KR100371062B1 - Injectable taxi brush compositions with improved stability and methods of formulating them - Google Patents

Abstract

Injectable taxol solutions with improved stability of the present invention have a pH of 8.1 or less, preferably 1 to 8, more preferably 5 to 7.5. The pH is adjusted by the addition of acid, preferably citric acid, and the preferred composition contains taxol, cremophor EL (TM), citric acid and ethanol.

Description

Injectable Taxol compositions with improved stability and methods of formulating the same

Taxol is a compound extracted from the bark of Western yew, Taxus brevifolia, and its antitumor properties are known. An example is described in the Merck Index, Eleventh Edition 1989, monograph 9049.

In 1977, Taxol was chosen for antitumor development because of its inherent mechanism of action and excellent cytotoxic activity against IP transplanted b16 melanoma and human MX-1 breast tumor xenografts.

Taxol is believed to act in vitro as a mitotic spindle poison and as a potent inhibitor against cell replication. Other mitotic spindle inhibitors (colchicine and podophyllotoxin) inhibit microtubule assembly. Taxol performs a different mechanism of action because it appears to shift the polymerization / depolymerization equilibrium towards the polymer assembly and to stabilize the microtubules against depolymerization under conditions that cause rapid degradation of the microtubules. Interference with the intracellular polymerization / depolymerization cycle appears to interfere with cell replication and migration.

After extensive preclinical examination in mouse tumor models, Taxol was introduced in 1983 in clinical trials. In the past few years, Taxol has been shown to be excellent in the treatment of ovarian and breast cancer patients who have not benefited from vinca alkaloid or cisplatin treatment. In addition, other types of cancer patients, including lung cancer, melanoma, lymphoma head and neck, have shown encouraging results.

For further information, see the US National Cancer Institute (NCL) Clinical Brochure for Taxol Revised in 1991 and Taxus and Taxol held in Alexandria, Virginia, September 23-24, 1992. Papers presented at the 2nd National Cancer Institute Workshop may be helpful.

The present invention relates to a taxol solution with improved stability.

Known formulations include Taxol, Cremophor, Cremophor EL (polyethoxylated castor oil that acts as a solubilizer) and ethanol. Known formulations have a disadvantage that the storage life of the formulation is not satisfactory because the quality of the internal taxol is not stored when stored at 8 ° C. or lower, thereby requiring a stable taxol solution.

Thus, in a general aspect the object of the present invention is to contain a solution comprising taxol, a pharmaceutically acceptable solubilizer (e.g. polyethoxylated castor oil) and a pharmaceutically acceptable organic solvent (e.g. ethanol), The addition of an acid provides a solution whose pH is adjusted to below 8.1, preferably in the range 1-8. Acids in powder form such as citric acid are preferred over acids containing water such as sulfuric acid. Most preferred acids for use in the present invention are citric anhydride, but a wide range of acids can be used, including the following acids:

Citric acid-monohydrate, citric acid-anhydride, citric acid-hydration,

Acetic acid, formic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, tartaric acid, diatrizoic acid, glutamic acid, lactic acid, maleic acid, succinic acid.

Taxols are generally prepared and dosed in a vehicle that includes ethanol and cremophor EL (polyethoxylated castor oil that acts as a solubilizer) because of its limited solubility in water. Solutions prepared with the formulations (known formulations) as described in the NCT Taxol clinical brochure have a pH 9.1.

As mentioned above, the present invention essentially adds an acid to the Taxol formulation to adjust the pH of the Taxol formulation to a range of 8.1 or less, preferably in the range of 1 to 8, more preferably in the range of 5 to 7.5.

Preferred processes adopted by the inventors are carried out by the following steps, but not limited thereto.

Mixing process

Solution 1

Citric acid was dissolved in ethanol at a rate of 1 g of citric acid relative to 8 ml of anhydrous alcohol, and the solution was stirred for 15 minutes.

Solution 2

Cremophor EL was injected into the main mixing vessel.

Solution 3

Solution 1 was added to Solution 2, and then the vessel used in Solution 2 was washed with a minimum amount of anhydrous alcohol to completely transfer citric acid. Solution 3 was mixed with nitrogen and bubbled for at least 15 minutes. Anhydrous alcohols were weighed using a ratio of 8 ml of anhydrous alcohols to 1 g of taxol and slurried with anhydrous alcohols. Slurry Taxol was added to Solution 3 and the slurry vessel was washed with a minimum amount of anhydrous alcohol. Solution 3 was adjusted to 75% of the desired volume with anhydrous alcohol and stirred sufficiently for at least 45 minutes until complete dissolution. Once completely dissolved, the desired volume was filled with anhydrous alcohol and the final solution was stirred for 5 minutes.

