WO2006126825A1

WO2006126825A1 - Composition comprising tetrafluorobenzyl derivatives or salts of thereof for injection

Info

Publication number: WO2006126825A1
Application number: PCT/KR2006/001934
Authority: WO
Inventors: Seung-Taek Oh; Sang-Heon Lee
Original assignee: Choongwae Pharmaceutical Co Ltd
Current assignee: Choongwae Pharmaceutical Co Ltd
Priority date: 2005-05-23
Filing date: 2006-05-23
Publication date: 2006-11-30
Anticipated expiration: 2007-11-23
Also published as: KR20060121721A

Abstract

This invention relates to an injectable pharmaceutical composition containing a tetraflu-orobenzyl derivative with increased stability of formulation and more particularly, to the injectable pharmaceutical composition containing a tetrafluorobenzyl derivative or its salt as an active ingredient with increased stability of formulation by adjusting the pH to 5-7. A further aspect of this invention provides the injectable pharmaceutical composition containing a tetrafluorobenzyl derivative, wherein sodium sulfite or sodium meta sulfite is added to the composition as an antioxidant; thereby improving the stability of formulation.

Description

COMPOSITION COMPRISING TETRAFLUOROBENZYL DERIVATIVES OR SALTS OF THEREOF FOR INJECTION

Technical Field

[1] This invention relates to an injectable pharmaceutical composition comprising a tetrafluorobenzyl derivative represented by Chemical Formula 1 or its pharmaceutically acceptable salt as an active ingredient; therapeutically effective for the prevention and treatment of acute and chronic neurodegenerative diseases.

[2]

[3] <Chemical Formula 1>

[4]

[5] [6] Wherein, R , R and R are hydrogen or halogen, respectively; R is hydroxy, alkyl, alkoxy, halogen, alkoxy substituted with halogen, alkanoyloxy or nitro, and R is carboxylic acid or ester of carboxylic acid substituted with C1-C4 alkyl, car- boxyamide, sulfonic acid, halogen or nitro.

[7]

Background Art [8] Tetrafluorobenzyl derivatives or their pharmaceutically acceptable salts, published in the PCT application (WO 2004/000786), are therapeutically effective for the prevention and treatment of acute and chronic neurodegenerative diseases. The tetrafluorobenzyl derivatives of this invention can effectively be used to prevent and treat neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease, convulsive brain diseases such as epilepsy, and ischemic brain diseases such as stroke.

[9] [10] Parenteral administration should be sought for patients with cerebral diseases such as stroke, as oral administration is inconvenient.

[H] [12] Although tetrafluorobenzyl derivatives are soluble in organic solvents such as alcohol, they are poorly soluble in water. In the case of injectable preparations or liquids containing tetrafluorobenzyl derivatives, the use of alcohol as an organic solvent may produce a water-insoluble substance due to alcohol's rapid evaporation in the injection site.

[13]

[14] Furthermore, the manufacture of tetrafluorobenzyl derivatives in the form of an injectable solution may produce a precipitate due to poor solubility. The use of such an injection for humans may cause life-threatening side effects such as vascular occlusion.

[15]

[16] The injectable solution containing a tetrafluorobenzyl derivative is susceptible to temperature or humidity, resulting in discoloration, precipitation, or loss of active ingredient during distribution or storage.

[17]

[18] The administration of such injectable solutions that have precipitates or harmful substances is associated with the possible development of serious side effects, or poor therapeutic efficacy in patients with serious disease or elderly patients. Thus, the injectable solution must be stable in order to optimize safety and efficacy.

[19]

[20] According to the conventional methods of stabilizing a drug in aqueous solution; dissolving the active ingredient in the form of dried powder or lyophilization in aqueous solution prior to use; or the active ingredient itself is dissolved in alcohol or plant oil.

[21]

[22] These methods, however, are not suitable for this invention. The complexity of administration makes the former method inappropriate for this invention, and the latter method is not suitable because the presence of an organic solvent may produce a precipitate.

[23]

[24] The inventors conducted intensive and thorough research in order to overcome the shortcomings associated with injectable solutions containing a tetrafluorobenzyl derivative as the active ingredient. By adjusting the pH, the inventors succeeded in sol- ubilizing the active ingredient to produce an injectable pharmaceutical composition with increased stability of formulation for long-term storage.

