JP2018115178A - Docetaxel formulation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a docetaxel formulation which is a single liquid formulation that can be administered to a patient sensitive to alcohol.SOLUTION: The present invention relates to a single liquid formulation for an intravenous drip infusion essentially consisting of docetaxel, polyethylene glycol, a pH adjuster, and a stabilizer. The single liquid formulation of the invention contains docetaxel at the concentration of 10-30 mg/mL, contains polyethylene glycol at the concentration of 490-600 mg/mL, and the pH is adjusted to 2.9-3.7.SELECTED DRAWING: None

Description

  The present invention relates to docetaxel formulations.

  Taxotere (registered trademark) intravenous infusion preparation (Non-patent Document 1), an anticancer agent manufactured and sold by Sanofi-aventis Co., Ltd., consists of an active ingredient docetaxel hydrate dissolved in polysorbate 80 and a 13% ethanol solution. It is a two-part preparation consisting of an attached dissolution solution. At the time of use, add the attached dissolution solution to the main drug vial in advance, or add the infusion solution to patients who are sensitive to alcohol, mix until uniform, mix the infusion solution, and infuse intravenously.

  As described above, Taxotere (registered trademark) requires preparation preparation at the time of use, and the mixing operation is complicated and takes time, and there is a problem that it takes 1 hour or more until foaming generated by the mixing operation disappears. .

  In order to remedy these problems, the company has released One-Taxotere (registered trademark) intravenous infusion preparation (Non-patent Document 2), which is a one-part preparation. Since One Taxotere (registered trademark) is diluted with absolute ethanol in advance, mixing operation is not necessary, and although problems associated with preparation of the preparation have been solved, there is a problem that it cannot be administered to patients who are sensitive to alcohol.

“Taxotere (registered trademark) for intravenous infusion 80 mg, 20 mg” package insert “One Taxotere (registered trademark) Intravenous Infusion 20 mg / 1 mL, 80 mg / 4 mL” package insert

  An object of this invention is to provide the docetaxel formulation which is a one-component formulation which can be administered also to the patient hypersensitive to alcohol.

  As a result of diligent studies to solve the above problems, the present inventors have found that by coexisting polyethylene glycol, a docetaxel preparation that is a one-part preparation that can be administered to alcohol-sensitive patients can be provided. Completed the invention.

  The docetaxel formulation of the present invention contains docetaxel and polyethylene glycol and does not contain alcohol.

  In one embodiment, the polyethylene glycol is contained at a concentration of 430-650 mg / mL.

  In one embodiment, the formulation has a pH of 2.9-4.2.

  ADVANTAGE OF THE INVENTION According to this invention, the docetaxel formulation which is a 1 liquid formulation which can be administered also to the patient hypersensitive to alcohol can be provided. The docetaxel formulation of the present invention is highly safe because it produces less related substances derived from docetaxel than the conventional formulation.

  The docetaxel formulation of the present invention contains docetaxel and polyethylene glycol.

Docetaxel is a compound belonging to taxoids, molecular formula C ₄₃ H ₅₃ NO ₁₄ , molecular weight 807.879, chemical name (−)-(1S, 2S, 3R, 4S, 5R, 7S, 8S, 10R, 13S) — 4-Acetoxy-2-benzoyloxy-5,20-epoxy-1,7,10-trihydroxy-9-oxotaxa-11-en-13-yl (2R, 3S) -3-tert-butoxycarbonylamino-2 -White powder of hydroxy-3-phenylpropionate. Highly lipophilic and hardly soluble in water. The mechanism of anticancer action is to promote tubulin polymerization to form stable microtubules and to suppress depolymerization of microtubules, thereby forming abnormally shaped microtubule bundles and the presence of cells. Inhibits mitosis.

  Docetaxel can be produced from a precursor (taxoid 10-deacetylbaccatin III) extracted from a yew plant. A solution obtained by dissolving docetaxel hydrate in polysorbate 80 is commercially available from Sanofi-aventis Co., Ltd. as a formulation for intravenous injection of Taxotere (registered trademark). The docetaxel of the present invention includes derivatives and similar compounds, and includes forms such as anhydrides, hydrates and salts. It does not specifically limit as a density | concentration of docetaxel, For example, it is 10-30 mg / mL, Preferably it is 15-25 mg / mL, More preferably, it is 18-22 mg / mL.

  The polyethylene glycol is not particularly limited, but is preferably macrogol, more preferably macrogol 400. Macrogol refers to polyethylene glycol that meets the standards listed in the Japanese Pharmacopoeia (Pharmacopeia) or Pharmaceutical Additives Standard (Pharmaceutical Addendum). Macrogol 400 is a viscous liquid at room temperature composed of molecules having an average molecular weight of 400. In the preparation, stabilizer, surfactant, plasticizer, lubricant, base, binder, gloss It is used as an agent, coating agent, solubilizer, emulsifier, disintegrant, solubilizer and the like. Although it does not specifically limit as a density | concentration of polyethyleneglycol, Preferably it is 430-650 mg / mL, More preferably, it is 490-600 mg / mL.

  The docetaxel formulation of the present invention does not contain alcohol.

  The docetaxel formulation of the present invention may contain a buffer, a pH adjuster, a stabilizer and the like used in a normal formulation as necessary. The buffer is not particularly limited. The pH adjuster is not particularly limited, and examples thereof include anhydrous citric acid and phosphoric acid. Preferably, it is anhydrous citric acid. The stabilizer is not particularly limited, and examples thereof include polysorbate 80 and polyoxyethylene castor oil. Polysorbate 80 is preferable.