Example 1

The solution was prepared using the following formulation.

Preparation: (Sample 1)

Cremophor EL: 0.5 ml

Citric acid (anhydrous): 2.0 mg

Taxol: 6.0 mg

Anhydrous alcohol: Add remaining amount until 1.00 ml of total solution is added.

The pH of this solution was measured at 6.1.

The stability of this sample was compared to a sample (sample 2) prepared by the formulation described below in the NCI Taxol Clinical Brochure (pH 2) with a pH of 9.1.

(Sample 2) per mL

Taxol: 6 mg

Cremophor EL: 0.5mL

Dehydrated Alcon USP: Add remaining amount until 1.00 mL of total solution is obtained.

This solution was filled into a 5 ml glass vial of Clear Type 1 and sealed with a rubber stopper.

The stability of the solution after 7 days at 40 ° C. was as follows.

It is evident that Sample 1 has significantly increased stability compared to Sample 2.

Example 2

The solution was prepared using the following formulation.

Formulation-Sample 3

Cremophor EL: 0.5ml

Taxol: 6mg

Anhydrous alcohol: Add remaining amount until 1.00 ml of total solution is added.

Adjust pH to 6.6 with 1.0 M acetic acid.

This solution is filled into 5 ml vials of clear type 1 and sealed with a rubber stopper.

The solution is stored at 40 ° C. for 7 days and then the specified stability results are compared to that shown for Sample 2.

It was again proved that the stability of the preparation of the present invention (sample 3) was quite good.

Additional test

Babies Tables 1, 2 and 3 summarize additional tests where formulations containing Cremophor EL, Taxol and anhydrous alcohols were added to specific pH levels to specific pH levels and tested for 4 weeks stability at 40 ° C.

Table 1

Total Impurities (by HPLC Region Standards)

*myriad

[Table 2]

Major impurities (by HPLC region standard)

Table 3

History (HLPC)

Best results are obtained with citric acid at pH 5 to 7.5, the citric acid being in anhydrous form, and it is clear that formulations at pH 6.1 exhibit the lowest levels of total impurities and individual main impurities. In general, it is to be understood that the invention is not limited to the foregoing detailed description.

Claims (13)

An injectable taxol composition comprising taxol, polyethoxylated castor oil, organic acid and ethanol, wherein the pH is from 5 to 7.5. The injectable taxol composition according to claim 1, wherein the composition has a pH of 5-7. 3. The injectable taxol composition according to claim 2, wherein the bath has a pH of 6.1. The injectable taxol composition according to claim 1, wherein the organic acid is selected from the group consisting of the following compounds. Citric acid-monohydrate, citric acid-anhydride, citric acid-hydrate, Acetic acid, formic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, Tartaric acid, diatrizoic acid, Glutamic acid, lactic acid, maleic acid, succinic acid. 5. The injectable taxol composition according to claim 4, wherein the organic acid is citric acid. The injectable taxol composition of claim 1, wherein the polyethoxylated castor oil is Cremophor EL (TM). (a) mixing the organic acid and ethanol as a carrier material to prepare a first solution, (b) mixing the first solution with polyethoxylated castor oil to prepare a second solution, (c) preparing a slurry by mixing taxol and ethanol, (d) mixing the slurry with the second solution to prepare a third solution; and (e) adding ethanol to calibrate the volume of the third solution to produce a Taxol solution of pH 5 to 7.5, wherein the storage stability improved injectable Taxol solution formulation method. An injectable taxol composition comprising taxol, cremophor EL (TM), citric acid and ethanol and having a pH between 5 and 7.5. The injectable taxol composition according to claim 8, wherein the pH of the composition is 5-7. 10. The injectable taxol composition according to claim 9, wherein the pH of the composition is about 6.1. (a) dissolving citric anhydride in ethanol to prepare a first solution, (b) mixing Cremophor EL (TM) with the first solution to prepare a second solution, (c) mixing taxol with ethanol to produce a slurry, (d) mixing the slurry with the second solution to produce a third solution, and (e) adding ethanol to fill the volume of the second solution to produce an injectable solution having a pH of 5 to 7.5. The method of claim 11, wherein the injectable solution has a pH of 5-7. The method of claim 12, wherein the injectable solution has a pH of about 6.1.