[25]

Disclosure of Invention Technical Problem

[26] The object of this invention is to provide an injectable composition containing a tetrafluorobenzyl derivative as the active ingredient; therapeutically effective for the treatment of neurodegenerative diseases. Also, the invention prevents the decomposition, discoloration or precipitation of the active ingredient during the manufacturing, distribution or storage of the injectable solution.

[27]

Technical Solution [28] This invention provides an injectable pharmaceutical composition containing a tetrafluorobenzyl derivative and its pharmaceutically acceptable salt with increased stability of formulation achieved by adjusting the pH of the injectable solution to 5-7.

[29] [30] A further aspect of this invention provides an injectable pharmaceutical composition containing an antioxidant to ensure improved stability of the pharmaceutical composition formulation.

[31] [32] The tetrafluorobenzyl derivatives contain the compound represented by the following formula 1 and its pharmaceutically acceptable salt.

[33] [34] <Formula 1> [35]

[36] [37] Wherein, R , R and R are hydrogen or halogen, respectively; R is hydroxy, alkyl, alkoxy, halogen, alkoxy substituted with halogen, alkanoyloxy or nitro, and R is carboxylic acid or ester of carboxylic acid substituted with C1-C4 alkyl, car- boxyamide, sulfonic acid, halogen or nitro.

[38] [39] Alkyl group is C1-C4 alkyl; and more preferably C1-C2 alkyl. Alkoxy group is C1-C4 alkoxy; and more preferably Cl - C2 alkoxy. Alkanoyloxy is C2-C10 alkanoyloxy; and more preferably C3-C5 alkanoyloxy.

[40] [41] The preferred tetrafluorobenzyl derivatives of this invention include 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid, 2-nitro-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid, 2-chloro-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid, 2-bromo-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid, 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-methylbenzylamino)-benzoic acid, 2-methyl-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid, 2-methoxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid, 5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-2-trifluoromethoxy benzoic acid, 2-nitro-4-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-phenol, 2-chloro-4-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-phenol, 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoamide, 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzensulfonic acid, methyl-2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid salts, 2-ethanoyloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid, 2-propanoyloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid or 2-cyclohexane carbonyloxy-

5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid; more preferred tetrafluorobenzyl derivatives of this invention include

2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid, 2-chloro-4-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-phenol, 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoamide, 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzensulfonic acid, 2-ethanoyloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid, 2-propanoyloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid or 2-cyclohexane carbonyloxy-

5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid, where the most preferred tetrafluorobenzyl derivative of this invention is 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid.

[42]

[43] The pharmaceutically acceptable salts of this invention include alkali metals such as lithium, sodium or potassium, and alkaline earth metals such as calcium or magnesium. Preferably, they include water-soluble salts selected from the group consisting of sodium salts, potassium salts or lithium salts.

[44]

[45] The tetrafluorobenzyl derivatives of this invention represented by Chemical

Formula I may be produced via a method described in WO 2004/000786.

[46]

[47] The injectable composition of this invention contains the tetrafluorobenzyl derivative of 0.1-50 mg/ml, preferably 0.2-10 mg/ml. [48]

[49] According to this invention, pH buffer solutions such as acidic aqueous solution or phosphate, may be used for injection. One or more pH buffer solutions may be selected from the group consisting of glacial acetate, citric acid, citrate, phosphate, sodium hydroxide, and potassium hydroxide. [50] [51] Phosphate used for this invention may be in the form of salts such as sodium or potassium, or of its anhydride or hydrate. Citric acid may be in the form of its anhydride or hydrate. [52] [53] Examples of phosphate buffer solutions include solutions of monobasic potassium phosphate and dibasic sodium phosphate; monobasic sodium phosphate-citric acid buffer solution; as well as solutions of monobasic potassium phosphate and sodium hydroxide. [54] [55] The pH-adjusting buffer solution may be used to adjust the pH of the injectable solution of this invention to 5-7. [56] [57] According to this invention, the water-insoluble tetrafluorobenzyl derivatives may be solubilized by adjusting the pH to 5-7, while preventing the occurrence of precipitate or harmful substances during distribution and storage and loss of active ingredient. [58] [59] As described in the following examples, the injectable solution of this invention containing a tetrafluorobenzyl derivative may produce a precipitate at an acidic pH

