JP6076744B2 - Pharmaceutical composition containing docetaxel - Google Patents

Description

  The present invention relates to a single liquid stable pharmaceutical composition containing docetaxel.

  The two-part formulation “Taxotere Intravenous Infusion” was approved on October 9, 1996, and the one-part formulation “One Taxotere Intravenous Infusion” was additionally approved on January 14, 2011. One-taxotere intravenous infusions include breast cancer, non-small cell lung cancer, gastric cancer, esophageal cancer, head and neck cancer, ovarian cancer, uterine cancer, and prostate cancer.

  The main components of One Taxotere intravenous infusion are docetaxel, polysorbate 80, and ethanol. Docetaxel is an active ingredient for intravenous administration of one taxotere.

Docetaxel (CAS 114977-28-5) is an antineoplastic agent that belongs to the taxoid family and was identified in 1986 as an alternative to paclitaxel. It is prepared by a semi-synthetic process starting from a precursor extracted from yew needles. Docetaxel is 4-acetoxy-2-benzoyloxy-5,20-epoxy-1,7,10-trihydroxy-9-oxotaxa-11-en-13-yl-3-tert-butoxycarbonylamino-2-hydroxy It is -3-phenylpropionate ester and has a chemical structure represented by the following chemical formula (1). Docetaxel is a white or substantially white powder and has a solubility in water of 6 to 7 μg / mL and is known as a poorly water-soluble drug.

  Docetaxel is a compound that is easily denatured by various conditions (for example, temperature, acidic medium, basic medium, oxidizing agent, reducing agent, light condition, etc.), and a modified product (for example, 2-dibenzoyl-2-pentanoyl docetaxel). , 6-oxodocetaxel, 4-epidocetaxel, 4-epi-6-oxodocetaxel, etc.) exhibit a pharmacological and / or toxicological profile different from docetaxel, which is the original active ingredient. For this reason, the formulation containing docetaxel (hereinafter also referred to as docetaxel formulation) generally has a problem of a short storage period.

  Patent Document 1 describes a liquid composition for injection having a pH in the range of 2.5 to 7 containing docetaxel, polyethylene glycols, and a water-insoluble solvent. Patent Document 2 describes that the formation of 7-epidocetaxel, which is a modified product of docetaxel, can be suppressed by including polysorbate 80 and a docetaxel degradation inhibitor. Patent Document 3 discloses that the stability of a docetaxel preparation is improved by containing a surfactant, absolute ethanol, and a pH adjuster and adjusting the pH to 5 or lower. However, none of these are sufficient to suppress the denaturation of docetaxel and enable long-term storage of the preparation, and the development of a docetaxel preparation with better storage stability has been desired.

Special table 2008-543789 Special table 2009-524700 gazette Special table 2011-513299 gazette

  To establish a more stable docetaxel formulation that can be stored for a long period of time. In particular, to establish a prescription that suppresses the generation of 4-epidocetaxel.

  As a result of extensive research, the present inventors have modified the active ingredient by adjusting the pH of the pharmaceutical composition containing docetaxel and / or a pharmaceutically acceptable salt thereof to 2.7 to 3.4. Has been found to be able to be suppressed, and further studies have been made to complete the present invention. In this specification, anhydrous docetaxel is referred to as anhydrous docetaxel.

That is, the present invention relates to the following.
(1) A pharmaceutical composition comprising docetaxel and / or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the composition has a pH of 2.7 to 3.4.
(2) The pharmaceutical composition according to (1), wherein the docetaxel is anhydrous docetaxel and / or a pharmaceutically acceptable salt thereof.
(3) In the above (1) or (2), containing at least one selected from the group consisting of citric acid, tartaric acid, ascorbic acid, fumaric acid, lactic acid, maleic acid, acetic acid and oxalic acid The pharmaceutical composition as described.
(4) The pharmaceutical composition according to any one of (1) to (3), which is in the form of an injection or intravenous drip.

  According to the present invention, there is provided a pharmaceutical composition capable of suppressing the formation of an undesired modified product, increasing the stability of docetaxel as an active ingredient and / or a pharmaceutically acceptable salt thereof, and storing for a long period of time. be able to.

FIG. 1 shows the results of the severe test (60 ° C./sequential relative humidity, 4 weeks) of Test Example 1.

  A pharmaceutical composition comprising docetaxel and / or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the composition has a pH of 2.7 to 3.4.

  In the present invention, the pH of the pharmaceutical composition refers to the pH of a solution obtained by diluting 1 g of the pharmaceutical composition in 4 mL of water according to the pH measurement method described in the 16th revised Japanese Pharmacopoeia General Test Method section. It means the value when measuring.

  In another preferred embodiment of the present invention, the pH of the pharmaceutical composition is usually pH 2.7 to 3.4, and preferably pH 3.0 to 3.2 from the viewpoint of docetaxel stability.

  In one embodiment of the present invention, an organic acid may be used as a pH adjuster. The organic acid is not particularly limited, and examples thereof include citric acid, tartaric acid, ascorbic acid, fumaric acid, lactic acid, maleic acid, acetic acid, and oxalic acid. These may be used alone or in combination of two or more. Can be used. These organic acids may be anhydrides or hydrates. The pH value to be adjusted may be in the above range.

