CA2308082A1 - Injectable compostion - Google Patents

Injectable compostion Download PDF

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Publication number
CA2308082A1
CA2308082A1 CA002308082A CA2308082A CA2308082A1 CA 2308082 A1 CA2308082 A1 CA 2308082A1 CA 002308082 A CA002308082 A CA 002308082A CA 2308082 A CA2308082 A CA 2308082A CA 2308082 A1 CA2308082 A1 CA 2308082A1
Authority
CA
Canada
Prior art keywords
acid
composition
matter
taxol
pharmaceutical formulation
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
Application number
CA002308082A
Other languages
French (fr)
Inventor
Paul Handreck
Robyn Elliott
Timothy R. Prout
David R. Carver
Hernita Ewald
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tapestry Pharmaceuticals Inc
Original Assignee
Paul Handreck
Robyn Elliott
Timothy R. Prout
David R. Carver
Hernita Ewald
Napro Biotherapeutics, Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=25644377&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CA2308082(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Paul Handreck, Robyn Elliott, Timothy R. Prout, David R. Carver, Hernita Ewald, Napro Biotherapeutics, Inc. filed Critical Paul Handreck
Publication of CA2308082A1 publication Critical patent/CA2308082A1/en
Abandoned legal-status Critical Current

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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

Abstract

A composition of taxol and polyethoxylated castor oil is pH balanced to have a pH less than 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

INJECTABLE COMPOSITION
This invention relates to a solution of taxol having improved stability.
This application is a division of copending Canadian Patent Application No. 2,149,150 filed November 18, 1993.
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. "TAXOL" is a registered trade-mark for the substance paclitaxel.
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.
5 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 invention claimed in the parent application, 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
In accordance with an aspect of the present invention, there is provided an article of manufacture comprising a sealable container and a pharmaceutical formulation contained therein, the pharmaceutical formulation comprising taxol; a pharmaceutically acceptable carrier; and an acid in sufficient amount 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 seven days; and wherein said pharmaceutical formulation has been sealed in said container for at least seven days.
In accordance with another aspect of the present invention, there is provided a composition of matter produced by the process of (a) obtaining a sealable container; (b) obtaining a pharmaceutical formulation comprising taxol, a pharmaceutically-acceptable carrier, and an acid in sufficient amount 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 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.
In accordance with an additional aspect of the present invention, there is provided a composition of matter comprising a sealable container and a pharmaceutical formulation contained therein, said pharmaceutical formulation comprising taxol; a pharmaceutically-acceptable carrier; and an acid, said formulation being such that at least 95% of the taxol potency is retained when said formulation is stored at 40°C for seven days; and wherein said pharmaceutical formulation has been sealed in said container for at least seven days.
In accordance with a further aspect of the present invention, there is provided a composition of matter produced by the process of (a) obtaining a sealable container; (b) obtaining a pharmaceutical formulation comprising taxol, a pharmaceutically-acceptable carrier, and an acid, said formulation being such that at least 95% of the taxol potency is retained 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.
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 5 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:
Mixina 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 5 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.
Exam~l a 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
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
Taxol 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 0.3% 5.1% impurity Total impurities 2.0% 12.2%
Clearly Sample 1 showed significantly increased stability over Sample 2.
Example 2 A solution was prepared with the following formulation:
Formulation: (Sample 3) Cremophor EL 0.5 mL
Taxol 6.0 mg Absolute Ethanol to 1 mL
pH adjusted to 6.6 with 1.OM 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 0.3% 5.1% impurity 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 (40)