(less than 4.82), but no precipitation is observed at a pH greater than 4.9. [60] [61] The injectable solution of this invention should also contain sodium sulfite or sodium meta sulfite to prevent discoloration and improve the stability of the solution. [62] [63] In general, examples of stabilizing agents for injection include para-hydroxybenzoic acid ester derivatives, alcohol, benzalkonium chloride, phenol derivatives, thimerosal, acetic anhydride, sorbic acid, boric acid, adipic acid, sodium carboxylate, lauryl sulfate, and antioxidants. [64] [65] Examples of the antioxidant include retinol, tocopherol or sodium ascorbate, ascorbic acid, sulfite compounds, amino acid such as L-cysteine, thiodipropionic acid, thiolactic acid, and monothioglycerol. [67] The Korean Patent Registration No. 10-0188318 discloses stabilizer against light, such as sulfurous acid, sulfite, ascorbate, L-cysteine, and tocopherol. [68] [69] The Korean Patent Examined No. 10-1990-0000746 discloses ascorbic acid as a stabilizer of injectable cefamandole nafate. [70] [71] The Korean Patent Unexamined No. 10-2003-0021935 discloses N-acetyl amino acid as a stabilizer of paclitaxel. [72] [73] The Korean Patent Examined No. 10-1992-0004097 discloses -tocopherol, sodium formaldehyde, or tertiary-butyl hydroquinone as an antioxidant used to ensure increased stability of doxorubicin hydrochloride that is unstable in aqueous systems. [74] [75] The U.K. Patent No. 2,158,714 discloses sodium sulfite as a stabilizer of injectable metoclopramide. [76] The Korean Patent Examined No. 10-1987-0002159 discloses sodium sulfite and sodium phosphate as a stabilizer of aminoglycoside antibiotics (e.g., sisomycin, netilmycin). [77] [78] The inventors, however, are aware that the common stabilizer fails to improve the stability of injectable solution. The application of ascorbic acid or citric acid; widely used in the manufacture of injectable preparations, is found to induce discoloration, precipitation or instability in acidic pH conditions due to accelerated acidification. [79] [80] The injectable solution of this invention may be further stabilized by using sodium sulfite or sodium meta sulfite as an antioxidant. [81] [82] The preferred amounts of sodium sulfite and sodium meta sulfite per 1 part by weight of the injectable solution of this invention are 0.01-0.5 parts by weight and

0.05-0.1 parts by weight, respectively. [83] [84] The injectable composition of this invention may also contain a pharmaceutically acceptable isotonic agent which reduces pain when injected. The pharmaceutically acceptable isotonic agent may include sodium chloride. [85]

Advantageous Effects [86] This invention provides a stabilized injectable composition containing a tetrafluoro derivative with the following combination of properties: 1) the water-insoluble compound may be solubilized by adjusting its pH to 5-7 for better stability of injectable preparation, 2) the application of sodium sulfite or sodium meta sulfite as an antioxidant may prevent the precipitation during the manufacture of the injectable solution, 3) the active ingredient is not discolored or precipitated, and may be stored under normal storage conditions without substantial degradation.

[87]

[88] In addition, the formulation of this invention allows it to be delivered as an injection to patients with neurodegenerative diseased and increases the stability of the active ingredient; thereby optimizing the injectable solution's safety and efficacy.

[89]

Best Mode for Carrying Out the Invention

[90] This invention will now be described by referring to the following examples and experimental examples. The examples are merely illustrative, and are not to be construed as a limitation of the scope of this invention.

[91]

[92] Example 1: Preparation of injectable composition

[93] 200 mg of

2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid was dissolved in 100 mL of WFI(water for injection) to prepare an injectable solution.

[94]

[95] Experimental example 1: Detection of precipitation occurring in injectable solution at different pHs

[96] <Procedure>

[97] The occurrence of precipitation in the injectable solution, as prepared in Example 1, was macroscopically identified at different pHs by using a dilute hydrochloric acid solution (0.01 N) and sodium hydroxide solution (0.1 N).

[98]

[99] Table 1 shows the occurrence of precipitation in the injectable solution at different pHs.

[100]

[101] Table 1 Occurrence of precipitation in the injectable solution at different pHs

[LEGEND] o precipitation observed

X no precipitation observed

[102] [103] The test results show that the injectable solution of this invention was precipitated at less than pH 4.9, while no precipitation was observed at pH 5 or higher.

