful in making a formulation comprising taxol, comprising the following steps:

obtaining a pharmaceutical carrier material which is a polyethoxylated castor oil; and mixing an acid with said carrier material to yield a carrier solution having a resulting pH of less than or equal to 7Ø
42. The method of claim 41, wherein said acid is a mineral acid.
43. The method of claim 41, wherein said acid is an organic acid.
44. The method of claim 43, wherein said acid is citric acid.
45. The method of claim 44, wherein said citric acid is anhydrous.
46. The method of claim 43, wherein said acid is acetic acid.
47. The method of claim 41, wherein said carrier solution has a resulting pH of from about 7 to about 5.
48. In a pharmaceutical carrier composition containing polyethoxylated castor oil and useful for combining with taxol to yield a taxol formulation, the improvement comprising mixing an acid with said carrier composition in such an amount as to yield a pH of less than or equal to 7Ø
49. The improved pharmaceutical carrier composition of claim 48, wherein said carrier composition further comprises ethanol.
50. The improved pharmaceutical carrier composition of claim 48 or 49, wherein said acid is a mineral acid.
51. The improved pharmaceutical carrier composition of claim 48 or 49, wherein said acid is an organic acid.
52. The improved pharmaceutical carrier composition of claim 51, wherein said organic acid is citric acid.
53. The improved pharmaceutical carrier composition of claim 52, wherein said citric acid is anhydrous.
54. The improved pharmaceutical carrier composition of claim 51, wherein said organic acid is acetic acid.
55. The improved pharmaceutical carrier composition of any one of claims 48 to 54, having a resulting pH of about 7 or less.
56. The improved pharmaceutical carrier composition of claim 55, having a resulting pH of from about 7 to about 5.
CA002149150A 1992-11-27 1993-11-18 Injectable taxol composition with improved stability Expired - Lifetime CA2149150C (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CA002308082A CA2308082A1 (en) 1992-11-27 1993-11-18 Injectable compostion

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
AUPL607492 1992-11-27
AUPL6074 1992-11-27
US99550192A 1992-12-22 1992-12-22
US07/995,501 1992-12-22
PCT/US1993/011209 WO1994012031A1 (en) 1992-11-27 1993-11-18 Injectable composition

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CA2149150A1 CA2149150A1 (en) 1994-06-09
CA2149150C true CA2149150C (en) 2000-08-01

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CA002149150A Expired - Lifetime CA2149150C (en) 1992-11-27 1993-11-18 Injectable taxol composition with improved stability

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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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