  In another embodiment of the present invention, an organic acid is used as a docetaxel denaturation inhibitor. The organic acid is not particularly limited, and examples thereof include citric acid, tartaric acid, ascorbic acid, fumaric acid, lactic acid, maleic acid, acetic acid, and oxalic acid. These may be used alone or in combination of two or more. Can be used. These organic acids may be anhydrides or hydrates. In this embodiment, the content of the organic acid is not particularly limited, but is usually 0.1 to 200 mg / mL in the pharmaceutical composition, and preferably 1 to 50 mg / mL in the pharmaceutical composition from the viewpoint of the effect of inhibiting denaturation of docetaxel. mL, more preferably 4 to 20 mg / mL in the pharmaceutical composition.

  In a preferred embodiment of the present invention, the concentration of docetaxel and / or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is appropriately selected according to the age, sex, application site, symptom level, etc. of the subject to be administered. However, it is usually about 90 mg / mL or less, preferably 10 to 50 mg / mL, more preferably 15 to 25 mg / mL from the viewpoint of medicinal effect.

  In the present invention, the pharmaceutically acceptable salt is not particularly limited. For example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a basic or acidic amino acid. And salt. Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt and ammonium salt. Preferable examples of salts with organic bases include, for example, salts with alkylamines such as trimethylamine and triethylamine; salts with heterocyclic amines such as pyridine and picoline; alkanolamines such as ethanolamine, diethanolamine and triethanolamine A salt with cycloalkylamine such as cyclohexylamine and dicyclohexylamine; a salt with an alkylenediamine derivative such as N, N′-dibenzylethylenediamine, and the like. Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salts with organic acids include salts with monocarboxylic acids such as formic acid, acetic acid, trifluoroacetic acid and propionic acid; salts with polyvalent carboxylic acids such as fumaric acid, oxalic acid and maleic acid; And salts with oxycarboxylic acids such as tartaric acid, citric acid, succinic acid and malic acid; salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; and salts with benzoic acid. Preferable examples of salts with neutral amino acids include, for example, salts with glycine, valine, leucine and the like, and preferable examples of salts with basic amino acids include, for example, arginine, lysine, ornithine and the like. Suitable salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid and the like.

  In a preferred embodiment of the present invention, an alcohol may be contained in the pharmaceutical composition as a docetaxel solubilizer. Although it will not specifically limit if it is pharmacologically acceptable alcohol, Ethanol can be used conveniently. From the viewpoint of increasing the stability of docetaxel, the purity of the ethanol used in the present invention is preferably 90% or more, more preferably 95% or more, and even more preferably absolute ethanol.

  In one embodiment of the present invention, the content of the alcohol is not particularly limited, but is preferably about 50 v / v% or less in the pharmaceutical composition, preferably from the viewpoint of docetaxel solubility and pharmaceutically acceptable. 30-50 v / v% in the composition, more preferably 45-50 v / v% in the pharmaceutical composition.

  In a preferred embodiment of the present invention, a surfactant such as a nonionic surfactant may be contained in the pharmaceutical composition as a dispersant. Although it does not specifically limit as said nonionic surfactant, For example, a polysorbate, a polyoxyethylene glycol ester, a polyoxyethylene castor oil derivative, etc. are mentioned. Among these, it is particularly preferable to use polysorbate.

  In one embodiment of the present invention, the content of the nonionic surfactant is not particularly limited, and is usually about 50 v / v% or less in the pharmaceutical composition, from the viewpoint of dispersion stability of the components in the pharmaceutical composition. Preferably, it is 30 to 50 v / v% in the pharmaceutical composition, more preferably 45 to 50 v / v% in the pharmaceutical composition.

  In one preferred embodiment of the present invention, the pharmaceutical composition contains anhydrous docetaxel, anhydrous ethanol, anhydrous citric acid. The content of each component may be as described above.

  Although the administration method of the pharmaceutical composition of this invention is not specifically limited, Parenteral administration is used preferably. Examples of parenteral administration methods include intravenous injection (intravenous injection), intramuscular injection, or subcutaneous injection. More specifically, it may be administered intravenously into an artery, peritoneum, submeningeal, intraventricular, urethral, intrasternal, intracranial, or the like, or by intravenous drip injection.

  Although the form of the pharmaceutical composition of the present invention is not particularly limited, it is preferably in the form of an injection or intravenous drip.

  The pharmaceutical composition of the present invention may optionally contain sufficient salts to make the solution isotonic with blood (eg, alkali metal salts of alkaline and alkaline earth metals such as sodium chloride, potassium chloride, magnesium bromide). Salt or the like) or glucose. The manufacture of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

  Next, the present invention will be described more specifically with reference to experimental examples and examples. However, the present invention is not limited to these examples, and many modifications are within the technical idea of the present invention. This is possible by those with ordinary knowledge in the field.