[104] [105] Example 2: Preparation of pH-ad justed injection composition of this invention [106] Using a dilute hydrochloric acid solution (0.01 N) and sodium hydroxide solution (0.1 N), the pHs of the injectable solution, as prepared in Example 1, were adjusted to 1.45, 3.25, 5.78, 6.75, 7.68, 8.91, and 12.02

[107] [108] Experimental 2: Stability test of injetable solution at different pHs [109] The injectable solution, as prepared in Example 2, was filled into a vial and sterilized in vacuo. The solution was then stored at 25⁰C for 6 months in order to observe the discoloration or precipitation of the solution. The amount of active ingredient were analyzed using HPLC.

[HO] [111] Table 2 shows the remaining amount of active ingredient in each injectable solution at different time intervals.

[112] [113] Table 2 Weight ratio of active ingredient at different time intervals (mean±standard deviation)

[LEGEND] o precipitation observed X no precipitation observed ^* extent of discoloration (ι e ^* somewhat discolored ^*extremely discolored)

[114] [115] The test results show that greater amounts of active ingredient were decomposed at basic pH conditions (7.68, 8.91 and 12.02) during the 6 months, but there was less decomposition at pH 5.78 - 6.75.

[116] [117] Thus, the pH of the injectable solution should be maintained at about 5 to 7 in order to ensure an increased stability under normal storage conditions.

[118] [119] Example 3: Preparation of injectable solution containing an antioxidant of this invention

[120] The injectable solution of this invention containing phosphate buffer solution was prepared in such a manner that

2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid was dissolved in phosphate buffer solution (pH 6.8) by weight of 0.2% and then, an oxidant selected from the group consisting of sodium sulfite, sodium meta sulfite, cysteine, and acetylcysteine was added to the reaction mixture by weight of 0.01-0.5%, as shown in Table 3. [121] [122] Hence, the phosphate buffer solution containing monobasic potassium phosphate by weight of 0.34% and dibasic sodium phosphate by weight of 0.335% was used.

[123] [124] Table 3

Injectable solution in phosphate buffer solution (pH 6 8)

[125] [126] Experimental 3: Stability test of injectable solution containing different antioxidants

[127] The injectable solution, as prepared in Example 3, was filled into a vial and sterilized in vacuo. The solution was then stored at 6O⁰C for 4 weeks to observe the discoloration or precipitation of the solution. The remaining amounts of active ingredient were analyzed using HPLC, as shown in Table 4.

[128] [129] Table 4

[LEGEND] o precipitation observed X no precipitation observed ^* extent of discoloration (ι e ^* somewhat discolored, **^***extremely discolored)

[130] [131] As noted in Table 4, samples containing L-cysteine or acetylcysteine as the antioxidant had relatively more changes in content and were discolored to a greater extent compared to those containing sodium sulfite or sodium meta sulfite as the antioxidant after 4 weeks.

[132] [133] Moreover, samples containing L-cysteine as an antioxidant had a bad odor, and a great amount of precipitation from the week 3.

[134] [135] There was no precipitation in specimens containing sodium sulfite or sodium meta sulfite, whereas samples containing L-cysteine were completely precipitated and discolored. The samples containing acetylcysteine were discolored from the week 4.

[136] [137] The test results show that sodium sulfite or sodium meta sulfite may contribute to increased stability of the injectable solution in terms of less discoloration.

[138] [139] The preferred amounts of sodium sulfite and sodium meta sulfite are 0.01-0.5 parts by weight and 0.05-0.1 parts by weight per 1 part by weight of a tetrafluorobenzyl derivative, respectively.

[140] [141] Example 4: Preparation of injectable solution containing antioxidant and isotonic agent

[142] The injectable solution of this invention containing phosphate buffer solution in the presence or absence of an isotonic agent, which appeases pain or hemolysis, was prepared in such a manner that

2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid was dissolved in phosphate buffer solution (pH 6.8) by weight of 0.2% and then, sodium sulfite by weight of 0.05% was added to the reaction mixture.

[143] [144] The phosphate buffer solution containing monobasic potassium phosphate by weight of 0.34% and dibasic sodium phosphate by weight of 0.335% was used. Sodium chloride was also used as an isotonic agent.