  Although pH of the docetaxel formulation of this invention is not specifically limited, Preferably it is 2.9-4.2, More preferably, it is 3.1-3.9. A pH below 2.9 or above 4.2 facilitates the production of related substances that are degradation products of docetaxel during storage of the formulation. Related substances include 10-oxo, 7-epi, and 7-epi-10-oxo. At pH 2.9 to 4.2, almost no 7-epi-10-oxo form is produced during storage of the formulation.

  The docetaxel preparation of the present invention is usually sealed in a glass container such as a vial and stored at room temperature, preferably in a cold place. At the time of use, it is diluted with a physiological saline solution or a glucose solution as necessary.

When applied to non-small cell lung cancer, for example, the docetaxel preparation of the present invention is intravenously infused once daily to adults at 60 mg / m ² (body surface area) as docetaxel at intervals of 3 to 4 weeks over 1 hour. To do.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated, this invention is not limited to these Examples.

Example 1
21.34 mg docetaxel hydrate (20 mg as docetaxel and 1.2 mg citric anhydride (manufactured by Komatsuya, Japan Pharmacopoeia) dissolved in 540 mg polysorbate 80 (manufactured by Sanyo Chemical Industries, Japan Pharmacopoeia), Macrogol 400 (Sanyo Chemical Industries, Japanese Pharmacopoeia) 560 mg was mixed to obtain a preparation.

(Comparative Examples 1 and 2)
A comparative example 1 was prepared by adding 395 mg of absolute ethanol to 500 μL of a commercially available Taxotere (registered trademark) intravenous infusion preparation. A preparation prepared in the same manner as in Example 1 except that propylene glycol was used in place of Macrogol 400 was used as Comparative Example 2.

(Test Example 1)
The preparations of Example 1 and Comparative Examples 1 and 2 were stored at 60 ° C. for 2 weeks, and docetaxel-related substances, which are degradation products of docetaxel, were quantified by HPLC. The results are shown in Table 1 together with the pH at the preparation of the preparation. The HPLC analysis conditions are as follows.

<HPLC analysis conditions>
Column: CAPCELLPAK C ₁₈ MGII (4.6 × 250 mm) manufactured by Shiseido Co., Ltd.
Mobile phase: water / methanol / acetonitrile (21/16/13)
Flow rate: The docetaxel retention time was adjusted to about 24 minutes.
Temperature: Constant temperature around 28 ° C Detection wavelength: 232 nm

  As is apparent from Table 1, after the preparation was stored, the preparation of Example 1 had an increased amount of related substances equivalent to the conventional preparation of Comparative Example 1. As related substances, 10-oxo, 7-epi and 7-epi-10-oxo were mainly observed. On the other hand, precipitates were observed in the preparation of Comparative Example 2.

(Examples 2 to 7)
Examples 2 to 7 were prepared in the same manner as in Example 1 except that the amount of citric anhydride added was changed to the formulation shown in Table 2 below and that docetaxel hydrate was changed to docetaxel. A commercially available one-taxotere (registered trademark) intravenous infusion preparation was designated as Comparative Example 3.

(Test Example 2)
The preparations of Examples 2 to 7 and Comparative Example 3 were tested in the same manner as in Test Example 1. The results are shown in Table 2 together with the pH at the preparation of the preparation. The HPLC analysis conditions are as follows. The docetaxel content in the preparation is also shown as the residual rate (%).

<HPLC analysis conditions>
Column: CAPCELLPAK C ₁₈ MGII (4.6 × 100 mm) manufactured by Shiseido Co., Ltd.
Mobile phase: water / methanol / acetonitrile (21/16/13)
Flow rate: The docetaxel retention time was adjusted to about 12 minutes.
Temperature: Constant temperature detection around 40 ° C Wavelength: 232nm

  As is apparent from Table 2, after the preparation was stored, the preparations of Examples 4 to 7 having a pH of 2.9 to 3.6 showed a smaller increase in the related substances than the conventional preparation of Comparative Example 3. In particular, the 7-epi-10-oxo form of a related substance was hardly observed in the preparation of Example 5 having a pH of 3.3.

(Examples 8 to 12)
Preparations prepared in the same manner as in Example 1 except that the addition amount of anhydrous citric acid was changed to the formulation shown in Table 3 below were designated as Examples 8 to 12.

(Test Example 3)
The preparations of Examples 8 to 12 and Comparative Example 3 were tested in the same manner as in Test Example 1 except that they were stored at 40 ° C for 1 month or 1.5 months instead of being stored at 60 ° C for 2 weeks. . The results are shown in Table 3 together with the pH at the preparation of the preparation.

  As is apparent from Table 3, after the preparation was stored, the preparations of Examples 8 to 12 having a pH of 2.9 to 3.7 had a smaller increase in related substances than the conventional preparation of Comparative Example 3.

  ADVANTAGE OF THE INVENTION According to this invention, the docetaxel formulation which is a 1 liquid formulation which can be administered also to the patient hypersensitive to alcohol can be provided.

Claims (6)

A one-part preparation for intravenous infusion consisting essentially of docetaxel, polyethylene glycol, a pH adjuster and a stabilizer,
The docetaxel is contained at a concentration of 10 to 30 mg / mL,
The polyethylene glycol is contained at a concentration of 490 to 600 mg / mL,
A one-part formulation wherein the pH is 2.9-3.7 and the stabilizer is polysorbate 80.   The one-pack preparation according to claim 1, wherein the polyethylene glycol is macrogol.   The one-pack preparation according to claim 1 or 2, wherein the polyethylene glycol is a viscous liquid at room temperature.   The one-pack preparation according to any one of claims 1 to 3, wherein the polyethylene glycol is contained at a concentration of 490 to 565 mg / mL.   The one-pack preparation according to any one of claims 1 to 4, wherein the pH is 2.9 to 3.6.   The one-pack preparation according to any one of claims 1 to 5, wherein the pH adjuster is anhydrous citric acid.