1. An article of manufacture comprising a sealable container and a pharmaceutical formulation contained therein, said pharmaceutical formulation comprising taxol; a pharmaceutically-acceptable carrier; and an acid in sufficient amount 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 seven days and wherein said pharmaceutical formulation has been sealed in said container for at least seven days.
2. The article of manufacture of claim 1, wherein said pharmaceutical formulation has a pH between 5 and 7, inclusive.
3. The article of manufacture of claim 1 or 2, further comprising ethanol as a constituent thereof.
4. The article of manufacture of any one of claims 1 to 3, wherein said pharmaceutically-acceptable carrier is polyethoxylated caster oil.
5. The article of manufacture of any one of claims 1 to 4, wherein said pharmaceutical formulation is anhydrous.
6. The article of manufacture of any one of claims 1 to 5, wherein said acid is a mineral acid.
7. The article of manufacture of any one of claims 1 to 5, wherein said acid is an organic acid.
8. The article of manufacture of any one of claims 1 to 5, wherein said acid is acetic acid.
9. The article of manufacture of any one of claims 1 to 5, wherein said acid is citric acid.
10. The article of manufacture of claim 9, wherein said citric acid is anhydrous.
11. A composition of matter produced by the process of:
(a) obtaining a sealable container;
(b) obtaining a pharmaceutical formulation comprising taxol, a pharmaceutically-acceptable carrier, and an acid in sufficient amount 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 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.
12. The composition of matter of claim 11, wherein said pharmaceutical formulation has a pH between 5 and 7, inclusive.
13. The composition of matter of claim 11 or 12, further comprising ethanol as a constituent thereof.
14. The composition of matter of any one of claims 11 to 13, wherein said pharmaceutically-acceptable carrier is polyethoxylated caster oil.
15. The composition of matter of any one of claims 11 to 14, wherein said pharmaceutical formulation is anhydrous.
16. The composition of matter of any one of claims 11 to 15, wherein said acid is mineral acid.
17. The composition of matter of any one of claims 11 to 15, wherein said acid is an organic acid.
18. The composition of matter of any one of claims 11 to 15, wherein said acid is acetic acid.
19. The composition of matter of any one of claims 11 to 15, wherein said acid is citric acid.
20. The composition of matter of claim 19, wherein said citric acid is anhydrous.
21. A composition of matter comprising a sealable container and a pharmaceutical formulation contained therein, said pharmaceutical formulation comprising taxol; a pharmaceutically-acceptable carrier; and an acid, said formulation being such that at least 95% of the taxol potency is retained when said formulation is stored at 40°C for seven days; and wherein said pharmaceutical formulation has been sealed in said container for at least seven days.
22. The composition of matter of claim 21, wherein said pharmaceutical formulation has a pH between 5 and 7, inclusive.
23. The composition of matter of claim 21 or 22, further comprising ethanol as a constituent thereof.
24. The composition of matter of any one of claims 21 to 23, wherein said pharmaceutically-acceptable carrier is polyethoxylated caster oil.
25. The composition of matter of any one of claims 21 to 24, wherein said pharmaceutical formulation is anhydrous.
26. The composition of matter of any one of claims 21 to 25, wherein said acid is mineral acid.
27. The composition of matter of any one of claims 21 to 25, wherein said acid is an organic acid.
28. The composition of matter of any one of claims 21 to 25, wherein said acid is acetic acid.
29. The composition of matter of any one of claims 21 to 25, wherein said acid is citric acid.
30. The composition of matter of claim 29, wherein said citric acid is anhydrous.
31. A composition of matter produced by the process of:
(a) obtaining a sealable container;
(b) obtaining a pharmaceutical formulation comprising taxol, a pharmaceutically-acceptable carrier, and an acid, said formulation being such that at least 95% of the taxol potency is retained 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.
32. The composition of matter of claim 31, wherein said pharmaceutical formulation has a pH between 5 and 7, inclusive.
33. The composition of matter of claim 31 or 32, further comprising ethanol as a constituent thereof.
34. The composition of matter of any one of claims 31 to 33, wherein said pharmaceutically-acceptable carrier is polyethoxylated caster oil.
35. The composition of matter of any one of claims 31 to 34, wherein said pharmaceutical formulation is anhydrous.
36. The composition of matter of any one of claims 31 to 35, wherein said acid is mineral acid.
37. The composition of matter of any one of claims 31 to 35, wherein said acid is an organic acid.
38. The composition of matter of any one of claims 31 to 35, wherein said acid is acetic acid.
39. The composition of matter of any one of claims 31 to 35, wherein said acid is citric acid.
40. The composition of matter of claim 39, wherein said citric acid is anhydrous.
CA002308082A 1992-11-27 1993-11-18 Injectable compostion Abandoned CA2308082A1 (en)

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

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
CA002149150A Division CA2149150C (en) 1992-11-27 1993-11-18 Injectable taxol composition with improved stability

Publications (1)

Publication Number Publication Date
CA2308082A1 true CA2308082A1 (en) 1994-06-09

Family

ID=25644377

Family Applications (2)

Application Number Title Priority Date Filing Date
CA002149150A Expired - Lifetime CA2149150C (en) 1992-11-27 1993-11-18 Injectable taxol composition with improved stability
CA002308082A Abandoned CA2308082A1 (en) 1992-11-27 1993-11-18 Injectable compostion

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CA002149150A Expired - Lifetime CA2149150C (en) 1992-11-27 1993-11-18 Injectable taxol composition with improved stability

Country Status (12)

Country Link
US (7) US5733888A (en)
EP (4) EP1500393A1 (en)
JP (1) JP2880292B2 (en)
AT (2) ATE274347T1 (en)
AU (1) AU5612694A (en)
CA (2) CA2149150C (en)
DE (2) DE69333605T2 (en)
DK (2) DK0835657T3 (en)
ES (2) ES2119996T3 (en)
GR (1) GR3027724T3 (en)
PT (1) PT835657E (en)
WO (2) WO1994012031A1 (en)

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