[145] [146] Table 5

[147] [148] Experimental 4: Stability test of injectable composition containing antioxidant and isotonic agent

[149] The injectable solution, as prepared in Example 4, was filled into a vial and sterilized in vacuo. The solution was then stored at 2O⁰C, 4O⁰C and 6O⁰C for 6 weeks in order to observe the discoloration or precipitation in the solution. The remaining amounts of active ingredient were analyzed using HPLC, as shown in Table 6, 7 and 8.

[150] [151] Table 6 Change in amounts of active ingredient under storage at 25°C (mean ± standard deviation)

[LEGEND]

X no precipitation observed

^* extent of discoloration

[152] [153] Table 7

Change in amounts of active ingredient under storage at 40°C (mean ±standard deviation)

Specimen Initial 2 months 4 months 6 months No.

Amount 100±0 60 99 00+0 64 96 23±1 53 96 54+1 86

12 Precipitation X X X X

Discoloration - . - -

Amount 100±0 57 99 35±0 32 96 92±1 11 95 60+2 61

13 Precipitation X X X X

Discoloration - - - -

Amount 100±0 27 85 50+2 85 87 oo±o 85 85 23+0 78

14 Precipitation X X X X

Discoloration - _*

[LEGEND]

X no precipitation observed * extent of discoloration

[154] [155] Table 8

Change in amount of active ingredient under storage at 60 °C (mean ±standard deviation)

[LEGEND]

X no precipitation observed

* extent of discoloration

[156] [157] As shown in Tables 6-8, the application of an isotonic agent did not affect the stability of the injectable solution. The pH-adjusted injectable solution containing sodium sulfite as an antioxidant had an excellent combination of properties such as increased stability, and less loss of active ingredients.

[158]

Claims

[1] A stabilized injectable pharmaceutical composition comprising a tetraflu- orobenzyl derivative of the following Formula 1 or its pharmaceutically acceptable salts, wherein the pH of the said derivative is adjusted to 5-7: <Formula 1>

Wherein, R , R and R are hydrogen or halogen, respectively; R is hydroxy, alkyl, alkoxy, halogen, alkoxy substituted with halogen, alkanoyloxy or nitro; and R is carboxylic acid or ester of carboxylic acid substituted with C1-C4 alkyl, carboxyamide, sulfonic acid, halogen or nitro. The alkyl and alkoxy groups are C1-C4 alkyl and alkoxy, and the alkanoyloxy group is C2-C10 alkanoyl.

[2] The stabilized injectable pharmaceutical composition according to claim 1, wherein tetrafluorobenzyl derivatives include

2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid, 2-nitro-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid, 2-chloro-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid, 2-bromo-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid, 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-methylbenzylamino)-benzoic acid, 2-methyl-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid, 2-methoxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid, 5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-2-trifluoromethoxy benzoic acid,

2-nitro-4-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-phenol, 2-chloro-4-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-phenol, 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoamide, 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzensulfonic acid, methyl-

2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid salt,

2-ethanoyloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid, 2-propanoyloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid or 2-cyclohexane carbonyloxy-

5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid; more preferred tetrafluorobenzyl derivative may be selected from the group consisting of 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid, 2-chloro-4-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-phenol,

2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoamide,

2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzensulfonic acid,

2-ethanoyloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid,

2-propanoyloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid and 2-cyclohexane carbonyloxy-

5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid . [3] The stabilized injectable pharmaceutical composition according to claim 1, wherein a tetrafluorobenzyl derivative is

2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid. [4] The stabilized injectable pharmaceutical composition according to any one of claims 1 to 3, wherein its pH is adjusted by one or more buffer solutions selected from the group consisting of glacial acetate, citric acid, citrate, phosphate, sodium hydroxide, and potassium hydroxide. [5] The stabilized injectable pharmaceutical composition according to claim 4, wherein its pH is adjusted by phosphate. [6] The stabilized injectable pharmaceutical composition according to claim 4, wherein an antioxidant is added to the composition. [7] The stabilized injectable pharmaceutical composition according to claim 4, wherein the antioxidant is selected from the group consisting of sodium sulfite and sodium meta sulfite. [8] The stabilized injectable pharmaceutical composition according to claim 6, wherein an isotonic agent is added to the composition.