Measurement of docetaxel content (Preparation of sample solution)
Weigh accurately 2 mL of sample, add 2 mL of ethanol (purity 99.5%), add diluent (water / acetonitrile / acetic acid = 100/100 / 0.1 (v / v / v)) to this, and accurately Use 50 mL to make the sample solution.
(Preparation of standard solution)
About 40 mg of docetaxel for quantification is accurately weighed and dissolved by adding 2 mL of ethanol (purity 99.5%), and a diluent is added to make exactly 50 mL to obtain a standard solution.
A sample solution and a standard solution (10 μL each) were accurately taken and measured by liquid chromatography (HPLC) under the following conditions.
(Measurement condition)
Device: Alliance (Nippon Waters)
Column: A stainless steel tube of φ4.6 mm × 150 mm packed with 3 μm octadecylsilylating agent for liquid chromatography was used.
Column temperature: around 45 ° C. constant mobile phase: water / methanol / acetonitrile (21/16/13 = v / v / v) mixed solution detector: ultraviolet absorptiometer (232 nm)
Flow rate: The docetaxel holding time was adjusted to be about 12 minutes.
(Calculation of content)
The content of docetaxel in the sample was calculated by the following formula.
Docetaxel content (mg) = Ws × Ar / As
Ws: Docetaxel content in standard solution (mg)
As: Peak area of docetaxel in standard solution Ar: Peak area of docetaxel in measurement sample solution

Docetaxel purity measurement (sample preparation)
Accurately measure 2 mL of the pharmaceutical composition, add 2 mL of ethanol (99.5%), and add a diluent (water / acetonitrile / acetic acid = 100/100 / 0.1 (v / v / v)) to this to accurately To make a measurement solution. For 10 μL of the sample solution, measurement by liquid chromatography (HPLC) was performed under the following conditions.
(Measurement condition)
Device: Alliance (Nippon Waters)
Column: A stainless steel tube of φ4.6 mm × 150 mm packed with 3 μm octadecylsilylating agent for liquid chromatography was used.
Column temperature: around 45 ° C. constant mobile phase A: water mobile phase B: acetonitrile gradient condition: A / B =
(72/28) → (72/28) (0 → 9 minutes)
(72/28) → (28/72) (9 → 39 minutes)
(28/72) → (0/100) (39 → 49 minutes)
(0/100) → (72/28) (49 → 50 minutes)
(72/28) → (72/28) (50 → 55 minutes)
Flow rate: 1.2 mL / min Detector: UV absorptiometer (232 nm)
(Calculation of docetaxel purity)
The purity of docetaxel in the sample was calculated as the ratio (%) of the area of the HPLC chromatogram of docetaxel after the test to the area of the HPLC chromatogram of docetaxel before the test.
Moreover, content (%) of the related substance (4-epidocetaxel) in a sample was computed by the following formula.
4-epidocetaxel content (%) = A _U / A _T × 100
A _U : Peak area of 4-epidocetaxel in the sample A _T : Total area of all detected peaks (excluding the solvent peak)

Example 1
Anhydrous docetaxel was dissolved in anhydrous ethanol and polysorbate 80, and an appropriate amount of anhydrous citric acid was added to adjust to pH 2.7 to obtain a pharmaceutical composition.
(Example 2)
The same procedure as in Example 1 was performed except that the pH was adjusted to 3.0.
(Example 3)
The same procedure as in Example 1 was performed except that the pH was adjusted to 3.2.
Example 4
The same procedure as in Example 1 was performed except that the pH was adjusted to 3.4.
(Comparative Example 1)
The same procedure as in Example 1 was performed except that the pH was adjusted to 3.7.

<Test Example 1>
The pharmaceutical compositions of Examples 1 to 4 and Comparative Example 1 were stored at 60 ° C./swelling humidity, and after 4 weeks, the docetaxel content and docetaxel purity were measured. The results are shown in Table 2 and FIG.

In the table, the content (%) of docetaxel ^* indicates a value relative to the docetaxel content at the start of the test, and the value of 4-epidocetaxel indicates the peak area ratio of the chromatogram measured by HPLC.

  In Examples 1 to 4, compared to Comparative Example 1, docetaxel in the pharmaceutical composition maintained high purity even after the stability test, and the production of modified compounds was significantly less.

  According to the present invention, a docetaxel-containing pharmaceutical composition capable of long-term storage can be obtained.

Claims (4)

Containing docetaxel and / or a pharmaceutically acceptable salt thereof , citric acid and polysorbate as an active ingredient, the concentration of docetaxel and / or a pharmaceutically acceptable salt thereof being 10 to 50 mg / mL, pH is 2.7 to 3.2 der is, a pharmaceutical composition characterized by containing no glycol.   The pharmaceutical composition according to claim 1, wherein the docetaxel is anhydrous docetaxel and / or a pharmaceutically acceptable salt thereof. Moreover, tartaric acid, ascorbic acid, fumaric acid, lactic acid, maleic acid, pharmaceutical composition according to claim 1 or 2, characterized in that it contains at least one selected from the group consisting of acetic acid and oxalic acid.   The pharmaceutical composition according to any one of claims 1 to 3, which is in the form of an injection or intravenous drip.